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Physicians' Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by educational grants from Bristol-Myers Squibb and Incyte Corporation.

Cancer Summaries and Commentaries™: Report from San Diego on Advances in the Treatment of GvHD


Release Date: December 30, 2018
Expiration Date: December 30, 2019
Media: Internet - based

Activity Overview

This online activity is designed to update physicians on data presented at the American Society of Hematology (ASH) Annual Meeting, held in December 2018 in San Diego, CA. PER’s Cancer Summaries and Commentaries™: Report from San Diego on Advances in the Treatment of Graft-Versus-Host Disease online CME activity facilitates critical assessment and clinical integration of new evidence when appropriate. The activity reviews 7 abstracts with some of the most compelling and clinically relevant graft-versus-host disease (GvHD) presentations from the meeting. For each abstract, a short summary of key clinical data is accompanied by expert perspectives that provide insight into how clinicians can apply these findings to their clinical practice to improve patient care.

Benefits of Participation:

  • Learn about emerging treatments for the management of GvHD
  • Hear about biomarkers that may identify those at high risk for GvHD
  • Learn how to manage GvHD in patients with hematologic malignancies
  • Explore future directions for the prevention of GvHD
  • Be informed about recent clinical trials and their impact on clinical practice decisions

Acknowledgement of Commercial Support

This activity is supported by educational grants from Bristol-Myers Squibb and Incyte Corporation.

Instructions for This Activity and Receiving Credit

  • You will need to log in to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review audio files/content until you finish the presentation.
  • At the end of the activity, educational content/audio files will be available for your reference.
  • In order to receive a CME certificate, you must complete the activity.
  • Complete the Posttest and pass with a score of 70% or higher, complete the Evaluation, and then click on “Request for Credit.” You may immediately download a CME certificate upon completion of these steps.


Target Audience

This activity is directed toward medical oncologists and hematologists who treat patients with hematologic malignancies. Fellows, nurses, nurse practitioners, physician assistants, and other healthcare professionals interested in the management of patients with hematologic malignancies are also invited to participate.

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

  • Summarize GvHD biology, pathogenesis, and evidence that best informs clinical practice to manage symptoms
  • Explain recent clinical trial results regarding novel compounds and strategies for patients with acute and chronic GvHD
  • Place presented trial evidence into the context of evolving treatment paradigms and strategies in the management of patients with GvHD resulting from treatment for hematologic malignancies

Faculty, Staff, and Planners' Disclosures

Faculty

James L. M. Ferrara, MD, DSc
Ward-Coleman Chair in Cancer Medicine
Professor of Medicine and Pediatrics
Director, Hematologic Malignancies Translational Research Center
Icahn School of Medicine at Mount Sinai
New York City, NY

Disclosures: Consultant: ViraCor, Incyte, Kamada, Mallinckrodt; Intellectual Property: Biomarkers for acute GvHD

Mark A. Schroeder, MD
Associate Professor of Medicine
Washington University School of Medicine
Division of Oncology, Section of Stem Cell Transplantation
St. Louis, MO
 

Disclosures: Consultant: Incyte, Amgen, Sanofi/Genzyme, Pfizer, Flatiron; Speaker’s Bureau: Merck, Takeda

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.
 

PER Pulse™ Recap

1 of 3
PER PulseTM Recap
 
Recent Data for the Prevention and Treatment of Acute and Chronic Graft-Versus-Host Disease
 
The standard first-line treatment for graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies is systemic corticosteroids. Long-term use of corticosteroids is associated with severe side effects, and there are currently no US Food and Drug Administration (FDA)-approved therapies for steroid-refractory GvHD. Various mechanisms of steroid-refractory GvHD have been proposed, including upregulation of the cytokines interleukin-17 (IL-17) and IL-21, which are controlled by the Rho-associated coiled-coil kinase 2 (ROCK2) signaling pathway. Preclinical murine models showed that the ROCK2 inhibitor KD025 reduced chronic GvHD (cGvHD) pathology, and inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation to decrease retinoic-acid-receptor-related orphan nuclear receptor gamma (RORγt) and B-cell lymphoma 6  (BCL6) protein expression in both murine and human cells.In the phase II KD025-208 study involving patients with steroid-refractory cGvHD treated with varying doses of KD025 over at least a 20-week period, KD025 was well tolerated and led to decreases in corticosteroid doses and improvement in Lee Symptom Scale (LSS) scores.2

