Stem Cell Transplantation PDF

# Stem Cell Transplantation - Shows a microscopic image of multiple stem cells. # Goal of Stem Cell Transplantation - The goal of stem cell transplantation is to replace a diseased, genetically compromised bone marrow stem cell population with one that is disease free and competent and thus abl...

# Stem Cell Transplantation - Shows a microscopic image of multiple stem cells. # Goal of Stem Cell Transplantation - The goal of stem cell transplantation is to replace a diseased, genetically compromised bone marrow stem cell population with one that is disease free and competent and thus able to generate functionally competent adult blood cells. - The transplant gives rise to a new set of undamaged stem cells that give rise to competent immune cells, white blood cells and platelets. - Normalizes hematopoiesis: the process by which the body produces blood cells. # What Diseases are Treated with Stem Cell Transplants? - Stem cell transplants are most used to treat patients with blood tumors. - Leukemias - Lymphomas - Multiple myelomas - Myelodysplastic syndromes - Neuroblastoma, Ewing sarcoma, brain tumors that have come back in children, germ cell tumors, and testicular cancer. # What is a Stem Cell? - A stem cell is a cell which has the potential to develop into many different types of adult cells in the body. - Stem cells serve as a repair system for the body. - How do stem cells differ from other cells in the body? - They can divide and renew themselves over a long time, the lifetime of an individual. - They are unspecialized, so they cannot perform specific functions in the body - But they have the potential to become specialized cells, such as muscle cells, blood cells, and brain cells. # There are two main types of stem cells: - Embryonic stem cells - Can differentiate into any cell type in the body and are a potential treatment for diseased organs and tissues; have greater plasticity. - Adult stem cells or somatic stem cells - Are found in a tissue or organ and can differentiate to yield the specialized cell types of that tissue or organ. # What is a Stem Cell? - A diagram depicts the location of Somatic Stem Cells in the body. The body has a red outline with sections for the brain, blood vessels, skeletal muscle, bone marrow, peripheral blood, teeth, skin, heart, liver and gut. # What is a blood stem cell? - Diagrams of different stem cells that form the body's blood cells. - Hematopoietic stem cell - Blood stem cell - Myeloid stem cell - Lymphoid stem cell - Myeloblast - Lymphoblast - Red blood cells - Platelets - White blood cells - **Differentiation:** The processes by which immature cells become mature cells with specific functions. # Bone marrow - An image shows an illustration of the bone marrow. # Tissue Blood - A diagram shows the development of blood cells from stem cells. # Overview of a stem cell transplant - Replace a damaged or pathological blood cell producing operation with one that produces normal functioning adult blood cells in appropriate numbers and doing so "in the heart of the enemy”!!!! - This new population of immune cells face a collection of billion of cells that they (the transplanted cells) are inclined to see as foreign!!! - This faceoff is chronic!!! # Sources of Hemopoietic Stem Cells - Bone marrow - Lower incidence of graft vs. host disease GVHD - Faster engraftment - Risk from anesthesia, injury to donor, lack of donors - Peripheral Blood Stem Cells - More rapid engraftment - Greater risk of GVHD - Cord Blood - Greater risk of HLA disparity without an increase in GVHD - Small #'s of cells, delayed engraftment (longer period of neutropenia) # Infusion of Hemopoietic Stem Cells - An image shows a patient receiving a stem cell transplant. - Donors can be the recipient themselves or a donor with a matching HLA type may volunteer. - Infusion may take several hours. - Please appreciate that transplant occurs at the end of extended chemotherapy & is often the last available treatment. # Tissue Matching - Self vs not-self (foreign) - How do your cells know they belong to you? - How does your body know that cells from your donor are not yours? - ABO blood type - HLA: Human Leukocyte Antigen - A table depicts Antigens and Antibody Types based on Blood types: A, B, AB and O. # Tissue Matching: HLA - HLA: Human Leukocyte Antigen, proteins we inherit from our parents. They tell an individual's immune system whether the cell they are on belongs or not. - HLA Antibodies: Proteins in the patient's blood against the donor's HLA that could