Tag Archives: #biomarker

Biology

Biomarker Predicts Bowel Cancer Recurrence (Biology)

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A biomarker in the blood of patients with bowel cancer may provide valuable insight into the risk of cancer relapse after surgery and the effectiveness of chemotherapy.

Research published in PLOS found circulating tumour DNA (ctDNA) measured before and after surgery provided a reliable marker for predicting whether the cancer would recur following chemotherapy treatment.

The ctDNA also provided a real-time measure of the effectiveness of chemotherapy, highlighting the potential for this test to provide an early indication of the success of chemotherapy in eradicating microscopic cancer.

At a glance

  • By measuring levels of ctDNA present in the blood of bowel cancer patients after surgery, researchers were able to predict the likelihood of the cancer recurring.
  • Measuring the presence of ctDNA after chemotherapy provided a real time indication of whether the chemotherapy had cleared the cancer.
  • ctDNA could be used as a biomarker in the future to improve patient care and treatment

Prognostic impact of ctDNA

Led by Associate Professor Jeanne Tie, who is also a medical oncologist at the Peter MacCallum Cancer Centre and Western Health, the research followed a group of patients with metastatic bowel cancer who had secondary cancer in the liver that had been removed by surgery. The study builds on earlier research reported in 2018.

The ctDNA test looks for fragments of tumour DNA in a patient’s blood before and after the removal of a cancerous tumour.

The presence of ctDNA in the blood of patients after surgery provides evidence of remaining microscopic tumours, enabling researchers to predict the likelihood of the cancer reoccurring.

Associate Professor Tie said the study once again confirmed the prognostic impact of ctDNA.

“What we found is that if ctDNA is present after surgery, it predicts an almost 100 per cent recurrence rate for these patients,” she said.

“In contrast, for patients who were ctDNA-negative after surgery, the likelihood of the cancer reoccurring was far lower, about 25 per cent.”

Measuring chemotherapy in real time

Associate Professor Tie said ctDNA also provided an indication of the effectiveness of chemotherapy.

“This biomarker could also identify whether patients would respond to chemotherapy treatment,” she said.

“Until now, we had no way of measuring the effectiveness of chemotherapy in real time. The usual process is to do the surgery to remove the cancer metastases, give the patient chemotherapy, and then follow up with CT scans every six to 12 months, to see if the cancer recurs. And if the cancer does recur, you know the treatment hasn’t worked. By measuring the ctDNA in the blood, we could immediately see whether the chemotherapy had cleared the cancer and were therefore able to predict the likelihood of the cancer recurring.”

Associate Professor Tie said ctDNA biomarkers might allow clinicians to intervene earlier.

“Cancer that can be detected on a CT scan is unlikely to be curable by chemotherapy. But if we are able to detect microscopic disease, that we can’t pick up on a scan, we can intervene earlier and potentially still offer the patient a chance of cure.”

Promising sign for the future of cancer treatment

Associate Professor Tie said while ctDNA technology was already being used in the US, further research was needed before it could be rolled out in Australia.

“The test needs to be very sensitive to be able to pick up microscopic cancer cells. I am hopeful the new technology coming through will have enough sensitivity that we will be able to use this technique in the years ahead to improve patient care and treatment,” she said.

“With further development of this technology, this could also mean patients with a low recurrence risk could avoid unnecessary chemotherapy.”

This work was made possible with support from the National Institutes of Health, the Virginia and D.K Ludwig Fund for Cancer Research, the Victorian Cancer Agency Clinical Research Fellowship, the Victorian Government, the Sol Goldman Sequencing Facility at Johns Hopkins, and the John Templeton Foundation.

Featured image: Crypts and buds in the small intestine and colon. © Dr. Maree Faux, WEHI.

Reference: Tie J, Wang Y, Cohen J, Li L, Hong W, Christie M, et al. (2021) Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study. PLoS Med 18(5): e1003620. doi:10.1371/journal.pmed.1003620

Provided by WEHI

Medicine

The First Blood Biomarker to Distinguish Between Myocarditis and Acute Myocardial Infarction (Medicine)

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Scientists at the CNIC have identified the first specific blood marker for myocarditis, allowing this disease to be distinguished from other conditions such as acute myocardial infarction

Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have identified the first blood biomarker for myocarditis, a cardiac disease that is often misdiagnosed as myocardial infarction. Nevertheless, the diagnosis of myocarditis continues to be challenging in clinical practice.

The study, led by Dr. Pilar Martín and published today in The New England Journal of Medicine, has detected the presence of the human homolog of micro RNA miR-721 in the blood of myocarditis patients.

CNIC General Director Dr. Valentín Fuster emphasizes that these results of paramount importance because they establish the first validated blood marker with high sensitivity and specifity (>90%) for myocarditis. This will allow clinicians to distinguish between this disease and other cardiomyopathies like acute myocardial infarction, myocardial infarction with nonobstructive coronary arteries (MINOCA), and other inflammatory diseases with an autoimmune origin.