The Janus kinase (JAK)1/2 signaling pathway is also involved in multiple steps of inflammation and tissue damage in GvHD. For example, common gamma chain signaling occurs via JAK1 and ultimately leads to T-cell activation.3 In addition, JAK1/2 signaling activates neutrophils, which are involved in the pathogenesis of acute GvHD (aGvHD).Further, dendritic cells (DCs), which depend on JAK1/2 activation for differentiation and maturation, may also reduce priming of incoming donor T cells by recipient DCs after alloHSCT.5 Results from the phase II REACH1 study of the JAK1/2 inhibitor ruxolitinib in combination with corticosteroids in steroid-refractory aGvHD showed a rapid and durable response by day 28 in approximately 55% of patients, many of whom had grade III/IV disease at baseline.6 The best overall response rate at any time was 73.2%, and most patients achieved sustained reductions in corticosteroid dose. At day 28, 43 patients were receiving ruxolitinib and corticosteroid treatment, and 55.8% of these patients had a 50% reduction from baseline in corticosteroid dose.

Another area of active research in the prevention of aGvHD is in the setting of allo-HSCT before or after exposure to immune checkpoint inhibitor (ICPi) therapy. Several ICPis, including monoclonal antibodies directed against the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) pathways, are under investigation for the treatment of relapsed or refractory hematologic malignancies.7,8 Encouraging results using ICPis have been reported in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but high rates of grade III-IV aGvHD have occurred. A recent analysis of patients diagnosed with AML or MDS and treated with the PD-1 inhibitor nivolumab or the CTLA-4 inhibitor ipilimumab, or a combination of both, showed that cyclophosphamide as prophylaxis post-allo-HSCT improves progression-free survival (PFS) when ICPis are given prior to transplantation.9 

Key Points:

  • ROCK2 inhibitors may reduce steroid-refractory cGvHD biology through inhibition of the STAT3 pathway.
  • JACK1/2 inhibitors in combination with corticosteroids have the potential to treat aGvHD.
  • Cyclophosphamide prophylaxis may improve PFS in allo-HSCT when ICPi blockade is given prior to transplantation.

References

  1. Flynn R, Paz K, Du J, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a STAT3-dependent mechanism. Blood. 2016;127(17):2144-2154. doi: 10.1182/blood-2015-10-678706. 
  2. Jagasia M, Salhotra A, Bachier CR, et al. KD025-208: A phase 2a study of KD025 for patients with chronic graft versus host disease – pharmacodynamics and updated results. Presented at the 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 602. https://ash.confex.com/ash/2018/webprogram/Paper111896.html. Accessed January 29, 2019.
  3. Hechinger AK, Smith BA, Flynn R, et al. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD. Blood. 2015;125:570-580. doi: 10.1182/blood-2014-06-581793.
  4. Nicholson SE, Oates AC, Harpur AG, et al. Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation. PNAS. 1994;91:2985-2988.
  5. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122:1192-1202. doi: 10.1182/blood-2013-03-484642.
  6. Jagasia M, Perales MA, Schroeder MA, et al. Results from REACH1, a single-arm phase 2 study of ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease. Presented at the 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 601. https://ash.confex.com/ash/2018/webprogram/Paper116342.html. Accessed January 29, 2019.
  7. Merryman RW, Armand P. Immune checkpoint blockade and hematopoietic stem cell transplant. Curr Hematol Malig Rep. 2017;12:44-50. doi: 10.1007/s11899-017-0362-5.
  8. Merryman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017;129:1380-1388. doi: 10.1182/blood-2016-09-738385.
  9. Oran B, Garcia-Manero G, Saliba RM, et al. Post-transplant cyclophosphamide improves progression free survival after allogeneic hematopoietic stem cell transplantation in AML/MDS patients with prior CTLA-4 or PD-1 blockade. Blood. 2017;130:3209.

 
2 of 3
PER PulseTM Recap
 
Predicting Risk of Graft-Versus-Host Disease for Prevention and Early Intervention
 
During the third phase of acute graft-versus-host disease (aGvHD), cellular and inflammatory effectors are released into the circulation representing both systemic biomarkers and organ-specific biomarkers.1 Systemic biomarkers include suppressor of tumorigenicity 2 (ST2); interleukin-6 (IL-6); and tumor necrosis factor receptor 1 (TNFR1). Organ-specific biomarkers include regenerating islet-derived protein 3 alpha (REG3A); the transmembrane protein, TIM3; and Trappin2/Elafin.2 Ongoing studies aim to develop biomarkers to identify GvHD prophylaxis and develop appropriate posttransplant treatment and monitoring strategies.
 
