Tag Archives: #carcinoma

Medicine

Moffitt Researchers Show Beta-Cutaneous HPV May Be Predictor of Squamous Cell Carcinoma (Medicine)

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Keratinocyte carcinomas, including basal cell and squamous cell carcinomas, are the most common types of cancer in the United States, with approximately 5.4 million cases diagnosed each year. Despite their low mortality rate, keratinocyte carcinomas are associated with significant medical problems caused by treatment and health care costs. Therefore, new biomarkers are needed to aid in identifying patients at risk of developing keratinocyte carcinomas. In a new article published online ahead of print in the journal Cancer Research, Moffitt Cancer Center researchers demonstrate a link between the presence of cutaneous human papillomavirus and the incidence of squamous cell carcinomas and identify key characteristics of infection that may contribute to development of the disease.

The identification of biomarkers that are associated with the development of keratinocyte carcinomas is an important component of disease management. This can pinpoint patients who may be at a higher risk of cancer and help promote individualized prevention strategies, such as more frequent or specialized skin cancer screenings. Previous studies have suggested that infections with cutaneous HPV may also be associated with keratinocyte carcinoma development; however, these studies had several limitations and were not conclusive.

“Unlike mucosal HPV types known to cause cervical, head and neck and anogenital cancers, the role of cutaneous HPV types in the development of cancer is less clear,” said Dana Rollison, Ph.D., lead study investigator and associate center director of Data Science at Moffitt. 

Moffitt researchers wanted to analyze the potential contribution of cutaneous HPV to keratinocyte carcinoma development. They looked at biomarkers of past and recent infection with cutaneous HPV beta and gamma types, as well as recent ultraviolet light exposure.

The researchers recruited 1,008 participants age 60 or older. The participants had blood, eyebrow hair and forearm skin swabs taken and analyzed for the presence of cutaneous HPV. The patients underwent total body skin examinations every six to 12 months and were monitored for a median of 792 days for the development of new basal cell and squamous cell carcinomas.

The results showed that the presence of beta-HPV at baseline, particularly in the skin swabs, significantly predicted the development of squamous cell carcinomas; however, the presence of antibodies to beta-HPV, which indicates past HPV infections, was not associated with squamous cell carcinomas. Interestingly, the researchers found that most of the beta-HPV types found in the skin swabs were not present in the squamous cell carcinoma tumors that eventually developed. Additionally, they discovered that less than 5% of squamous cell carcinoma tumors contained beta-HPV types, but those that contained beta-HPV occurred more frequently in areas of UV skin damage compared to squamous cell carcinoma tumors without beta-HPV, suggesting that UV exposure and HPV may act in a cooperative manner to promote squamous cell carcinoma development. The researchers did not find any links between beta-HPV and the development of basal cell carcinomas or between gamma-HPV and the development of squamous cell or basal cell carcinomas.

These combined observations suggest that beta-HPV could ultimately prove to be a useful biomarker to help identify people at an increased risk of developing cutaneous squamous cell carcinomas.

This study was supported by the National Cancer Institute (R01 CA177586, P30 CA076292).

Featured image: Electron micrograph of a negatively stained human papilloma virus (HPV) which occurs in human warts. Credit: public domain

Reference: Dana E. Rollison et al, Cutaneous human papillomaviruses and the risk of keratinocyte carcinomas, Cancer Research (2021). DOI: 10.1158/0008-5472.CAN-21-0805

Provided by H. Lee Moffitt Cancer Center & Research Institute

Medicine

Oncotarget: Cutaneous Apocrine Sweat Gland Carcinoma (Medicine)

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Oncotarget published “Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma” which reported a rare metastatic case with a PALB2 aberration identified previously as a familial susceptibility gene for breast cancer in the Finnish population.

As PALB2 exhibits functions in the BRCA1/2-RAD51-dependent homologous DNA recombination repair pathway, we sought to use ex vivo functional screening to explore sensitivity of the tumor cells to therapeutic targeting of DNA repair.

Drug screening suggested sensitivity of the PALB2 deficient cells to BET-bromodomain inhibition, and modest sensitivity to DNA-PKi, ATRi, WEE1i and PARPi.

