Anemia is a common condition of cancer patients. This is because cancers cause inflammation that decrease red blood cell production. In addition, many chemotherapies are myelosuppressive, meaning they slow down the production of new blood cells by the bone marrow.
The paper discussed iron homeostasis and anaemia in pulmonary tuberculosis. Iron (Fe) is one of the most abundant elements in the earth’s crust and an essential nutrient for almost all known organisms. It is able to receive and release electrons during conversion from Fe (II) to Fe (III) and plays a major role in DNA production and in energy generation. A system of highly regulated mechanisms is in place to control iron homeostasis. Regulation occurs at both the systemic and cellular levels and influences a number of iron-associated proteins. The iron regulatory protein, hepcidin, plays an important role in the mechanisms responsible for AI and the inflammation-mediated alteration of iron homeostasis. Specifically, hepcidin binds to and degrades the iron export protein ferroportin and down-regulates expression of the iron importer DMT1.Since hepcidin transcription is induced by the pro-inflammatory cytokine, interleukin-6 (IL-6), inflammation leads to a reduction in iron absorption and causes iron to be sequestered in macrophages and enterocytes.The inflammatory cytokines that are released upon innate recognition of a pathogen induce changes in plasma concentrations of other proteins. This phenomenon is referred to as the acute phase response (APR) and the affected proteins are considered acute phase proteins (APPs). The iron homeostasis proteins ferritin, transferrin and hepcidin are considered APPs, as are C-reactive protein (CRP) and alpha-1-antichymotrypsin (ACT), both of which are often utilized in studies as markers of inflammation. In the context of infection, iron’s limited availability within the human body and its physiological importance to both hosts and microbes make it a valuable commodity. Many microbes depend on host-acquired iron and, in response; hosts use their complex system of iron regulation to modify their iron metabolism and restrict iron availability. Evidence links iron with PTB pathogenesis both from the perspective of the pathogen and the host. Upon infection, host immune recognition of Mtb induces a pro-inflammatory reaction that restricts iron access. Most strikingly, a pattern of altered host iron status characterized by high ferritin, low transferrin, and low hemoglobin has been identified as a risk factor for progression to PTB. Decreasing iron availability (regardless of the mechanism) reduces Mtb growth, and addition of iron to Mtb almost always enhances growth.
The paper discussed iron homeostasis and anaemia in pulmonary tuberculosis. Iron (Fe) is one of the most abundant elements in the earth’s crust and an essential nutrient for almost all known organisms. It is able to receive and release electrons during conversion from Fe (II) to Fe (III) and plays a major role in DNA production and in energy generation. A system of highly regulated mechanisms is in place to control iron homeostasis. Regulation occurs at both the systemic and cellular levels and influences a number of iron-associated proteins. The iron regulatory protein, hepcidin, plays an important role in the mechanisms responsible for AI and the inflammation-mediated alteration of iron homeostasis. Specifically, hepcidin binds to and degrades the iron export protein ferroportin and down-regulates expression of the iron importer DMT1.Since hepcidin transcription is induced by the pro-inflammatory cytokine, interleukin-6 (IL-6), inflammation leads to a reduction in iron absorption and causes iron to be sequestered in macrophages and enterocytes.The inflammatory cytokines that are released upon innate recognition of a pathogen induce changes in plasma concentrations of other proteins. This phenomenon is referred to as the acute phase response (APR) and the affected proteins are considered acute phase proteins (APPs). The iron homeostasis proteins ferritin, transferrin and hepcidin are considered APPs, as are C-reactive protein (CRP) and alpha-1-antichymotrypsin (ACT), both of which are often utilized in studies as markers of inflammation. In the context of infection, iron’s limited availability within the human body and its physiological importance to both hosts and microbes make it a valuable commodity. Many microbes depend on host-acquired iron and, in response; hosts use their complex system of iron regulation to modify their iron metabolism and restrict iron availability. Evidence links iron with PTB pathogenesis both from the perspective of the pathogen and the host. Upon infection, host immune recognition of Mtb induces a pro-inflammatory reaction that restricts iron access. Most strikingly, a pattern of altered host iron status characterized by high ferritin, low transferrin, and low hemoglobin has been identified as a risk factor for progression to PTB. Decreasing iron availability (regardless of the mechanism) reduces Mtb growth, and addition of iron to Mtb almost always enhances growth.
Neurodegeneration: Factors Involved and Therapeutic Strategiesinventionjournals
Neurodegenerative disorders are disorders of the nervous system which are characterized by a loss of neuronal structure and function. These changes lead to a loss of several abilities that include cognition and movement as observed in Alzheimer’s and Parkinson’s. Several factors like oxidative stress and protein misfolding have been found to play a vital role in the etiology of common neurological disorders. Whether these factors contribute to the progression of the disorders or are a consequence still remains elusive. Inspite of attempts to elucidate the molecular and pathological mechanisms of these pathways, many aspects still remain unclear. However, newer areas of therapeutic interventions like stem cell therapy and anti-oxidant therapy are now being explored as potential treatments. The aim of this review is to study the various factors that are associated with neurodegeneration along with recent therapeutic strategies that are being employed in an attempt to treat neurodegenerative disorders.
Small Linear/ Cyclic Bioactive/Synthetic peptides for the treatment of Iron Deficiency Anaemia. Softwares used were licenced versions. Method is specific for laboratory scale only, for fine crystals, Glycine / Alanine are better starting materials.
Drug Repurposing: Recent Advancements, Challenges, and Future Therapeutics fo...JohnJulie1
Cancer is a prime public health burden that accounts for approximately 9.9 million deaths worldwide. Despite recent advances in treatment regimen and huge capital investment in the pharmaceutical sector, there has been little success in improving the chances of survival of cancer patients.
Abnormal Sodium and Chlorine Level Is Associated With Prognosis of Lung Cance...JohnJulie1
The imbalance of sodium and chloride ions occurs frequently in patients with lung cancer. However, the correlation between ion concentration change and patients prognosis have not been studied thoroughly. Our research will fill the gap, especially for high ion concentration.