A phase I clinical trial monitoring ST2, REG3A, TNFR1, and Trappin/-2/Elafin as biomarkers to predict patient response to combination itacitinib and steroids for the treatment of aGvHD found that nonresponders had increased expression of ST2 and TNFRI.3  Soluble ST2 acts as a receptor for IL-33, limiting access to T helper 2 (Th2) cells and promotes the Th1 phenotype that is associated with aGvHD pathophysiology.4,5 These results are in line with what has been seen in previous studies of corticosteroid response in aGvHD, which have shown a correlation between ST2 level and steroid-refractory aGvHD—high ST2 levels indicate less probability of responding to therapy.6 TNFα is an inflammatory cytokine associated with the pathogenesis of aGvHD and is the most frequently reported marker to be elevated prior to GvHD onset.7  TNF1 is considered a surrogate marker for TNFα, and studies have found that increased levels of TNFR1 at day 7 that are ≥2.5 times that at baseline correlate with the development of severe aGvHD.8-10
 
The pathophysiology of chronic GvHD (cGvHD) is less known, but research has shown that it involves both donor B cells and T cells.11 Identification of biomarkers would also be beneficial for treatment of moderate-to-severe cGvHD because it rarely responds completely to immunosuppressive therapy. A previous study identified 5 molecular pathways that significantly differed in their gene expression profiles in cGvHD: cell cycle–associated pathways, cell-mediated immune–associated pathways, cell motility–associated pathways, and myogenesis-associated pathways.12 A more recent study looked at a gene panel consisting of 591 immunity-related genes, and identified 12 genes that differed between patients who developed cGvHD and those who did not: highly upregulated T-cell activation and proliferation markers (CD3D, CD3E, CCR7, and CD5); TNFR superfamily markers (B- and T-lymphocyte attenuator-BTLA, CD27, and CD40LG); and costimulatory molecules (inducible T-cell costimulatory [ICOS] and CD28).13
 
Key Points:

  • Systemic and organ-specific effectors released in the circulation during the third phase of aGvHD represent potential biomarkers for GvHD prophylaxis.
  • Increased expression of ST2 and TNFRI may predict nonresponders to itacitinib and steroid for treatment of aGvHD.
  • Expression of specific immunity-related genes may identify risk of developing cGvHD. 

References

  1. Ferrara JL, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J  Hematol. 2003;78(3):181-187.
  2. Ali AM, DiPersio JF, Schroeder MA. The role of biomarkers in the diagnosis and risk stratification of acute graft vs host disease (aGvHD): a systematic review. Biol Blood Marrow Transplant. 2016;22(9):1552-1564. doi: 10.1016/j.bbmt2016.04.022.
  3. Pratta MA, Liu H, Arbushites MC, et al. Plasma biomarker association with response in acute GvHD subjects treated with the combination of itacitinib and corticosteroids in a phase 1 clinical trial. Presented at the 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 4559. https://ash.confex.com/ash/2018/webprogram/Paper116330.html. Accessed January 29, 2019.
  4. Reichenbach DK, Schwarze V, Matta BM, et al. The IL-33/ST2 axis augments effector T-cell responses during acute GvHD. Blood. 2015;125(20):3183-3192. doi: 10.1182/blood-2014-10-606830.
  5. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479-490. DOI: 10.1016/j.immuni.2005.09.015.
  6. Vander Lugt MT, Braun TM, Hanash S, et al. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013;369(6):529-539. doi: 10.1056/NEJMoa1213299.
  7. Remberger M, Ringden O, Markling L. NF alpha levels are increased during bone marrow transplantation conditioning in patients who develop acute GvHD. Bone Marrow Transplant. 1995;15(1):99-104.
  8. Choi SW, Kitko CL, Braun T, et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GvHD and survival. Blood. 2008;112(4):1539-1542. doi: 10.1182/blood-2008-02-138867.
  9. Kitko CL, Paczesny S, Yanik G, et al. Plasma elevations of tumor necrosis factor-receptor-1 at day 7 postallogeneic transplant correlate with graft-versus-host disease severity and overall survival in pediatric patients. Biol Blood Marrow Transplant. 2008;14(7):759-765. doi: 10.1016/j.bbmt.2008.04.002.
  10. Willems E, Humblet-Baron S, Dengis O, et al. Elevations of tumor necrosis factor receptor 1 at day 7 and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. Bone Marrow Transplant. 2010;45(9):1442-1448. doi: 10.1038/bmt.2009.360.
  11. Socié G, Ritz J. Current issues in chronic graft-versus-host disease. Blood. 2014;124(3):374-384. doi: 10.1182/blood-2014-01-514752.
  12. Oh SJ, Cho SB, Park S-H, et al. Cell cycle and immune-related processes are significantly altered in chronic GVHD. Bone Marrow Transplant. 2008;41:1047-1057. doi: 10.1038/bmt.2008.37.
  13. Kalra A, Dharmani-Khan, Patel S, et al. Early prediction of moderate-severe chronic GvHD by immunity related transcriptome. Presented at the 2018 American Society of Hematology Annual Meeting; December 1-4, 2018, San Diego, CA. Abstract 70. https://ash.confex.com/ash/2018/webprogram/Paper119926.html. Accessed January 29, 2019.


