Hematological Malignancies - Science topic

Park Sowon

your AI tool summarized a very limited amount of information, which is correct but does by no means reflect the complexity of genetic alterations involved in the development and progression of leukemia. All of us may use such AI tools, so I personally think that AI generated answers are not very helpful.

Moreover, as far as I understood the question, Penumala Manoj Varma was asking what are the causes that lead to the genetic alterations.

Hello Younas Masih

It is not the right choice. You need to work on blood cancer and bone cancer separately.

The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and is the soft, spongy tissue that has many blood vessels. There are two types of bone marrow: red and yellow. Red bone marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Bone marrow makes nearly all the components of your blood responsible for creating billions of red blood cells daily, along with white blood cells and platelets. Bone marrow also stores fat that turns into energy as needed.

A blood cancer is a disease in which abnormal blood cells reproduce rapidly and begin interfering with the body’s usual operations. Cancers of this type originate in the bone marrow, where red blood cells, white blood cells, and platelets are produced. There are three primary blood cancers: leukemia, lymphoma, and myeloma.

You may refer to the article below for the genes related to hematologic malignancies.

On the other hand, bone cancer is an uncommon type of cancer that begins when cells in the bone start to grow out of control. The cause of most bone cancers is unknown. A small number of bone cancers have been linked to hereditary factors, while others are related to previous radiation exposure. Primary bone cancer is cancer that forms in cells of the bone. Some types of primary bone cancer are osteosarcoma, Ewing sarcoma, malignant fibrous histiocytoma, and chondrosarcoma. Secondary bone cancer is cancer that spreads to the bone from another part of the body (such as the prostate, breast, or lung).

You may refer to the article below which has summarized the whole genome and/or whole exome genomic studies and placing these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma.

In the following paper, the authors go on to enumerate the genetic and epigenetic defects identified in osteosarcoma.

Best.

There was a time bone marrow transplant, especially allogeneic, used to be very expensive compared the conventional chemotherapy. But those days are, regrettably, gone. Most of the recent anti-leukaemia/lymphoma/myeloma treatments ('targeted therapies') are so expensive that the BMT looks relatively cheap (especially autologous). If you really want to explore economical treatment options, you may have to either (1) use conventional drugs (most of them cost a fraction of the new ones) or (2) use drugs that are out of patent. Generic formulations are considerably cheaper.

Remember, not all the new 'wonder drugs' are not so wonderful as the drug companies claim. Some of them offer few months of response at a cost of tens of thousands of dollars.

Good luck

Siva

More clinical data than those described here should be considered, but there are records of a low 5-year survival in patients with multiple therapy who do not respond to treatment. That is, it is an advanced disease that leaves the patient without conditions for surgery.

A treatment based on high-dose methotrexate alternated with ifosfamide is an option, but the odds are not favorable and you may fall into therapeutic obstinacy, therefore in some cases, a treatment that limits pain has been chosen, a treatment focused on palliative care and the proximity of care with the family.

Rodrigo Gómez Ayala

E. Borrego-Paredesa,∗, E. Prada-Chamorro et.al. (2017) Sarcoma de Ewing, análisis de supervivencia a los 6 años con terapia multidisciplinar. Revista española de cirugía ortopédica y traumatología, ISSN 1888-4415, Vol. 63, Nº. 2, 2019, págs. 86-94

Hi Muttuswamy Sivakumaran ,

I want to prove tumor-promoting activity of neutrophils as previously described in N2-polarized TANs. I found this area of research to be very heterogenous and yet without any common standards for functional assays- unlike in MDSC. So I was wondering whether somebody maybe had any suggestions or references.

Cheers

For the care of Prof.Mona

@Mona Ellaithi

Regards

I have several publications on acute and chronic leukemias as well as on hematological diseases including hematological malignancies. You can read them at my profile

leukemia

I think the best reference in hematology malignancies professor Barbara.

Well.. it will depend on the type and quality of your review. It has to be really good to publish in Blood, British Journal of Haematology, Haematologia, Blood Reviews and other high calibre journals. If I were you, I would first do a literature search (eg PubMed) and find out the journals that haven't published a review article on this subject recently.