attack transplanted or transfused cells. - It is important in stem cell transplantation to see that the blood type is a perfect match and how closely the HLA make up of the transplant recipient matches the HLA make up of the stem cell donor. # Tissue Matching: HLA - The HLA "match" is the number of HLA molecules that any two people have in common. HLA matching is usually based on six HLA molecules. The more molecules two people share, the better the match. - The better the match, the less likely the two immune systems will see each other as "foreign" and are therefore less likely to attack each other. - Siblings are the most likely to share these same 6 molecules. - The donor stem cell phenotype and host microenvironment determine the outcome of a stem cell transplant. # Types of Transplants - **Autologous** - Stem cells are collected from the patient and then reinjected. - Reduced risk of rejection (no foreign antigens). - Partial engraftment may be beneficial. - **Syngeneic** - The source of the stem cells is an identical twin. - An image depicts a man with an arrow pointing to an autologous cell therapy. # Types of Transplants - **Allogeneic** - Stem cells are collected from a matching donor - Types of allogeneic transplant - **A) Matched related donor** (close family member) - **B) Matched unrelated donor (MUD)** (share some common HLA antigens - **C) a mismatched family donor** - 75% of all recipients) - An image depicts a woman with an arrow pointing to a syringe labeled "Allogeneic cell therapy". # Patient Preparation for Transplantation - Want to kill all of the native blood stem cell populations and then transplant a new population of stem cells to start fresh. - Myeloablation - A treatment regime of chemotherapy and whole-body high Intensity radiation - Agents: Cyclophosphomide; busulfan; fludarabine, etoposide - Results in a severe form of myelosuppression # Infusion - An image depicts a stem cell transplant process showing: - Stem cells removed from donor - Patient receives treatment to destroy blood-forming cells - Patient receives stem cells # Engraftment - The process where the donated stem cells migrate to the bone marrow and establish a stem cell population which begins to produce new, adult blood cells of all types. - During this time the graft is essentially "taking root" and becoming functional within the body - This is a crucial step in the transplant process - Takes 14-28 days to achieve # Engraftment - Success is defined by maintaining a minimum number of WBC and platelets for a minimum amount of time. - WBC: - Absolute Neutrophil Count (ANC) > 0.5 X 10⁹ cells per liter - Platelet count > 20 X 10⁹ cells per liter - Hemoglobin > 80 g/l - Free of transfusion requirements - These numbers are maintained for 3 consecutive days - Takes 14-28 days to achieve these criteria # Engraftment - Engraftment: - Absolute neutrophil count (ANC) - A calculated value that more closely reflects the true number of neutrophils. - 500 cells/mm³ - A table shows the different categories of ANC based on cell count. # Engraftment - Nadir: The period during which white blood cell and platelet counts are at their lowest after a stem cell transplant. - Period of greatest risk of infection!!! - Neutropenia - Thrombocytopenia-Low platelet count - Given colony-stimulating factor to help white blood cell counts recover more quickly # Engraftment - A diagram shows the nadir in blood cell count. # Engraftment - A diagram shows the different stages of the stem cell transplant process. - day-10 - Infusion day 0 - day 30 - day 100 - 1 year # Graft vs Host Disease (GVHD) - "Curious if there are any patients here suffering from GVHD. I have been fighting it since my second bone marrow transplant in 2017. It has destroyed my eyes(blind in one eye), lungs (6 collapsed lungs and on supplemental oxygen) skin (scleroderma with limited range of motion) mouth (had to have all my teeth pulled I'm only 33) and liver. Oh and I'm down to 98 pounds. Curious if anyone has any good treatment options?" - An image of a patient's skin affected by GVHD. # Acute Graft vs Host Disease (GVHD) - A serious complication that can occur shortly after a bone marrow or stem cell transplant. - Happens when the donor's white blood cells attack the recipient's body tissues as if they were foreign. - Affects the skin, GI tract, liver, and other organs. - Causes fibrosis - A rash develops over some if not all of the body - Fever # Graft vs Host Disease (GVHD) - Acute GVHD occurs in 50% or more of patients receiving stem cell transplants. - Acute