This document discusses leukemia, specifically chronic myeloid leukemia (CML). It begins by providing background on leukemia and its classification. It then describes the history and epidemiology of CML. CML is caused by a reciprocal translocation between chromosomes 9 and 22, forming the Philadelphia chromosome and BCR-ABL fusion gene. This results in unregulated tyrosine kinase activity and proliferation of myeloid cells. The document outlines the clinical features, progression from chronic to accelerated to blast crisis phases, hematological and chromosomal findings, and management of CML.
an update of lymphoma classification for practicing pathologists, hematologists, oncologists, residents, and fellows; important for the prognosis and treatment of lymphoma patients.
an update of lymphoma classification for practicing pathologists, hematologists, oncologists, residents, and fellows; important for the prognosis and treatment of lymphoma patients.
this is powerpoint presentation comprising of latest updates and theory of lymphoma and plasma cell dyscrasias WHO 2016. restricted to all lymphomaniacs.
A comprehensive review of Cutaneous Lymphomas - both B-Cell and T-Cell with latest treatment strategies. Target audience are oncologists, dermatologists, oncology physicians, dermatology and oncology fellows
plastic anemia is a rare bone marrow failure disorder in which the bone marrow stops making enough blood cells (red blood cells, white blood cells, and ...
this is powerpoint presentation comprising of latest updates and theory of lymphoma and plasma cell dyscrasias WHO 2016. restricted to all lymphomaniacs.
A comprehensive review of Cutaneous Lymphomas - both B-Cell and T-Cell with latest treatment strategies. Target audience are oncologists, dermatologists, oncology physicians, dermatology and oncology fellows
plastic anemia is a rare bone marrow failure disorder in which the bone marrow stops making enough blood cells (red blood cells, white blood cells, and ...
Chronic myelogenous leukemia (CML) - pluripotential stem cell disease
A malignancy the treatment of which has been revolutionised over the last decade.
Here is a comprehensive discussion on the disease
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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
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.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
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.
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
5. INTRODUCTION
• Malignant disorders of the haematopoietic stem cell
compartment, characteristically associated with increased
numbers of white blood cells in the bone marrow and/or
peripheral blood
• Incidence is 10/100000 per annum. Males are affected more
frequently than females (acute leukemia 3:2, chronic
lymphocytic leukemia 2:1, chronic myeloid leukemia 1.3:1)
• Acute leukemia occurs at all ages, chronic leukemia occur
mainly in middle and old age
6. HISTORY
• The discovery of leukemia is largely contributed to German physician
Rudolf Ludwig Karl Virchow (1821-1902) and
• English physician, pathologist and physiologist John Hughes Bennett
(1812-1875) as they were the first to observe the disease
• In 1845 Edinburgh pathologist Bennett reported a “case of
hypertrophy of the spleen and liver in which death took place from
suppuration of the blood” in the Edinburgh medical journal.
• Few weeks later Virchow in berlin published a very similar case.
• Bennett thought that the patient had an infection, Virchow suspected
a neoplastic disorder that he soon called white blood disease or
leukemia
9. MYELOID NEOPLASMS
• Includes neoplasms of myeloid cell lineage
• There are 5 categories
Myeloproliferative disorders
Myeloproliferative/myelodysplastic diseases
Myelodysplastic syndromes (MDS)
Acute myeloid leukemia
Acute biphenotypic leukemia
10. LYMPHOID NEOPLASMS
• Leukemias of lymphoid lineage and lymphomas of B, T or NK cell origin
• Includes B cell neoplasms ( including plasma cell disorders), T cell
neoplasms, NK cell neoplasms and Hodgkin’s disease
HISTIOCYTIC NEOPLASMS
• Neoplastic proliferations of histiocytes in Langerhans cell histiocytisis
11. CONTD….
• In acute leukemia there is proliferation of primitive stem cells leading to
an accumulation of blasts, predominantly in the bone marrow, which
causes bone marrow failure
• In chronic leukemia the malignant clone is able to differentiate,
resulting in an accumulation of more mature cells
• Lymphocytic and lymphoblastic cells are derived from the lymphoid
stem cell (B cells and T cells)
• Myeloid refers to the other lineage, i.e. precursors of red cells,
granulocytes, monocytes and platelets
13. DEFINITION
They are a group of clonal myeloid
neoplasms in which a genetic alteration occurs in a
hematopoietic progenitor cell leading to its
proliferation resulting in an increase in the peripheral
blood white blood cells (WBCs), red blood cells
(RBCs), platelets, or a combination of these cells.