Neurodegeneration: Factors Involved and Therapeutic Strategiesinventionjournals
Neurodegenerative disorders are disorders of the nervous system which are characterized by a loss of neuronal structure and function. These changes lead to a loss of several abilities that include cognition and movement as observed in Alzheimer’s and Parkinson’s. Several factors like oxidative stress and protein misfolding have been found to play a vital role in the etiology of common neurological disorders. Whether these factors contribute to the progression of the disorders or are a consequence still remains elusive. Inspite of attempts to elucidate the molecular and pathological mechanisms of these pathways, many aspects still remain unclear. However, newer areas of therapeutic interventions like stem cell therapy and anti-oxidant therapy are now being explored as potential treatments. The aim of this review is to study the various factors that are associated with neurodegeneration along with recent therapeutic strategies that are being employed in an attempt to treat neurodegenerative disorders.
Small Linear/ Cyclic Bioactive/Synthetic peptides for the treatment of Iron Deficiency Anaemia. Softwares used were licenced versions. Method is specific for laboratory scale only, for fine crystals, Glycine / Alanine are better starting materials.
Drug Repurposing: Recent Advancements, Challenges, and Future Therapeutics fo...JohnJulie1
Cancer is a prime public health burden that accounts for approximately 9.9 million deaths worldwide. Despite recent advances in treatment regimen and huge capital investment in the pharmaceutical sector, there has been little success in improving the chances of survival of cancer patients.
Abnormal Sodium and Chlorine Level Is Associated With Prognosis of Lung Cance...JohnJulie1
The imbalance of sodium and chloride ions occurs frequently in patients with lung cancer. However, the correlation between ion concentration change and patients prognosis have not been studied thoroughly. Our research will fill the gap, especially for high ion concentration.
Diagnostic Accuracy of Raised Platelet to Lymphocyte Ratio in Predicting Heli...JohnJulie1
Helicobacter Pylori (HP) infection is prevalent among patients with dyspepsia in developing countries with low socioeconomic status. The gold standard investigation is invasive method gastric biopsy through upper GI endoscopy, however non-invasive methods (stool for HP antigen) are not reliable up to the mark also need to wait for two weeks without symptomatic treatment. It is important to have a reliable, cost effective and easily accessible non-invasive marker to diagnose patients with H. pylori infection. Several non-invasive laboratory have been predicted in having the role in diagnosis of H.pylori infection. Therefore, the aim of our study was to determine the diagnostic accuracy of platelet to lymphocyte ratio in predicting H.Pylori infection in patients with dyspepsia.
IRF5 Promotes the Progression of Hepatocellular Carcinoma and is Regulated by...JohnJulie1
The IRF family of proteins involves in the tumor progression. However, but the functions of IRF5 in the tumorigenesis are largely unknown. Here, IRF5 was found to be up-regulated in hepatocellular carcinoma (HCC). Interfering with IRF5 inhibited the growth and tumorigenic ability of HCC cells.
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Fibrous
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Fibro glandular
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Adipose (Fatty)
What is Tomosynthesis?
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Is a 3 dimensional projection
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Reduces overlapping tissue seen with 2D only
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15 projections are taken with each combo exposure (7.5) (-7.5)
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With an average breast (18*24) 3D dose is 1.34, combo is 2.56 Milligrey. (3 Milligrey FDA) (2D is 1.2
Alterations of Gut Microbiota From Colorectal Adenoma to CarcinomaJohnJulie1
Gut microbiota has been implicated as a critical role in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). However, few basic research has revealed the association between gut microbiota and the development of CRA and CRC. We aim to compare the diversity and composition of intestinal flora in CRA and CRC patients, to reveal the changes of intestinal microorganism in the evolution of normal intestinal mucosa-CRA-CRC axis, and to explore potential biomarkers.
Prognosis of Invasive Micropapillary Carcinoma of the Breast Analyzed by Usin...JohnJulie1
Invasive micropapillary carcinoma (IMPC) is a rare type of breast cancer with high frequency of regional lymph node metastasis. However, the prognosis of IMPC has remained controversial for decades. We aimed to compare the differences of prognosis between IMPC and Invasive ductal carcinoma(IDC) of the breast by utilizing Surveillance, Epidemiology, and End Results (SEER) database.
Uretero-Enteric Anastomosis Stricture after Urinary Diversion; Detailed Analy...JohnJulie1
To report the lessons we have learned in the management of uretero-enteric anastomosis stricture (UEAS) in a tertiary urology center over a decade of experience.
Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastr...JohnJulie1
Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore correlation and prognostic value of them in gastric cancer (GC).
Combined Analysis of Micro RNA and Proteomic Profiles and Interactions in Pat...JohnJulie1
Liquid Chromatography Tandem Mass Spectrometry
The Liquid Mass System(LMS) includes an Easy nLC1000 (Thermo Fisher) coupled ultra-high resolution mass spectrometer Orbitrap Fusion Lumos (Thermo Fisher) with a Thermo Fisher electrospray source. Each injection is sent to a preset column (Acclaim PepMap C18, 100 μm x 2 cm, Thermo Scientific) for adsorption at a flow rate of 3 L/min. The sample is then sent to the analyzer column (Acclaim PepMap C18, 75 μm x 15 cm, Thermo Scientific) for separation.
Skeletal muscle channelopathy are rare heterogeneous episodic disorders with marked genotypic and phenotypic variability resulting in periodic paralysis, and falls in young people which often misdiagnosed or undiagnosed due to its rarity, often the symptoms are miscommunicated to the treating phycision due to its episodic nature and not uncommonly physical examination by the time patient attend the clinic or hospital will be unremarkable apart from periodic muscle paralysis where patient will presented to ED with flaccid weakness,
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...JohnJulie1
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Follow-Up Strategies in Focal Liver Lesions And Treatment MethodsJohnJulie1
Today, advances in cross-sectional imaging have led to the detection and early recognition of incidental/focal liver lesions (FCL). In approximately 17,000 cases of chest CT, incidental liver lesions were found in 6% [1]. In general, FCL consists of hepatocytes, biliary epithelium, mesenchymal tissue, connective tissue, or metastasized cells from distant sites. Most incidental lesions are benign, some may require careful management and treatment.