graft rejection tends to be treatable and has the best prognosis, with patients living over 5-10 years. - GVHD is not the same as rejection - The recipient's immune system attacks the transplanted tissue. - Not all of the recipient's immune cells have been removed. - Graft recipients receive heavy doses of anti-immunity drugs such as cortisone, cyclosporin, tacrolimus, Mycophenolate mofetil, prednisolone, # Bad things can happen during the engraftment period. - An image show images of a person's back, mouth, and a magnified picture of the skin. - A diagram depicting the affects of chronic GVHD on the skin, hair, and nails. # Physical Therapy Involvement - During engraftment - In room treatment - Reconditioning - Patient education - After engraftment and discharge - Reconditioning - Balance # Exercise Behavior Acute Post Transplant - A table depicts the mean, standard deviation, and range of exercise time during hospitalization. - Courneya et al. Psycho-Oncology 9: 127–136 (2000) # Physical Functional Status - A diagram shows the strength training of a training group and a control group. - Baumann et al. Bone Marrow Transplant. 2010;45:355. # Post Transplant Setting - Isolation - What is a PT going to do? - An image shows a patient working out with a stability ball. - An image shows a patient using a stationary bike. - An image shows medical supplies, including exercise bands, a slide board, and a weight. # What Else? # Post Transplant Setting - Other things: - Good days-bad days treatment plans - Have them do something!!! - Involve family - Monitor blood counts - Which will you be most interested in? - Ports with multiple bags # Post Transplant Setting - > 6 hrs. OOB daily - At least 30 min of aerobic activity daily - May be broken up into 10 min bouts - In room bicycle ergometer - ROM - Stretching - Resistance Ex - Bands # Post Transplant Setting - Evaluation - 6- min walk test (if possible) - Cycling test (time to fatigue) - 30 sec STS - TUG - Assess balance - Remember: Patient status is fragile! # Post Transplant Setting - If not in Isolation - Unit specific gym with treadmills and weight machines - Out of Room programs - Brassil KJ et al. Cancer Nurs. 2014 S;37(5):345-54 - Hallway circuit training - An image shows the text "CIRCUIT TRAINING keeping things interesting". # Subacute Setting - 30-100 days - 30 min from hospital - Other limitations? - Family support & financial resources - Outpatient vs HEP!!! - Ports with multiple bags - Avoid (for up to 1 yr.) - Swimming pools, hot tubs, public gyms - High impact activities, contact sports, fishing, gardening, household chores (↑ risk of infection) - Activities placing head below level of heart (yoga) # Exercise Behavior of Cancer Survivors - A diagram shows the relationship between the 6-minute walk test and how many days have passed since the transplant. - Morris et al. BMT. 2009; 45:755-761 # Subacute Setting - Continuation of inpatient treatment plans - Receiving lots of IV medications - Aerobic exercise - Strengthening - Balance - Flexibility - Fall prevention # Subacute Transplant Setting - Evaluation - 6- min walk test (if possible) - Cycling test (time to fatigue) - 30 sec STS - TUG - Assess balance - Strength - Daniels & Worthingham alternative strength tests - Remember: Patient status is fragile! # Subacute Setting - Continuation of inpatient treatment plans - Receiving lots of IV medications - Aerobic exercise - Strengthening - Balance - Flexibility - Fall prevention # Causes of Death after Unrelated Donor HCT done in 2014-2015 - A diagram shows the causes of death for patients who died within 100 days after the transplant and patients who died at least 100 days after the transplant. Each circle is divided into segments, showing the percentage breakdown. - *Data reflects 3-year mortality* - CIBMTR CENTER FOR INTERNATIONAL BLOOD & MARROW TRANSPLANT RESEARCH # HEART TRANSPLANTATION - An image shows a doctor watching a patient's heart. # Heart Transplantation - Introduction - Candidates: Refractory acute and chronic heart failure, those requiring mechanical support(IABP) and ionotrophic support, chronic HF, Acute heart failure - First heart transplant carried out Dec. 3, 1967 - Patient died 18 days later - Improvement in immunosuppressive drugs rescued this procedure. - Cyclosporine (1983) - Mycophenolate mofetil (1994) - Tacrolimus (1994) # Heart Transplantation - Worldwide, almost 5000 transplants are being performed each year. - Median survival for adult heart transplant recipients varies and ranges from 10.7 to 12.2 years