A study protocol for clinico-pathological diagnosis of hematological malignancies in a tertiary care hospital in central India

Priya Chatterjee; Kishore Hiwale; Sunita Vagha; Snehlata Hingway

doi:10.12688/f1000research.138519.1

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Study Protocol

A study protocol for clinico-pathological diagnosis of hematological malignancies in a tertiary care hospital in central India

[version 1; peer review: awaiting peer review]

Priya Chatterjee ¹, Kishore Hiwale¹, Sunita Vagha¹, Snehlata Hingway¹

PUBLISHED 05 Oct 2023

Author details Author details

¹ Department of Pathology, Jawaharlal Nehru Medical College and Hospital, Datta Meghe Institute of Higher Education & Research, Sawangi, Wardha, Maharashtra, 442005, India

Priya Chatterjee
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Kishore Hiwale
Roles: Conceptualization, Methodology, Writing – Review & Editing

Sunita Vagha
Roles: Conceptualization, Methodology, Writing – Review & Editing

Snehlata Hingway
Roles: Conceptualization, Methodology, Writing – Review & Editing

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REVIEWER STATUS AWAITING PEER REVIEW

This article is included in the Oncology gateway.

This article is included in the Datta Meghe Institute of Higher Education and Research collection.

Abstract

There is a paucity of a relevant national registry or any individual center study on clinico-pathological profiles of acute/chronic leukemias and multiple myeloma from central India. The proposed observational, prospective, longitudinal study in a rural tertiary center hospital in central India therefore intends to combine diagnostic techniques like peripheral blood smears, immunophenotyping via flow cytometry, bone marrow aspiration, and cytogenetic studies along with World Health Organisation and French-American-British classification for sub-typing, to accurately diagnose acute/chronic leukaemia and multiple myeloma. A total of 55 patients with any clinical suspicion of leukaemia and myeloma will be followed-up for a one-year period post diagnosis to ascertain if the patient is in complete or partial remission, or in a relapsed disease state. Furthermore, these diagnostic techniques will be compared in terms of their effectiveness and if these could substitute or complement each other keeping the limitations of Indian health settings in mind.

Keywords

Leukemia, Multiple Myeloma, Lymphoma, Hematology, FAB, WHO,AML,CML,ALL,CLL

Corresponding author: Priya Chatterjee

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2023 Chatterjee P et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Chatterjee P, Hiwale K, Vagha S and Hingway S. A study protocol for clinico-pathological diagnosis of hematological malignancies in a tertiary care hospital in central India [version 1; peer review: awaiting peer review]. F1000Research 2023, 12:1269 (https://doi.org/10.12688/f1000research.138519.1) First published: 05 Oct 2023, 12:1269 (https://doi.org/10.12688/f1000research.138519.1) Latest published: 05 Oct 2023, 12:1269 (https://doi.org/10.12688/f1000research.138519.1)

Introduction

The absence of a national comprehensive registry of hematological malignancies and reports suggesting significant loco-regional variations in the disease patterns within India, increase the significance of single-center studies.¹^,² Data from these individual centers provide insights into the regional epidemiological trends of hematological malignancies like acute and chronic leukemias and multiple myeloma.¹^,² Moreover, data generation on the acute leukemias and multiple myeloma morphological and genetic features within these individual center studies helps in providing a more comprehensive picture of the disease pathology prevalent within the concerned region.³ This helps both pathologists and hematologists in arriving at a well-informed, accurate and timely diagnosis, which in turn guides therapeutic decision-making process effectively and helps improve the patients' prognosis.³ Considering the resource constraints, sensitivity as well as the turnaround time of the various molecular and genetic identification techniques, discretion needs to be exercised while utilizing them at an individual case level of leukaemia and multiple myeloma.⁴ Our literature search revealed a paucity of such studies performed in an adult population in central India, which is home to a significant pool of the hematological malignancy population in India.⁵ Therefore, this study will be conducted at a rural tertiary hospital in central India (Maharashtra) with the primary objective of studying the clinico-pathological features of acute and chronic leukemias and multiple myeloma in this region. These will be diagnosed using a combined approach of techniques like peripheral blood smear and immunophenotyping via flow cytometry, bone marrow aspiration, cytogenetic studies along with World Health Organisation (WHO) and French-American-British (FAB) classification for sub-typing wherever possible.⁶^,⁷ Furthermore, we plan to compare these different methods to determine how these techniques could substitute or complement each other keeping the limitations of Indian health settings in mind. As an exploratory objective, we will also try to ascertain the impact of various disease clinical and pathological features that may potentially impact the one-year outcomes of the patients.