Contextual Factors Associated with Health-Related Quality of Life in Older Ad...JohnJulie1
The purpose of this study was to examine contextual factors associated with physical and mental health-related quality of life (HRQOL) in older adult cancer survivors.
Pancreatic Adenocarcinoma with Isolated Venous Involvement: Is Neoadjuvant Tr...JohnJulie1
Neoadjuvant Treatment (NAT) is indicated in locally advanced tumors and improves the results of subsequent surgery. In borderline tumors, the place of this preoperative treatment is more controversial, probably because borderline tumors are a heterogeneous group. We focused on the tumors with venous involvement without any arterial involvement and studied the results of neoadjuvant treatment in this particular group.
Predictive Value of Biomarkers Fibrinogen Like Protein-2 and A-Fetoprotein fo...JohnJulie1
Data concerning the utility of biomarkers for accurate early HCC detection in cirrhotic patients are lacking. 1.2. Methods: We evaluated 112 consecutive Caucasian cirrhotic patients with (n=28) or without (n=84) concomitant HCC at baseline for serum AFP and plasma fibrinogen like protein-2 (FGL-2) levels. Patients without confirmed HCC at baseline were further followed up every six months with ultrasound and serum AFP levels, according to HCC surveillance program. Imaging as well as histological confirmation of HCC was established in patients with new lesions.
The Black Fungus is One of the Bad Consequences of COVID 19JohnJulie1
Recently, since the emergence of the Covid 19 pandemic, the whole world has been waiting for what comes after Corona and when that pandemic will disappear and how to get rid of it. Therefore, all countries, whether Arab or foreign, sought to empty scientific research to produce a vaccine to treat this pandemic
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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.
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.
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
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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.
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.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
2. clinicsofsurgery.com 2
Volume 6 Issue 9 -2022 Research Article
4.1. Alterations in Iron Metabolism
a. Low serum iron with increased iron stores,
b. Less iron absorption.
c. Shortening of the serum half-life of iron.
d. Decrease in the release of iron from its deposits, which would
decrease both plasma levels and the iron available to be incorpo-
rated into erythropoiesis.
We will stop to analyze iron metabolism alterations in more depth,
since the ACS highlights the relationship between iron metabolism
and immunity.
Iron is a fundamental component for all living cells, since it is a co-
factor for the enzymes of the mitochondrial respiratory chain, the
citric acid cycle, DNA synthesis, as well as a fundamental compo-
nent for the transport of O2 through hemoglobin and myoglobin.
On the other hand, the intracellular accumulation of metabolically
active iron can be deleterious for the surrounding cells and tissues,
since it is capable of catalyzing the formation of highly toxic hy-
droxyl radicals. That is why a delicate regulation of iron homeo-
stasis is essential for the maintenance of cellular functions as well
as to avoid cell damage.
4.1.1. Iron Homeostasis
The maintenance of iron homeostasis is regulated at the post-tran-
scriptional level through the interaction of cytoplasmic proteins
called IRON REGULATORY PROTEINS (IRP) 1 AND 2, which
interact with ring structures of messenger RNA (mRNA) called
RESPONDING ELEMENTS. TO THE IRON (IRE).
4.1.2. IREs Are Located
− at the 5’ end of the heavy and light chain mRNA of ferritin (core
iron storage protein)
− at the 5’ end of the mRNA of erythroid amino levulinic acid
synthetase or e-ALA (central protein of iron consumption since it
is the key enzyme in heme synthesis)
− at the 3’ end of the transferrin receptor mRNA (the most impor-
tant protein for iron entry into the cell)
Cellular iron deficiency stimulates the binding of IRPs to IREs,
which determines the blockage of ferritin and e-ALA expression,
and an increase in the expression of the transferrin receptor. In
contrast, the increase in metabolically active intracellular iron re-
duces the affinity for the IRP-IRE binding, which determines a
stimulus for the synthesis of ferritin and e-ALA, while the trans-
ferrin receptor mRNA is degraded by RNAses by losing the pro-
tection conferred by its union with IRP. The affinity of the IRP-IRE
bond is not only regulated by iron needs, but also depends on the
production of free radicals by activated immune cells (nitric oxide
and hydrogen peroxide).
Likewise, a set of cytokines can affect iron homeostasis, either by
altering the production of these radicals that they modify IRP affin-
ity, or by inducing independent IRP/IRE regulations that affect the
transcription and translation of critical proteins such as ferritin or
the transferrin receptor. Numerous recent publications have high-
lighted the role of hepcidin in the regulation of iron homeostasis.
Hepcidin, a 25 amino acid peptide produced in the liver, which
was described by Tomas Ganz, is currently considered a mediator
of natural immunity and a regulator of iron 7 homeostasis. Its syn-
thesis is stimulated by inflammation and by the amount of deposit
iron. In transgenic murine models, it has been shown that hepcidin
plays an important role in the regulation of iron metabolism, since
it inhibits its absorption in the small intestined08, its transport
through the placenta, and its release from macrophages. Support-
ing these findings, hepcidin gene mutations have been found in
members of two families with severe juvenile hemochromatosis,
with affected patients being homozygous for the mutation. Also, it
has been shown that a poor hepcidin response to iron deposition
could contribute to iron overload in the more common moderate
forms of hemochromatosis.
Although it is accepted that hypoferremia is a common response to
infection and/or generalized inflammatory processes, and that its
development in these circumstances requires the synthesis of hep-
cidin, it is not clear which of the inflammatory mediators that regu-
late this synthesis. In this sense, the studies carried out by Nemeth
et al., both in human hepatic cell lines, as well as in murine models
and in volunteers, seem to indicate that 1L-6 would be necessary
and sufficient by itself to induce hepcidin synthesis, which would
increase more than 100 times in anemia of inflammation. This
would explain the sequestration of iron in the system.
