This document provides an overview of hematopoietic stem cell transplantation (HSCT) for pediatric patients with congenital or acquired hematopoietic disorders. It discusses the historical background of HSCT, including early animal studies and the first human transplants. It also covers the basic principles and indications for autologous and allogeneic HSCT, including the use of different stem cell sources like bone marrow, peripheral blood, and cord blood. Key factors like human leukocyte antigen matching between donor and recipient and the need for cytoreduction prior to transplant are also summarized.
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
This presentation is about chronic lymphocytic leukemia (CLL), its epidemiology and incidence, staging, molecular characteristics, clinical features and management.
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
This presentation is about chronic lymphocytic leukemia (CLL), its epidemiology and incidence, staging, molecular characteristics, clinical features and management.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
1. HEMATOPOIETIC STEM CELL TRANSPLANTATION
FOR THE TREATMENT OF PEDIATRIC PATIENTS
WITH
CONGENITAL OR ACQUIRED
HEMATOPOIETIC DISORDERS
OVERVIEW
2. NUMBERS TO PUT THINGS IN CONTEXT
Number of patients diagnosed with cancer in the US – 2007
~30,000/yr potentially treatable with SCT
• Adult Cancer
-Overall 1,445,000
-Prostate 218,000
-Breast 178,000
-Lung 214,000
-Colon 154,000
-Leukemia 44,000
• Pediatric Cancer
-Overall 13,400
-Leukemia 3,400
3. HISTORICAL BACKGROUND
Animal Studies
Early 1950s
High doses of total body irradiation caused
fatal damage to the GI and CNS systems
lower doses resulted in late death from hemorrhage and infection
Marrow from animals genetically identical to treated animals averted death
Marrow from non-identical animals led to an immunologic reaction
methotrexate prevented that reaction
induced tolerance to skin grafts
Cyclophosphamide also permitted engraftment of allogeneic marrow.
4. HISTORICAL BACKGROUND
1939 Osgood Infusion of a few ml of marrow into patients
with aplastic anemia no benefit
1959 Thomas Infusion of large volumes of marrow into
patients with refractory leukemia
one patient with transient engraftment
First paper on BMT in humans
1960’s van Rood Human Leukocyte Antigens (HLA) defined
Dupont Attempts at sibling donor transplants
1968 Good First successful BMT in 2 patients
Bortin (SCID and WAS)
5. THE FIRST 100 ALLO TRANSPLANTS
Fred Hutchinson Cancer Research Center - Seattle
6. WHAT HAPPENED – 1980s to 2007
Progress in the field of transplantation
- Early 1980’s: Autologous and matched sibling SCT
- Mid 1980s GvHD prophylaxis w/CSA and MTX
First T cell depletion techniques
- Late 1980’s: Unrelated Donor Allogeneic SCT
- Mid 1990’s: Mobilized stem cells from peripheral blood
Stem cells from placental cord blood
- Late 1990’s: Mismatched related family donors
Non-myeloablative (mini) transplants
8. NUMBER OF TRANSPLANTS AT MSKCC
ADULT ALLO PEDIATRIC ALLO
2002 58 2002 41
2003 60 2003 31
2004 58 2004 37
2005 68 2005 51
2006 97 2006 41
ADULT AUTO PEDIATRIC AUTO
2002 128 2002 31
2003 154 2003 14
2004 127 2004 13
2005 195 2005 7
2006 142 2006 3
9. DEFINITIONS
&
BASIC PRINCIPLES
OF
TRANSPLANTATION
10. AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANT
PURPOSE
• ALLOGENEIC
– Replace marrow that has a cancer (ex: leukemia) or 1 or more
abnormal hematopoietic lineages (ex: SCID or AA)
– Give a patient allogeneic (immune) T-cells to create a graft-
versus-tumor effect (ex: renal cell carcinoma)
– Donor can be
• Related – syngeneic, HLA matched or mismatched
• Unrelated – HLA matched or mismatched
• AUTOLOGOUS
– Treat a cancer that responds to high dose therapy (dose
intensity) and rescue marrow suppression by giving