A phenotypic RNAi screen of 300 DNA repair genes was undertaken to assess DNA repair targeting in more detail.

RNAi inhibition of RAD52-dependent HR on the other hand potentiated the efficacy of a novel BETi ODM-207.

Together these Oncotarget results describe the first ever CAC case with a BRCAness genetic background, evaluate combinatorial DNA repair targeting, and provide a data resource for further analyses of DNA repair targeting in PALB2 deficient cancers.

Together these Oncotarget results describe the first ever CAC case with a BRCAness genetic background

Dr. Juha K. Rantala from The University of Sheffield as well as The Misvik Biology Oy said, “Metastatic cutaneous apocrine gland carcinoma (CAC) is an extreme rare malignancy arising from a sweat gland with < 30 reported cases in the literature.“

The tumorigenesis of these rare cancers is largely unclear, but histologically cutaneous apocrine gland carcinomas mimic metastatic apocrine breast cancer or apocrine carcinomas arising in ectopic breast tissue.

Given the rarity of metastatic CAC tumors and the heterogeneity of the treatments used, the survival benefits of cytotoxic agents in treatment of metastatic CAC remains unclear, as does the use of targeted therapies, which have been reported for a few individual patients.

The authors used multiomics methods for ex vivo analysis of the patient derived tumor cells with the aim to inform the treatment of the patient after relapse following 9 previous treatment regimens.

Of these, two different BET-bromodomain inhibitors; JQ1 and ODM-207 were the most potent drugs with known DNA repair targeting mechanisms. To assess DNA repair pathways essential for the tumor cells and contributing to sensitivity/resistance of the tumor cells to BETi, we use ex vivo functional RNAi screening to discover biological insights on the different DNA repair pathways with the PALB2 deficient cells.

To extend the analysis beyond the patient derived cells, the authors go on to assess with publicly available drug screening data the correlation between efficacy of PARP inhibitors Olaparib, Talazoparib and BETi on 800 model cell lines divided to unaltered or PALB2 altered cell lines.

The Rantala Research Team concluded in their Oncotarget Research Outlet that although the efforts here ultimately did not result in successful treatment of the patient, the significance of this study is its demonstration that this type of functional ex vivo analyses if performed in the early stages of disease could provide valuable insights into treatment of rare cancers where there is limited data available to base treatment decisions on.

Their analyses of sensitivity of PALB2 deficient cancer cells to inhibition of the different DNA repair pathways also offer a valuable data resource for testing and building new hypothesis on.

In summary, by interrogating the patient-derived cells, they identify a potential therapeutic opportunity for targeting PALB2 deficient cells through inhibition of DNA repair with BETi or PARPi.

Moreover, they identify the PALB2 c.1592delT mutation as a potential susceptibility factor for non-melanoma skin cancer in the high cancer risk families carrying this founder mutation.

DOI – https://doi.org/10.18632/oncotarget.27961

Full text – https://www.oncotarget.com/article/27961/text/

Featured image: Analysis of efficacy of targeting different DNA repair pathways on PALB2 mutated CAC cells. (A) Bar graphs showing the mean z-score and standard deviation of 3 individual siRNAs against core HR pathway genes. In each graph the left two bars show the viability z-score and right two bars the γH2Ax z-score in control condition (black) and with 500 nM ODM-207 (grey). (B) Distribution of the RNAi loss-of-function effects of the core HR genes divided according to the associated DNA repair pathway on untreated and BETi treated CAC cells. (C) ODM-207 and Olaparib exhibit a combinatorial additive effect on the PALB2 deficient cells. Dose–response matrix of percent of viability inhibition (left) and percent of cells with more than 5 nuclear γH2Ax foci (center) in response to increasing doses of ODM-207 (BETi) and Olaparib (PARPi). The combinatorial cytotoxicity was quantitatively analyzed by combination index (CI) combination index. With 1:4 molar ratio the CI50 of the drugs was 0.61, with 1:2 molar ratio 0.71, and with 1:1 molar ratio 0.89. (D) Representative 10× fluorescence microscopy images of the CAC cells stained for γH2AX (red) following 7d exposure to the combination of ODM-207 and Olaparib at 1:4 molar ratio. DNA staining shown in blue. Scale bars 100 μm. © Makela et al.

