Dog owners are being warned to 'remain vigilant' after a second fatal case of Alabama Rot in 2023 has been confirmed in Berkshire, tragically killing six-year-old Hungarian Vizsla Marnie

Pet owners are being warned to spot the signs of Alabama Rot after the deadly disease took the life of Marnie the six-year-old Hungarian Vizsla in Berkshire. Also known as cutaneous and renal glomerular vasculopathy (CRGV), Alabama Rot is an extremely rare disease which claims the lives of 90 percent of infected dogs.

The caution comes after a three-year-old Labrador sadly died last month, marking two deaths already in 2023. Marnie's owner, Sabina Richardson, wants to highlight the early symptoms of the canine disease, including sores on paws, to ensure other pet parents are fully aware of the warning signs of CRGV.

Sabina told the Mirror: "Marnie's first symptoms were sores on her paws which then began to spread onto her legs. She also stopped eating and started to vomit.

"We took her to local vets who gave her antibiotics but she couldn't keep the tablets down and continued to deteriorate.

"By this point, we were very concerned and visited another vets, who said they feared it was Alabama Rot.

"They gave Marnie an injection of antibiotics and took blood tests which confirmed her kidneys were failing.

"That was such a shock and it was really tough when we finally had to make the heart-breaking decision to put her to sleep."

The anguish was all the more acute as a dog belonging to Sabina's partner, a two-year-old whippet called Goose, had shown similar symptoms but, thankfully, survived.

Sabina added: "Goose had very similar sores that were oozing puss and had the same sort of treatment but he survived and is absolutely fine now.

"It's so hard to understand. We keep going over it all and trying to identify where they could have come in touch with such a rare disease.

"We have re-traced our walks and can't think of anywhere we went that was unusual.

"Everyone in the village tends to walk their dogs in the same spots so it's baffling how there haven't been more cases."

Anderson Moores Veterinary Specialists has been leading research since 2012 and confirmed the latest case, which is the second in the county in the past six weeks.

Josh Walker, from Anderson Moores, told the Mirror: "There were 11 cases recorded across the UK in 2022, so to report two deaths in Berkshire in a six-week period is unusual.

"However, I must emphasise this is a very rare disease and we're advising dog owners to remain calm but vigilant and seek advice from their vet if their dog develops unexplained skin lesions.

"Treatment largely revolves around management of the sudden onset kidney failure and is only successful in around 10 per cent of cases."

Josh advises pet owners to use the veterinary specialists' bespoke online map to see the exact location of confirmed cases in the UK.

Do you have a dog story to share? Email nia.dalton@reachplc.com.

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Urgent warning to dog owners as new deadly Alabama Rot case confirmed in UK - The Mirror

Physicians speak on personalizing treatment for graft-versus-host disease, arming CAR T cells against macrophages

ORLANDO, FL Two experts from Roswell Park Comprehensive Cancer Center are delivering presentations this week at an international conference highlighting research aimed at extending and improving the lives of patients with blood-related cancers. Nataliya Buxbaum, MD, from the Department of Pediatric Oncology and Marco Davila, MD, PhD, Vice Chair for Cellular Therapies and Senior Vice President and Associate Director for Translational Research, were invited to highlight their work in podium talks at the 2023 Tandem Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR) this week in Orlando, Florida.

A biology-based approach to GvHD

Dr. Buxbaum, a member of the Chronic GvHD National Institutes of Health (NIH) Consensus Project Biology Task Force, described recent advances in understanding the biology of chronic graft-versus-host disease (GvHD) a potentially fatal condition that affects between 25% and 75% of patients who undergo allogeneic hematopoietic cell transplant. She also discussed her research on the immunometabolism of GvHD that may lead to new imaging approaches and therapy for this condition.

If its successful, the strategy may:

We are still uncovering the complex biological underpinnings of GvHD, Dr. Buxbaum observes. For four decades we treated all patients with the same systemic treatment corticosteroids. Not only do many patients not respond, but those who do respond end up being on them a long time, and they have many side effects.

She notes that preclinical work has opened insights into the biological pathways involved in GvHD and has led to the development of targeted therapies for this transplant barrier. At the same time, the work of the NIH Consensus Project Biology Task Force has better defined the disease, laying the groundwork for the FDA to approve three drugs for chronic GvHD and one to prevent acute GvHD in the last five years alone. Thats groundbreaking, she says.

However, while blood-based biomarkers are being developed for GvHD, it is still challenging to pinpoint the exact areas of the body where GvHD is developing based on blood sampling alone. Because there currently is no diagnostic imaging for detecting GvHD, a minimum of 28 days must elapse after the start of treatment before a biopsy can determine whether or not the disease has responded to treatment and a biopsy is challenging to do in somebody whos sick, Dr. Buxbaum notes. If the initial treatment hasnt worked, a different drug is started and more time is needed before re-evaluation for response.

Locating areas of high glucose metabolism is key to detecting the presence of cancer. This is currently accomplished with a positron emission tomography (PET) scan after having the patient ingest a radioactive sugar molecule. PET is then able to map where glucose is being absorbed by cancer cells. But high sugar metabolism can also indicate the presence of GvHD: When you first start getting GvHD, the immune system fires up the T cells, and they start using a lot of sugar, explains Dr. Buxbaum.

She and her team see great potential in performing metabolic imaging with magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce images and, unlike PET, does not require radioactive sugar molecules. Within the next six to 12 months, Dr. Buxbaum and her colleagues hope to run a pilot study to gauge the effectiveness of locating GvHD with metabolic MRI, using a sugar molecule labeled with deuterium, a nonradioactive form of hydrogen.

Targeting this metabolic pattern of high glycolysis is something we should do therapeutically, says Dr. Buxbaum. Were studying it in preclinical models right now and having some success. She says previous work with preclinical models has shown that GvHD can be detected this way in the liver and gut, and we think the same can happen in a human being. We then use a drug that inhibits the processing of sugar to ameliorate GvHD.

Allogeneic stem cell transplants are especially challenging. Each time its a unique mismatch between the host and donor, if theyre unrelated, says Dr. Buxbaum. Its a unique situation every time, so it requires personalized therapy.

Dr. Buxbaums talk, Biology of GvHD, was presented Wednesday, Feb. 15, from 11-11:30 a.m. EST.

Identifying the cause of poor outcomes in CAR T-cell therapy for B-cell malignancies

Dr. Davila will discuss his teams efforts to determine why some patients with B-cell malignancies do not respond well to CAR T-cell therapy targeting CD19, a surface protein expressed by most B cells. What accounts for poor outcomes in those patients?

Using patient samples, the investigators identified gene signatures and cell signatures showing that the lymphoid tissue in those patients contained high numbers of myeloid cells, which originate in the bone marrow and can develop into various types of adult blood cells, including macrophages, which are capable of killing tumor cells and other cells. They then developed assays of CD19-targeted CAR T cells, tumors and macrophages, and cultured them together and discovered that certain types of macrophages were capable of killing CAR T cells.