16. COMMON FEATURES
• Common pathologic feature of the myeloproliferative disorder is the
presence of mutated, constitutively activated tyrosine kinases
• Hematopoietic growth factors act on normal progenitors by binding
to surface receptors and activating tyrosine kinases, which turn on
pathways that promote growth and survival
• Then mutated tyrosine kinase circumvent normal controls and lead to
the growth factor-independent proliferation and survival of marrow
progenitors
• Most myeloproliferative disorders originate from multipotent myeloid
progenitors
17. CONTD…
• Increased proliferative drive in the bone marrow
• Homing of the neoplastic stem cells to secondary
hematopoietic organs, producing extramedullary
hematopoiesis
• Variable transformation to a spent phase characterized by
marrow fibrosis and peripheral blood cytopenias
• Variable transformation to acute leukemia
18. CONTD…
• The diagnosis of leukemia is usually suspected from an
abnormal blood count, often a raised white count, and is
confirmed by examination of the bone marrow
• This includes the morphology of the abnormal cells, analysis
of cell surface markers (immunophenotyping), clone
specific chromosome abnormalities and molecular changes
• The features in the bone marrow not only provide an
accurate diagnosis but also give valuable prognostic
information
20. DEFINITION
A clonal expansion of a hematopoietic stem cell
possessing a reciprocal translocation between
chromosome 9 and 22 resulting in head to tail fusion
of the breakpoint cluster region (BCR) gene on
chromosome 22q11 with ABL1 (named after Abelson
murine virus) gene located on chromosome 9q34
21. INTRODUCTION
• Chronic myeloid leukemia (CML) accounts for about 14% of
all leukemia
• It is one of the family of myeloproliferative neoplasms
(MPNs)
• Almost exclusively a disease of adults with the peak of
presentation between 40-60
• Philadelphia chromosome demonstrated
cytogenetically(95%) or molecularly(5%)
• Slowly progressive
22. HISTORY
• The Philadelphia cytogenecists Peter Nowel and David
Hungerford discovered an abnormally small G-group
chromosome that we now call the Philadelphia chromosome
(Ph)
• 13yrs later Janet Rowley recognized that Ph was the
product of a reciprocal translocation between chromosome
9 and 22
• In 1980s the translocation partners were identified as BCR
and ABL, followed by the discovery that unregulated
tyrosine kinase activity is critical to BCR-ABL’s ability to
transform cells
23. EPIDEMIOLOGY
• Incidence
0.2 to 2.0 per 100000 people per year
• Gender
Higher in men than in women (1.3:1)
• Age
Incidence increases slowly with age until the middle
forties there after rises rapidly
Median age is 66yr
24.
25. CONTD…
• Geographic and/or ethnic variations might contribute to
the variability of incidences
• Most of the patients who get admitted medical therapy
studies are 50 to 60yr (median approximately 53yr)
• Patients in bone marrow transplantation studies are even
younger (median age approximately 40yr)
30. • CML was the first malignancy to be linked to a clear genetic
abnormality
• Approximately 95% of the patients with CML have a chromosome
abnormality known as the Philadelphia (Ph) chromosome
• This is a shortened chromosome 22 resulting from a reciprocal
translocation of material with chromosome 9
• The break on chromosome 22 occurs at breakpoint cluster region
(BCR)
• The fragment from chromosome 9 carries the abl oncogene which
forms a chimeric gene with the remains of the BCR
31.
32. CONTD…
• This BCR ABL chimeric gene codes for a 210kDa protein with tyrosine
kinase activity
• The chimeric gene is transcribed into a hybrid BCR-ABL1 mRNA in
which exon 1 of ABL1 is replaced by variable numbers of 5’ BCR exons
• Bcr-Abl fusion proteins p210BCR-ABL1 are produced that contain NH2-
terminal domains of Bcr and COOH-terminal domains of Abl
• A rare breakpoint occurring within 3’ region of the BCR gene yields a
fusion protein of 230 kDa, p230BCR-ABL1
• Bcr-abl fusion protiens can transform hematopoietic progenitor cells in
vitro
33.