Reference: Mäkelä R., Härmä V., Fajardo N. Badra, Wells G., Lygerou Z., Sangfelt O., Kononen J., Rantala J. K. Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma. Oncotarget. 2021; 12: 1100-1109. Retrieved from https://www.oncotarget.com/article/27961/text/

Provided by Impact Journals LLC

Medicine

Pancreatic Carcinoma: Study Sheds Light on the Mechanisms of Metastasis in the Particularly Aggressive Subtypes (Medicine)

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A study led by MedUni Vienna (Institute of Cancer Research and Comprehensive Cancer Center Vienna) sheds light on the mechanisms that lead to extremely aggressive metastasis in a particular type of pancreatic cancer, the basal subtype of ductal adenocarcinoma. The results contribute to a better understanding of the disease. The study has recently been published in the leading journal “Gut“.

The most prevalent form of pancreatic cancer, Pancreatic Ductal AdenoCarcinoma (PDAC) is usually divided into two subtypes, a classical subtype and a basal subtype. The latter is highly aggressive and tends towards early metastasis. One of the distinguishing features between the two subtypes is that the classical subtype exhibits the protein GATA6. This is no longer present in the basal subtype, while the protein DeltaNp63 can be detected in this type.

The study team led by Paola Martinelli, who, at the time of the study, was research group leader at the Institute of Cancer Research and member of the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital, found that the switch-over of the cancer cells from the classical to the basal type occurs in two stages: first of all, GATA6 is lost but this is not yet sufficient for the expression of DeltaNp63. Only after the concomitant loss of two additional proteins, transcription factors HNF1A and HNF4A, does DeltaNp63 emerge and the tumour switch to the aggressive form. Martinelli comments: “This suggests that reinstating the classical subtype could serve to reduce metastasis. Moreover, the tumour would once again be easier for the immune system to detect, since GATA6 not only hinders the ability of tumours to adapt to their surroundings but also blocks the mechanisms that hide tumours from the immune system.”

The study was financed by an Austrian Science Fund (FWF) research grant and contributions from Fellinger Cancer Research and the Ingrid Shaker-Nessmann Cancer Research Association.

Service: Gut
A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer. Bernhard Kloesch, Vivien Ionasz, Sumit Paliwa, Natascha Hruschka, Jaime Martinez de Villarrea, Rupert Öllinger, Sebastian Mueller, Hans Peter Dienes, Martin Schindl, Elisabeth S Gruber, Judith Stift, Dietmar Herndler-Brandstetter, Gwen A Lomberk, Barbara Seidler, Dieter Saur, Roland Rad, Raul A Urrutia, Francisco X Real, Paola Martinelli. LINK: http://dx.doi.org/10.1136/gutjnl-2020-321397

Provided by Medical University of Vienna

Medicine

Oncotarget: Genomic and Neoantigen Evolution in Head and Neck Squamous Cell Carcinoma (Medicine)

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Oncotarget published “Genomic and neoantigen evolution from primary tumor to first metastases in head and neck squamous cell carcinoma” which reported that prior work has characterized changes in the mutation burden between primary and recurrent tumors; however, little work has characterized the changes in neoantigen evolution.

These authors characterized genomic and neoantigen changes between 23 paired primary and recurrent head and neck squamous cell carcinoma (HNSCC) tumors.

Within these tumors, they identified 6 genes which have predicted neoantigens in 4 or more patients.

Within HNSCC tumors examined in this Oncotarget research paper, there are neoantigens in shared genes by a subset of patients.

The presence of neoantigens in these shared genes may promote an anti-tumor immune response which controls tumor progression.

Dr. Brian A. Van Tine from The Washington University in St. Louis, The St. Louis Children’s Hospital as well as The Siteman Cancer Center said, “Head and neck cancer are a group of heterogeneous tumors with an estimated 644,000 new cases per year worldwide.“

The infiltration of immune cells, including T cells, into tumors is associated with improved outcomes and longer survival in HNSCC.