approximately, with 82% one-year survival and 69% at five-years. - Highest mortality first 6 months - The mortality rate decreases to 3.4% per year. # Heart Transplantation - Introduction - **Orthotopic heart transplant** involving excision of the recipient's heart and implantation of a donor's heart in the chest of the recipient. - **Heterotropic heart transplant** in which the recipient's heart is not excised and the donor's heart is implanted into the recipient's chest. - A diagram shows a donor heart connected to a recipient's heart. # Heart Transplantation Contraindications to transplant - Chronic liver disease (cirrhosis) - Advanced kidney disease (glomerular filtration rate of less than 30 ml/min/1.73m²). - Recent stroke or symptomatic, untreated peripheral vascular disease. - Uncontrolled diabetes mellitus with end-organ damage. - Active malignancy, - Severe lung disease with a forced expiratory volume (FEV1) and forced vital capacity(FVC) less than 50% predicted. - Severe pulmonary hypertension # Heart Transplantation Pre-Transplant Evaluation - Laboratory Tests - Diagnostic Tests - Dental Clearance, Ophthalmology consult, DEXA scan - Colonoscopy - Diaphragm Nerve Conduction Study - Medical & Surgical Evaluation - Psychosocial Evaluation - Psychiatric Evaluation - Nutrition Evaluation - Financial Evaluation # Heart Transplantation The Matching Process - Factors that affect ranking on the transplant list - Severity of the disease - blood type, tissue type (HLA), size of the organ, and patients' medical urgency - time spent on the waiting list and distance between the donor and the transplant center - The surgeon and/or the transplant team can reject an organ. # Heart Transplantation - A diagram shows the heart transplant process. - The diseased heart is cut out of the patient. - The donor heart is placed in its place. # Heart Transplantation Immunosuppression - Antirejection drugs: - Cyclosporine-renal toxin - Tacrolimus - Mycophenolate Mofetil - Sirolimus - Everolimus - Prednisone - Antibiotics # Heart Transplantation Early Problems - Renal Failure - Drug induced damage to kidneys; reduced renal blood flow - Rejection-Acute - Heart Biopsy - Rejection- Chronic - The tissue of - Cardiac tissue is scarred secondary to inflammation - Transplant Coronary Artery Disease (TCAD) and Cardiac Allograft Vasculopathy (CAV) - These vessels harden and narrow compromising blood flow # Heart Transplantation Cardiac Biopsy - The biopsy schedule is as follows: - First biopsy is collected 5-7 days after transplantation. - Then, once a week for the first month after transplant. - Then every other week during the second month. - Then monthly until six-month anniversary. - Then every other month until you reach you first annual date of receiving your transplant. - No anesthetic used - Sample collected is about the size of a pin. - The tissue is examined for the presence of immune cells and other indices of inflammation. # Heart Transplantation Physical Activity - The transplanted heart is a denervated heart. - HR &CO can be regulated by: - Circulating catecholamines - Bainbridge reflex: reflex that increases the heart rate in response to increased blood volume in the right atrium of the heart; adjusts HR to preload. - Because HRs in these hearts do not change rapidly, pay attention to Warm up/cool down. - Precautions - Sternal precautions - Do not push or pull objects greater than 10 pounds; No sit-ups, pull-ups, or push-ups. # Heart Transplantation Post transplant CV and skeletal muscle alterations - Cardiovascular alterations - Chronotropic incompetence - Impaired diastolic function - High resting heart rate - Reduced maximum cardiac output - Endothelial dysfunction - ↑ Sympathetic activation - ↑ Peak exercise systemic vascular resistance - Musculoskeletal alterations - ↓ Total body mass - ↓ Type I oxidative fibers - ↓ Oxidative enzyme capacity - ↓ Capillary/fiber ratio - ↓ Peak exercise arteriovenous oxygen difference - ↓ Bone density - Figure 1 Cardiovascular and musculoskeletal alterations in recipients after heart transplantation. # Heart Transplantation Post transplant CV and skeletal muscle alterations - Transplanted heart is denervated and loses efferent and afferent autonomic connections. - The regulation and function of the CV system has been affected and its reflex reactions are reduced. - These patients are hypertension and have peripheral vasoconstriction-reduced blood flow to working muscle - HR driven by the higher intrinsic rate of the atrium. - Peak exercise CO in heart transplant recipients