34. CONTD…
Attachment of the BCR sequences to ABL1 results in 3
critical functional changes
Abl protein becomes constitutively active as a tyrosine
kinase (TK) enzyme, activating downstream kinases that
prevent apoptosis
The DNA-protein-binding activity of Abl is attenuated; and
The binding of Abl to cytoskeletal actin microfilaments is
enhanced
35. CONTD..
• Chromosomal instability of the malignant clone is a basic
feature of CML
• Heterogeneous structural alterations of the TP53 gene, as
well as structural alterations and lack of protein production
of the retinoblastoma 1 (RB1) gene and the catalytic
component of telomerase, is associated with disease
progression
• Rare patients show alterations in the rat sarcoma viral
oncogene homologue (RAS)
36. CONTD…
• Sporadic reports also document presence of an altered v-
mync myelocytomatosis viral oncogene homologue (MYC) gene
• Progressive de novo DNA methylation at BCR-ABL1 locus
and hypomethylation of the LINE-1 retrotransposon
promoter promotes blastic transformation
• Interleukin 1β may be involved in the progression of CML to
the blastic phase
• Functional inactivation of the tumour suppressor protein
phosphatase A2
38. SYMPTOMS
• Insidious in onset, some are asymptomatic others may
present with fatigue, malaise and weight loss or have
symptoms resulting from splenic enlargement, such as early
satiety and left upper quadrant pain or mass
• Less common features related to granulocyte or platelet
dysfunction are infection, thrombosis or bleeding
• Occasionally leukostatic manifestations due to severe
leukocytosis or thrombosis such as vasoocclusive disease,
CVA, MI, venous thrombosis, priapism, visual disturbances,
pulmonary insufficiency
39. SYMPTOMS AT PRESENTATION
Symptom Present (%)
Tiredness
Weight loss
Breathlessness
Abdominal pain and discomfort
Lethargy
Anorexia
Sweating
Abdominal fullness
Bruising
Vague ill health
37
26
21
21
13
12
11
10
7
7
40.
41. PROGRESSION OF CML
Characterised by worsening of symptoms
• Unexplained fever
• Significant weight loss
• Increasing dose requirements
• Bone and joint pain
• Bleeding, thrombosis and infection
Less than 10-15% of newly diagnosed patients present with
accelerated disease or with de novo blastic phase CML
42. SIGNS
• Minimal to moderate spenomegaly
• Mild hepatomegaly
• Persistent splenomegaly despite continued
medication is a sign of disease acceleration
• Lymphadenopathy and myeloid sarcomas are
unusual
43. CHRONIC PHASE
• Approximately 85% of the patients with CML are in this phase at the
time of diagnosis
• It is sometimes called the stable phase
• Patients are usually asymptomatic (25 to 60%)
• In symptomatic patients, the most common presenting signs and
symptoms are
Fatigue
Left upper quadrant pain or mass
Weight loss
Palpable spleen in 30 to 70% of patients
Liver is enlarged in 10 to 20%
44. CONTD…
• Patients with very high WBC counts may have
manifestations of hyperviscosity, including priapism, tinnitus,
stupor, visual changes and CVA
• If untreated or treated with drugs that do not significantly
affect the Philadelphia- chromosome cells in the marrow,
chronic phase is associated with a median survival of 4 to 5
yrs
• In the absence of treatment chronic phase progresses to
this phase
45. ACCELERATED PHASE
• This is an ill-defined transitional phase
• The criteria used in all the studies with interferon and tyrosine
kinase inhibitors include the presence of any one of the
following factors
46.