Good luck

Siva

In normal person detection of plasma cell as an reactive cell especially in infective or inflammatory process is possible

The term "Artificial blood" is a misnomers and can't be prepared in laboratory. There is a limitation of stem cells culture in vitro and component in whole blood is much more complex.

As mentioned in the previous answers journals have impact factors and papers do not. This paper was published in a journal with an impact factor of 3.083.

Hi Monika,

Companies such as IDT can provide modified gene fragments. You can design a fragment with the rare mutation as the positive control, you can also have a WT fragment as a reference and mix these two at different concentrations, so you can test the LOD (limit of detection).

Did you succeed to culture innate lymphoid cells in vitro ?

How did you do it and what culture medium did you use?

Thanks for you answer

Dear Qureshi , as you know skin epidermis has no blood supply and takes oxygen and nutrition from superficial papillary dermal plexus, so in dry gangrene epidermis get dry as no perfusion from dermis, here melanosomes that injected from melanocytes in keratinocytes get dry too which stain epidermis black.

 Based on our experience in the molecular monitoring of CML patients treated with 1st or 2nd generation TKI, the adherence to the treatment correlates with changes of bcr-abl transcript leves and in some instances we can predict whether a patient has stopped treatment by the increase pattern of transcripts level in sequential samples. 

Very important practical questions. As to the question of frequency of testing, the answer would be 'depending on the blood counts'. If a patient's blood counts have recovered fully, there is no need to repeat them too frequently. The standard practice is to start repeating weekly and then fortnightly and then gradually reducing the frequency (two monthly, three monthly... and so on). The important thing is the stability of the counts- ie if there is a change in any of the cellular parameters, the frequency of testing should be increased.

The answer to your second question is 'extremely variable and unpredictable and will depend on several factors that are unique to each disease category( and any associated prognostic factor(s). Just to give you one example, a young patient with common ALL with no adverse prognostic markers may enjoy a long period of remission. On the other hand, an elderly patient with Philadelphia chromosome positive ALL, the situation will be different. So the bottom line is  'one cannot have a uniform policy for all disease categories in all the patients. Should be patient specific. Hope that makes sense. Best wishes.

HemaApp measures hemoglobin levels and screens for anemia non-invasively by illuminating the patient’s finger with a smartphone’s camera flash.

                                                                          OR

ToucHb is a completely non-invasive (no blood!), portable, instant and cost-effective (affordable!) hemoglobin screening device to diagnose and monitor anemia in rural areas in developing countries.

The current debate is so interesting that I would also like to obtain some additional and CHALLENGING references from you.

I am responding to you in two separate sections.

The current one describes my very personal view about "MTT versus cytotoxicity".

In the second one, I will send you some additional references about "problems" that can be encountered with colorimetric assays in general, and with the MTT one in particular.

Best regards

Robert

"Cytotoxicity" cannot be determined by means of the colorimetric MTT assay. You must use other tests than the MTT one if you want to measure cytotoxicity. The MTT test enables you to evaluate "cell viability".

Cytotoxic means direct "cell killing effects" induced by the drug of interest.

Cytostatic means that the compound of interested lowers the growth rate of a given cell population without direct cell killing effects. Cell death will occur as a consequence of a too long cytostatic effect.

A colorimetric assay can only bring "relative global growth inhibition information" because it is a relative test in which you compare the ODs of a treated cell population to the ODs of a control condition (untreated cells) arbitrarily scaled at 100%.

Thus, the IC50 / GI50-related values obtained by means of a colorimetric assay do actually not translate “cytotoxic” effects.

If one wants to determine actual cytotoxic effects for a compound of interest, the MTT colorimetric assay can be completed with the lactate dehydrogenase (LDH) test.

LDH is a soluble cytosolic enzyme that is released into surrounding culture medium upon cell damage or lysis during apoptosis or necrosis for example. The quantitative determination of LDH in the cell culture medium can be used as a marker for cytotoxicity.