Soon, the discovery of hepcidin and its role in iron metabolism is
likely to have implications for new therapies for hemochromatosis
and anemia of inflammation.
4.1.3. Iron and Immunity
Sufficient iron is known to be important for immune preservation
due to its role in promoting the growth of cells of the immune
system. However, iron deficiency, as well as its excess, have del-
eterious effects on the immune status by altering the proliferation
and activation of T, B and NK cells. Available cellular iron partic-
ipates in the modulation of differentiation towards Th1 and Th2
lymphocyte subtypes and their proliferation. A certain amount of
metabolically active iron is required by macrophages and neutro-
phils because iron catalyzes the formation of free hydroxyl radi-
cals directed against invading pathogens and tumor cells. Howev-
er, an excessive accumulation of iron in immune cells reduces the
effectiveness of the effector mechanisms of cellular immunity by
reducing the activity of the central cytokine of T cells: interferon
y. In short, immune function and iron homeostasis regulate each
other. In this way, ACS could be considered an “immune disease”,
to the extent that various pathways involved in erythropoiesis are
affected by immunological effector molecules and this determines
the pathophysiology of ACS.
3. clinicsofsurgery.com 3
Volume 6 Issue 9 -2022 Research Article
The Cytokines Involved and Their Effects On Iron Homeostasis
Would Be the Following:
− TNF α and IL 1: produce serum hypoferremia and induce ferritin
synthesis in macrophages and in the liver. This would increase the
deposit of iron in the monocyte-macrophage system, limiting its
availability for erythropoiesis.
− IL 1 and IL 6: inhibit the expression of transferrin receptor
mRNA.
− They stimulate the synthesis of the divalent metal transporter
(DMT-l), which is a transmembrane protein capable of allowing
the entry of ferrous iron from the duodenal lumen. IL 6 would
induce an increase in hepcidin synthesis, which would affect the
intestinal absorption of iron and its release from macrophages
− IFN γ: stimulates the transcription of ferritin, but at the same
time inhibits its translation.
− It inhibits the expression of transferrin receptor mRNA, which
blocks transferrin receptor-mediated iron incorporation, but in-
creases the expression of DMT-1, thus increasing the entry and
retention of ferrous iron.
− It also decreases the mRNA of a transmembrane protein called
ferroproteins. Since ferroprotein is responsible for the export of
iron from cells, its decrease induced by IFN γ; promotes iron re-
tention within monocytes.
− IL 4, IL 3, and IL 10: Anti-inflammatory cytokines modulate iron
homeostasis in activated macrophages.
− Activated murine macrophages, they inhibit the formation of ni-
tric oxide, which increases the translation of ferritin.
− They increase the mRNA of the transferrin receptor, which
would tend to reverse the effect of interferon y. In summary, cy-
tokines derived from Th2 cells would be able to increase the incor-
poration and storage of iron in activated macrophages mediated by
the transferrin receptor.
Together, the cytokines derived from Th1 and Th2 lymphocytes
would participate in the induction of hypoferremia and hyperfer-
ritinemia during the chronic inflammatory process. This would be
secondary to divergent effects on:
1. incorporation of iron bound to transferrin, via modulation of
transferrin receptor expression
2. the incorporation of ferrous iron, via regulation of the formation
of DMT (divalent metal transporter) and hepcidin
3. iron retention, via reduction of ferroproteins expression
4. the export and storage of iron, via induction of ferritin and hep-
cidin synthesis.
Acute-phase proteins such as alpha 1 antitrypsin and alpha 2 mac-
roglobulin contribute to impaired iron homeostasis by inhibiting
transferrin receptor-mediated incorporation into erythroid progen-
itors.
4.2. Decreased Half-Life of Red Blood Cells
This is a usually moderate decrease (approximately 62 to 90 days,
compared to the normal 120 days). It would be secondary to var-
ious mechanisms: increased phagocytic activity of macrophages
− RBC membrane damage due to hyperthermia tumor hemolysins
or hemolytic bacterial toxins
− some degree of mechanical injury to the RBC when traversing
damaged tissues
− splenomegaly
Although the evidence in humans is insufficient, there are indi-
cations that cytokines could decrease erythrocyte survival and
stimulate erythrophagocytosis by macrophages. In vitro, TNF α
has been shown to increase phagocytosis of RBCs. To the extent
that some patients develop splenomegaly, an increase in eryth-
rophagocytosis and a shortened RBC half-life cannot be ruled out.
This explains the increase in GR-derived iron observed in splenic
macrophages and Kupffer cells under inflammatory conditions.
Hemolysis is infrequent during ACS, but it can contribute to short-
ening the half-life of RBCs in certain infections such as subacute
endocarditis or TB.
4.3. Inhibition of The Proliferation and Differentiation of
Erythroid Progenitors
The inhibition of the proliferation and differentiation of erythroid
progenitors would be secondary to certain cytokines present in the
bone marrow microenvironment, produced by adherent cells of
the bone marrow (monocytes and macrophages), which inhibit the
growth of erythroid progenitors. TNF α, IFN γ and type 1 inter-
ferons block the formation of BFU-E and CFU-E colonies. Of all
of them, IFN γ appears to be the most potent inhibitor by directly
blocking the proliferation of CFU-E, which explains the inverse
relationship between IFN levels and on the one hand and hemoglo-
bin concentration and reticulocyte levels on the other. It has been
suggested that the inhibition could depend on a direct inhibitory
effect on the formation and/or function of erythropoiesis growth
factors such as EPO or could be a consequence of the induction of
apoptosis and growth arrest of stem cells. The pro-apoptotic role of
TNF on erythroid precursors has been demonstrated in the ACS of
rheumatoid arthritis. Graph 1 shows how various cytokines (IFN
y, TNF and EPO), regulate the survival and apoptosis of erythroid
progenitors (Graph 1), It has been mentioned that the inhibitory
effect of IFNy and TNFa would depend in part on their ability to
induce the formation of nitric oxide and other free radicals, Fi-
nally, the decrease in circulating EPO levels would also play an
important role in the inhibition of erythropoiesis, Likewise, the
suppression of erythropoiesis can be observed because of the di-
rect invasion of the BM by tumor cells or microorganisms, as well
as being secondary to toxic products derived from them, as occurs
in HIV infection or malaria.