47. CONTD…
• Cytogenetic evolution with new abnormalities in addition to
Philadelphia chromosome
• The classification used may affect the expected outcome
of a group of patients
• More frequently symptomatic, including fever, night sweats,
weight, progressive splenomegaly
• Accelerated phase indicates that the disease is progressing
and transformation to blast crisis is imminent
• With imatinib therapy 4 yr survival rate exceeds 50%
48. BLAST CRISIS
• This is the final phase in the evolution of CML, behaves like
an acute leukemia with rapid progression and short survival
• It is diagnosed if any of the following is present
> 20% blasts in the marrow or peripheral blood
Large clusters of blasts in the bone marrow on biopsy
Development of chloroma (solid focus of leukemia outside
the bone marrow- CNS, lymph nodes, skin etc)
49. CONTD…
• Recent evidence suggests patients with 20 to 29% blasts
have a significantly better prognosis than those having at
least 30% blasts
• Approximately 70% of these patients have a myeloid
phenotype, 25% have a lymphoid phenotype and 5% have
an undifferentiated phenotype
• Symptoms include weight loss, fever, night sweats, bone pain
• Anemia, infectious complications and bleeding are
common
50. CONTD…
• Subcutaneous nodules or hemorrhagic tender skin
lesions, lymphadenopathy and signs of CNS
leukemia may be present
• Patients in blastic phase usually die within 3 to 6
months
• Prognosis is slightly better in lymphoid blastic phase
52. • Elevated white blood cell count with increase in both
immature and mature granulocytes
• <5% circulating blasts and <10% blasts and promyelocytes
with majority of cells being myelocytes, metamyelocytes and
band forms
• Elevated platelet counts
• Mild degree of normocytic normochromic anemia
• Leukocyte alkaline phosphatase is low in CML cells
• Basophilia resulting in production of Histamine
53.
54. • Bone marrow cellularity is increased with increased myeloid-
to-erythroid ratio
• Marrow blast percentage may be normal or slightly elevated
• Marrow or blood basophilia, eosinophilia, and monocytosis
• Collagen fibrosis in the marrow is unusual but reticulin stain-
measured fibrosis are noted in half of the patients
55.
56. DISEASE ACCELERATION
• Increasing degree of anemia unaccounted for by bleeding
• Cytogenitic clonal evolution
• Blood or marrow blasts between 10 and 20%
• Blood or marrow basophils ≥ 20%
• Platelet count <100000/µl
57. • Blast crisis is defined as acute leukemia with blood or
marrow blasts ≥ 20%
• Hypopigmented neutrophils may appear (pelger-huet
anomaly)
• Blast cells can be classified as myeloid, lymphoid, erythroid,
or undifferentiated based on morphologic, cytochemical
and immunologic features
60. • Hallmark of CML is t(9;22) found in 90-95% of the patients
• Shortened chromosome 22 designated as the Philadelphia
chromosome that arises from the reciprocal t(9;22)
• Some have complex translocations- variant translocations
involving 3,4,5 chromosomes
• Investigations that can be done are karyotyping,
fluorescence in-situ hybridization (FISH), quantitative RT-PCR
64. LABORATORY FINDINGS
I. Blood picture:
a. Anemia- usually of moderate degree and is normocytic
normochromic in type. Occasional normoblasts may be
present.
b. White blood cells-
Marked leucocytosis ( approximately 2,00,000/µl or more at
the time of presentation )
The natural history of CML consists of 3 phases-chronic,
accelerated and blastic.
65. Chronic phase
- begins as a myeloproliferative disorder and consists of
excessive proliferation of myeloid cells ( mainly myelocytes
and metamyelocytes ) and mature segmented neutrophils.
-Myeloblasts usually do not exceed 10% of cells in the
peripheral blood and bone marrow.
-Increase in basophils upto 10% is a characteristic feature
of CML.
- A rising basophilia is indicative of impending blastic
transformation.
66. Accelerated phase
-There is progressively rising leucocytosis
-Associated with thrombocytosis or thrombocytopenia and
spleenomegaly
-Increasing degree of anemia
-Blast count in blood or marrow is b/w 10-20%
-Marrow basophils 20% or more
67.
68.
69.
70. Blastic phase or blast crisis
-It resembles the acute leukemia in having blood or
marrow blasts > or =20%.
-These blasts cells may be myeloid, lymphoid, erythroid or
undifferentiated and are established by morphology,
cytochemistry or immunophenotyping.
-Myeloid blast crisis is more common and resembles AML
-However, unlike AML, Auer rods are not seen
73. (2) Bone marrow examination
examination of marrow aspiration yields the following
results
Cellularity
-there is hypercellularity with total or partial replacement of
fat spaces by proliferating myeloid cells.
Myeloid cells
-they predominate in the bone marrow with ↑sed M:E ratio
-The differential counts of myeloid cells in the marrow show
similar findings as seen in the peripheral blood with
predominance of myelocytes
74. Erythropoiesis
-Is normoblastic but there is reduction in erythropoietic cells
Megakaryocytes
-are conspicuous but are usually smaller in size than normal
Cytogenetic studies on blood and bone marrow cells
show the characteristic chromosomal abnormality called
the philadelphia (Ph) chromosome seen in 90-95 % cases
of CML.