The infiltrating T cells release granules containing perforin and granzyme A and B which directly kill tumor cells or release other cytokines and chemokines that promote the anti-tumor immune response and alter the tumor microenvironment.

For example, infiltrating T cells release interferon gamma which increases expression of PD-L1 and CTLA-4, which may increase the efficacy of immune checkpoint therapy.

Multiple studies have characterized changes in mutation burden in HNSCC, when comparing primary and metastatic tumors, no studies have characterized the shifting neoantigen burden between primary and metastatic tumors within HNSCC.

In this Oncotarget study, the authors characterized the mutational and neoantigen burden between primary and first recurrence tumors in 23 patients with HNSCC.

In this Oncotarget study, the authors characterized the mutational and neoantigen burden between primary and first recurrence tumors in 23 patients with HNSCC

The Van Tine Research Team concluded in their Oncotarget Research Output that there is a shifting neoantigen burden as there are unique neoantigens in primary tumors and different unique neoantigens in the recurrent/metastatic tumors.

The patients which have these neoantigens in shared genes are patients which have higher total numbers of neoantigens.

What is clear is that patients with neoantigens in these shared genes also tend to have increased duration of survival with disease.

The increase in neoantigens and duration of survival with disease tends to be associated with increased CD3 CD8 density in the tumor and CD8A expression.

This suggests that patients with these shared neoantigens are associated with increased CD8 T cell infiltration and increased cytotoxic activity, which extends the patient’s life.

Featured image: Properties of patients who have neoantigens in shared genes. (A) The total number of neoantigens was graphed for primary tumors with neoantigens in Ryr3 (n = 4), DNAH7 (n = 5), TTN (n = 5), or no neoantigens (Pri neoAg-, (n = 13)) or relapse tumors with neoantigens in TTN (n = 4), PIK3CA (n = 5), USH2A (n = 5), or no neoantigens (Rel neoAg-, (n = 12)). The numbers under the X axis are the mean of neoantigens. *indicates p < 0.05. (B) The duration of disease for patients with predicted neoantigens in the Primary tumor (Ryr3 (n = 4), DNAH7 (n = 5), TTN (n = 4)) and relapse tumor (TTN (n = 4), PIK3CA (n = 4), and USH2A (n = 5)), or no predicted neoantigens in these genes (neoAg-, (n = 9)). Patients with neoantigens in multiple genes are placed in all neoantigens. The asterisks indicate patients who were alive as of writing. (C) The density of CD3+ CD8+ cells in the tumor graphed by presence of neoantigens in shared genes. Primary RYR3 (n = 4), Primary DNAH7 (n = 5), Primary TTN (n = 5), Primary no neoantigens (n = 11), relapse TTN (n = 4), relapse PIK3CA (n = 5), relapse USH2A (n = 5) relapse no neoantigens (n = 10)). Numbers under the X axis are the mean of the density. (D) The Log2 (TPM +1) expression of CD8A was graphed by the presence of neoantigens in shared genes. Pri NeoAg- (n = 10), Pri Ryr3+ (n = 2), Pri DNAH7+ (n = 1), Pri TTN+ (n = 4), Rel neoAg- (n = 8), Rel TTN+ (n = 2), Rel PIK3CA+ (n = 5), Rel USH2A+ (n = 1). The number under the X axis is the mean for each column. (E) The CTL activity was graphed by neoantigen status. CTL activity was calculated as described in Figure 4. Pri NeoAg- (n = 10), Pri Ryr3+ (n = 2), Pri DNAH7+ (n = 1), Pri TTN+ (n = 3), Rel neoAg- (n = 8), Rel TTN+ (n = 2), Rel PIK3CA+ (n = 5), Rel USH2A+ (n = 1). The number under the X axis is the mean for each column.

Reference: Schutt C. R., Sun H., Pradham J. Sarin, Saenger Y., Ley J., Adkins D., Ingham M., Ding L., Van Tine B. A. Genomic and neoantigen evolution from primary tumor to first metastases in head and neck squamous cell carcinoma. Oncotarget. 2021; 12: 534-548. Retrieved from https://www.oncotarget.com/article/27907/text/

Provided by Impact Journals LLC

Medicine

Researchers Reveal Mechanism of Hepatitis B-induced Venous Metastasis & Immune Escape of Hepatocellular Carcinoma (Medicine)

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In China, about 70 million people are infected with hepatitis B virus (HBV), and more than 80% of liver cancer is caused by HBV.