Protocol

Ethics statement

This study protocol has been approved by the Datta Meghe Institute of Medical Sciences (Deemed to be University) institutional ethics committee on 27^th June 2022 with study number - DMIMS (DUIEC/2022/1066) and will be conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and according to the Helsinki Declaration of 1975, as revised in 1983.

Study design and setting

This observational, prospective, longitudinal, single center study will be carried out in the outpatient department (OPD) of Jawaharlal Nehru Medical College and Acharya Vinoba Bhave Rural Hospital, Sawangi (Meghe) in central India (Maharashtra).

Patient selection

A total of 55 patients, presenting to the OPD and satisfying the below listed inclusion and exclusion criteria will be recruited in this study over a period of one year (June 2023–May 2024) after obtaining written informed consent.

Inclusion criteria:

Patients presenting with any of these clinical findings and with a suspected provisional differential diagnosis of a leukemia or multiple myeloma:

a) Severe pallor
b) Loss of weight
c) Loss of appetite
d) Night sweats
e) Any active bleeding
f) Organomegaly
g) Evening rise of temperature
h) Body ache
i) Dragging pain in abdomen
j) Generalized weakness
k) Chronic bone pain
l) Increased frequency of urination

Exclusion criteria:

a) Known or proven cases of leukemia
b) Hematological cancers undergoing chemotherapy or radiotherapy
c) Relapse of the disease

Sample size calculation

Sample size calculation was conducted using the sample size formula with desired error of margin:

\frac{n \geq Z_{1 - \frac{α}{2}}^{2} \times P \times (1 - p)}{d^{2}}

Where –

α: Type I error at 5% level of significance = 1.96

β: Type II error at 20% (1-β) = 0.8

Estimated proportion (p) = 10.3% = 0.103⁸

Estimation of error d = 5%

N = {1.96}^{*} {0.103}^{*} (0.897) / (0.08) 2 = 55

Hence, the total number of patients will be 55.

Study procedure

After obtaining written informed consent, the study subjects will be recruited into the study and the following study procedures will be carried out and recorded as per the clinical case proforma (Table 1):

1. Detailed clinical history, including history of presenting illness and past history will be recorded.
2. Clinical examination:
Radiological investigation findings will be recorded (only if already available).
3. Hematological investigations:
- a. Cytomorphological examination of air-dried Leishman-stained peripheral blood and bone marrow smears.

Table 1. Clinical case history proforma.

Sl. No	Parameter	Value/report
1.	Age
2.	Gender
3.	MRD No.
4.	Chief complaints
5.	History of presenting illness
6.	Personal history
7.	Past history
8.	General and systemic examination findings
9.	Hematological findings a. CBC b. ESR
10.	Peripheral smear findings
11.	Bone marrow aspiration findings
12.	Trephine biopsy findings
13.	Immunophenotyping findings
14.	Cytogenetics evaluation findings, including risk grouping (favorable, intermediate and unfavorable)
15.	Clinical and pathological diagnosis

Procedure for the Leishman stain:

1. The peripheral smear will be prepared freshly after collecting 2 mL of blood in ethylene diamine tetra acetic acid (EDTA) and the smear will undergo rapid drying.
2. The film will be covered with Leishman stain (0.15 g) and allowed to stand for one minute, with 100 mL of absolute methanol added to the stain to fix the film.
3. Double the volume of distilled water (approximately the same amount as Leishman’s stain) will be added to the slide and mixed well.
4. The diluted stain will be allowed to act for a minimum of 10–12 minutes.
5. The film will be washed with distilled water or phosphate buffer of pH 6.8.
6. The peripheral smear will be drained, dried and examined.

Procedure for the bone marrow aspiration:

1. The patient will be positioned in the left lateral or right lateral position with the site of aspiration being the posterior or anterior iliac crest.
2. Imaging guidance such as computed tomography may be employed to facilitate the procedure.
3. Salah’s aspiration needle will be used to aspirate the material, and slides may be directly prepared, or the sample collected in an EDTA tube and stained.

Procedure for bone marrow trephine biopsy:

1. The site for the biopsy is the posterior iliac crest.
2. Using a Jamshidi’s bone marrow biopsy needle the biopsy will be performed with a twisting motion, the specimen should measure at least 1.5 cm.
3. The specimen will immediately be placed in a fixative and after fixation it will be decalcified in 10% nitric acid and embedded in paraffin wax.
4. Thin sections will be cut and stained with Hematoxylin and Eosin stain (H & E).
5. The section will be examined and reported in a systematic manner.
- b. Cytochemical analysis (Pathozyme Diagnostics) of air-dried peripheral blood and/or bone marrow smears will be performed using: Sudan black B (SBB) stain, naphthol AS-D chloroacetate esterase, a naphthyl acetate esterase, periodic acid Schiff (PAS), acid phosphatase, and neutrophil alkaline phosphatase (NAP).