While macrophages might kill up to 90% of the CAR T cells, the remaining 10% that survive proliferate and persist, says Dr. Davila, which means it would be possible for the surviving CAR T cells to continue attacking the cancer cells. But how well would they function? We compared them to other CD19-targeted T cells that had never been exposed to macrophages, and they performed worse, he explains. They didnt kill as well, they didnt secrete as much cytokine which can stimulate the immune system and they didnt proliferate as well.

Further investigation using preclinical models revealed the specific metabolic pathways that Dr. Davila and his colleagues believe are key to how macrophages trigger this dysfunction in CD19-targeted CAR T cells. Our goal now, he says, is to retrain the CAR T cells to be more resistant to this metabolic dysfunction. We hope this will result in better outcomes for patients.

Dr. Davila will present Mechanisms of Resistance to CD19-Targeted CAR T Cells: Lessons from Mice and Patients, Friday, Feb. 17, from 3-3:30 p.m. EST, World Center Marriott, Cypress 3.

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Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancers grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at http://www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.

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Prasad V, Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Intern Med. 2017;177:156975.

Article PubMed PubMed Central Google Scholar

DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:2033.

Article PubMed Google Scholar

Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:60714.

Article CAS PubMed PubMed Central Google Scholar

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig. 2001;108:116774.

Article CAS PubMed PubMed Central Google Scholar

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:13045.

Article PubMed PubMed Central Google Scholar

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife. 2014;3:e02242.

Article PubMed PubMed Central Google Scholar

Fendt SM, Bell EL, Keibler MA, Davidson SM, Wirth GJ, Fiske B, et al. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 2013;73:442938.

Article CAS PubMed PubMed Central Google Scholar

Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67:674552.

Article CAS PubMed Google Scholar

Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:35160.

Article CAS PubMed Google Scholar

Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:21426.

Article CAS PubMed PubMed Central Google Scholar

Blandino G, Valerio M, Cioce M, Mori F, Casadei L, Pulito C, et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012;3:865.

Article PubMed Google Scholar

Lochhead PA, Salt IP, Walker KS, Hardie DG, Sutherland C. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes. 2000;49:896903.

Article CAS PubMed Google Scholar

Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab. 2003;88:132332.

Article CAS PubMed Google Scholar

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:25660.

Article CAS PubMed PubMed Central Google Scholar

Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499503.

Article CAS PubMed PubMed Central Google Scholar

Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020;16:27683.

Article CAS PubMed PubMed Central Google Scholar

Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, et al. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab. 2018;28:679688.e674.

Article CAS PubMed PubMed Central Google Scholar

Lord SR, Collins JM, Cheng WC, Haider S, Wigfield S, Gaude E, et al. Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin. Br J Cancer. 2020;122:25865.

Article CAS PubMed Google Scholar

Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, et al. Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA.32 randomized clinical trial. J Am Med Assoc. 2022;327:196373.

Article CAS Google Scholar

Goodwin PJ, Dowling RJO, Ennis M, Chen BE, Parulekar WR, Shepherd LE, et al. Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial. NPJ Breast Cancer. 2021;7:74.

Article CAS PubMed PubMed Central Google Scholar

Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19:674150.

Article CAS PubMed Google Scholar

Tsakiridis T, Pond GR, Wright J, Ellis PM, Ahmed N, Abdulkarim B, et al. Metformin in combination with chemoradiotherapy in locally advanced non-small cell lung cancer: the OCOG-ALMERA randomized clinical trial. JAMA Oncol. 2021;7:133341.

Article PubMed PubMed Central Google Scholar

Skinner H, Hu C, Tsakiridis T, Santana-Davila R, Lu B, Erasmus JJ, et al. Addition of metformin to concurrent chemoradiation in patients with locally advanced non-small cell lung cancer: the NRG-LU001 phase 2 randomized clinical trial. JAMA Oncol. 2021;7:132432.

Article PubMed Google Scholar

Alghandour R, Ebrahim MA, Elshal AM, Ghobrial F, Elzaafarany M, MA EL. Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED). Urol Oncol. 2021;39:831.e810.

Article Google Scholar

Arrieta O, Barron F, Padilla MS, Aviles-Salas A, Ramirez-Tirado LA, Arguelles Jimenez MJ, et al. Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5:e192553.

Article PubMed PubMed Central Google Scholar

El-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clin Exp Metastasis. 2016;33:33957.

Article CAS PubMed Google Scholar

Marrone KA, Zhou X, Forde PM, Purtell M, Brahmer JR, Hann CL, et al. A randomized phase II study of metformin plus paclitaxel/carboplatin/bevacizumab in patients with chemotherapy-naive advanced or metastatic nonsquamous non-small cell lung cancer. Oncologist. 2018;23:85965.

Article CAS PubMed PubMed Central Google Scholar

Yee D, Isaacs C, Wolf DM, Yau C, Haluska P, Giridhar KV, et al. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer. NPJ Breast Cancer. 2021;7:131.

Article CAS PubMed PubMed Central Google Scholar

Gulati S, Desai J, Palackdharry SM, Morris JC, Zhu Z, Jandarov R, et al. Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer. Cancer. 2020;126:35462.

Article CAS PubMed Google Scholar

Trucco M, Barredo JC, Goldberg J, Leclerc GM, Hale GA, Gill J, et al. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin. Pediatr Blood Cancer. 2018;65:e27224.

Article PubMed Google Scholar

Khawaja MR, Nick AM, Madhusudanannair V, Fu S, Hong D, McQuinn LM, et al. Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. Cancer Chemother Pharm. 2016;77:9737.

Article CAS Google Scholar

Ashton TM, Fokas E, Kunz-Schughart LA, Folkes LK, Anbalagan S, Huether M, et al. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun. 2016;7:12308.

Article CAS PubMed PubMed Central Google Scholar

Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, et al. Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer. Clin Cancer Res. 2021;27:245969.

Article CAS PubMed PubMed Central Google Scholar

Lissanu Deribe Y, Sun Y, Terranova C, Khan F, Martinez-Ledesma J, Gay J, et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat Med. 2018;24:104757.

Article CAS PubMed Google Scholar

Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature. 2014;508:10812.

Article CAS PubMed PubMed Central Google Scholar

Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2013;49:24150.

Article CAS PubMed Google Scholar

Deng XS, Wang S, Deng A, Liu B, Edgerton SM, Lind SE, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:36776.

Article CAS PubMed Google Scholar

Tosic I, Frank DA. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications. Neoplasia. 2021;23:116778.

Article CAS PubMed PubMed Central Google Scholar

Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80:593543.

Article PubMed PubMed Central Google Scholar

Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018;24:191929.