HBV-associated hepatocellular carcinoma (HCC) is often accompanied by severe vascular invasion and portal vein tumor thrombus leading to a poor prognosis. However, the underlying mechanism of this disease remains obscure.

In a study published in Cancer Research, Prof. YANG Pengyuan and Prof. WANG Fan at the Institute of Biophysics (IBP) of the Chinese Academy of Sciences (CAS) revealed how HBV infection induced HCC venous metastasis and immune escape through a chemokine-based network.

The researchers firstly established a cytokines/chemokines array and screened the proinflammatory cytokine IL-8 as a potential target responsively to HBV infection. Multiple models and mechanistic study identified that HBV-induced IL-8 expression can be activated by HBx-mediated MEK-ERK signaling pathway, which enhanced permeability of the endothelium via endothelial CXCR1, the receptor of IL-8.

Based on the identification of IL-8-CXCR1 axis promoting tumor vascular metastasis in vivo, they then constructed a transgenic mouse that selectively express human CXCR1 in endothelial cells.

Interestingly, the IL-8-CXCR1 axis on vascular endothelium dramatically increased liver tumorigenesis and metastasis, and the increase in lung metastasis was observed through overexpression of IL-8, but exogenous CXCR1 overexpression did not further enhance lung metastasis. Mechanistically, the IL-8-CXCR1 axis selectively induced GARP-latent-TGF-β in liver sinusoidal endothelial cells (LSECs) and subsequently provoked preferential regulatory T cell polarization to suppress antitumor immunity.

This study identifies a hepatitis B-induced IL-8/CXCR1/TGF-β signaling cascade that suppresses anti-tumor immunity and enhances metastasis in hepatocellular carcinoma, providing new potential targets for therapeutic intervention.

Featured image: Working model of IL-8-CXCR1 axis promoted venous metastasis and intrahepatic Treg accumulation in HBV-associated HCC (Image by Dr. YANG Pengyuan’s group)

Reference: Changlu Zhang, Yanan Gao, Chengzhi Du, Geoffrey J. Markowitz, Jing Fu, Zhenxing Zhang, Chunliang Liu, Wenhao Qin, Hongyang Wang, Fan Wang and Pengyuan Yang, “Hepatitis B-induced IL-8 Promotes Hepatocellular Carcinoma Venous Metastasis and Intrahepatic Treg Accumulation”, Cancer Res March 2 2021 DOI: 10.1158/0008-5472.CAN-20-3453

Provided by Chinese Academy of Sciences

Medicine

Physics of Tumours: Cancer Cells Become Fluidised and Squeeze Through Tissue (Medicine)

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Hope for improved diagnosis and therapy of cancer

Working with colleagues from Germany and the US, researchers at Leipzig University have achieved a breakthrough in research into how cancer cells spread. In experiments, the team of biophysicists led by Professor Josef Alfons Käs, Steffen Grosser and Jürgen Lippoldt demonstrated for the first time how cells deform in order to move in dense tumour tissues and squeeze past neighbouring cells. The researchers found that motile cells work together to fluidise tumour tissue.

Käs led the research project in cooperation with Professor Lisa Manning from Syracuse University (US) and Professor Bahriye Aktas from Leipzig University Hospital. They have now published their findings in “Physical Review X“, a leading journal that primarily publishes groundbreaking research results.

“These first observations of a phase transition in human tumours change our basic concepts of tumour progression and could improve cancer diagnosis and therapy,” said Käs, who has been studying the physical properties of cancer cells for years. He said the research showed that human tumours contain solid and fluid cell clusters, which would be a breakthrough in scientists’ understanding of tumour mechanics. He added that the results form the basis for the first procedure with which metastatic cancer cells can already be detected in the tumour.