autologous stem cells afterwards (ex: neuroblastoma or
lymphoma)
– harvested prior to therapy and frozen
12. HEMATOPOIETIC SCT
Leukemias
Lymphomas Allogeneic Stem cells
Aplastic Anemia
SCID
= Treatment
Other marrow disorders
some solid tumors
Brain Tumors
Retinoblastoma
Breast CA (no longer) Autologous Stem cells
Ovarian CA
Wilms Tumor = Rescue
Lymphomas HD-NHL
13. ALLOGENEIC STEM CELL TRANSPLANTATION
INDICATIONS
Eliminate a defective hematopoietic system
and replace it with a normal/healthy one
Defective hematopoietic system:
Any disease in which the pathology is caused by a
1. A hematologic malignancy
Ex: Leukemias, MDS
2. A defective marrow with multilineage involvement
Ex: AA, Fanconi anemia
3. A defective single hematopoietic cell lineage
Ex: SCID, Hemoglobinopathies
14. INDICATIONS FOR HEMATOPOIETIC SCT
UNITED STATES
2005
5,500
5,000
4,500 Allogeneic (Total N=7,880)
4,000
Transplants
Autologous (Total N=10,840)
3,500
3,000
2,500
2,000
1,500
1,000
500
0
Multiple NHL AML Hodgkin ALL MDS/MPD CML Aplastic Other Other Non-
Myeloma Disease Anemia Leuk Cancer Malig
Disease
19. MAJOR HISTOCOMPATIBILITY COMPLEX
HUMAN LEUCOCYTE ANTIGENS
Graft-Versus-Host Disease
HOST
DONOR HLA
Rejection
• HLA antigens are glycoproteins expressed on the surface of cells
• They are transmitted genetically (chromosome 6)
• They determine the presence or absence of reactions between
T-cells of donor and patient, and therefore, determine the outcome
of allogeneic transplants
• Parallel: HLA antigens are for allogeneic transplants, what ABO
blood types are to transfusion
20. MAJOR HISTOCOMPATIBILITY COMPLEX
HUMAN LEUCOCYTE ANTIGENS
Low A2 B4 DR1 C05 DQB1 01
Resolution A11 B44 DR13 C17 DQB1 03
High A0203 B4101 DRB1 0102 C 0502 DQB1 0101
Resolution A1102 B4402 DRB1 1301 C 1701 DQB1 0301
6 Antigens
10 Antigens
21. MAJOR HISTOCOMPATIBILITY COMPLEX
HUMAN LEUCOCYTE ANTIGENS
Mother Father
a A1 B8 DR7 c A2 B44 DR4
b A3 B7 DR2 d A29 B44 DR7
a a b b
A1 B8 DR7 A1 B8 DR7 A3 B7 DR2 A3 B7 DR2
A2 B44 DR4 A29 B44 DR7 A2 B44 DR4 A29 B44 DR7
c d c d
a
HLA-matched
A1 B8 DR7
Siblings
A2 B44 DR4
c
22. MAJOR HISTOCOMPATIBILITY COMPLEX
HUMAN LEUCOCYTE ANTIGENS
Mother Father
aA01 B08 DR7 A01 B08 DR7 c A02 B44 DR4
b A03 B7 DR2 A02 B44 DR4 d A29 B44 DR7
a A0101 B0803 DR704
c A0202 B4403 DR401
3/6 (haplo) 0/6 3/6
A0104 B0807 DR701 A0104 B0802 DR701 A0101 B0807 DR701
A0202 B4403 DR401 A0201 B4401 DR404 A0201 B4403 DR401
HLA-matched unrelated A0101 B0803 DR704
donor A0202 B4403 DR401
23. A B C DR DQ
Patient a/b 3201 4002 0202 0701 0202
c 0201 5101 1604 1406 0301
Father a 3201 4002 0202 1301 0603
b 2401 4005 0301 0701 0202
1 1 1 1 1
Mother c 0201 5101 1604 1406 0301
d 0101 1302 0608 1101 0301
1 1 1 1 1
Sister b 2401 4005 0301 0701 0202
d 0101 1302 0608 1101 0301
Sister a 3201 4002 0202 1301 0603
c 0201 5101 1604 1406 0301
2 2 2 1 1
24. PRIORITY OF ALLOGENEIC TRANSPLANTS
Patient candidate for allogeneic transplant
Family HLA typing
HLA-matched Sibling No HLA-matched Sibling
(25-30%)
Search for an unrelated donor
(NMDP – Cord Blood Banks)
Transplant
HLA-matched Unrelated Donor No matched
(50-80%) Unrelated Donor
Transplant High Risk Disease Non-High risk Disease
Transplant Transplant No Transplant
Risk (MM Related Donor)
26. HEMATOPOIETIC STEM CELL SOURCES
SOURCE OF HEMATOPOIETIC STEM CELLS
Marrow cord blood PBSCs
Average cell dose (TNC/kg) 5 x 108 2 x 106 10 x 108
how harvesting is performed Under GA at birth G-CSF
mobilization
and pheresis
risks/excluded Risk of GA None Hypercoag
quality of states
product SS carriers
cell dose sufficient for Limiting in Higher
conventional or adults
sized matched
can the product be manipulated Yes No Yes
(dose limiting)
risk of GvHD with conventional graft Standard Lower Higher
availability of more cells, cells for CTLs Yes No Yes