Article CAS PubMed PubMed Central Google Scholar

Broadfield LA, Saigal A, Szamosi JC, Hammill JA, Bezverbnaya K, Wang D, et al. Metformin-induced reductions in tumor growth involves modulation of the gut microbiome. Mol Metab. 2022;61:101498.

Article CAS PubMed PubMed Central Google Scholar

Han K, Fyles A, Shek T, Croke J, Dhani N, DSouza D, et al. A phase II randomized trial of chemoradiation with or without metformin in locally advanced cervical cancer. Clin Cancer Res. 2022;28:526371.

Article CAS PubMed Google Scholar

Fu Z, Mowday AM, Smaill JB, Hermans IF, Patterson AV. Tumour hypoxia-mediated immunosuppression: mechanisms and therapeutic approaches to improve cancer immunotherapy. Cells. 2021;10:1006.

Article CAS PubMed PubMed Central Google Scholar

Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res. 2017;5:916.

Article CAS PubMed Google Scholar

Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell. 2018;71:60620.e607.

Article CAS PubMed PubMed Central Google Scholar

Zhang Z, Li F, Tian Y, Cao L, Gao Q, Zhang C, et al. Metformin enhances the antitumor activity of CD8(+) T lymphocytes via the AMPK-miR-107-Eomes-PD-1 pathway. J Immunol. 2020;204:257588.

Article CAS PubMed Google Scholar

Li L, Wang L, Li J, Fan Z, Yang L, Zhang Z, et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 2018;78:177991.

Article CAS PubMed PubMed Central Google Scholar

Chiang CF, Chao TT, Su YF, Hsu CC, Chien CY, Chiu KC, et al. Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-kappaB signaling. Oncotarget. 2017;8:2070618.

Article PubMed PubMed Central Google Scholar

Wang JC, Sun X, Ma Q, Fu GF, Cong LL, Zhang H, et al. Metformins antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J Cell Mol Med. 2018;22:382536.

Article CAS PubMed PubMed Central Google Scholar

Davis SR, Robinson PJ, Jane F, White S, Brown KA, Piessens S, et al. The benefits of adding metformin to tamoxifen to protect the endometrium-A randomized placebo-controlled trial. Clin Endocrinol. 2018;89:60512.

Article CAS Google Scholar

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Bernese Mountain dogs were originally bred as farm dogs in Switzerland. Today, theyre popular family dogs, as they are intelligent, tolerant of other pets, and good with kids. If youre looking to add a dog to your family, an important factor to consider is the lifespan of your chosen breed.

A Bernese Mountain dog lover named Karlo Laforteza has kept an informal database of Bernese Mountain dogs that have reached old age. While these individuals are not verified, this anecdotal list provides a snapshot of this dogs lifespan.

These are 10 of the oldest Bernese Mountain dogs:

There are unsubstantiated reports of a Bernese Mountain dog that lived to be 25 years old! The dog lived in Ronsberg, Bavaria. Considering the oldest verified dog on earth is younger than that, the likelihood that this German dog lived 25 years is highly unlikely.

Bernese Mountain dogs originally arrived in the USA via a farmer from Kansas in 1926. The American Kennel Club, an organization for purebred dogs registered in the USA, officially recognized the breed in 1937.

The oldest verified Bernese mountain dog lived 15 years and two months, as documented by the AKC.

iStock.com/Kriste Sorokaite

Since these dogs are a large breed, their life expectancy is on the short side. In fact, this breed has the shortest lifespan of all dog breeds. Females live almost nine years, while males dont quite reach eight. This means that the average dog, regardless of gender, may live between eight and nine years.

In comparison, the average lifespan across all dog breeds is about 10 years old. No one is quite sure why smaller dogs live longer than large ones. It may have something to do with cell division in the larger mass of tissue present in bigger animals.

All dogs are prone to diseases. However, Bernese Mountain dogs are uniquely susceptible to certain ailments. These diseases include histiocytosis, gastric volvulus, and joint dysplasia.

Some diseases that affect old Bernese Mountain dogs are:

Making sure that your pet is as healthy as it can be is undoubtedly your top priority. Before purchasing a Bernese Mountain dog, request genetic testing that will help you avoid some of these common ailments. However, it is not possible to predict every malady that may affect your dog.

Gastric volvulus, a condition in which gas becomes trapped in the stomach, comes on fast and may kill a dog if not addressed. However, only about two percent of afflicted dogs end up losing their lives. It is common in large dogs, so its important for owners to know the signs and symptoms.

Common symptoms include bloating and retching, caused by a gas buildup in the stomach. Sometimes it resolves itself but can quickly become fatal.

In extreme cases, both entrances of the stomach become blocked. Immediate care from a veterinarian is required at this stage for the dog to survive. Older dogs are more at risk and need to be monitored closely.

Progressive retinal atrophy is an eye disease that often causes blindness in affected individuals. Blindness comes on slowly and is usually preceded by a sensitivity to light at nighttime. It isnt painful and sometimes it goes unnoticed until its advanced.

This disease is related to the retina, which refers to a cell layer on the back of the eyeball. This cell layer detects incoming light and turns it into electrical stimuli, which the brain interprets into images. Progressive retinal atrophy occurs when these retina cells slowly degrade and die.

This disease is genetic. Because of its recessive nature, both dog parents must carry the genes for the disease to appear in their offspring.

Some other affected breeds include Bedlington terriers, American cocker spaniels, rottweilers, golden retrievers, and English springer spaniels.

Over half of Bernese Mountain dogs die because of some form of cancer. More than 25 percent of this breed dies from histiocytosis in particular.

The two particular diseases associated with the term histiocytosis include systemic histiocytosis and malignant histiocytosis. Both involve the immune system cells called histiocytes. However, systemic histiocytosis affects younger dogs and is treatable, while malignant histiocytosis afflicts older dogs and is almost always fatal.

Histiocytosis is a genetic disease. As a result, the family members of affected dogs are at risk of developing the disease. Additionally, this disease skips generations, making predictions more complicated.

When the histiocytes of the immune system begin malfunctioning, they sometimes cause tumors throughout a dogs body. Fever, appetite loss, lethargy, and a quick drop in weight are common and observable symptoms.

Affected dogs will show symptoms once tumor formation causes organ degradation. Commonly afflicted organs include the spinal cord, lungs, spleen, kidneys, lymph nodes, and liver. There is no cure for this disease and symptoms usually only occur once it is advanced.

How about the fastest dogs, the largest dogs and those that are -- quite frankly -- just the kindest dogs on the planet? Each day, AZ Animals sends out lists just like this to our thousands of email subscribers. And the best part? It's FREE. Join today by entering your email below.