Coming back to a colorimetric assay such as the MTT one, when one obtains a concentration (for a given compound) decreasing by 50% the global growth (after x days (usually 2 or 3)), i.e. the GI50 concentration (or the IC50 as commonly used in the literature) you do not know whether your compound of interest killed 50% of the cells (cytotoxic effects), whether it inhibited 50% of the cell proliferation (cytostatic effects), whether it detached 50% of the cells (anti-adhesive, i.e. "in vitro antimetastatic" effects), etc..., etc...

Once you have determined the GI50 / IC50 concentration for a given compound on a given cell line, you must use complementary biochemical and/or morphological techniques to determine whether your compound is cytotoxic, cytostatic, anti-adhesive, etc..., etc...

The two attached articles by Galluzzi and colleagues (2012, 2015; Appendix-1 and Appendix-2) are of great help in this domain.

The attached article by Kornienko et al. (2013; Appendix-3) reviewed various chemicals that are able to induce non-apoptotic cell deaths in cancer cells.

Coming back to the IC50 / GI50 values obtained by means of a colorimetric assay (as for example the MTT one):

in the Mathieu et al. (2009 (Appendix-4) and 2015 (Appendix-5)) articles, the MTT test-related GI50 concentrations relate to actual cytotoxic effects.

In the Lefranc – Nunzo et al. (2013; Appendix-6) article, the MTT test-related GI50 concentrations relate to cytotoxic effects that in turn do not relate to apoptosis …

This means that each cytotoxic effect does not “universally” translate into pro-apoptotic ones.

In the Van Goietsenoven et al. (2010; Appendix-7) article, the MTT test-related GI50 concentrations relate to cytostatic effects, neither to cytotoxic nor to pro-apoptotic ones.

Be aware that you cannot always translate the MTT test-related growth inhibition of a given compound into a precise GI50 value. Some compounds reach a “plateau” of inhibition (see Lefranc – Nunzo et al., 2013; Appendix-6).

Lastly, you can also have "false" data generated with colorimetric assays (see the attached article by Chan et al. (2013; Appendix-8) and the first NCI-60-cell line-related article (Shoemaker, 2006 (Appendix-9)).

The US NCI set up a fantastic tool to characterize the effects of a given drug in terms of growth inhibition in a panel of 60 cancer cell lines belonging to >10 histopathological types (Shoemaker, 2006; Appendix-9).

The US NCI clearly defined by means of the combination of the GI50 (growth inhibition), the LD50 (lethal dose by 50%) and the TGI (total growth inhibition) how to make the difference between a cytotoxic and a cytostatic compound:

The US NCI-related GI50 value corresponds to a global growth decrease by 50% induced by a compound on a given cell line “x” days after having cultured the cells with the drug and in comparison to an untreated control condition (= 100%) grown during the same time;

The US NCI-related LD50 value corresponds to the a global growth decrease by 50% induced by a compound on a given cell line “x” days after having cultured the cells with the drug and in comparison to the initial number of cells in the untreated control condition;

The TGI is the US NCI-related parameter to determine the concentration needed to kill 100% of the treated cells.

It is by comparing the GI50 to the LD50 value that one can determine whether a compound is cytotoxic or cytostatic, and not at all with the sole GI50 value.

We are using morphological approaches in the research unit to which I belong for determining whether a compound is cytotoxic or cytostatic (see Lefranc-Nunzo et al., 2013 (Appendix-6); Mathieu et al. 2009 (Appendix-4), 2015 (Appendix-5); Van Goeitsenoven et al., 2010 (Appendix-7)).

The US NCI is not so far for having tested about 800,000 anticancer drugs, whose data are publicly available on the NCI website https://dtp.cancer.gov/databases_tools/data_search.htm

I actually benefited several times from the amazing help of the NCI in identifying the mechanism of action of an innovative anticancer compound (see for example Frederick et al. JMC 2011 (Appendix-10)).

Dear Peter Kubisz, we do evaluate the patients for thrombophilia which also includes ruling out other causes of thromboses( factor 5 maiden, thrombomodulin gene mutation, Anticardiolipin ab, factor deficiencies etc)We do follow the protocol usually. 