27. UNRELATED STEM CELL SOURCES
BY RECIPIENT AGE
1999-2006
100
Bone Marrow (BM)
Bone Marrow (BM)
Peripheral Blood (PB)
Transplants, %
80 Cord Blood (CB) (PB)
Peripheral Blood
Cord Blood (CB)
60
40
20
0
1997-2000 2001-2004 1997-2000 2001-2004
Age ≤20 yrs Age >20 yrs
28. ALLOGENEIC TRANSPLANTS IN PATIENTS <20yo,
REGISTERED WITH THE CMBTR – 1989 -2008
BY DONOR TYPE AND GRAFT SOURCE
5,000
Related
4,500 Unrelated – BM or PB
Unrelated – CB
4,000
Transplants
3,500
3,000
2,500
2,000
1,500
1,000
500
0
1989-90 1991-92 1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06
29. BASIC PRINCIPLES OF HEMATOPOIETIC
STEM CELL TRANSPLANTATION
CYTOREDUCTION
• In order to perform an allogeneic transplant successfully, we need
to give a cytoreduction prior to the stem cell infusion for:
Immunosuppression
Myeloablation
Anti-leukemic effect
• This is done by using
- Radiation therapy (Total body irradiation – TBI)
and/or
- Chemotherapy (Busulfan, Cyclophosphamide, melphalan,
Thiotepa, fludarabine, …)
• How much of each effect you need varies by the underlying
disease, type of transplant and degree of match
34. 100 DAY POST-TRANSPLANT MORTALITY
2001-2006
HLA-identical Sibling Autologous
)
GVHD (13%)
y (7%
ic it
Other
Relapse (41%) tox Infection
(16%) (8%)
Relapse (70%)
Infection Other (13%)
(17%)
Toxicity
(13%)
35. ACUTE GRAFT VERSUS HOST DISEASE
• Immune reaction caused by Donor T-cells in the graft, which are
activated by minor or major HLA-disparities between donor and
host, and attack target organs (skin, GI, liver + BM and immune
system)
• Occurs after engraftment - day 14-28 (prior to day 100)
• Reaction dependent upon HLA-disparities
– HLA mismatch: 3 Ag > 2 Ag > 1 Ag
• Related donor: Mismatch > Match
• Donors: Unrelated > Related
39. Lancet 2005 Wagner et al Effect of graft-versus-
host disease prophylaxis on 3-year disease-free
survival in recipients of unrelated donor bone
marrow (T-cell Depletion Trial): a multi-centre,
randomised phase II–III trial
41. Incidence of grade II GvHD 8% (no grade III or IV)
Incidence of chronic GvHD 9%
Jakubowski, A. A. et al. Blood 2007;110:4552-4559
42. GRAFT REJECTION
• Immune reaction caused by Host T-cells which survived the
cytoreductive regimen, and are activated by specific minor or
major HLA-disparities between donor and host. They attack the
donor’s stem cells with subsequent aplasia and pancytopenia
• Occurs early (day 10-20) or late (day 40-60)
• Reaction dependent upon HLA-disparities
• HLA mismatch: 3 Ag > 2 Ag > 1 Ag
• Related donor: Mismatch > Match
• Donors: Unrelated > Related
• Multiply transfused patients (AA, Hemoglobinopathies) at higher
risk because of prior T-cell sensitization
43. INFECTIONS POST TRANSPLANT
• 0-30 days Bacterial* All
Fungal Candida
Viral RSV, HSV
• 1-3 months Fungal* Aspergillus
Viral CMV, Adeno, HHV6
VZV, EBV
Parasitic Toxo, PCP
• 3-6 months Viral CMV, Adeno, HHV6
VZV, EBV
Parasitic Toxo, PCP
*After 30 days, the risk of bacterial and fungal infections persists if GvHD
49. BONE MARROW FAILURE SYNDROMES
APLASTIC ANEMIA
• Disorder of hematopoiesis characterized by severe generalized
reduction of all hematopoietic lineages in the bone marrow and
peripheral pancytopenia.
• Two groups:
– ACQUIRED
Idiopathic or secondary to drugs, infections, chemicals or
irradiation
– CONSTITUTIONAL comprises several genetic disorders
Fanconi Anemia Dyskeratosis Congenita
Schwachman Diamond Osteopetrosis
• Indications for SCT:
All patients
52. SEVERE APLASTIC ANEMIA
ALLOGENEIC STEM CELL TRANSPLANTATION
vs
IMMUNOSUPPRESSION TREATMENT
Overall Since 1988
BMT
BMT N=25
OS = 75.6%
IST
IST N=23
OS = 73.8%
53. Impact of fludarabine on survival in patients with FA treated with
unrelated donor BMT. Wagner JE, Eapen M, MacMillan ML, Harris RE,
Pasquini R, Boulad F et al. Blood 2007; 109: 2256–2262.