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10 of the Oldest Bernese Mountain Dogs - AZ Animals

Yago L. Nieto, MD, PhD, professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses findings from a phase 2 trial investigating panobinostat (Farydak), gemcitabine, busulfan, and melphalan plus autologous stem cell transplant (ASCT) in patients with high-risk or relapsed/refractory multiple myeloma.

This trial enrolled 80 patients to 1 of 2 cohorts. The first cohort consisted of patients who were receiving a first transplant for relapsed/refractory disease or as frontline consolidation for disease with high-risk cytogenetics, Nieto says. The second cohort consisted of patients who were receiving a second transplant after progressing on a previous transplant, Nieto explains.

This trial showed that the combination of panobinostat, gemcitabine, busulfan, and melphalan plus ASCT was safe, with manageable toxicities, Nieto notes. This regimen was also associated with high overall response rates and complete response rates, at 67% and 40%, respectively, in cohort 1 and 93% and 64%, respectively, in cohort 2, Nieto emphasizes. Additionally, minimal residual disease (MRD) negativity rates improved after transplant in both cohorts, and MRD negativity conversion was associated with better outcomes, Nieto says. The MRD negativity rate increased from 8.5% to 23% after transplant in cohort 1 and from 34% to 55% in cohort 2.

The second part of this trial was a comparison between both cohorts of the study and a concurrent control cohort consisting of patients who were eligible for the trial but instead received off-trial transplant with either busulfan and melphalan or melphalan alone, Nieto explains. A matched pair analysis showed progression-free survival (PFS) superiority with the study regimen vs the control arm in patients receiving a first transplant, Nieto says. Conversely, the matched pair analysis of patients receiving a second transplant showed no significant difference in PFS between the study regimen and control arm, Nieto notes.

Based on these findings, the investigators concluded that panobinostat, gemcitabine, busulfan, and melphalan plus ASCT is more effective than standard-of-care transplant with busulfan and melphalan or melphalan alone in patients receiving a first transplant for relapsed/refractory or high-risk multiple myeloma, Nieto concludes.

Editors Note:Dr. Nieto has received research funding from Novartis, Secura Bio, AstraZeneca, and Affimed.

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Dr. Nieto on High-Dose Chemotherapy and ASCT in R/R Multiple ... - OncLive

Carmelo Carlo-Stella, MD, PhD, Department of Biomedical Sciences, Humanitas University, Department of Oncology and Hematology, IRCCS Humanitas Research Hospital in Rozzano, Italy, discusses the evaluation of subcutaneous and intravenous (IV) RG6234 in relapsed/refractory multiple myeloma.

A phase 1 dose-escalation trial (NCT04557150) evaluated both subcutaneous and IV RG6234 in patients with heavily pretreated multiple myeloma who previously received treatment with an immunomodulatory drug and proteasome inhibitor and are intolerant to or have no other option for standard-of-care treatment.

Updated results presented at the 2022 ASH Annual Meeting showed that patients who received IV RG6234 experienced an overall response rate (ORR) of 71.4%, and those in the subcutaneous RG6234 cohort had an ORR of 63.6%. Notably, 50% of patients in the IV cohort achieved a very good partial response or better. Additionally, 71.4% of patients who achieved complete remission (CR) became minimal residual disease negative.

RG6234 is a GPRC5DxCD3 T-cell engaging bispecific antibody that targets CD3 cells and multiple myeloma plasma cells, Carlo-Stella explains. Upon the antibody aligning with the bindings of the T-cells and myeloma cells, the T-cells are activated, in turn producing cytokines that target myeloma plasma cells, Carlo-Stella says.

Due to their off-the-shelf nature and ease of use, bispecific antibodies have gained more traction across hematologic malignancies in recent years, Carlo-Stella notes, adding that this shift has largely occurred across the landscape of lymphoproliferative disorders. These agents have created high expectations for both physicians and patients, Carlo-Stella emphasizes.

At this stage in development, RG6234 remains under evaluation in a phase 1 clinical trial that has enrolled 108 patients with relapsed/refractory multiple myeloma. Approximately half of these patients have been treated with IV RG6234, and the other half were treated subcutaneously, Carlo-Stella notes. Investigators hope to develop RG6234 as a subcutaneous drug as a fixed-duration therapy, Carlo-Stella concludes.

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Dr. Carlo-Stella on the Investigation of RG6234 in R/R Multiple ... - OncLive

The Jockey Club Press Release

LEXINGTON, Ky.The board of directors of Grayson-Jockey Club Research Foundation announced today that it has authorized expenditure of $1,498,077 to fund 12 new projects and nine continuing projects at 13 universities as well as two career development awards. The 2023 slate of research brings Graysons totals since 1983 to more than $34.1 million to underwrite 426 projects at 45universities.

The Grayson Foundation is dedicated to tackling a variety of equine health challenges, which is clearly reflected in our selected projects for this year, said Jamie Haydon, president of Grayson. Our research projects and career development awards wouldnt be possible without the kindness of our donors, and we thank them for their understanding of the significance of equine veterinary research.

Below is an alphabetical list by school of the new projects:

Transcriptomic Response To OsteoarthritisLynn Pezzanite, Colorado State UniversityThis study will highlight the role that cells of the immune system play to contributing to disease progression of osteoarthritis toward the goal of developing treatments for each stage of disease.

Efficacy of Recombinant Equine Lubricin for OsteoarthritisHeidi Reesink, Cornell UniversityThis study will assess efficacy of recombinant equine lubricin (rEqLub) in mitigating equine joint disease and identify gene and protein pathways affected by rEqLub in equine joints.

Treatment Of Meniscal Injury With Mesenchymal Stem Cells

Aimee Colbath, Cornell University

This study will determine whether intra-articular mesenchymal stem cells lead to improved meniscal healing, providing an immediate impact on how veterinarians treat equine meniscal disease.

Stem Cell Neotissue Implants for Equine Tendon HealingMandi J. Lopez, Louisiana State UniversityThis study will determine if viable neotissue implants generated from stem cells will augment current therapies to treat debilitating tendon injuries in equine athletes and companions.

Gallium Nitrate to Treat Bacterial Endometritis in MaresDale Kelley, Oklahoma State UniversityThis study proposes to develop new, safe, and efficacious antimicrobial strategies to treat antimicrobial resistance.

A VapA mRNA Vaccine for R. equi PneumoniaNoah Cohen, Texas A&M AgriLife ResearchThis grant evaluates an mRNA vaccine administered intramuscularly to foals to protect against pneumonia caused by the bacterium Rhodococcus equi, a major cause of disease and death in foals worldwide.

Genomics of Thoroughbred Stallion Subfertility

Terje Raudsepp, Texas A&M University

This project aims to identify candidate genes and regulatory variants underlying impaired acrosome reaction and subfertility in Thoroughbred stallions using multi-platform genomics.

Validation of Biomarkers for Equine NeurodegenerationCarrie J. Finno, University of California DavisIt is expected that this study will improve the diagnosis of spinal cord disease in horses.