Procedure for the Sudan Black B stain:

1. Air dried bone marrow aspiration slides will be taken and fixed in 10% formalin for 10 minutes.
2. Slides will be washed well with tap water for 5 minutes, rinsed in distilled water, followed by draining of the excess water.
3. Propylene glycol (85%) will be added in two changes, each of 5 minutes.
4. SBB stain (0/3 g in 100 mL ethanol) will be added and left for agitation for 7 minutes.
SBB/Propylene will be prepared by slowly dissolving 0.7 g Sudan Black B in 100 mL propylene glycol while stirring. This solution will be heated to 100°C for a few minutes while stirring constantly. The solution will be filtered using Whatman 2 filter paper and cooled. The solution will be filtered again using a frittered glass filter with medium porosity. The solution will be stored at 60°C in an oven. The solution will remain stable for 1 year.
5. 85% Propylene glycol will be added, left again for 3 minutes and rinsed with distilled water.
6. The slide will be counterstained without further fixation with Leishman stain or May–Grunwald–Giemsa stain.

Results and interpretation of Sudan Black B staining:

The presence of black granular pigments indicates a positive SBB stain.

As lipids are present in azurophilic and secondary granules of myelocytic cells, this stain is strongly positive in myeloid series cells. As the myeloid cells mature, the stain becomes more intense. On the other hand, monocytic cells are negative to weakly positive and lymphoid cells are negative (exception being 3% of ALL cells). In this study, SBB positivity will be considered to be diagnostic for myeloid leukemias.

Procedure for the PAS stain:

1. The tissue will be deparaffinized by washing in distilled water.
2. Then the tissue sections will be oxidized in 0.5% periodic acid solution (prepared by mixing 0.5 g periodic acid crystals in 100 mL distilled water) for 5 minutes.
3. Then the tissue will be rinsed with distilled water.
4. The tissue will be placed in Schiff’s reagent for 15 minutes (Sections become light pink color during this step).
5. Then, the tissue will be washed in lukewarm tap water for 5 minutes (Immediately sections turn dark pink color).
6. Counterstaining will be done in Mayer’s hematoxylin for 1 minute. Mayer’s hematoxylin will be prepared by dissolving 50 g alum in 1000 mL distilled water, followed by adding 1 g hematoxylin once the alum has dissolved and then adding 0.2 g sodium iodate and 20 mL glacial acetic acid once the hematoxylin is completely dissolved by boiling and cooling it.
7. Then, the tissue section will be washed in tap water for 5 minutes and rinsed using distilled water before the last step.
8. The tissue section will be dehydrated and placed under a coverslip and mounted using a synthetic mounting media.

Results and interpretation of the PAS stain:

PAS stains glycogen related compounds. Hence, it is useful for the identification of lymphoid cells. In this study, PAS stain will be used to distinguish ALL from AML. PAS stains lymphoblasts in ALL, hence is positive for ALL patients, whereasmost types of AML cases are negative for PAS.

Procedure for the non-specific esterase: Indoxyl acetate method

1. After suitable fixation, the sections are brought next to tap water.
2. It should be incubated at 37°C for 15–60 minutes.
3. Next it should be rinsed in tap water.
4. To be counterstained in Mayer’s carmalum for another 5 minutes.
5. It should be rinsed in tap water.
6. Then, mount in glycerin jelly, or
7. It can be dehydrated through graded alcohol to xylene.
8. The last step is to mount in Dibutyl phthalate in xylene (DPX).

Results and interpretation of the non-specific esterase: Indoxyl acetate method:

• Esterase activity - blue
• Nuclei - red
• Positive in monoblasts and monocytes.
• It differentiates the monocytic lineage from the lymphoid and other myeloid lineage cell types. Negative in lymphoid and myeloid lineage tumors like AML MO, M1, M2, M3, lymphoblastic lymphoma/leukemia.

Procedure for the Leucocyte Alkaline Phosphatase (LAP):

Neutrophil Alkaline Phosphatase or LAP is simply performed by drawing venous blood from the patient and measuring the LAP score. Low LAP scores are suggestive of CML.