However , in arterial thromboses ( after opening of the artery either surgically or thrombolysis) we use continuous infusion of heparin initially, followed by oral anticoagulants. If a patient does not respond to warfarin I shift to dabigatran / or other recent congeners. If I am not able to find the cause for arterial thromboses ,the patient has to be on life long anticoagulants and only on anti platelets for venous thromboses. However if there is recurrence of thromboses on anti platelets in the latter , we shift the pt to  oral anticoagulatants.

Little evidence of added efficacy at this point.

Would be surprising that 1-2 Bortezomib doses would add efficacy over many previous doses pre-transplant + high-dose melphalan.

Randomized trial ongoing at IFM.

The regimen suggested by Dr. Romon is good providing you have access to amsacrine. If that is a problem, you can use CLAG-M regimen and take the patient to an allogeneic HSCT afterwards. I have seen good results with this regimen.

Cladribine (2-CdA) 5 mg/m2/d iv over 2 hrs d1-5

Cytarabine (Ara-C) 2 g/m2/d iv over 4 hrs starting 2 hrs after cladribine d1-5

Mitoxantrone (Novantrone) 10 mg/m2/d iv d1-3

Filgrastim (Neupogen) 300 mcg sc d0-5 

Wierzbowska A et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol 2008; 80:115

You are welcome and best of luck.

Was the transplant performed in CR? If not, I'm afraid your (her) case is quite bad. Even if you performed the transplant in CR, the prognosis is terrible. 

The experience of a second allo after early relapse is usually bad, unless your patient is very young and very fit and you perforded a RIC transplant. You can add toxicity witout actually doing anything of consequence.

I tink you have done the best you can. As the comment above points out, the best would be to try new drugs that aren't too agressive. Clofarabine or even gemcitabine i associtation with other drugs  could be of help. If you achieve some kind of remission, then you can plan other things.

Besides, I'd inform the patient of her ominous situation. 

Sorry for writing this, but there is enough literature out there that gives you ideas. Just google cell separation.

Several antineoplastic agents do have antimicrobial effect. See for instance this article below. That the drugs lack clinical significance as antimicrobials can have many explanations the most obvious being that at the time of highest infection risk the drugs have already been excreted,

J Clin Pathol. 1993 Dec; 46(12): 1124–1125.

PMCID: PMC501725

Antimicrobial activity of cytotoxic drugs may influence isolation of bacteria and fungi from blood cultures.

V Peiris and B A Oppenheim

Abstract

The potential antimicrobial activity of cyclophosphamide, vincristine, and adriamycin against Gram positive and negative bacteria and Candida albicans was examined. The time taken for different microbial inocula to turn a simulated blood culture positive in the presence of different concentrations of these drugs was measured. Doxorubicin retarded the growth of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus sanguis in a concentration dependent manner. Cyclophosphamide and vincristine showed minimal antimicrobial activity. Escherichia coli and Pseudomonas aeruginosa were unaffected by any of the drugs. An inoculum dependent effect was seen with some combinations of microbial inocula and cytotoxic drug concentrations.

The production of health-associated reference values and the subsequent estimation of the reference interval for a given analyte must be carried out in accordance with a well-defined protocol. This involves following a sequence of operations as outlined here. This outline should be applied when establishing

reference values for a new analyte, for a different group of individuals, or for a new analytical method with improved analytical sensitivity and specificity for a previously measured analyte:

(1) Establish a list of analytical interferences and sources of biological variability from medical and scientific literature (in the case of a totally new analyte, the literature may not be helpful, which necessitates a new laboratory investigation of these matters).

(2) Establish selection (or exclusion) and partition criteria and an appropriate questionnaire designed to reveal these criteria in the potential reference individuals.

(3) Execute an appropriate written consent form for participation in the reference interval study and have the reference individual complete the questionnaire.

Even though performing a reference interval study is not—strictly speaking research, questionnaires, consent forms, and even the nature of the exercise may need to be reviewed by the institution’s Internal Review Board or Human Subjects Committee. Laboratories are urged to familiarize themselves with their local policies.

(4) Categorize the potential reference individuals based on the questionnaire findings and results of other appropriate health assessments.