PET MRI Sport Horse FetlockMathieu Spriet, University of California DavisThis study will compare 18F-NaF positron emission tomography (PET) with magnetic resonance imaging (MRI) for assessment of fetlock injuries in sport horses.

Antibiotic Effects On Uterine Microbiome and ResistomeIgor Canisso, University of IllinoisThis is a study of uterine microbiome and resistome of mares resistant and susceptible to endometritis treated with post-mating antibiotics.

Nanoparticle Vaccines For Equine Rotavirus BFeng Li, University of KentuckyThe vaccine candidate developed from this project will help the equine industry to control and prevent equine rotavirus B infection.

An efficacious EPM vaccine is on the waySharon Witonsky, Virginia-Maryland CVMThis study plans to identify potential MHC class I CD8 and MHC class II CD4 protective epitopes for an efficacious vaccine against Equine Protozoal Myeloencephalitis due to Sarcocystis neurona.

Career Development Awards

The Storm Cat Career Development Award, inaugurated in 2006, grants $20,000 to an individual considering a career in equine research. This year, Graysonawarded Dr. Shun Shune Kimura of University of Georgia. Dr. Kimuras research will investigate how immune and metabolic responses in systemic inflammatory response syndrome (SIRS) impact disease severity, and determine if metformin has beneficial anti-inflammatory and metabolic effects in equine SIRS.

The Elaine and Bertram Klein Career Development Award was first awarded in 2015 and grants $20,000 to a prospective equine researcher. This years recipient isDr. Bethanie Cooper of North Carolina State University. Dr. Coopers research, entitled, Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) protein as a therapeutic target in equine asthma, will examine this new protein-based therapy as a potential treatment for horses suffering with equine asthma.

The track record of Graysons career development awards in supporting up-and-coming equine researchers is undeniable, and we are thrilled to extend grants to two deserving recipients this year, said Dr. Johnny Mac Smith, who serves as a consultant for the research advisory committee and is the A. Gary Lavin Chair of the foundation.

Click here for Details on the new projects.

Grayson-Jockey Club Research Foundation is traditionally the nations leading source of equine research funding. The projects it supports enhance the health and safety of horses of all breeds. Additional information about the foundation is available atgrayson.jockeyclub.org.

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Grayson-Jockey Club Research Foundation Approves 2023 Funding - Past The Wire

While cryptocurrency may be a fitting investment for some portfolios, you don't need to put your hard-earned cash into speculative investments in order to pursue market-beating returns. If you have money to put into the stock market right now, there are plenty of companies just begging to be bought with tremendous growth potential to tap into in the years ahead.

These are three such stocks to consider adding to your portfolio right now.

Vertex Pharmaceuticals (VRTX 0.23%) is coming off of another robust year of growth in 2022. The company delivered approximately $9 billion on the top line in the 12-month period, paired with earnings of $3.3 billion and operating income of $4.3 billion. These three metrics represented increases of 18%, 42%, and 66%, respectively, from the prior year.

Vertex isn't content to rest on the success of its cystic fibrosis treatments. It's aggressively building out a pipeline of products, primarily targeting various segments of the rare disease drug market, each of which could represent multi-billion-dollar revenue opportunities for the company.

Among some of the most promising candidates in Vertex's pipeline are a rare blood disorder treatment that the company developed with CRISPR Therapeutics (which could be approved as soon as this year), an MRNA-based cystic fibrosis therapy it's working on with Moderna, and a non-opioid drug to treat acute pain. The company also acquired ViaCyte last year, a company that's working on developing stem-cell based treatments for type 1 diabetes.

Vertex's continued footprint in the cystic fibrosis market includes the only medicines currently approved for targeting the root protein malfunction that leads to the genetic illness, and its rapidly evolving pipeline could be set for a wave of several new approvals in the coming years. For these reasons, investors should consider a long-term position in this healthcare stock.

Pinterest (PINS -0.91%) hasn't delivered the mouth-watering growth that some investors became accustomed to in the earlier days of the pandemic, but its business is still demonstrating promise that could yet yield strong returns in the years to come. After a few quarters of unfavorable year-over-year comparisons to peak growth during the earlier part of the pandemic, user metrics are on the upswing, and Pinterest is continuing to monetize new and existing users very well.

For all of 2022, Pinterest reported total revenue of $2.8 billion, up 9% from 2021, with average revenue per user coming in 10% higher than the prior year. The company closed out the year with 450 million monthly active users, up 4% compared to 2021. And while Pinterest reported a net loss for the 12-month period, it turned back to profitability in the final quarter of the year, generating GAAP net income to the tune of $17 million for the three-month period.

Pinterest remains an incredibly attractive platform for companies to advertise on, with the bulk of all its revenue coming from ad dollars spent by both small businesses and large merchants. Companies won't be able to scale back on ad spend indefinitely. As economic conditions improve, Pinterest's continued acquisition of users and the image-centric model of its platform will build upon a foundation that can continue to draw consistent ad spending, flowing back to the tech stock's top and bottom lines, and into favorable shareholder returns.

Chewy (CHWY 3.07%) is rapidly expanding its potential beyond that of an online pet store, and this has translated to steady growth.

In the third quarter of 2022, the company reported net sales of $2.5 billion, a robust 15% increase from the prior-year period. Meanwhile, its gross margin expanded 200 basis points year over year, while the company pulled in net income of $2.3 million for the three-month period. This followed earnings of $19 million and $22 million in the first and second quarters of 2022, respectively.

Right now, Chewy is investing heavily in building out its business as well as its fulfillment infrastructure, which may weigh on the bottom line now but can reap manifold returns for shareholders in the years ahead. For example, the company is working on building out its network of automated fulfillment centers, which shorten processing times and cut down operating costs overall. It's launched a beta version of a sponsored ads program that would allow pet vendors to market to buyers on the Chewy platform.

The company also recently announced the upcoming launch of additional pet health insurance plans, and its first private label pet supplement line. The pet health insurance and non-prescription pet wellness industries alone represent respective addressable markets of $10 billion and $2.4 billion. Given the varied sub-sectors of the broader pet industry, Chewy could still be in the very early stages of its growth story -- a compelling buying proposition for long-term investors.

Rachel Warren has no position in any of the stocks mentioned. The Motley Fool has positions in and recommends CRISPR Therapeutics, Chewy, Pinterest, and Vertex Pharmaceuticals. The Motley Fool recommends Moderna. The Motley Fool has a disclosure policy.