In tumour samples from patients at Leipzig University Hospital, the researchers found regions with motile cells as well as stable, solid-like regions with no cell movement. From a physical point of view, cells should not be able to move in the dense tumour mass – tumours are so densely crowded with cells that motion would be inhibited in any typical material.

The researchers therefore developed a new approach to live tumour microscopy by fluorescently staining human tumour samples immediately after surgery, allowing them to observe cell movement live. This led them to discover that, contrary to all previous findings, this cell motility does indeed take place and is associated with strong nuclear deformation. They observed how cells and their nuclei literally squeeze through the tissue by becoming severely deformed.

“Cells in biological tissues behave much like people in a bar. At low densities, they can move freely. However, movement becomes difficult when things get very crowded. But even in a crowded bar, you can still squeeze past if you turn sideways. This is exactly the effect we see in tumour tissues,” said Käs. The researchers believe this phase transition explains how cells can move and multiply in a tumour, eventually leading to metastasis. The fluid tissues showed elongated, deformed cells and nuclei. Static images of elongated cell and nuclear shapes could thus serve as a fingerprint for the metastatic aggressiveness of a tumour.

“These are spectacular results from the field of cancer physics. We now need to investigate whether the fluid regions can predict tumour aggressiveness. Here we have found a cancer marker that indicates active, motile regions and that is based on a simple physical mechanism,” said Steffen Grosser. Professor Käs is currently embarking on a clinical trial to investigate the potential of cell and nuclear shape as a new tumour marker that could be used to examine and treat patients in a much more targeted way than before.

Featured image: Researchers at Leipzig University found fluid and solid regions in breast and cervical tumours. The fluid regions can be recognised by elongated cells that squeeze through the dense tumour tissue. © Steffen Grosser, Leipzig University

Reference: Steffen Grosser, Jürgen Lippoldt, Linda Oswald, Matthias Merkel, Daniel M. Sussman, Frédéric Renner, Pablo Gottheil, Erik W. Morawetz, Thomas Fuhs, Xiaofan Xie, Steve Pawlizak, Anatol W. Fritsch, Benjamin Wolf, Lars-Christian Horn, Susanne Briest, Bahriye Aktas, M. Lisa Manning, and Josef A. Käs, “Cell and Nucleus Shape as an Indicator of Tissue Fluidity in Carcinoma”, Phys. Rev. X 11, 011033 – Published 17 February 2021. https://journals.aps.org/prx/abstract/10.1103/PhysRevX.11.011033

Provided by University of Leipzig

Medicine

A Very Aggressive Cancer Defeated In Three Months (Medicine)

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A team from UNIGE and HUG managed to save a woman whose aggressive cancer left her with only five months to live. This “miracle” highlights the importance of treatments based on immunotherapy.

The fight against cancer does not always end in victory. The main treatments today are surgical removal of the tumor, chemotherapy, radiation therapy and, to a lesser extent, stimulation of the immune system. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) treated a patient who developed a tumor on the transplant kidney that she received nine years earlier. In this case, the cancer was very aggressive, leaving her with only five months of life expectancy. Specific to this case: the tumor originated from the donor’s kidney and not from the patient herself. This peculiarity enabled scientists to attack the tumor with a dramatic boost of her immune system, which saved her life. Now, seven years later, this woman is doing well and has no cancer recurrence. The results of this study, now published in the journal Transplantation, demonstrate the importance of the development of immunotherapy.

People with type 1 diabetes experience a major disruption of sugar absorption from the blood. Over time this condition affects various organs of the body, including the kidneys, eyes and the heart. “Kidney failure in diabetic patients is a recurrent problem, says Raphaël Meier, researcher at the Department of Surgery of the Faculty of Medicine of UNIGE and Former senior resident at the Department of Visceral and Transplant Surgery of HUG. When the kidneys are no longer doing their job properly, dialysis becomes mandatory, then a combined kidney and pancreas transplant allows them to improve quality of life.” Thanks to transplantation, patients no longer have to inject themselves with insulin every day, but they still have to take immunosuppressive medication for life so that their immune system does not reject the transplanted organs. “This results in an increased risk of contracting infections, or even developing tumors,” says the Geneva researcher.