55. OS 94.4%
Overall Survival
β−thalassemia
MSKCC Experience
N = 20
DFS 91.7%
Disease Free Survival
DFS 44.8%
56. OS 91.7%
Overall Survival
Sickle Cell Anemia
MSKCC Experience
N = 12
DFS 91.7%
Disease Free Survival
57. SCID – OVERALL EXPERIENCE
Since 1973: 94 transplants for SCID
14 (2-4/year) over the past 5 years.
Transplant Type
T cell depleted HLA Haplo-disparate related donors
SBA-E- bone marrow 69
CD34+E- PBSC 4
Unmodified HLA matched and partially mismatched
bone marrow grafts 21
Cytoreduction
Matched sibling none
Haplo-disparate TCD 37/69
Basis for cytoreduction
NK function
58. SURVIVAL BY TIME TO DIAGNOSIS OF SCID
1
MREL <3 months = 100% n=8
0.9
0.8
0.7
MREL >3 months = 72.73% n=11
0.6
Proportion
0.5
0.4
0.3
0.2
0.1
0
0 10 20 30 40 50 60
Time Post Transplant (months)
59. LATE COMPLICATIONS OF ALLOGENEIC SCT
Immunologic
– Chronic Graft versus-Host Disease (GvHD)
– Infections
Long term organ toxicity
- Endocrine: Growth, Gonadal, Thyroid
- CNS - Cardiac - Pulmonary - Hepatic
- Renal - Other
Secondary Malignancies
- Solid Tumors
Psychological Late effects
61. WHAT’S NEW AND EXCITING
NON-MYELOABLATIVE TRANSPLANTS
(MINI- TRANSPLANT)
ADOPTIVE CELL THERAPY
Use of broad unselected or selected donor lymphocytes
prophylaxis or treatment of infections or disease
Use of NK cells
VACCINES
of donor (in the pre-transplant period) or host (in the post-transplant period)
GENE THERAPY
for inborn errors
especially those where a selective advantage may exist for corrected cells
62. NON-MYELOABLATIVE TRANSPLANTS
Principle:
•avoid use of high dose therapy
•decreases toxicity in older or heavily pre-treated
•high doses of donor T-cells
•Cytoreduction limited to immuno-ablation
•Advantages:
•Transplants less toxic
•Graft versus leukemia (or tumor)
•Dis-advantages
•higher incidence of GvHD – especially chronic
•takes time to establish full donor chimerism
63. CONVENTIONAL CYTOREDUCTION
Graft-Versus-Host Disease
Donor Host
(Graft) Rejection
(Patient)
T-cells T-cells
Bone Marrow Bone Marrow
NON-MYELOABLATIVE CYTOREDUCTION
Graft-Versus-Host Disease
Donor Host
(Graft) Rejection (Patient)
T-cells T-cells
Bone Marrow Bone Marrow
65. ADOPTIVE CELL THERAPY – NK CELLS
• Adoptive transfer of NK cells to enhance
engraftment and leukemia resistance.
• Selection of KIR*-mismatched HLA-compatible
donors conferring NK-mediated leukemia
resistance
*KIR = Killer-cell Immunoglobulin-like Receptor
66. GENE THERAPY
Insertion of a normal gene into deficient stem cell
Already trials for X-linked SCID, ADA-SCID, CGD
Other target genes already in or close to trials:
- ADA-deficient SCID
- Thalassemia / Sickle cell disease
- Wiskott Aldrich Syndrome
- Fanconi Anemia
- Hemophilia
67. THALASSEMIA
Gene Therapy
E A
N D
C G-CSF
R M Infusion
a
O I Autologous
t
L S Hematopoietic
h
L S
M
e
I
Busulfan Stem Cells
t Transduced
E O
Pre-SCT e Pre-SCT
Screening N N with THALAGEN
Work-up1 r Work-up 2
Work-up T
PBSCT
Cytotherapy Lab
CD34 selection
Gene Therapy Lab
Lentiviral mediated human β Globin Gene transfer
Slide 10: The graft source used for unrelated donor transplantation has changed significantly over the past decade. Bone marrow was still the main graft source for unrelated transplantation in recipients younger than 20 years; however, more than one third of these patients received umbilical cord blood grafts. Among adults, peripheral blood stem cells are the most common graft source for unrelated donor transplants.