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3 Growth Stocks With More Potential Than Any Cryptocurrency - The Motley Fool

Johannes Schetelig, MD, MSc

In patients with relapsed or refractory acute myeloid leukemia (AML), those who received an allogeneic hematopoietic cell transplant (alloHCT) attained similar overall survival rates compared with those who first received intense salvage chemotherapy to achieve complete response (CR), according to results from the phase 3 ETAL3-ASAP trial (NCT02461537). These findings run counter to the common practice of offering stem cell transplantation only to patients who have achieved CR, suggesting that patients may skip salvage chemotherapy before receiving a transplant. Results were presented during a press briefing at the 64th American Society of Hematology Annual Meeting and Exposition.1

Patients were randomized 1:1 to a remission induction strategy (RIST arm) with 3 g/m2 cytarabine (1 g/m2 for patients >60 years) twice daily on days 1-3 plus 10 mg/m2 mitoxantrone on days 3 to 5 and subsequent alloHCT or to disease control (DISC arm) prior to sequential conditioning and alloHCT.

Findings from the phase 3 clinical trial showed that the primary end point of disease-free survival (DFS) at day 56 was reached by 84.1% of those in the DISC arm (n = 139) and 81.3% of those in the RIST arm (n = 137; P = .047). Although this missed statistical significance against the 1-sided level of 2.5%, the probability that the true success rate in the investigative arm is below the noninferiority margin is only 4.7%, said study author Johannes Schetelig, MD, MSc, of the University Hospital Carl Gustav Carus in Dresden, Germany, in a presentation of the data.

Schetelig said the authors acknowledged that DFS at day 56 is not an accepted surrogate end point following transplantation. At a median follow-up of 37 months, no difference in leukemia-free survival from day 56 (P = .061) or overall survival (OS) from randomization (P = .047) was observed between the DISC and RIST arms.

Our conclusions are that patients with poor response after first induction chemotherapy or first relapse of AML do not benefit from salvage chemotherapy with high-dose cytarabine plus an anthracycline prior to transplantation, Schetelig said.

Watchful waiting and sequential conditioning prior to allogeneic transplantation result in comparable CR rates and OS and may be the preferred option whenever a stem cell donor is readily available. In patients with AML, CR before alloHCT is known to be a favorable risk factor. Intensive chemotherapy can be given prior to alloHCT to try to induce CR, but it is unknown whether those with relapsed or refractory disease derive a benefit from this approach. Sequential conditioning with high-dose cytarabine or melphalan followed by reduced intensity conditioning and alloHCT has resulted in long-term disease control for this population. In the study, the induction chemotherapy comprised high-dose cytarabine and mitoxantrone followed by alloHCT in patients with relapsed or refractory AML. Our hypothesis was that salvage chemotherapy would not provide a net benefit for patients with high-risk AML, Schetelig said.

To test this hypothesis, investigators enrolled adult patients with high-risk AML following first induction therapy or first untreated relapse who were fit for intensive chemotherapy and alloHCT. Patients were required to have a matched sibling donor, a human leukocyte antigen (HLA)- compatible unrelated donor, or an ongoing donor search with 2 potential unrelated donors and an HLA-matching probability of at least 90%.

Study participants were randomly assigned 1:1 to the RIST arm or the DISC arm. Those in the RIST arm received salvage chemotherapy with cytarabine at 3 g/m2 (1 g/m2 for those older than 60 years) twice daily on days 1 to 3 plus mitoxantrone at 10 mg/m2 on days 3 to 5 followed by alloHCT. In the DISC arm, watchful waiting was recommended, but low-dose cytarabine and single doses of mitoxantrone were allowed for disease control. This was followed by sequential conditioning and alloHCT.

The primary end point of the trial was treatment success, which was defined as DFS at day 65 following alloHCT. Investigators sought to demonstrate noninferiority for the DISC arm, with a margin of 5% and a 1-sided level of 2.5%. OS from randomization and leukemia-free survival from day 65 served as key secondary end points.

The median age in the DISC and RIST arms was 61 years. Less than half of patients were female (45% vs 42%, respectively), and most patients had an ECOG performance status of 0 or 1 (88% vs 90%). Patients had active diseasetwo-thirds defined by poor induction response and one-third defined by relapsed AML, Schetelig noted.

In the DISC arm, the median time to transplantation was 4 weeks, and of note, 76% of patients were cared for by watchful waiting only during that period. Sixteen weeks from being randomly assigned, 97% of the intention-to-treat population had undergone transplant.

In the RIST arm, Schetelig noted that every second patient achieved a CR with salvage chemotherapy. The median time to transplantation was 8 weeks. I would like to highlight that most patients who had not achieved a CR still proceeded to transplantation72% after sequential conditioning, he said. In this arm, 93% of patients received transplants by week 17 after random assignment.

The incidence of adverse effects of grade 3 or above was lower in the DISC arm vs the RIST arm, at 23% and 64%, respectively (P<.001). Notably, those in the DISC arm also spent less time in the hospital prior to transplantation vs those in the RIST arm, at a mean of 19 days (range, 7-63) vs 42 days (range, 9-75; P<.001). The mortality rates on day 28 from time of random assignment were 3.6% in the DISC arm vs 1.5% in the RIST arm.

In the DISC arm, 4 patients did not undergo transplant because of death due to sepsis (n=2), leukemia (n=1), or a decision against alloHCT (n=1). In the RIST arm, 6 patients did not undergo alloHCT because of death due to pneumonia (n=3), immune checkpoint blockade (n=1), refractory AML (n=1), or a decision against it (n=1).

Time to discharge and in-hospital mortality did not differ between the 2 arms, Schetelig added. A more general conclusion and forward-looking statement is that the benefit of any treatment [aimed] at better results after allogeneic transplantation by inducing a CR prior to transplantation should be demonstrated in prospective clinical trials, Schetelig said.

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No Survival Advantage When Chemotherapy Is Given Prior to ... - Targeted Oncology

The expansion of Bruton tyrosine kinase (BTK) inhibitors in the treatment of patients with mantle cell lymphoma (MCL) has led to unique combinations that have resulted in improved progression-free survival (PFS) compared with standard-of-care therapy. These novel combinations have demonstrated promising efficacy in patients who have significant unmet needs. At the same time, BTK inhibitors have refined the use of autologous stem cell transplant (ASCT). Recent findings that stratify the use of BTK inhibitors in combination with ASCT were explored during major medical conferences in 2022.