3 of 3
PER PulseTM Recap
 
Preventing Lower Gastrointestinal GvHD After Allogeneic Hematopoietic Stem Cell Transplant 

The pathogenesis of lower gastrointestinal (GI) graft-versus-host disease (GvHD) involves the migration of peripheral alloreactive T lymphocytes to lower GI-associated lymphoid tissues. The T-lymphocyte α4β7 integrin is an important instigator of this process and to the development of lower GI GvHD.1 Vedolizumab is a gut-selective antibody targeting α4β7 integrin and is approved for the treatment of inflammatory bowel disease because of its gut-specific anti-inflammatory activity. Blocking α4β7 integrin also interferes with gut-trafficking of immunocompetent donor T‑lymphocytes and may prevent lower GI acute GvHD (aGvHD). The 6-month results of the phase Ib study examining intravenous vedolizumab post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) demonstrated a low incidence of grade II-IV and grade III-IV aGvHD, and no cases of lower GI aGvHD greater than stage 1.2

Another strategy for the prevention of GI aGvHD involves preventing the domination of enterococci in the gut microbiome. The gut immune system has evolved simultaneously to protect against ingested microorganisms and other substances, and to tolerate beneficial bacteria so that we can live in symbiosis with our intestinal microbiota.3 Studies suggest that the intestinal microbiome and imbalances in the gut microbiota contribute to the pathophysiology of aGvHD in allo-HSCT. Conditioning regimens, antibiotics, immunosuppressants, and foreign donor lymphocytes significantly change the composition of the gut microbiota.4-6
 
Although enterococci are commensurate bacteria in healthy immunocompetent individuals, they are increasingly frequent in the alloHSCT setting, with Enterococcus faecium (E. faecium) as the predominant species and a marker of unfavorable clinical status and comorbidities.7 Previous studies have shown that the shift toward Enterococcus is pronounced in patients receiving allo-HSCT and antibiotic prophylaxis and treatment for neutropenic infections, and is particularly dominant in patients who develop GI GvHD.8 In a recent study, Enterococcus mono-domination in post-allo-HSCT transplantation samples ranged from 20% to 60%, primarily attributable to E. faecium and associated with a significant increased risk for grade II-IV aGvHD.9
 
As with E. faecium, Enterococcus faecalis (E. faecalis) resides in the GI tract as commensal bacteria, and is emerging as a notable cause of hospital-acquired infection and drug resistance in individuals with compromised immune systems.10,11 In a study examining 3 different mouse models of GvHD, a transient bloom of E. faecalis bloomed approximately 7 days post-alloHSCT in models of GvHD, but did not occur in models of T-cell-depleted allograft without GvHD.9
 
Both E. faecalis and E. faecium are species of lactic acid bacteria and use lactose as a major carbohydrate source for growth and expansion.12-15 In mice models of GvHD, a lactose-free diet significantly decreases the Enterococcus bloom after transplantation in allo-T-cell recipients, and attenuates lethal GvHD in first survival experiments, suggesting a relationship between Enterococcus in intestinal flora and the development of aGvHD, which may be prevented or ameliorated by a lactose-free diet.9
 
Key Points:

  • Targeting the underlying pathogenesis of lower GI GvHD may improve patient outcomes after allo-HSCT.
  • Enteroccocus is predominant in the gut of patients receiving allo-HSCT and increases risk of grade II-IV aGvHD.
  • E. faecalis and E. faecium use lactose as a major source of growth and expansion, and a lactose-free diet reduces the risk of lethal GvHD in mouse models.