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Graph 1: TNFα inhibits erythropoiesis by direct and indirect effects.
4.4. Relative Erythropoietin Deficiency
Although the serum levels of EPO are increased, this increase is
lower than expected for the degree of anemia of the patient. How-
ever, these EPO levels vary according to the underlying disease.
1L 1 AND TNF a decrease EPO secretion. Only 1L 6 would act by
stimulating the production of EPO. Likewise, the responsiveness
to EPO depends on the severity of the underlying disease and the
levels of circulating cytokines, as well as adequate availability of
iron for cell proliferation and synthesis of hemoglobin, a condition
that is not met in the ACS. The relative deficiency of EPO would
be one of the main pathogenic mechanisms of ACS and constitutes
the rational basis for the therapeutic use of EPO in these patients.
4.5. Other Mechanisms
Other nutritional deficiencies (folates and vitamin B12) could con-
tribute to anemia and poor response to EPO in a subgroup of pa-
tients with ACS hospitalized for a long time in intensive care units.
5. Pathophysiology Effects of ACS
For some years now, ACS has been recognized as a syndrome as-
sociated with certain inflammatory cytokines, such as interleukins
(1L) 1 and 6, turnoral necrosis factor (TNF) and interferons (1FN)
α, β and γ. Many of these cytokines are increased in inflammatory,
infectious, and neoplastic diseases, and their levels correlate with
the degree of disease activity. As previously mentioned, these cy-
tokines would participate in the various pathogenic mechanisms
of ACS.
The role of the cytokines mentioned in simple chronic anemia as-
sociated with tumor disease is summarized in Graph 2. The devel-
opment of the ACS could play a beneficial role in the host since it
would contribute to the control of the underlying disease. This is
since iron is an essential component for all living cells and prolif-
erating organisms. In this way, the alteration of the iron metabo-
lism of the ACS with its disappearance from tumor cells and mi-
croorganisms and its accumulation in the monocyte-macrophage
system, would limit the availability of this essential nutrient for
cells in rapid proliferation and growth. This agrees with the works
that mention that the greater availability of iron would be asso-
ciated with greater risk of tumors, faster progression of turnoral
cells or an unfavorable course of infections. The decrease in he-
moglobin in ACS would reduce the oxygen transport capacity of
the blood, limiting the proliferation of tumor cells and microor-
ganisms. Iron would directly modulate the effectors of the immune
system (monocytes and macrophages), and therefore the host’s
response to the invasion of pathogens and tumor cells.
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Graph 2: Mechanisms regulating hepcidin synthesis in cancer-related anemia
6. Diagnosis
ACS is the most common anemia in hospitalized patients. It is ob-
served in multiple clinical situations involving chronic inflamma-
tory conditions, such as cancer, chronic infections, or autoimmune
diseases. In chronic diseases, various mechanisms that produce
anemia are usually associated, such as: iron deficiencies or other
nutritional deficiencies, blood loss, hemolysis, renal failure, fibro-
sis, and marrow infiltration. The diagnosis is simple and is based
on the finding of the underlying disturbance of iron metabolism,
characterized by the removal of iron from the sites of erythropoie-
sis and from the circulation, towards the storage sites in the mono-
cyte-macrophage system, which determines the coexistence of
hypoferremia with hyperferritininemia. In short, the diagnosis of
ACS can be made against a normocytic or microcytic anemia, with
decreased serum iron and transferrin saturation, with normal or de-
creased levels of transferrin and increased iron deposits (measured
by the level of ferritin).
Some authors maintain that a ferritin greater than 50 mg/ml ex-
cludes the possibility of some component of iron deficiency even
in inflammatory states. However, it must be considered that a nor-
mal or high ferritin is often difficult to interpret since ferritin is an
acute phase reactant protein. Diagnosis of ACS frequently requires
a BM examination to rule out tumor infiltration, fibrosis, and in-
fection, exclude myelodysplastic syndromes, and fundamentally
carry out an evaluation of iron deposits and their incorporation into
erythropoiesis. In this sense, the Perls stain for iron shows in ACS
the presence of iron deposits in the monocyte-macrophage system
(positive hemosiderin), with negative sideroblasts.
Some algorithms have been developed to diagnose or rule out
ACS.
− The combination of ferritin will be less than 70 ng/ml and eryth-
rocyte ferritin less than 4 ag per erythrocyte, it would have a spec-
ificity of 0.97 and a positive predictive value of 0.822. LB.
− For patients with rheumatoid arthritis and serological evidence
of ACS, certain algorithms are used. A hemoglobin of less than 11
and a serum ferritin of less than 40 in men are considered probable
iron deficiency, while if the MCV is greater than 85 and the trans-
ferrin saturation is greater than 7%, they are considered carriers of
ACS. This formula allows a correct diagnosis in 89% of cases 2.
− More recently, the value of the soluble transferrin receptor in the
differential diagnosis between iron deficiency and ACS has been
established, so that the association of erythrocyte sedimentation
rate, serum ferritin and soluble transferrin receptor would allow
differentiation between the two entities. Some authors are some-
what more skeptical about the contribution of the soluble trans-
ferrin receptor to the differential diagnosis. The soluble transferrin
receptor is a truncated fragment of the membrane receptor that is
regulated by the level of intracellular iron available according to
the interaction between IRE / IRP. In patients without inflamma-
tory conditions, the level of soluble transferrin receptor is direct-
ly related to the need for iron for erythropoiesis. Because soluble
transferrin receptor levels are regulated by cytokines, its concen-
tration in the ACS is affected in opposite directions by proinflam-
matory cytokines and by erythroid iron deficiency. The use of the
formula: soluble transferrin receptor/log ferritin has been proposed
to differentiate patients with ACS and functional iron deficiency
from patients with true iron deficiency. This formula provides an
estimate of the iron requirement for erythropoiesis: a low ratio is
typical of functional iron deficiency, while a ratio greater than 3
would indicate true iron deficiency in the ACS patient.