In younger, fit patients, standard of care for patients with MCL consists of cytarabine, followed by ASCT and rituximab (Rituxan) maintenance.1 In patients who are less fit, the standard-of-care regimen consists of less intense immunotherapy, such as the combination of bendamustine-rituximab, followed by rituximab maintenance therapy.2

Now recent findings from the phase 3 TRIANGLE study (NCT02858258) presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition have suggested that adding the BTK inhibitor ibrutinib (Imbruvica) to standard chemoimmunotherapy induction, followed by ASCT and maintenance with ibrutinib for 2 years improved outcomes compared with chemoimmunotherapy and ASCT alone.3

Based on failure-free survival, the combination of ASCT plus ibrutinib is significantly superior to ASCT alone, lead author Martin Dreyling, MD, said during a presentation of the data. ASCT is not superior to ibrutinib without ASCT. Currently, there [are] no decisions about whether autologous stem cell transplant adds to ibrutinib, but certainly right now toxicity favors ibrutinib only. Dreyling is a professor of medicine and head of the Lymphoma Program in Medical Clinic III at Grosshadern Clinic at Ludwig-Maximilians-University in Munich, Germany. The open-label 3-arm trial (N=870) randomly assigned patients to arm A, arm B, and arm C. All 3 arms received 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine [Oncovin], and prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin).

In arm A (n=288) following R-CHOP/R-DHAP, patients underwent ASCT and observation. In arm B (n=292), patients underwent ASCT, followed by 2 years of ibrutinib maintenance and observation. The third arm (n=290) was treated with 2 years of ibrutinib and observation. Patients in all 3 arms received rituximab maintenance (58% in arm A, 57% in arm B, and 54% in arm C). The trial was designed to detect an HR of 0.60 and 1-sided of 0.01665, powered at 90%.

The median age of patients was 57 years (range, 27-68), and most patients (76%) were male. Overall, baseline characteristics were balanced across all 3 arms.

The 3-year failure-free survival rate was 72% with standard induction and ASCT vs 88% with ibrutinib added to induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; P=.0008). Investigators reported that the 3-year overall survival rate (OS) was 86% in arm A, 91% in arm B, and 92% in arm C.3

The objective response rate (ORR) after induction therapy was determined to be 94% in arm A, and patients had a complete response (CR) rate of 36%. When combining the findings from both arm B and arm C (n=559), the ORR was 98% and the CR rate was 45%.3

Dreyling said the CR rates were comparable to other US-based trials and noted that, This [study] is CT based. It is not PET [positron emission tomography]CT based. It is in line with previously published data [using this method], and when we looked at other induction regimens, this is highly comparable.

To further refine the use of ASCT, in the phase 3 SHINE study (NCT01776840), older patients with MCL who were not candidates for intensive chemotherapy or ASCT because of toxicities received ibrutinib with bendamustine-rituximab and rituximab maintenance.4 The patients were stratified by low-, intermediate-, or highrisk disease based on the MCL International Prognostic Index and randomly assigned to receive ibrutinib (560 mg daily) or placebo, plus 6 cycles of bendamustine (90 mg/m2) and rituximab (375 mg/m2).

During the 2022 American Society of Clinical Oncology Annual Meeting, Michael Wang, MD, reported on data showing that at a median follow-up of 84.7 months, treatment with the ibrutinib-based regimen (n = 261) induced a median PFS of 6.7 years (80.6 months) compared with a median of 4.4 years (52.9 months) in the placebo-based arm (HR, 0.75; 1-sided P = .011). This was a 50% improvement compared with placebo and standard of care, Wang noted.

I think this is huge progress [in the MCL landscape], Wang, lead study author and Puddin Clarke Endowed Professor, Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Targeted Therapies in Oncology.

Transplant will not be replaced totally, but I think its use will decrease dramatically based on this study.

The median age of the patients at study entry was 71 years (range, 65-87). Additional results demonstrated a CR rate of 65.5% in the ibrutinib arm and 57.6% in the placebo arm (P = .0567). However, there was no statistical significance in OS between the 2 treatment arms (P = .648).4

Wang said that based on findings from SHINE, in the frontline setting for patients older than 65 years, the combination of ibrutinib, bendamustine, and rituximab will be useful.

Despite its benefits, patients treated with BTK inhibitors will eventually experience resistance, so the search for next-generation BTK inhibitors continues. Clinicians can look towards the approval of pirtobrutinib (Jaypirca) for relapsed or refractory MCL after at least 2 lines of systemic therapy.5 Efficacy was based on findings from the phase 1/2 BRUIN study (NCT03740529), which also explored unique combinations explored during the 2022 ASH meeting.

Updated findings from the BRUIN study demonstrated durable efficacy for pirtobrutinib.6 Previously treated patients with B-cell malignancies were eligible to participate in which pirtobrutinib monotherapy was given in either the dose-escalation or dose-expansion portion of the multicenter study.

In 90 heavily pretreated patients with MCL, 77 (86%) received the recommended phase 2 dose of pirtobrutinib (200 mg once daily). The ORR was 58% (95% CI, 47%-88%) and included 18 CRs (20%) and 34 partial responses (PRs; 38%).6

The median duration of response (DOR) at the 12-month follow-up was 22 months (95% CI, 7.5-not estimable [NE]), according to investigators. The 12-month and 18-month estimated DOR rates were 57% (95% CI, 39%-72%) and 52% (95% CI, 34%68%), respectively.6

In the safety cohort that included all patients treated with pirtobrutinib (n=725), study investigators reported that the most common treatment-emergent adverse event (TEAE) of grade 3 or higher was neutropenia (20%; n=143). The most common any-grade treatment-emergent AEs, regardless of attribution, were fatigue (26%; n=191), diarrhea (22%; n=160), and contusion (19%; n=16). Neutropenia was the most common grade 3 or greater TEAE, according to Wang et al. They concluded that the agent was well tolerated with few drug-related toxicities.6

Another noncovalent BTK inhibitor, CG-806 (luxeptinib), is undergoing evaluation in early-phase clinical trials for patients with relapsed/refractory (R/R) hematologic malignancies, including MCL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma. Investigators demonstrated that the agent disrupts B-cell receptor signaling and induces metabolic reprogramming and apoptosis in MCL. The investigators noted that targeting BCL2 using CG-806 warrants further exploration.7

The combination of ibrutinib with zilovertamab (NCT03088878) was explored in patients with MCL and CLL in data presented during the 2022 ASH meeting. Results from the dose-finding and dose- expansion cohorts revealed ORRs of 89.3% and 91.2%, respectively, in patients with MCL (n=25) and CLL (n=31).8

We are excited [to see these data] in patients with MCL and CLL who were treated with this combination, lead author Hun Ju Lee, MD, an assistant professor of medicine in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in an interview with Targeted Therapies in Oncology.

In the MCL population, investigators reported a median DOR of 34.1 months (95% CI, 13.67-NE).

At the 6-month, 12-month, and 26-month follow-ups, the CR rate was 29.6%, 37%, and 40.7%, respectively.