“Our finding has great potential as a valuable clinical tool for the precise and noninvasive diagnosis of myocarditis from small drops of blood,” says Dr. Martín, whose project is funded by a Fundación BBVA Beca Leonardo award.

The diagnosis of myocarditis is challenging, and the availability of a sensitive and specific marker of acute myocardial inflammation could have a major clinical impact, improving the diagnosis of myocarditis both generally and particularly in its early phases.

An inflammatory disease of the heart

Myocarditis is an inflammatory disease of the heart caused by infection, toxins, drugs, or autoimmune disorders. If untreated, myocarditis can progress to potentially fatal dilated cardiomyopathy, requiring heart transplant.

The prevalence of myocarditis remains uncertain because it is often difficult to achieve a confirmed diagnosis.

Myocarditis, says study co-first author Rafael Blanco-Domínguez, “is often the final diagnosis in patients with MINOCA, which accounts for 10-20% of patients meeting the criteria for myocardial infarction.”

Myocarditis is usually diagnosed after coronary angiography or computed tomography scans have discarded coronary artery disease, followed by confirmation of the diagnosis by magnetic resonance imaging (MRI).

However, not all centers have access to MRI technology, and the current gold standard for myocarditis diagnosis is endomyocardial biopsy, an invasive procedure normally reserved for severe cases. There is thus a pressing clinical need for the development of reliable and accessible tools for the early diagnosis of acute myocarditis.

Moreover, adds Raquel Sánchez-Díaz, “myocarditis is a side effect that, although very rare, is potentially serious in cancer patients who are receiving treatment with immunotherapy drugs called “immune checkpoint inhibitors”.

There are currently no specific markers for the diagnosis of patients susceptible to developing myocarditis during cancer immunotherapy.

“We identified miR-721 in the blood plasma of mice with autoimmune or viral myocarditis. This miRNA is produced by autoimmune Th17 cells that recognize cardiac antigens derived from proteins such as alpha-myosin,” says Rafael Blanco-Domínguez. Continuing, study co-first author Raquel Sánchez-Díaz explains that “these cells attack the myocardium, and are in large part responsible for the pathophysiology of the disease.”

The research team went on to identify, clone, and validate the previously unknown human homolog of miR-721. The study confirmed that this miRNA is synthesized in the Th17 cells of myocarditis patients and its expression is exclusively detected in the plasma of these patients.

The biomarker was validated by cardiologists and researchers at numerous hospitals in Spain and abroad. In Spain, key contributors include Drs. Francisco Sánchez-Madrid, Hortensia de la Fuente, Jesús Jiménez-Borreguero, Fernando Alfonso, Isidoro González, and Esteban Dauden of Hospital de La Princesa/ IIS Princesa; Dr. Valentín Fuster of the CNIC, Dr. Borja Ibáñez of Fundación Jiménez Díaz and the CNIC; Dr. Héctor Bueno of Hospital Universitario Doce de Octubre; Dr. Amaia Martínez of Hospital Central de Asturias; Dr. Leticia Fernández Friera of HM Montepríncipe; Dr. Domingo Pascual-Figal of Hospital Virgen de la Arrixaca, and Dr. Villar Guimerans of Hospital Ramón y Cajal y and Instituto de Investigación IRYCIS. Key international contributors include the University of Padua in Italy, Zürich University Hospital in Switzerland, and Massachusetts General Hospital and the Mayo Clinic in the USA.

The researchers are currently designing studies to evaluate the potential of the biomarker as a predictor of short-term and long-term risk, the persistence of myocardial inflammation, and the risk of relapse, clinical progression, and adverse ventricular remodeling.

The CNIC is the sole owner of a patent related to the biomarker and its use for the diagnosis of miocarditis. The CNIC is now exploring licensing agreements with industrial partners to develop and commercialize this technology in order to make it available for clinical use.

For Dr. Fuster, “this study is a shining example of how the basic research carried out at the CNIC contributes to societal wellbeing through the translation of the knowledge gained in the center’s laboratories to clinical practice.”

Featured image: First biomarker in blood that distinguishes myocarditis from an acute myocardial infarction © CNIC

Provided by CNIC

Medicine

Tuberculosis: New Biomarker Indicates Individual Treatment Duration (Medicine)

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The treatment of tuberculosis (TB) is long, demanding, and expensive. In particular, the ever increasing emergence of resistant tuberculosis bacteria requires a lot of patience: In these cases, the WHO generally recommends a standard treatment duration of at least 18 months, as there are no reliable biomarkers for an early termination. Under the leadership of the DZIF scientists at the Research Center Borstel, six years of research have now succeeded in identifying a biomarker that points to an individual end of therapy based on the activity of 22 genes. In many cases, this probably allows the treatment to be shortened safely.