References

  1. Coltoff A, Lancman G, Kim S, Steinberg A. Vedolizumab for treatment of steroid-refractory lower gastrointestinal acute graft-versus-host disease-a quality initiative. Bone Marrow Transplant. 2018;53(7):900-904. doi: 10.1038/s41409-018-0094-8.
  2. Chen YB, Shah NN, Renteria AS, et al. A phase 1b study of intravenous vedolizumab plus standard of care for graft-versus-host disease prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies: 6-month results. Presented at the 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 605. https://ash.confex.com/ash/2018/webprogram/Paper111143.html. Accessed January 29, 2019.
  3. Staffas A, Burgos da Silva M, van den Brink MRM. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood. 2017;129(8):927-933. doi: 10.1182/blood-2016-09-691394.
  4. Shono Y, Docampo MD, Peled JU, et al. Intestinal microbiota-related effects on graft-versus-host disease. Int J Hematol. 2015;101:428-437. doi: 10.1007/s12185-015-1781-5.
  5. Taur Y, Jebg RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124:1174-1182. doi: 10.1182/blood-2014-02-554725.
  6. Shono Y, Docampo MD, Peled JU, et al. Increased GvHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8:339ra71. doi: 10.1126/scitranslmed.aaf2311.
  7. Gudiol C, Ayats J, Camoez M, et al. Increase in bloodstream infection due to vancomycin-susceptible enterococcus faecium in cancer patients: risk factors, molecular epidemiology and outcomes. PLoS One. 2013;8(9):e74734. doi: 10.1371/journal.pone.0074734.
  8. Holler E, Butzhammer P, Schmid K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(5):640-645. doi:  10.1016/j.bbmt.2014.01.030.  
  9. Stein-Thoeringer CK, Peled JU, Gomes ALC, et al. Intestinal Enterococcus is a major risk factor for the development of acute GvHD. Blood. 2018;132:358. doi: 10.1182/blood-2018-99-119887.
  10. Lebreton F, Willems RJL, Gilmore MS. Enterococcus diversity, origins in nature, and gut colonization. In: Gilmore MS, Clewell DB, Ike Y, Shankar N, eds. Enterocci: From Commensals to Leading Causes of Drug Resistant Infection. Boston, MA: Massachusetts Eye and Ear Infirmary; 2014. https://www.ncbi.nlm.gov/books/NBK190427/. Accessed January 29, 2019.
  11. Lukášová J, Šustáčková A. Entercocci and antibiotic resistance. Acta Vet Brno. 2003;72(2):315-323. doi: 10.2754/avb200372020315.
  12. Penna ALB, de Paula AT, Casarotti SN, et al. Overview of the functional lactic acid bacteria in fermented milk products. In: Ravishankar VR, Jamuna AB, eds. Beneficial Microbes in Fermented and Functional Foods. Boca Raton, FL: CRC Press; 2015:113-148.
  13. Chen X, Song YQ, Xu HY, et al. Genetic relationships among Enterococcus faecalis isolates from different sources are revealed by multilocus sequence typing. J Dairy Sci. 2015;98(8):5183-5193. doi: 10.3168/jds.2015-9571.
  14. Delgado S, Mayo B. Phenotypic and genetic diversity of Lactococcus lactis and enterococcus spp. strains isolated from northern Spain starter-free farmhouse cheeses. Int J Food Microbiol. 2004;90(3):309-319.
  15. Silvetti T, Morandi S, Brasca M. Biopreservation potential of enterococcus faecalis isolated from Italian traditional raw milk cheeses. Cyta-J Food. 2014;12(3):210-217. https://doi.org/10.1080/19476337.2013.825327.Terzic-Vidojevic A, Veljovic K, Begovic J, et al. Diversity and antibiotic susceptibility of autochthonous dairy enterococci isolates: are they safe candidates for autochthonous starter cultures? Front Microbiol. 2015;6:954. doi: 10.3389/fmicb.2015.00954.
  16. Terzic-Vidojevic A, Veljovic K, Begovic J, et al. Diversity and antibiotic susceptibility of autochthonous dairy enterococci isolates: are they safe candidates for autochthonous starter cultures? Front Microbiol. 2015;6:954. doi: 10.3389/fmicb.2015.00954.


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