The median PFS was 35.9 months (95% CI, 17.3-NE) after a median follow-up of 15.1 months, and the landmark PFS rate was approximately 70% at 30 months.8

In a subpopulation of patients with tumors harboring TP53 mutations, the ORR was 83.3% (with 1 CR and 4 PRs), median DOR was 13.84 months (95% CI, 11.3-NE), median PFS was 17.3 months (95% CI, 2.85NE), and landmark PFS rate at 12 months was greater than 80%. In patients whose Ki67 index score was 30% or greater (n=14), the ORR was 85.7%, with 5 CRs and 7 PRs.8

The combination of ibrutinib and ixazomib (Ninlaro) was evaluated in patients with relapsed/refractory (R/R) MCL.9

In the phase 1 portion, patients could be either ibrutinib nave or ibrutinib pretreated. In phase 2, patients were divided into 2 cohorts: ibrutinib nave or ibrutinib pretreated. Investigators noted that the ibrutinib-pretreated cohort was closed early because of slow enrollment.

In the phase 1 portion (n=12), 2 dose levels of ixazomib were evaluated (3 mg and 4 mg on days 1, 8, and 15 of a 28-day cycle) with ibrutinib at 560 mg daily. Treatment continued until disease progression or unacceptable toxicity.

Thirty-five patients who were ibrutinib-nave were enrolled in phase 2. The CR rate was 42.9% (95% CI, 26.3%-60.6%), and the ORR was 77.1% (95% CI, 59.9%-89.6%).

Median DOR was 8 cycles (range, 1-23), with 23% of patients remaining on treatment after a median of 12 cycles (range, 6-19). Twenty-seven patients discontinued treatment because of AEs (n=13), progression (n=9), death due to an AE (n=1), physician discretion (n=1), and treatment delay (n=1).

The primary end point for the phase 2 portion was CR within the first year of the study treatment.9

Grade 3 AEs including hypertension, lymphopenia, neutropenia, thrombocytopenia, rash, syncope, and atrial fibrillation were reported in 1 patient or more. AEs leading to treatment discontinuation included rash (n=2), atrial fibrillation (n=2), and hepatic failure, sepsis, fatigue/anorexia, peripheral neuropathy, muscle spasms, arthralgia, thrombocytopenia, diarrhea, and heart failure (n=1 each).9

Twelve patients with previously untreated MCL were enrolled in a phase 2 study (NCT04783415).10 Acalabrutinib (Calquence) 100 mg was given twice daily, umbralisib (Ukoniq) 800 mg was given daily, and ublituximab-xiiy (Briumvi) 900 mg was given intravenously on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. After 6 cycles, patients continued maintenance with oral agents and ublituximab every 2 cycles (planned for 24 cycles).

The primary end point was efficacy as determined by CR rate, and the secondary end point was safety. Enrollment was suspended by the FDA in February 2022 due to general safety concerns with umbralisib and other PI3K inhibitors.11

Because the first 2 patients who enrolled developed grade 3 and 4 aspartate aminotransferase and alanine transaminase levels, the trial design was amended so that umbralisib was given on days 1 through 14 of cycle 1 and days 1 through 7 of subsequent cycles. Four patients were unable to continue taking acalabrutinib because of elevated aspartate aminotransferase and alanine transaminase levels and continued on umbralisib/ublituximab alone.10

All 12 patients achieved CR (ORR, 100%; CR, 100%). As of data presented at the 2022 ASH meeting, 10 patients remained on therapy. Danilov et al concluded that the combination of continuous umbralisib and acalabrutinib resulted in liver function abnormalities but that intermittent dosing of umbralisib was well tolerated.10

BTK inhibitors in combination with cellular therapies such as chimeric antigen receptor (CAR) T-cell therapy are under evaluation in ongoing trials. Whether to use these agents sequentially or concomitantly remains to be determined.12 The TABLE13-16 summarizes a sample of trials that explore the combination of CAR T-cell therapy with BTK inhibitors.

The evolution of BTK inhibitors in MCL has established this class of agent as a mainstay in the R/R setting, and their potential for further benefit continues to be explored. Unique combinationsincluding those that pair BTK inhibitors with targeted therapies or cellular therapies and second-generation agents further enhance the efficacy of BTK inhibitors, and their use remains a backbone approach moving forward.

REFERENCES

1. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260. doi:10.1056/NEJMoa1701769

2. Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23. doi:10.1016/S2352-3026(16)30185-5

3. Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/ blood-2022-163018

4. Wang M, Jurczak W, Jerkeman M, et al. Primary results from the double-blind, placebo-controlled, phase III SHINE study of ibrutinib in combination with bendamustine-rituximab (BR) and R maintenance as a first-line treatment for older patients with mantle cell lymphoma (MCL). J Clin Oncol. 2022;40(suppl 17):LBA7502. doi:10.1200/JCO.2022.40.17_ suppl.LBA7502

5. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. Accessed January 30, 2023. http://bit.ly/40oYhYC

6. Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed / refractory mantle cell lymphoma: additional patients and extended follow-up from the phase 1/2 BRUIN study. Blood. 2022;140(suppl 1):9368-9372. doi:10.1182/blood-2022-159425

7. Thieme E, Liu T, Bruss N, et al. Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma. Cell Death Dis. 2022;13(3):246. doi:10.1038/s41419-022-04684-1.

8. Lee HJ, Choi M, Siddiqi T. et al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or marginal zone lymphoma (MZL). Blood. 2022;140(suppl 1):566-568. doi:10.1182/ blood-2022-167153

9. Cohen JB, Jegede O, Portell CA, et al. Ibrutinib and ixazomib in relapsed/refractory mantle cell lymphoma: Precog 0404. Blood. 2022;140(suppl 1):6487-6488. doi:10.1182/ blood-2022-164710

10. Danilov AV, Muir A, Melgar I, et al. A phase II trial of acalabrutinib in combination with PI3K inhibitor umbralisib and the anti-CD20 antibody ublituximab (AU2) in patients with previously untreated mantle cell lymphoma (MCL). Blood. 2022;140(suppl 1): 3633-3634. doi:10.1182/ blood-2022-159805

11. FDA investigating possible increased risk of death with lymphoma medicine Ukoniq (umbralisib). Accessed January 10, 2023. https://bit.ly/3ZmWZg6.

12. Jacobson CA, Maus MV. C(h)AR-ting a new course in incurable lymphomas: CAR T cells for mantle cell and follicular lymphomas. Blood Adv. 2020;4(22):5858-5862. doi:10.1182/ bloodadvances.2020003391

13. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

14. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. Blood. 2020;136(suppl 1):10-11. doi:10.1182/ blood-2020-136158

15. Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: real world experience from the US Lymphoma CAR T Consortium. Blood. 2021;138(suppl 1):744. doi:10.1182/blood-2021-147563

16. Romancik JT, Goyal S, Gerson JN. Analysis of outcomes and predictors of response in patients with relapsed mantle cell lymphoma treated with brexucabtagene autoleucel. Blood. 2021;138(suppl 1):1756. doi:10.1182/blood-2021-153277

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BTK Inhibitors Stretch Frontline Approaches in Mantle Cell Lymphoma - Targeted Oncology