When can tuberculosis therapy be stopped without risk of relapse? Doctors are faced with this question time and again, because the lack of detection of the tuberculosis pathogen Mycobacterium tuberculosis is no guarantee for a permanent cure of the lung infection. Patients who respond to the standard therapy may be out of treatment after six months. But for resistant cases, more than 18 months of treatment duration is currently advised. “This is a very long time for those affected, who often have to take more than four antibiotics every day and suffer from side effects”, explains Prof. Dr Christoph Lange, Clinical Director at the Research Center Borstel and director of the study, conducted at the German Center for Infection Research (DZIF) in cooperation with the German Center for Lung Research (DZL). “We urgently need a biomarker that enables the implementation of an individualised treatment duration,” he emphasises. After all, not every patient needs so long to recover. 

Since the absence of bacteria in the sputum does not justify a safe stop in therapy, the team around Christoph Lange set out to find alternative biomarkers in the patient. In collaboration with international tuberculosis centres, on the basis of patient cohorts a model for the end of therapy could be developed that is based on an RNA determination in the blood. From many thousands of genes, 22 have been identified whose activity correlates with the course of the disease. “The production of RNA of these 22 genes in human blood can tell us whether the patient is cured,“ PD Dr Jan Heyckendorf from the FZ Borstel sums it up. Together with Maja Reimann and Dr Sebastian Marwitz, he is the lead author of the study. “It is an RNA signature from 22 genes identified on two cohorts and validated on another three cohorts,” adds the scientist. “No other published transcriptom marker shows comparable properties so far.”

To identify this individual biomarker, the scientists within the DZIF have established five different patient cohorts. In all cases, these were adults who had contracted pulmonary TB, partly from non-resistant, partly from resistant forms. In addition to cohorts in Germany, patients in Bucharest (Romania) were also included, where the DZIF supports a study centre.

”The individualisation of the treatment duration is an important milestone on the road to precision medicine for tuberculosis,” affirms Christoph Lange. Even without progression values, one could risk to end a patient’s treatment on the basis of this RNA determination. As a next step, the researchers are planning a prospective study at the DZIF. The aim is for patients in one study arm to receive treatment for as long as the biomarker suggests, while patients in the other arm receive treatment for as long as the national tuberculosis programme recommends. The scientists then want to see whether the biomarker makes a shorter treatment duration possible. The team around Christoph Lange is confident.

“Hopefully, it will then be possible for patients with multidrug-resistant tuberculosis to save about one-third of treatment on average,” says Lange.

Featured image: The treatment of tuberculosis (TB) is long, demanding, and expensive.© DZIF/scienceRELATIONS

Reference: Jan Heyckendorf, Sebastian Marwitz, Maja Reimann, Korkut Avsar, Andrew DiNardo, Gunar Günther, Michael Hoelscher, Elmira Ibraim, Barbara Kalsdorf, Stefan H.E. Kaufmann, Irina Kontsevaya, Frank van Leth, Anna Maria Mandalakas, Florian P. Maurer, Marius Müller, Dörte Nitschkowski, Ioana D. Olaru, Cristina Popa, Andrea Rachow, Thierry Rolling, Jan Rybniker, Helmut J.F. Salzer, Patricia Sanchez-Carballo, Maren Schuhmann, Dagmar Schaub, Victor Spinu, Isabelle Suárez, Elena Terhalle, Markus Unnewehr, January Weiner 3rd, Torsten Goldmann, Christoph Lange, “Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model”, European Respiratory Journal 2021; DOI: 10.1183/13993003.03492-2020

Provided by DZIF

Chemistry

A Novel Gel Electrophoresis Technique for Rapid Biomarker Diagnosis Via Mass Spectrometry (Chemistry)

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Development of a rapid recovery method of target protein biomarkers using dissolvable polyacrylamide gel and its application to mass spectrometry

Mass spectrometry (MS) is a powerful method for biomarker analysis because it enables highly sensitive and accurate measurement of target molecules in clinical samples. The application of MS to clinical diagnosis, such as neonatal metabolic screening, has been progressing with a focus on metabolite markers. MS measurement of proteins is currently mainly used for novel marker discovery studies, but there is a growing interest in its application in clinical marker diagnosis as an alternative to immunoassays.

MS-based quantification of protein biomarkers is mainly performed by a bottom-up approach using peptide fragments obtained by enzymatic protein digestion with trypsin. Standard digestion protocols require a reaction time of more than 20 hours, which is a rate-limiting factor in sample preparation workflows.

Although protein quantification by MS is highly sensitive, plasma and serum proteome are highly complex, and interference by other components poses a significant challenge. For high-precision detection of target markers, approaches for pre-removal of major serum protein components such as albumin or selective enrichment of target markers using antibody columns have been reported, but the off-target effect on quantitative results and the difficulty of processing multiple samples remain obstacles.