is 30% to 40% lower than age-matched healthy controls. # Heart Transplantation Post transplant CV and skeletal muscle alterations - Transplant patients present with 20% lower peak exercise end-diastolic volume and stroke volume than healthy people. - **Endothelial dysfunction** is a major cause of disability and lower life expectancy in heart transplant recipients. - Lower peak VO2. - systemic vascular resistance is approximately 50% higher. # Heart Transplantation Post transplant CV and skeletal muscle alterations - Cardiovascular alterations - Chronotropic incompetence - Impaired diastolic function - High resting heart rate - Reduced maximum cardiac output - Endothelial dysfunction - ↑ Sympathetic activation - ↑ Peak exercise systemic vascular resistance - Musculoskeletal alterations - ↓ Total body mass - ↓ Type I oxidative fibers - ↓ Oxidative enzyme capacity - ↓ Capillary/fiber ratio - ↓ Peak exercise arteriovenous oxygen difference - ↓ Bone density - Figure 1 Cardiovascular and musculoskeletal alterations in recipients after heart transplantation. # Heart Transplantation Effects of Exercise - Beneficial for the acute and long-term outcomes of heart transplant patients. - Improve LV contractility, calcium function in the heart and cardiomyocytes size. - Proliferation of cardiomyocytes, - Suppresses the generation of free radicals and oxidative stress and increase the bioavailability of NO. # Heart Transplantation Effects of Exercise - Improves endothelial function. - Reduces systolic blood pressure. - Beneficial effect on inflammatory indices such as CRP, blood platelets and angiogenesis. - Peak VO2 increased 26% in the trained patients. - Positively respond to resistance training. # Heart Transplantation Exercise Protocols - A diagram shows different protocols for exercise training. - Kourek C et al. Rehabilitation after heart transplantation. # Cardiac Transplantation Cardiac Rehabilitation - Transplant recipients should be referred to cardiac rehabilitation. - Cardiac rehabilitation appears to be safe in heart transplant patients. - Employs the standard 3 phases of cardiac rehabilitation. - Initiate in In-patient; may be delayed until patient is out-patient. - Regular aerobic exercise may start in the second or third week after transplantation while resistance exercise should be added after 6 to 8 wk. # Cardiac Transplantation Cardiac Rehabilitation - Advocates for Cardiopulmonary Exercise Testing. - Nutrition consult. - Psychosocial management is being considered as an important element in each cardiac rehabilitation program. Patients usually present high levels of depression, apprehensiveness or anxiety. # Cardiac Transplantation Cardiac Rehabilitation - Psychosocial management is being considered as an important element in each cardiac rehabilitation program. Patients usually present high levels of depression, apprehensiveness or anxiety. # World Journal of Transplantation - An image shows text for an article on exercise training in heart transplantation. - Submit a Manuscript: https://www.f6publishing.com. - DOI: 10.5500/wjt.v11.111.466. - World J Transplant 2021 November 18; 11(11): 466-479. - ISSN 2220-3230 (online). - MINIREVIEWS - Exercise training in heart transplantation. - Christos Kourek, Eleftherios Karatzanos, Serafim Nanas, Andreas Karabinis, Stavros Dimopoulos. # Lung Transplantation - An image shows the process of lung transplantation, with the recipient's lung replaced by a donor lung. # Lung Transplantation - A surgical procedure that replaces a patient's diseased lungs with healthy lungs from a donor. It's an option for people with end-stage lung disease when other treatments have failed. - People of almost all ages, from newborns to adults up to age 65 are candidates. - Rejection of the new lung, blood clots, diabetes, osteoporosis, hyperlipidemia, increased risk of infections, organ damage, future risk for certain cancers. - May involve replacing 1 or both lungs or both lungs and the heart. # Lung Transplantation Why lung transplants are performed? - Chronic obstructive pulmonary disease (COPD), including emphysema. - Scarring of the lungs (pulmonary fibrosis). - Cystic fibrosis (involves replacing both lungs). - High blood pressure in the lungs (pulmonary hypertension). # Lung Transplantation Factors that may affect your eligibility - Have an active infection. - Have a recent personal medical history of cancer. - Have serious diseases such as kidney, liver or heart diseases. - Are unwilling or unable to make lifestyle changes necessary to keep your donor lung