There are other parameters that are not necessary for the diagnosis
of ACS but can help estimate the iron requirement for erythropoie-
sis and could have a role in predicting the response of ACS to EPO
treatment:
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− Zinc-bound protoporphyrin IX: it is formed in erythroid progeni-
tors when the iron availability of these cells is reduced. It increases
in the ACS and reflects a demand for iron for erythropoiesis.
− Percentage of hypochromic erythrocytes and reticulocytes.
− Serum EPO level: would have no value for the diagnosis of ACS
but would have implications for treatment.
7. Treatment
ACS is generally a moderate, well-tolerated anemia that does not
require correction, especially if other contributing factors can be
reversed. However, in some cases, ACS can be severe, affecting
the functional status and quality of life of patients (example: ane-
mia in cancer patients). In rheumatoid arthritis, the intensity of
the anemia correlates with the activity and duration of the disease.
The optimal treatment of ACS is the correction of the underlying
disease, which is difficult and even impossible in some cases.
Therefore, if the anemia is symptomatic or severe, treatment is
required for it.
7.1. Iron Supplement
Generally, the absorption of iron by vein is reduced in ACS, which
is why it would be more effective when administered parenterally.
However, in patients with ACS secondary to chronic infections or
tumors, the administration of iron should only be strictly avoided,
in order not to favor the growth and proliferation of microbes and
tumor cells and not to alter immune effector mechanisms. In con-
trast, an iron supplement may be beneficial in patients with ACS
secondary to autoimmune diseases or rheumatic diseases. It has
been speculated that iron-induced reduction of cellular immunity
(by reducing TNF alpha formation) might reduce disease activity
and thereby improve ACS by counteracting the activity of TNF α
or interferon γ.
7.2. Transfusion
Transfusion therapy is the most common and rapid form of treat-
ment for symptomatic anemia, but it is expensive and potentially
dangerous (transmission of infectious diseases, alloimmunization,
graft-versus-host disease), and it is a limited resource.
Blood Transfusion Produces Divergent Effects On Immune Func-
tion:
− Transfusion of white blood cells, which can circulate in the re-
cipient for more than a year, inducing immunological effects com-
parable to graft-versus-host disease at a lower level. New transfu-
sion preparation techniques allow depletion of white blood cells
to minimize these effects − Blood transfusion induces a state of
anergy in the host, secondary to a decrease in Th1 lymphocytes
and an increase in Th2.
− It constitutes a very efficient route of iron supply (approximately
200 mg of iron for each unit of 350 to 450 ml), which would have
the potentially negative effects described above.
7.3. Recombinant Erythropoietin
The use of EPO was since although its levels are usually high in
these patients, the degree of increase is not appropriate for the de-
gree of anemia 16. It was also possible to demonstrate in vitro stud-
ies that EPO could reverse the inhibition of erythropoiesis caused
by certain cytokines. EPO is more cost-effective than transfusion
therapy. It constitutes a therapeutic option in ACS associated with
tumors, chronic infections, or autoimmune diseases. The adminis-
tration of EPO reduces the transfusion requirement and improves
the quality of life of these patients. Doses used range from 150 U/
kg three times per week to 40,000 U per week. Response rates are
sometimes low, which is why a pre-treatment evaluation is recom-
mended to detect the most beneficial patients with this therapy. In
patients with ACS associated with rheumatoid arthritis, an EPO
dose of 50 to 150 U/kg three times a week allows a six-point in-
crease in hematocrit after at least four weeks of treatment. RA pa-
tients who respond to EPO are those with low levels of C-reactive
protein.
HIV-positive patients with anemia treated with EPO (especially if
endogenous EPO levels are less than 500 VI/l), show a marked de-
crease in transfusion requirements. Predictors of response to EPO
in tumor-associated anemia will be discussed later.
The Mechanisms by Which The EPO Would Act in The ACS
Would Be the Following:
− Increased expression of the transferrin receptor in erythroid pro-
genitors by transcriptional and post-transcriptional mechanisms.
− Stimulation of protoporphyrin synthesis which would contribute
to iron influx and hemoglobin synthesis.
− Interaction with the activity of cytokines, reducing their antipro-
liferative effect on erythroid progenitors.
Given the decreased response of erythroid progenitors to EPO, it
is likely that more EPO is required to induce a biological response.
Being the availability of iron one of the main determinants of the
response to EPO, the combination of EPO + iron would have a
better response. Despite this, considering the potential risks of the
use of iron in ACS associated with tumors or infections, an ade-
quate evaluation of the amount of iron that should be administered
is required, so that it contributes to increasing the efficacy of EPO
without promoting the growth of tumor cells or impairing immune
mechanisms.
8. Anemia of the Cancer Patient
The anemia of the cancer patient deserves some considerations
8.1. Incidence
It constitutes a significant problem, since 20 to 60% of cancer
patients develop anemia, which will be of different intensity ac-
cording to the type of tumor, the nature, and the intensity of the
treatment. Approximately 30% of cancer patients receive at least
one transfusion during their treatment.
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8.2. Prognostic Impact
Anemia in cancer patients worsens their physical and emotional
state (producing fatigue, dyspnea, favoring cardiovascular disease
and worsening quality of life). It would also have effects on the
evolution of patients, by reducing the therapeutic response of those
treatments that require optimal oxygen availability, increasing the
relapse rate and decreasing survival.
There is much evidence on the prognostic importance of anemia in
various types of tumors:
− In a study of 451 patients with stages III and IV of squamous
cell cancer of the head and neck, it was possible to demonstrate
that pre-treatment hemoglobin levels constituted, in the multivari-
ate analysis, a significant prognostic factor for overall survival and
rate of death. 10 co-regional relapse6.
− In a study published in 1998 on 206 patients with ovarian cancer
treated with surgery, anemia prior to surgery was an independent
factor in the multivariate analysis to predict overall survival.