A very aggressive cancer

A pre-dialysis diabetic woman since the age of 10 underwent a kidney-pancreas transplant at the age of 41 at HUG. The transplanted organs were from a 20-year-old male donor. “Everything went very well, his blood sugar and kidney function immediately stabilized and normalized,” recalls Raphael Meier. However, nine years later, during the annual check-up, the doctors noticed a lump in the kidney. They decide to have it operated on immediately and found a large tumor, with metastases that had already spread to the intestines, liver and lungs. “This type of tumor, called Bellini cancer, has a life expectancy of about five months with treatment, it is one of the most aggressive cancers,” says Raphael Meier.

Following the discovery of the tumor, a question arises: where does it come from? Is it a tumor developed by the patient herself, or is it a tumor that comes from the organ donor? To find out, the team of surgeons analyzes the genotype of the tumor. They discovered that the likely cause of the tumor was  BK virus, which is also present in the metastases. They also found that the tumor contained Y chromosomes, therefore of male donor origin.  

A triple attack by interleukin 2

Given the cause and the origine of the tumor, scientists relied on powerful treatment to try to save this woman. “We opted for interleukin 2. This treatment is based on a molecule which activates the immune system in an extreme way,” explains Raphaël Meier. However, this treatment is difficult to control, and the side effects are numerous and hard to tolerate for the patient, which is why it is not routinely prescribed. “This allowed us to carry out a triple attack which led to the destruction of the tumor,” he says. This treatment was particularly suited to this case, because the tumor did not come from the patient herself but from the donor. The boosted immune system attacked the non-self, tumor cells, very aggressively. In addition, anti-tumor Natural Killer cells were particularly active in this woman. Finally, with the cause of the tumor being of viral origin, the white blood cells specialized in eradicating viruses also kicked in.

For three months, the patient endured the treatment, so that six months later, there was no trace of the tumor and its metastases. “No longer being able to take her anti-rejection drugs, costed her her kidney and pancreas transplants, and the patient is on dialysis again. But now, seven years later, there is no trace of this aggressive cancer; a new transplant could now be considered,” Raphael Meier says.

Immunotherapy, the future of oncology treatments?

This case demonstrates the essential role of the immune system in the management of cancers. “The story of this woman showed us that there is always hope for a cure, even when it seems impossible. He underlines the courage of patients who are fighting to survive, and finally, he notes that research on immunotherapies must continue; the right angle of attack can allow our body to overcome tumors, and above all to prevent them from reappearing again years later,” concludes Raphael Meier.

Featured image: PET-CT-scanner showing the kidney tumour with liver and lung metastases (left, arrows). PET-CT-scanner after complete disappearance of the tumours at 6 months (right). © UNIGE

Reference: Meier RPH, Muller YD, Dietrich PY, Tille JC, Nikolaev S, Sartori A, Labidi-Galy I, Ernandez T, Kaur A, Hirsch HH, McKee TA, Toso C, Villard J, Berney T. Immunologic Clearance of a BK Virus-associated Metastatic Renal Allograft Carcinoma. Transplantation. 2021 Feb 1;105(2):423-429. doi: 10.1097/TP.0000000000003193. PMID: 32091486; PMCID: PMC7837753.

Provided by University of Geneve

Food

Vegan Diets Improve Liver Function (Food)

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Vegan diets improve liver function in patients with nonalcoholic fatty liver disease (NAFLD), according to research published in the Journal of Gastrointestinal and Liver Diseases. Researchers followed 26 participants with NAFLD on a vegan diet for six months and tracked body weight, calorie intake, and liver function. Dietitians supported participant dietary adherence via monthly phone calls or clinic visits. Results showed weight loss and improvements in liver enzymes toward normal levels. Increased consumption of plant-based foods improved antioxidant intake and gut microbiota beneficial to liver enzymes. These findings support plant-based dietary approaches for liver disease treatment and the prevention of associated chronic conditions including hepatitis, fibrosis, cirrhosis, or hepatocellular carcinoma.