In this study, we focused on dissolvable polyacrylamide gels using N,N’-Bis(acryloyl)cystamine (BAC) as a cross-linker to solve these problems. BAC cross-linked polyacrylamide gels readily dissolve by reduction treatment, allowing the recovery of proteins that have escaped into the solution. We found that the recovered proteins were suitable for rapid trypsin digestion under high temperature conditions, and we succeeded in establishing a high-throughput sample preparation method for MS-based biomarker quantification, which we named BAC-DROP (BAC-Gel Dissolution to Digest PAGE-Resolved Objective Proteins).

High-resolution proteome fractionation with BAC-DROP is particularly effective for MS quantification of targeted trace marker proteins derived from clinical samples. By introducing BAC-DROP into the MS-based quantification workflow of the inflammatory biomarker C-reactive protein (CRP), we were able to complete the sample pretreatment in only 5 hours and successfully quantified CRP from a 0.5 μL human serum sample. We also succeeded in a serological diagnosis of hepatitis B virus (HBV) infection by HBsAg quantification combined with BAC-DROP and MS. Recently, interest in MS diagnosis of viral infections has been rapidly increasing, as exemplified by the diagnosis of COVID-19. The high-throughput sample preparation approach by BAC-DROP shown in this study will be applicable not only to HBV but also to other infectious viral disease samples.

This research was conducted by a collaborative research group of Ehime University, Hamamatsu University School of Medicine, and Kitasato University, and the research results were published online in the Journal of Proteome Research of the American Chemical Society on December 24, 2020.

Featured image: Dissolvable BAC cross-linked gels allow rapid and lossless recovery of protein biomarkers separated by SDS-polyacrylamide gel electrophoresis and facilitate analysis by mass Spectrometry © Reprinted with permission from Journal of Proteome Research © 2020 American Chemical Society (ACS)

Reference: Ayako Takemori, Jun Ishizaki, Kenji Nakashima, Takeshi Shibata, Hidemasa Kato, Yoshio Kodera, Tetsuro Suzuki, Hitoshi Hasegawa, and Nobuaki Takemori, “BAC-DROP: Rapid Digestion of Proteome Fractionated via Dissolvable Polyacrylamide Gel Electrophoresis and Its Application to Bottom-Up Proteomics Workflow”, J. Proteome Res. 2020.
https://doi.org/10.1021/acs.jproteome.0c00749

Provided by Ehime University

Biology

Role of Cell Cycle on Analyzing Telomerase Activity With a Fluorescence Off-on System (Biology)

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Cancer is a significant cause of death worldwide and many efforts have been devoted to the development of methods for early detection. Telomerase are considered as a tumor biomarker for early diagnosis because the telomerase of more than 80% immortalized cells are reactivated and provides the sustained proliferative capacity of these cells, but the telomerase activity are not detectable in normal somatic cells. Telomerase is a ribonucleoprotein complex that is thought to add telomeric repeats onto the ends of chromosomes during the replicative phase (S phase) of the cell cycle.

Recently, Xia Wu, Jun Wu, Feng Wu, Xiaoding Lou, Fan Xia from the China University of Geosciences and Jun Dai, Biao Chen, Zhe Chen, Shixuan Wang from Huazhong University of Science and Technology made exciting progress and investigated the role of cell cycle progression on analyzing telomerase activity in cancer cells based on an AIEgen-based fluorescence detecting system. The fluorescence signal of cancer cells gradually increased from G0/G1, G1/S to S phase. In contrast, both cancer cells arrested at G2/M phase and normal cells exhibited the negligible fluorescence intensities, which demonstrates that future studies on tumor biomarkers analyzing, such as TERT mRNA and telomerase activity should consider the phase of cell cycle.

First, PyTPA-DNA and Silole-R bioprobe were used to investigate the expression of TERT mRNA and telomerase activity under different cell cycle of HeLa cells. Upon progression through the cell cycle, the PyTPA-DNA faintly fluoresced in G0/G1 stage but demonstrated an enhancement of fluorescence when responded to G1/S phase, finally reached the strongest output in S stage. However, cells arrested at G2/M phase showed the weakest fluorescence in contrast to the other three cell cycle. Furthermore, cell cycle-dependent alterations of TERT mRNA expression in HeLa cells was reconfirmed by qPCR. The similar responses of telomerase activity were also given by evaluated with using Silole-R bioprobe in different cell cycle. Moreover, TRAP assay was selectively analyzed and found to be the strongest expression levels in S stage.