healthy, such as not drinking alcohol or not smoking. - Do not have a supportive network of family and friends. - Recipients undergo the same rigorous pre-transplant work up as recipients for other solid organs. # Lung Transplantation Reasons for receiving a lung transplant - Interstitial lung disease (ILD) [fibrosis] - Advanced chronic obstructive pulmonary disease (COPD) - Cystic fibrosis (CF) - Emphysema due to alpha-1 antitrypsin deficiency - Pulmonary arterial hypertension (PAH) # Lung Transplantation Procedure - Single Lung - Double Lung - Heart-Lung - A lobe of the lung - Please refer to Dr. Brueilly's lecture on solid organ transplant, slides 8-25. - Denervated - Loss of autonomic innervation - Loss of cough reflex in the donor lung - Delay in bronchial dilation and impairment of ciliary function → sputum retention and pneumonia # Lung Transplantation - It is difficult to preserve lung function during recovery and transportation to the transplantation location!! - Death is accompanied by a surge of catecholamines which lead to disruption of pulmonary vascular beds and pulmonary edema. - Contusions, physical injury. - Ventilatory acquired trauma. # Lung Transplantation Transporting the donor lungs -Ex-Vivo Lung Perfusion (EVLP) - An image shows a container holding a donor lung. - It is estimated that only 5-10% of donor lung offers meet "standard or ideal conditions.” # Lung Transplantation Opening the Chest - An image shows the procedure of opening the chest during a lung transplant. # Lung Transplantation The Connections - A diagram shows the donor lung heart connected to the recipient's heart and lungs in the chest. # Lung Transplantation - An image shows the surgical process of connecting the donor lung to the recipient's body. # Lung Transplantation - An image shows the surgical process of connecting the donor lung to the recipient's body. - Vagus nerve. - Phrenic nerve. # Lung Transplantation What needs to be Preserved? - Nerves to the vocal cords, esophagus, and diaphragm. - Lymphatic channels that bring lymph fluid from the body to the central veins. - The esophagus, heart, and aorta are all carefully protected throughout the procedure. # Side Note - An image shows a series of images comparing the lungs of a patient before, 6 months after, and 2 years after a transplant. - Native-lung complications following single-lung transplantation for interstitial lung disease: # Lung Transplantation Impact of Immune Suppression - Wash your hands regularly. - Brush your teeth and gums regularly. - Avoid contact with pets and avoid cleaning pet areas. - Protect your skin from scratches and sores, such as from razors or nail files. - Avoid sharing utensils. - Avoid crowds and people who are ill. - Receive appropriate vaccinations. # Lung Transplantation Post Transplant Complications - Rejection - Infection [greater risk than for heart transplant [Why] - Is it rejection or infection? - Infection: greater sputum production & productive cough - Candida, Aspergillus - It is critical for the recipients to practice good hand hygiene, aware of infection risk in public places, etc. - Environmental air - Compromised nutrition and swallowing # Lung Transplantation Post Transplant Care - Breathing exercises to improve lung function and prevent pneumonia - Incentive Spirometry: - Engage in pulmonary hygiene techniques. - Gradual exercise progression, starting with walking and advancing to more vigorous activities as tolerated. - Note: Not only is the patient recovering from major surgery but also a serious pulmonary disease. # Lung Transplantation Post Transplant Physical Therapy Care - Functional Recovery After Lung Transplantation Using a Comprehensive Rehabilitation Model - DiPerna, Christen L.; Tucker, Lindsay K.; Rice, Danielle E.; More - Cardiopulmonary Physical Therapy Journal. 34(3):141-149, July 2023. - Exercise Progression Protocol for Lung Transplant GO: A Multicomponent Telerehab Exercise Intervention for Patients After Lung Transplantation - Hergenroeder, Andrea L.; Willey, Bryan M.; Vendetti, Melissa L.; More - Cardiopulmonary Physical Therapy Journal. 34(1):2-12, January 2023. - Implementing Standard Physical Therapy Guidelines With Patients Acutely After Single or Bilateral Lung Transplant: A Quality Improvement Project in the Hospital Setting - Connors, Catherine; Betts, Traci; Lawrence, Shelby; More - Cardiopulmonary Physical Therapy Journal. 34(4):177-182, October 2023. # Lung Transplantation Post Transplant Physical Therapy Care - https://journals.lww.com/cptj/pages/video.aspx?v=11