- is identified by microsatellite PCR/ by FISH
75. NORMAL ADULT BONE MARROW
COUNTS
• Fat /cell ratio: 50:50
• Myeloid / Erythroid ratio: 2 to 4 : 1( mean 3:1)
• Myeloid series : 30-45%
• Erythroid series : 10-15%
• Myeloblasts : 0.1- 3.5%
• Promyelocytes: 0.5-5%
• Megakaryocytes : 0.5%
• Lymphocytes : 5-20%
• Reticulocytes : 0.1-2%
76. (3) Cytochemistry
- The only significant finding on cytochemical stains is
reduced scores of neutrophil alkaline phosphatase (NAP)
which helps to distinguish CML from myeloid leukaemoid
reaction
-Leukaemoid reaction is defined as a reactive excessive
leucocytosis in the peripheral blood resembling that of
leukemia in a patient who does not have leukaemia. Here
NAP is increased.
77. • (4) Other investigations
➔ Elevated serum vitamin B12 and vitamin B12 binding
capacity- is due to ↑ in the transcobalamin present in
neutrophil granules
➔ Elevated serum uric acid levels
➔ Elevated serum LDH
➔ Blood sugar may be falsely reduced due to glucose
uptake and metabolism by leucocytes
78. TREATMENT
• Pathophysiology of CML:
● The t(9,22) involves fusion of BCR(breakpoint cluster
region) gene on chr 22q11 with ABL(abelson murine
leukaemia virus) gene located on chr 9q34.
● The fusion product so formed is termed “Ph chromosome
t(9,22)(q34;11),BCR/ABL”
● This brings about the following functional changes
● -ABL protein is activated to function as a tyrosine kinase
that in turn activates the other kinases which inhibits
apoptosis
79.
80. -Ability of ABL to act as DNA binding protein is altered
-Binding of ABL to actin of the cytoskeleton is increased
Exact mechanism of progression of CML to the blastic
phase is not known. But following mechanisms may be
responsible
-structural alterations in p53 and Rb gene
-alterations in RAS and MYC oncogenes
81. TREATMENT
• A) Treatment of chronic phase
• 1. Imatinib
MOA- competitively inhibits the ATP binding site of the
ABL kinase and thus promotes the apoptosis in BCR/ABL
+ve cells and thus eliminates them
It reduces the uncontrolled proliferation of white cells
Recommended as 1st line therapy in chronic phase
82. Produces complete cytogenetic response[
disappearance of Ph chromosome ] in 76% cases at 18
months of therapy
Patients are monitered by repeated bone marrow
examination until a complete cytogenetic response, and
then by 3 monthly microsatellite PCR/ by FISH
Side effects: fluid retention, nausea, muscle cramps,
diarrhoea, skin rash, myelosuppression
Resistance to imatinib results from over expression of BCR-
ABL gene or genetic alteration
83. If a patient fails to respond to imatinib then
2nd generation tyrosine kinase inhibitors{ dasatinib and
nilotinib } can be used
or
Allogenic bone marrow transplantation
or
Classical cytotoxic drugs such as hydroxyurea(hydroxy
carbamide), melphalan, busulphan
or
Interferon
84. 2. ALLOGENIC B.M
TRANSPLANTATION
● Indicated in patients <35 years who have a suitable
donor
● Best results are obtained when the transplantation is done
in early chronic stable phase
● It can result in permanent disappearance of philadelphia
chromosome +ve clone and hence can cure CML in
early stages
85. Procedure:
- healthy marrow or blood stem cells from a donor are
infused I.V. Into the recipient, who has been suitably
'conditioned'.
-The conditioning treatment (chemotherapy with or without
radiotherapy) destroys the malignant cells and
immunosuppresses the recipient, as well as ablating the
recipient's haematopoietic tissues
-The injected donor cells home to the marrow engraft and
produce enough erythrocytes, granulocytes and platelets
for the patient's needs after about 3-4 weeks
86. -During this period of aplasia patients are at risk of infection
and bleeding, and require intensive supportive care
-It may take several years to regain normal immunological
function
-ADVANTAGE: is that the donor's immunological system can
recognise the residual malignant recipient cells and
destroy them. This can be boosted post-transplantation by
the infusion of T cells taken from the donor, so called donor
lymphocyte infusion(DLI)
88. 3. CYTOTOXIC DRUGS
● Hydroxy urea was previously used widely for initial control
of disease, and is still useful in this this context or in
palliative situations.