Second, the intracellular imaging of TERT mRNA and telomerase activity during different stages of cancer cell cycle also demonstrated that the cell cycle has dramatic effects on the localization of TERT mRNA and telomerase activity, which S phase-specific boost and G2/M phase-specific reduce of TERT mRNA and telomerase activity in human cancer cells.

Then, the expression level of TERT mRNA and telomerase activity in different period of HeLa cells were compared with human lung fibroblasts (HFL-1) cells (normal cells) and found that somatic cells have almost no activation of telomerase during three phase of cell cycle. The level of TERT mRNA and active telomerase in most phases of cell cycle (G0/G1, G1/S, S) are above normal cells, while, cells arrested in G2/M phase exhibited almost the same level of normal cells.

In addition, a map of transcriptome information during different phases of cell cycle was performed. The parameters of CA9, CDKN1A, TK1 and EGFR were significantly elevated in G1/S stage and the activities of KRAS, CYC1 and PLOD3 were remarkably weakened in G0/G1 and G1/S phases. These results indicated that different tumor markers were highly diversified and varied in functions of different cell cycle.

It is worth noting that cell cycle served as a major role for the cellular processes and held the ability to modulate various biomarkers. These results, therefore, suggested that future studies on tumor biomarkers analyzing, such as TERT mRNA and telomerase activity should consider the phase of cell cycle.

This research received funding from the National Key R&D Program of China (2020YFA0211200), the National Natural Science Foundation of China (21722507, 21525523, 21974128, 21874121), the Natural Science Foundation of Hubei Province (2019CFA043), the project funded by China Postdoctoral Science Foundation (2020M672436) and the Hubei Postdoctoral Innovative Research Foundation (to Jun Wu).

Featured image: AIEgen-based fluorescence detecting system for analysis of TERT mRNA and telomerase activity in different phases of cell cycle (G0/G1, G1/S, S and G2/M phase). © Science China Press

Reference: Xia Wu, Jun Wu, Jun Dai, Biao Chen, Zhe Chen, Shixuan Wang, Feng Wu, Xiaoding Lou and Fan Xia
Role of cell cycle progression on analyzing telomerase in cancer cells based on aggregation-induced emission luminogens
Natl Sci Rev,2021, link: https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwaa306/6058720
https://doi.org/10.1093/nsr/nwaa306

Provided by Science China Press

Medicine

New Biomarker May Predict Which Pancreatic Cancer Patients Respond to CD40 Immunotherapy (Medicine)

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Systemic inflammation, not T cell activation, was associated with patient outcomes

Inflammation in the blood could serve as a new biomarker to help identify patients with advanced pancreatic cancer who won’t respond to the immune-stimulating drugs known as CD40 agonists, suggests a new study from researchers in the Abramson Cancer Center of the University of Pennsylvania published in JCI Insight.

It is known that pancreatic cancer can cause systemic inflammation, which is readily detectable in the blood. The team found that patients with systemic inflammation had worse overall survival rates than patients without inflammation when treated with both a CD40 agonist and the chemotherapy gemcitabine.

The purpose of CD40 agonists is to help “push the gas” on the immune system both by activating antigen-presenting cells, such as dendritic cells, to “prime” T cells and by enhancing anti-tumor macrophage activity. However, CD40 agonist-combination approaches only shrink tumors in a little more than half of patients, past studies have shown. Now, identifying systemic inflammation as a mechanism of resistance could help guide treatment decisions and future studies, as well as offer up new targets for researchers to explore.

“CD40 is a really exciting target, especially in pancreatic cancer, where agonistic monoclonal antibodies have shown a lot of promise, but we know that these agonists still face obstacles in certain patients that weaken the drug’s intended effects,” said lead author Max M. Wattenberg, MD, a clinical instructor of Medicine in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania. “We believe we have not only identified a potentially robust biomarker, but also important players in the immune system we didn’t see before that may drive mechanisms of resistance.”

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and currently the third leading cause of cancer deaths in the United States. Despite the fact that it only accounts for about three percent of new cancer cases, it is responsible for more than seven percent of all cancer deaths, and just 10 percent of patients survive five years with the disease.

The researchers analyzed blood samples from 22 patients with PDAC to gain insight into the immunological mechanisms underway after treatment with chemoimmunotherapy. The team observed a depletion of B cells, monocytes, and dendritic cells as well as activation of CD4+ T cells over eight days in most patients. Surprisingly, a closer look revealed no consistent evidence of CD8+ cell activation and no association between T cell activation and outcomes. These findings challenge preclinical studies that have suggested that T cell activation sparked by CD40 agonists would associate with outcomes.

Rather, overall survival outcomes were associated with a measurable characteristic in the patients’ blood found before treatment: systemic inflammation. Systemic inflammation is marked by the increased presence of neutrophils, inflammatory cytokines (including IL-6 and IL-8) and acute phase reactants in the peripheral blood, and is a known symptom of pancreatic cancer and other cancer types.