References

Chiarioni G, Popa SL, Dalbeni A, et al. Vegan diet advice might benefit liver enzymes in nonalcoholic fatty liver disease: An open observational pilot study. J Gastrointestin Liver Dis. Published online February 4, 2021. doi: 10.15403/jgld-3064.

Provided by Physicians Committee for Responsible Medicine

Medicine

Yale Researchers Develop Injection to Treat Skin Cancer (Medicine)

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Yale researchers are developing a skin cancer treatment that involves injecting nanoparticles into the tumor, killing cancer cells with a two-pronged approach, as a potential alternative to surgery.

The results are published in the Proceedings of the National Academy of Sciences.

“For a lot of patients, treating skin cancer is much more involved than it would be if there was a way to effectively treat them with a simple procedure like an injection,” said Dr. Michael Girardi, professor and vice chair of dermatology at Yale Medical School and senior author of the study. “That’s always been a holy grail in dermatology — to find a simpler way to treat skin cancers such as basal cell carcinoma and squamous cell carcinoma.”

For the treatment, tumors are injected with polymer-based nanoparticles carrying a chemotherapy agent. Key to the treatment’s success is that the nanoparticles are bioadhesive — that is, they bind to the tumors and remain attached long enough to kill a significant number of the cancer cells.

“When you inject our nanoparticles into a tumor, it turns out that they’re retained within that tumor very well,” said co-author Mark Saltzman, the Goizueta Foundation Professor of Biomedical Engineering, Chemical and Environmental Engineering, and professor of physiology. “They accumulate and bind to the tumor matrix, so one single injection lasts for a very long time — the particles stay there and slowly release the compounds. You need that to get rid of the lesion.”

For comparison, the same drug was injected freely into tumors of control models without the nanoparticles. They found that the tumors were significantly more diminished when the drugs were delivered by nanoparticles.

Also critical to the therapy is that the treatment can be combined with an agent that stimulates the body’s immune system.

“I call the phenomenon ‘kill and thrill,’” Girardi said. “You don’t want to just kill the cells and leave them there, you want to stimulate the immune system to clean up the mess and also react against cells that might not have been killed directly. So it’s a two-pronged attack on the cancer.”

In many cases, ridding tumors with an injection could eliminate the need for surgery, the researchers said. It may also then avoid potential wound infections and other complications. Additionally, some patients with other medical conditions are poor candidates for surgery.

An injection-based therapy would also mean that patients could have multiple tumors treated in a single visit.

“In these studies, we did just a single injection, and that’s how we’d like it to work clinically,” Saltzman said. “You go to a dermatologist, they see a lesion and inject into it, and it’s gone and you don’t have to come back.”

Saltzman’s lab, which specializes in nanoparticles, worked to optimize the particles’ drug-carrying ability to deliver as much of the chemotherapy agent in a single dose as possible. Because the contents of the nanoparticle remain at the site of the tumor, the delivery system allows for the use of particularly powerful drugs. Conventional chemotherapy affects the entire body and can have severe side effects, so the toxicity of drugs is more limited.

Girardi and Saltzman are working with the start-up company Stradefy Biosciences Inc., which plans to advance the technology’s preclinical development and then conduct clinical trials.

“Mike and Mark have been doing outstanding science together for a number of years,” said Brian R. Dixon, president and CEO of Stradefy. “It’s really hard to beat that kind of team. We believe that their groundbreaking work is going to lead to truly helpful therapies for patients.”

Other Yale investigators involved in the project included Jamie K. Hu, Hee-Won Suh, Munibah Qureshi, Julia Lewis, Sharon Yaqoob, Zoe Moscato, Sofia Griff, Alison Lee, and Emily Yin.

Featured image: Bioadhesive nanoparticles (white) after being taken up by skin cancer tumor cells during in virtro culture. (Image credit: Julia Lewis)

Reference: Jamie K. Hu, Hee-Won Suh, Munibah Qureshi, Julia M. Lewis, Sharon Yaqoob, Zoe M. Moscato, Sofia Griff, Alison K. Lee, Emily S. Yin, W. Mark Saltzman, Michael Girardi, “Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles”,
Proceedings of the National Academy of Sciences Feb 2021, 118 (7) e2020575118; DOI: 10.1073/pnas.2020575118

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