● It does not diminish the frequency of the Ph chr or affect
the onset of blast cell transformation.
89. 4. INTERFERON Α
-It can induce remission and maintain control in chronic
stable phase.
- Not effective in accelerated or blast phase.
-Dose: 3-9 mega units/day i.m or s.c
-may be combined with cytosine arabinoside.
-It brings about:
↓ in bone marrow cellularity
↓ in no. of Ph +ve cells in 20% of cases
Elimination of Ph chromosome in 5% of cases
Reduction of platelet count when it is very high.
91. LEUKAPHERESIS AND
SPLENECTOMY
Leukapheresis :
-It may control the blood count in chronic phase CML
-But, expensive and cumbersome
-Useful in emergencies where leukostasis related complications like pulmonary
failure or CVA are likely.
-Also useful in pregnant women, in whom it is to avoid potentially teratogenic
drugs.
92. Splenectomy :
-It was used in the past because of the suggestion that evolution to the acute
phase might occur in spleen.
-However, this is not the case, and splenectomy is now reserved
a) For symptomatic relief of painful splenomegaly unresponsive to imatinib or
chemotherapy.
b) For significant anemia or thrombocytopenia associated with hypersplenism.
Splenic irradiation is used rarely to reduce the size of the spleen.
93. B) ACCELERATED PHASE
1. Imatinib
2. Hydroxycarbamide ( can be an effective single agent)
3. Low dose cytarabine
94. C) WHEN BLAST TRANSFORMATION
OCCURS
The type of blast cell should be determined
1. If disease is lymphoblastic, treatment is similar to acute
leukaemia and response to the treatment is better.
-Aim is to destroy the leukaemic clone of cells without
destroying the residual normal stem cell from which
repopulation of the haematopoietic tissues will occur.
-there are 3 phases
95. • Phase 1[Remission induction]→ The bulk of the tumour is
destroyed by combination chemotherapy. They require
intensive supportive care.
• Phase 2[Remission consolidation]→ This consists of a no. of
courses of chemotherapy which attacks the residual
disease.
• Phase 3[Remission maintenance]→ consisting of a
repeating cycles of drug administration. This may extend
for up to 3 years.
97. INTENSIVE SUPPORTIVE CARE
Anemia : is treated with red cell concentrate transfusions.
Bleeding :
-Thrombocytopenic bleeding requires platelet transfusions,
unless the bleeding is trivial.
-Prophylactic platelet transfusion should be given to
maintain the platelet count above 10x10 9/L.
-coagulation abnormalities occur and need accurate
diagnosis and treatment as appropriate
98. Control of infections with appropriate antibiotics
Metabolic problems:
-cellular breakdown during chemotherapy releases
intracellular ions and nucleic acid breakdown products
causing hyperkalaemia, hyperuricaemia,
hyperphosphataemia, and hypocalcaemia
-this may cause renal failure
-Allopurinol and I.V. Hydration are given to try to prevent
this.
99. - Prophylactic rasburicase(a recombinant urate oxidase
enzyme) can be used.
-occasionally, dialysis may be required.
Psychological problems:
-Delusions, hallucinations are not uncommon.
-patient should be kept informed, and their questions
answered and fears allayed as far as possible
-An optimistic attitude from the staff is vital.
101. Fatigue : The diseased WBC’S crowd out healthy RBC’S and anemia occurs.
This leads to tiredness, easy fatiguability, generalized weakness, lethargy and
headache.
• Treatment of CML also can cause a drop in RBC’S
Excess bleeding:
• -is due to ↓ in platelet count.
• -epistaxis, bleeding from gums, petechiae
Pain : CML can lead to bone pain or joint pain as the bone marrow expands
when excess WBC build up.
102. Enlarged spleen:
- some of the extra blood cells produced in CML are stored in
spleen.
- This causes splenomegaly and it takes up space in the
abdomen and makes the patient feel full even after small
meals.
- Or causes pain in the left upper part of the abdomen.
Infections :
• -Although people with CML have too many WBC, these cells
are often diseased an don’t function properly.
• -In addition, treatment can cause further ↓ in WBC
Thrombosis : is due to leukostasis which may lead to pulmonary
failure and CVA.