Patients with systemic inflammation before treatment with a CD40 agonist and gemcitabine, the authors report, had a median overall survival of 5.8 months versus 12.3 months for patients without inflammation from the start of treatment.

Also surprising, the data suggest that gemcitabine chemotherapy may eliminate monocytes and dendritic cells, which are fundamental to facilitating T cell immune responses. However, the team has previously shown that a CD40 agonist can sensitize PDAC to gemcitabine chemotherapy, and thus, T cells may not always be needed for successful outcomes with treatment using CD40 agonists in combination with chemotherapy.

“These latest findings support the fact that inflammation seems to place the immune system at a disadvantage and in doing so prevents the ability of immune therapies to work,” said senior author Gregory L. Beatty, MD, PhD, an associate professor of Hematology-Oncology at Penn’s Perelman School of Medicine. “Next, we’re interested to learn how to pair a T cell immune response with a CD40 agonist, so we are studying combinations that will help make the inflammatory response less suppressive and the components of the immune system more capable of triggering a T-cell response.”

Penn co-authors on the study include Veronica M. Herrera, Michael A. Giannone, Whitney L. Gladney, and Erica L. Carpenter.

The study was supported by the National Institutes of Health (T32-HL007439-41, K12-CA076931-21, P30-CA016520, R01-CA197916 and R01-CA245323, the Penn Pancreatic Cancer Research Center and the Robert L. Fine Cancer Research Foundation.

Reference: Max M. Wattenberg, … , Erica L. Carpenter, Gregory L. Beatty, “Systemic inflammation is a determinant of outcomes to CD40 agonist-based therapy in pancreatic cancer patients”, JCI Insight. 2021. https://doi.org/10.1172/jci.insight.145389.

Provided by Penn Medicine

Psychiatry

Automated Imaging Reveals Where TAU Protein Originates in the Brain in Alzheimer’s Disease (Psychiatry)

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Researchers have developed an automated method that can track the development of harmful clumps of TAU protein related to Alzheimer’s disease in the brain, according to work involving 443 individuals. The method revealed that TAU primarily emerged in an area of the brain called the rhinal cortex before spreading elsewhere, suggesting that targeting TAU here could potentially slow the progression of Alzheimer’s disease.

Four views of the origin of tauopathy in vivo. Left, TAU PET images for a cognitively normal person; right: top, 3D rendering of brain surface with TAU PET overlay; bottom, flat map showing topographic detail of surface anatomy with TAU origin identified in white outline. This material relates to a paper that appeared in the Jan. 20, 2021, issue of Science Translational Medicine, published by AAAS. The paper, by J.S. Sanchez at Massachusetts General Hospital in Boston, MA; and colleagues was titled, “The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography.” Credit: Justin Sanchez and Keith Johnson, Massachusetts General Hospital

The buildup of toxic amyloid-beta and TAU proteins is responsible for many of the symptoms and damage to neurons seen in Alzheimer’s disease. However, current therapies have shown reduced efficacy, at least in part because the therapies were administered long after the protein had spread throughout the brain. Developing more effective interventions therefore requires a better understanding of where TAU pathology originates and how it spreads.

The researchers investigated TAU protein with PET imaging in the rhinal cortex (yellow) in the brains of patients. This material relates to a paper that appeared in the Jan. 20, 2021, issue of Science Translational Medicine, published by AAAS. The paper, by J.S. Sanchez at Massachusetts General Hospital in Boston, MA; and colleagues was titled, “The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography.” Credit: J.S. Sanchez et al., Science Translational Medicine (2021)

Justin Sanchez and colleagues designed an automated anatomic sampling method that uses PET imaging to track the presence of TAU in the brain. The team applied their technique to 443 adult participants – including 55 patients with Alzheimer’s – and discovered that TAU deposits first emerged in the rhinal cortex independently from amyloid-beta before spreading to the temporal neocortex.

Patients who had higher amounts of amyloid-beta protein at the start of the study (middle, right) showed a greater subsequent increase in the TAU protein in the brain. This material relates to a paper that appeared in the Jan. 20, 2021, issue of Science Translational Medicine, published by AAAS. The paper, by J.S. Sanchez at Massachusetts General Hospital in Boston, MA; and colleagues was titled, “The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography.” Credit: J.S. Sanchez et al., Science Translational Medicine (2021)

A two-year experiment with 104 subjects showed that people with the highest initial levels of TAU or amyloid beta displayed the most spread of TAU throughout the brain by the end of the study. “These findings suggest that [the rhinal cortex] is a biomarker of downstream TAU spread … with potential utility for therapeutic trials in which reduction of TAU spread is an outcome measure,” the authors conclude.