− Anemia is recognized as a prognostic factor in numerous onco-
hematological diseases:
− Chronic myeloid leukemia
− Chronic lymphatic leukemia (CLL)
− Multiple myeloma (MM)
− Hodgkin lymphomas
− Non-Hodgkin lymphomas (NHL)
8.3. Etiopathogenesis
There are numerous factors involved in anemia in cancer patients,
such as:
− Hemodilution
− Bleeding
− Hypersplenism, hemophagocytosis
− Kidney failure
− Hemolysis (autoimmune, microangiopathic)
− Nutritional deficiencies (global les, iron, folates, B12)
− BM damage (metastasis, pure red cell aplasia, myelodysplasia)
− Related to the specific treatment
− Chemotherapy (QT): drugs, dose, administration scheme
− Radiotherapy: dose, field, fractionation
− Combined treatments
− Surgery (blood loss)
− Anemia of chronic disorders
Chemotherapy drugs induce anemia through various mechanisms
− Myelosuppression (cyclophosphamide, doxorubicin, etoposide)
− Renal toxicity (cisplatin)
− Immunohemolytic anemia (fludarabine)
− Microangiopathy (hemolytic uremic syndrome)
(Mitomycin C, gemcitabine, oxaliplatin)
Table 2
Chemotherapy-induced anemia has been particularly reported in
cisplatin treatments (ovarian cancer, small cell lung tumor), it in-
creases with the number of treatment cycles and the hemoglobin
nadir correlates inversely with the cumulative dose platinum.
In 1998, a French group published a proposal for a model to pre-
dict anemia and the need for transfusion in patients undergoing
chemotherapy.
On a total of 1051 patients (subsequently the study was validat-
ed with the inclusion of another 1000 patients), it was possible
to determine the factors that in the multivariate analysis showed
predictive value for transfusion:
− initial hemoglobin < 12 gr / dl (most significant factor)
− performance status > 1
− Initial lymphocytes < 700 per microliter.
The type of chemotherapy, age, sex and underlying disease did not
show significant value.
Baseline hemoglobin <12 was given a value of 3 points, and per-
formance status >1 and lymphocyte count <700 per microliter
were given a value of 1 point.
Based on this, a score was created with various probabilities of
transfusion, as shown in Table 3 and Graph 3.
Before the use of EPO in the treatment of anemia associated with
cancer, transfusion of sedimented RBCs was the only therapeutic
resource.
It offers a temporary and short-term increase in Hb levels, being
reserved for patients with severe anemia (Hb less than 8 g%), not
forgetting the potential risks of transfusion.
Recombinant human erythropoietin has been available since 1989
for the treatment of anemia of renal failure.
There is abundant evidence of the symptomatic benefit and quality
of life of EPO in patients with cancers (hematological and solid
tumors).
As cancer treatments have improved life expectancy, more empha-
sis has been placed on quality of life. Fatigue is a very common
symptom associated with cancer treatment. Although it is difficult
to directly correlate fatigue and other quality of life factors with
anemia levels, increasing hemoglobin levels could improve qual-
ity of life.
In cancer patients, the response to EPO is observed globally in 140
to 80% of cases, after 4 to 8 weeks of treatment, with differences
according to the oncological diagnosis.
The American Society of Clinical Oncology and the American So-
ciety of Hematology have published a series of recommendations
based on clinical evidence on the use of EPO in anemia associated
with tumors, which are listed below:
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1. The use of EPO is recommended in patients with anemia associ-
ated with CT with hemoglobin (Hb) equal to or less than 10 gr/dl.
Transfusions are a therapeutic option depending on the severity of
anemia and clinical conditions.
2. For patients with less severe anemia (Hb < 12 but > 10 g/dl), the
decision to use EPO immediately or wait for Hb to approach 10 g/
dl will depend on clinical conditions. Transfusion in these cases is
a therapeutic option.
3. The recommended starting dose is 150 V/kg subcutaneously
three times a week for a minimum of 4 weeks. In patients who
have not responded to this initial dose, it is recommended that the
dose be increased to 300 V/kg three times a week for a further 4 to
8 weeks. Although the evidence is less, an alternative regimen of a
weekly dose of 40,000 V can be considered, which can be similar-
ly increased in the absence of response.
4. Patients who after 6 to 8 weeks have not increased Hb levels
(at least with an increase of 1 to 2 g), having increased the dose of
EPO, will be considered non-responders. Other factors of failure
must be ruled out (progression of underlying disease, iron defi-
ciency), and consider stopping EPO treatment.
5. The objective will be to bring the Hb to a level close to 12 gr /
dl. At that time, the EPO dose will be decreased, trying to maintain
said Hb level. The initial dose of EPO will be restored if the Hb
decreases to values close to 10 g/dl. There are not enough data to
justify normalizing Hb to values greater than 12 g/dl.
6.Irony, transferrin, transferrin saturation and ferritin values should
be monitored at baseline and periodically. Replace iron as needed
to minimize EPO requirements. There is still not enough evidence
to determine the optimal time and periodicity for such monitoring.
7. There is sufficient evidence for the use of EPO in anemia of low-
risk myelodysplastic syndromes. There is insufficient evidence for
the use of EPO in anemia of MM, CLL and NHL in the absence
of CHT. For patients diagnosed with MM, CLL, NHL, and anemia
associated with CT, the above recommendations will be used.
8. In patients with CLL, MM and NHL, treatment with corticos-
teroids and/or CT will be started first and the hematological re-
sponse will be observed before considering the use of EPO. If,
after starting the oncospecific treatment, no response of anemia
is obtained, the use of EPO should be considered following the
previous considerations. Blood transfusions are also a therapeutic
alternative (Table 4).
Effect of recombinant human erythropoietin (EPO) on transfusion
rates and quality of life (QoL) in controlled, randomized studies
A series of factors have been listed that would predict a good re-
sponse to EPO, such as:
− Low pre-treatment serum EPO concentration (<200 U/litre if Hb
is less than 10 gr/dl). A study of 80 patients with various neoplastic
diseases identified two important predictors of response to EPO:
serum EPO level and serum ferritin concentration. EPO response
was less when EPO was >100 mU/mL and/or serum ferritin was
>400.