(5) Exclude individuals from the reference sample group based on the exclusion criteria or other assessments indicating a lack of good health.

(6) Decide on an appropriate number of reference individuals in consideration of desired confidence limits.

(7) Prepare, properly and consistently, the selected persons for specimen collection for the measurement of a given analyte consistent with the routine practice for patients.

(8) Collect and handle the biological specimens properly and in a manner consistent with the routine practice for patient specimens.

(9) Collect the reference values by analyzing the specimens according to the respective analytical methodology under well-defined conditions and consistent with the routine practice for patient specimens.

(10) Inspect the reference value data and prepare a histogram to evaluate the distribution of data.

(11) Identify possible data errors and/or outliers.

(12) Analyze the reference values, ie, select a method of estimation and estimate reference limits and the reference interval (include partitioning into subclasses for separate reference intervals, if appropriate).

(13) Document all of the previously mentioned steps and procedures.

there are lots of relevant data--possible the best summary can be found by reviewing the classic teaching text by Eric Hall from Coilumbia--"Radiobiology for the Radiologist". You could then do a quickie lit search by combining "..Radiologist  with Cancer..." on a Google search platform or equivalent.

Roger M. Macklis, MD

Have alook at: Use of tigecycline for the treatment of prolonged bacteremia due to a multiresistant VIM-1 and SHV-12 beta--lactamase-producing Klebsiella pneumoniae epidemic clone.

Cobo J, Morosini MI, Pintado V, Tato M, Samaranch N, Baquero F, Cantón R.

Diagn Microbiol Infect Dis. 2008 Mar; 60(3):319-22. Epub 2007 Nov 9

There is a good publication on Augmented Hyper-CVAD that combines Hyper-CVAD with Peg-Aps (and much more steroids than classical Hyper-CVAD). This is associated with toxicities (mainly sepsis/necrotising fascitis!). We at SQUH Oman usu the classical Hyper-CVAD augmented with Peg-Aps (2500 units/m2 I.V.) on Day 1 of A  part and Day 5 of B part and i think it is of major benefit based on previous studies assessing the addition of peg asp to a number of protocols. 

Your answer indicates that SCF might be involved

That would be great John, here is my university email

Performing a bone marrow biopsy will be very important to detemine the grade of infiltration as well as to evaluate the presence of reticulin fibrosis. If you have cytopenias in peripheral blood it will also provide you information about red cells, leukocytes and platelets precursors.

Dear Ondrej

Please see this reference

Leukemia. 2012 Jan;26(1):13-22. doi: 10.1038/leu.2011.221. Epub 2011 Aug 19.

Deregulation of microRNAs in myelodysplastic syndrome.

Rhyasen GW1, Starczynowski DT.

Author information

Abstract

Myelodysplastic syndromes (MDSs) consist of a family of hematopoietic stem cell (HSC) disorders characterized by ineffective differentiation of hematopoietic progenitors, bone marrow dysplasia, genetic instability and a propensity to develop acute myeloid leukemia. The development of MDS is poorly understood and therefore, effective treatment options are limited. Recent progress has been made in identifying altered signaling pathways and understanding the HSC defects, which are thought to contribute to the pathogenesis of MDS. Several of these findings have implicated aberrant expression and function of microRNAs (miRNAs). Unique miRNA expression patterns have been identified in MDS patients and modeled in mice to recapitulate features of MDS. Here, we review miRNA expression profiles identified in MDS patients, and describe the association of miRNA expression with MDS subtypes and disease outcome, clinical implications of miRNAs in MDS and deregulation of miRNAs in mouse model systems of MDS.

If you use the download function you get all the data and can import them into Excel. e.g. File:CosmicCellLineProject_v65_280513.tsv.gz

AML de novo is different from AML from previous hematologic disease ie. MDS, PV, TE or myelofibrosis, secondary post chemo or RT for other malignancies, or in elderly when response can go from 70-80% down to 20 to 30%. Identification or personalized approach can show good prognosis in Inversion 16 chromosome, t(7;21), or molecular markers like NPM1 or CeBPa with normal cytogenetics. Multiple complex chromosome of FLT3ITD mutations identify bad ones.