Reference: Justin S. Sanchez, J. Alex Becker, Heidi I. L. Jacobs, Bernard J. Hanseeuw, Shu Jiang, Aaron P. Schultz, Michael J. Properzi, Samantha R. Katz, Alexa Beiser, Claudia L. Satizabal, Adrienne O’Donnell, Charles DeCarli, Ron Killiany, Georges El Fakhri, Marc D. Normandin, Teresa Gómez-Isla, Yakeel T. Quiroz, Dorene M. Rentz, Reisa A. Sperling, Sudha Seshadri, Jean Augustinack, Julie C. Price, Keith A. Johnson, “The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography”, Science Translational Medicine  20 Jan 2021: Vol. 13, Issue 577, eabc0655 DOI: 10.1126/scitranslmed.abc0655 https://stm.sciencemag.org/content/13/577/eabc0655

Provided by American Association for the Advancement of Science

Psychiatry

Brain Imaging Predicts PTSD After Brain Injury (Psychiatry)

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Brain volume measurement may provide early biomarker.

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder brought on by physical and/or psychological trauma. How its symptoms, including anxiety, depression and cognitive disturbances arise remains incompletely understood and unpredictable. Treatments and outcomes could potentially be improved if doctors could better predict who would develop PTSD. Now, researchers using magnetic resonance imaging (MRI) have found potential brain biomarkers of PTSD in people with traumatic brain injury (TBI).

The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

“The relationship between TBI and PTSD has garnered increased attention in recent years as studies have shown considerable overlap in risk factors and symptoms,” said lead author Murray Stein, MD, MPH, FRCPC, a Distinguished Professor of Psychiatry and Family Medicine & Public Health at the University of California San Diego, San Diego, La Jolla, CA, USA. “In this study, we were able to use data from TRACK-TBI, a large longitudinal study of patients who present in the Emergency Department with TBIs serious enough to warrant CT (computed tomography) scans.”

The researchers followed over 400 such TBI patients, assessing them for PTSD at 3 and 6 months after their brain injury. At 3 months, 77 participants, or 18 percent, had likely PTSD; at 6 months, 70 participants or 16 percent did. All subjects underwent brain imaging after injury.

“MRI studies conducted within two weeks of injury were used to measure volumes of key structures in the brain thought to be involved in PTSD,” said Dr. Stein. “We found that the volume of several of these structures were predictive of PTSD 3-months post-injury.”

Specifically, smaller volume in brain regions called the cingulate cortex, the superior frontal cortex, and the insula predicted PTSD at 3 months. The regions are associated with arousal, attention and emotional regulation. The structural imaging did not predict PTSD at 6 months.

The findings are in line with previous studies showing smaller volume in several of these brain regions in people with PTSD and studies suggesting that the reduced cortical volume may be a risk factor for developing PTSD. Together, the findings suggest that a “brain reserve,” or higher cortical volumes, may provide some resilience against PTSD.

Although the biomarker of brain volume differences is not yet robust enough to provide clinical guidance, Dr. Stein said, “it does pave the way for future studies to look even more closely at how these brain regions may contribute to (or protect against) mental health problems such as PTSD.”

Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, said of the work, “This very important study uses magnetic resonance imaging to take the field a step closer to understanding why some people develop PTSD after trauma and others do not. It also lays the groundwork for future research aimed at using brain imaging to help predict that a person is at increased risk and may benefit from targeted interventions to reduce the clinical impact of a traumatic event.”

Reference: Murray Stein, Esther Yuh, Sonia Jain, David Okonkwo, Christine Mac Donald, Harvey Levin, Joseph Giancino, Sureyya Dikmen, Mary Vassar, Ramon Diaz-Arrastia, Claudia Robertson, Lindsay Nelson, Michael McCrea, Xiaoying Sun, Nancy Temkin, Sabrina Taylor, Amy Markowtiz, Geoffrey Manley, Pratik Mukherjee, “Smaller Regional Brain Volumes Predict Posttraumatic Stress Disorder at 3 Months after Mild Traumatic Brain Injury,” Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, 2020. https://doi.org/10.1016/j.bpsc.2020.10.008

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About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is an official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2019 Impact Factor score for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 5.335. http://www.sobp.org/bpcnni

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Medicine

PET Imaging Tracer Proves Effective For Diagnosing and Managing Rare CNS B-cell Lymphoma (Medicine)

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Positron emission tomography (PET) imaging with 68Ga-pentixafor is an effective diagnostic tool for central nervous system (CNS) B-cell lymphoma, according to a proof-of-concept study published in the December issue of The Journal of Nuclear Medicine. Targeting the CXCR4 biomarker involved in the growth, survival and dissemination of aggressive B-cell lymphoma, 68Ga-pentixafor PET imaging shows excellent contrast characteristics between lymphoma lesions and surrounding healthy brain tissue and may be suitable for risk stratification and response assessment.