− Hemoglobin value
− Increase in Hb greater than or equal to 0.5 gr / dl after 2 weeks
of EPO at less than 100 U/kg.
− Increase in the absolute number of reticulocytes to more than
40,000/ml and increase in Hb equal to> 0.5 gr/dl after two weeks
of treatment with EPO.
− Increase in Hb equal to> 0.3 gr / dl AND decrease in basal level
of EPO at two weeks. Increase in soluble transferrin receptor equal
to or > 25% at two weeks.
Negative response to EPO is predicted by: duration of the neo-
plasm, treatment of the same, involvement of BM and diagnosis of
hematological tumors compared to solid tumors.
It has been postulated that if after two weeks of treatment with
EPO, the serum EPO level is >100 mU/mI and Hb has not in-
creased by at least 0.5 g/dI, or that if after two weeks of treatment,
serum ferritin is >400 ng/mL, therapeutic response to EPO is un-
likely.
Lastiri et al. recently published their proposed score to predict re-
sponse to EPO. They treated 36 patients with solid tumors and
anemia (hemoglobin < 9.9 g/dI and hematocrit < 30%) with EPO
doses of 150 U/kg, 3 times a week, for 12 weeks. They obtained
73.5% of responses with 64% of complete remissions (Hct > 36%).
In this experience, predictors of favorable response were an in-
crease in hemoglobin >0.5 gr/dI at the second week of treatment,
CT with cisplatin and pre-treatment serum ferritin >1100 ng/d1.
Bone marrow infiltration by tumor was a predictive variable of
failure, and pretreatment EPO concentration, early reticulocyte
peak at the second week, and pretreatment cytokine dosages (IL 1
and 6, TNF) had no value in predicting response. . Based on this,
they developed a predictive score for response to EPO (Table 5).
The percentages of complete responses with EPO treatment ac-
cording to the score and therapeutic recommendation are shown
in Table 6.
Table 2: Model to calculate the risk of developing anemia dependent
transfusion in patients undergoing chemotherapy
risk of developing
anemia
Result
Score Probability of
transfusion
− Hb < 12 g % 3 0 1%
− Functional status > 1 1 1 4%
− Lymphocytes
< 700 /
microliter 1
2-3 11%
4 30%
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Graph 3: Treatment of anemia in cancer patients
Table 3: Correlation between sum and probability of transfusion requirement. To indicate patients with transfusion requirement the cut-off point was
set at 3 points
Sum (coefficient) Probability of transfusion requirement
0 0.2%
2.5 2.9%
3 5%
6 50%
9.5 97%
Table 4: Effect of recombinant human erythropoietin (EPO) on transfusion rates and quality of life (QoL) in controlled, randomized studies
Reference n Evaluated
Response control versus
EPO (%)
Transfused control versus EPO
(%)
QoL rise by EPO
Abels 1992 [27] 413 118a
11 vs 32 38 vs 33 Sig.
153b
14 vs 58 49 vs 41b
Sig.
132c
7 vs 48 69 vs 53d
Sig.
Cascinu, 1994 [31] 100 99 2 vs 82 58 vs 20 ND
Osterborg 1996 [31] 155 121 24 vs 60 82 vs 61e
ND
Kurz 1997 [32] 35 35 0 vs 57 67 vs 22 NS
Del Mastro 1997 [33] 62 62 ND 6 vs 0 ND
Italian Co-operative Study Group 1998 [41] 87 75 10.8 vs 36.8 ND ND
ten Bokkel 1998 [34] 122 120 ND 39 vs 4 ND
Thatcher 1999 [35] 130 130 ND 59 vs 33f
Sig.
Carabantes 1999 [36] 35 35 ND 87 vs 20 Sig.
Oberhoff 1998 [37] 227 189 9 vs 38 41 vs 26 ND
Thompson 2000 [42] 66 66 5 vs 9 90 vs 76 ND
Dammacco 2001 [38] 145 125 9 vs 58 47 vs 27 NS
Littlewood 2001 [39] 375 359 19 vs 71 36 vs 23 Sig.
a
Without chemotherapy.
b
With chemotherapy, see also Case et al. [28].
c
With platinum containing chemotherapy, see also Henry et al. [30].
d
Over the total study course.
e
Results from two study arms with different EPO dosages were summarised, first 4 weeks of treatment excluded.
f
Result from two study arms with different EPO dosages were summarised.
Sig., significant; ND, not determined; NS not significant.
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Table 5: Predictive score of response to EPO
1 − Increase in hemoglobin> 0.5 gr / dl at the second week 6
2 − Absence of marrow infiltration 5
3 − Chemotherapy with cisplatin 4
4 − Basal ferritin > 1100 ng/dl 3
5 − Reticulocyte peak at the second week 1
6 − EPO dosage <100 microgs/dl 1
Table 6: Complete response according to predictor score and therapeutic
recommendation
Score % of CR Recommendation
0 – 4 0 No EPO
5 – 14 54.5
15 – 20 100 Yes EPO
9. Conclusions and Future Perspectives
− ACS is one of the main causes of anemia in clinical practice,
observable in numerous circumstances.
− Frequently coexists with other causes of anemia, which should
be investigated, to carry out the optimal treatment of these patients.
− There is multiple clinical evidence on the therapeutic role of re-
combinant erythropoietin in patients with ACS, especially in rheu-
matoid arthritis, HIV infection and cancer.
− In this last group of patients, the subgroup of patients potentially
most benefiting from treatment with EPO should be adequately
defined, to optimize the economic cost of said treatment.
− Knowledge of the intimate physio pathogenic mechanisms will
open new therapeutic perspectives in the future, such as the inno-
vative clinical use of monoclonal antibodies against TNF, which
have begun to be used in patients with rheumatoid arthritis with
promising results.
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