CXCR4-directed PET correlates with MRI-determined lymphoma lesions. Depicted are representative MR images (T1c- and FLAIR- sequences), and the corresponding CXCR4- directed PET images and fusion images (MRI-FLAIR and PET), of two patients with PCNSL and SCNSL, respectively. Credit: Images created by Department of Nuclear Medicine, School of Medicine, Technische Universität München, Munich, Germany.

“CNS B-cell lymphoma is a rare malignancy that has several clinical challenges, including diagnosis, risk stratification and optimization of treatment,” said Ulrich Keller, MD, Ph.D., head of the department of hematology, oncology, and tumor immunology at Universtitätsmedizin Berlin (Campus Benjamin Franklin), in Berlin, Germany. “Magnetic resonance imaging (MRI) is the current standard imaging technology for this disease, and while it provides high sensitivity, it offers only moderate specificity. Novel molecular and functional imaging strategies are urgently required for this patient population.”

In a retrospective analysis to investigate this issue, 11 patients were imaged with 68Ga-pentixafor PET (four with PET/computed tomography and seven with PET/MRI). Lesions were analyzed, and immunohistochemistry was conducted. In the seven patients for whom post-treatment MRI scans were available, response to treatment was compared between the pre-treatment MRI and CXCR4-directed PET scans.

CXCR4-directed PET imaging with 68Ga-pentixafor was found to be positive in all active CNS lymphoma lesions, with a high tumor-to-background ratio that offered exceptional contrast. CXCR4 expression in vivo was validated by positive immunohistochemistry for CXCR4; in nine out of 11 patients for whom lymphoma biopsies were available, CXCR4 was highly expressed in the lymphoma lesions. Additionally, CXCR4-directed PET uptake values were found to have a significant prognostic value, indicating that lymphoma lesions with lower CXCR4 tracer uptake values were associated with a better response to standard treatment.

“This is significant for CNS B-cell lymphoma patients, as CXCR4-directed PET imaging with 68Ga-pentixafor could not only facilitate diagnostic work-up and response assessment but could also serve as a biomarker for selecting patients with a dismal prognosis who could benefit from more intense treatment options,” noted Peter Herhaus, MD, hemato-oncologist in the department for internal medicine III at the School of Medicine at Technische Universität München in Munich, Germany. “CXCR4-targeted theranostics thus moves nuclear medicine further on the track toward biomarker-informed molecular medicine.”

The authors of “CXCR4-Targeted Positron Emission Tomography Imaging of Central Nervous System B-Cell Lymphoma,” include Peter Herhaus and Florian Bassermann, Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany; Jana Lipkova, Benedikt Wiestler and Wolfgang Weber, Department of Neuroradiology, School of Medicine, Technische Universität München, Munich, Germany; Felicitas Lammer and Stefan Habringer, Department of Hematology, Oncology, and Tumor Immunology (Campus Benjamin Franklin), Charité-Universitätsmedizin Berlin, Berlin, Germany; Igor Yakushev, Tibor Vag and Markus Schwaiger, Department of Nuclear Medicine, School of Medicine, Technische Universität München, Munich, Germany; Julia Slotta-Huspenina, Institute of Pathology, Technische Universität München, Munich, Germany; Constantin Lapa, Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany, and Department of Nuclear Medicine, University Hospital Augsburg, Augsburg, Germany; Andreas K. Buck, Department of Nuclear Medicine, Universitätsklinikum Würzburg, Würzburg, Germany; Tobias Pukrop, Internal Medicine III, Universitätsklinikum Regensburg, Regensburg, Germany; Dirk Hellwig, Department of Nuclear Medicine, Universitätsklinikum Regensburg, Regensburg, Germany; Martina Deckert, Institute of Neuropathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Hans-Jürgen Wester, Institute of Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany; Björn Menze, Informatics Department, Technische Universität München, Munich, Germany; and Ulrich Keller, Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany, Department of Hematology, Oncology, and Tumor Immunology (Campus Benjamin Franklin), Charité – Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany, and German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.

Reference: Peter Herhaus et al, CXCR4-Targeted PET Imaging of Central Nervous System B-Cell Lymphoma, Journal of Nuclear Medicine (2020). DOI: 10.2967/jnumed.120.241703

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About the Society of Nuclear Medicine and Molecular Imaging

The Journal of Nuclear Medicine (JNM) is the world’s leading nuclear medicine, molecular imaging and theranostics journal, accessed close to 10 million times each year by practitioners around the globe, providing them with the information they need to advance this rapidly expanding field. Current and past issues of The Journal of Nuclear Medicine can be found online at http://jnm.snmjournals.org.

JNM is published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), an international scientific and medical organization dedicated to advancing nuclear medicine and molecular imaging—precision medicine that allows diagnosis and treatment to be tailored to individual patients in order to achieve the best possible outcomes. For more information, visit http://www.snmmi.org.