4. Immunophenotyping will be done for select cases for the purpose of sub-typing where peripheral and bone marrow smear are not confirmatory):
- a. Flow-cytometry (Ten colour Navios Ex by Beckman Coulter by ClearLLab Solutions 10C system) using a panel of monoclonal antibodies (cCD3, CD3, CD5, CD7, CD10, CD19, cCD79a, MPO, CD13, CD33, CD14, CD34, HLA-DR and SmIg) – (outsourced to National Cancer Institute, Nagpur)
Conjugated antibodies and antibody cocktails
CD19: IM3628U; Fluorochrome – PC7; IgG1 monoclonal mouse; Clone – J3-119.
CD 3: 6607013; Fluorochrome – PC5; monoclonal mouse.
CD 7: B16892; Fluorochrome – APC-Alexa Fluor 750; IgG2a monoclonal mouse; Clone 8H8.1.
CD 5: A60790; Fluorochrome – APC; Clone BL1a.
CD 10: IM0471U; Fluorochrome – FITC; IgG2a monoclonal mouse; Clone ALB2.
HLA-DR: IM0464U; Fluorochrome – PE; IgG2b monoclonal mouse; Clone – B8.12.2.
MPO: IM2743; Fluorochrome – FITC, PE.
CD 13: A46528; Fluorochrome – PC7; Igg1 monoclonal mouse; Clone Immu103.44.
CD14: A22331; Fluorochrome – PC7; IgG2a; Clone RM052.
CD33: A54824; Fluorochrome – PC7; IgG1 monoclonal mouse; Clone – D3HL60.251.
CD34: IM1420; Fluorochrome – PE; IgG1 monoclonal mouse; Clone – Immu133.
5. Cytogenetic analysis using fluorescence in situ hybridization (FISH) using a locus specific identifier (LSI) DNA probe will be performed for selected cases. This would be outsourced to the National Cancer Institute (NCI), Nagpur as a part of the memorandum of understanding signed with our tertiary care hospital.

FISH method

a. The chromosomal DNA is denatured on the slides in 70% formamide 2XSSC solution at 68–70°C for 2 minutes.
b. The slides are dehydrated and air-dried.
c. The hybridization mixture containing the DNA probe is added to the slide and covered with a cover slip and incubated in a humidity chamber at 37°C for 6–12 hours.
d. Slides are washed, dried and then immersed in blocking buffer (I x PBS, 0.1% Triton-100) for 2 minutes, and rinsed in phosphate buffered saline (PBS) for 5 minutes at room temperature.
e. The semidried slide is treated will 100 μL of 1:100 rabbit antibiotin antibody (RevMAb Biosciences, USA, Catalog no-41-1014-00) and incubated in a humidity chamber at 37°C for 5 minutes.
f. Slides are washed with PBS and immersed in 100 μL of diluted antibody (FITC-conjugated goat anti-rabbit antibody (RevMAb Biosciences, USA, Catalog no-42-1030-00), 1:100 in dilution buffer) and incubated in the humidity chamber at 37°C for 30–60 minutes.
g. After washing, 60 μL of an antifade solution (p-phenylenediamine 10mg/mL, 90% glycerol, and propidium iodide 1μg/mL as a counter stain) is added on each slide.
h. The slide is to be observed with fluorescence microscopy using a B2 or B-2A filter cassette.

6. Bone marrow trephine biopsy is indicated only when a dry tap is obtained, or whenever there is inadequate bone marrow aspirate for diagnosis.
7. Subtyping using the FAB and WHO classification.

Post diagnosis, the patients will be tracked and followed up to a period of one year post diagnosis to ascertain the patient’s clinical outcome as ‘in complete remission’ or ‘in partial remission’ or ‘relapsed’.

Objectives

1. Primary objective:
- a. The distribution of the study subjects based upon the various population demographic features like age, sex, ECOG status etc, clinical manifestations like fever >38 degree Celsius, CNS involvement, hepatomegaly, splenomegaly, lymphadenopathy, type of malignancy with sub-typing included and clinical outcomes post one-year of follow-up (remission – complete/partial and relapsed) will be depicted using appropriate tables and graphs.
- b. The results of the cytochemical analysis for each type of acute/chronic leukaemia and multiple myeloma will be tabulated for each of the stains utilized. Similarly, the pattern of immunological markers and a summary of cytogenetic analysis in relation to the different subtypes of leukaemia and multiple myeloma will also be presented in tables.
2. Secondary objective: The comparative assessment of various diagnostic procedures pertaining to their diagnostic efficiency, cost and turnaround time will be summarized to provide practical insights into making an optimal choice of diagnostic techniques tailored to clinical disease under suspicion in each subject.
3. The relation of one-year clinical outcome to various disease characteristics in the study subjects like patient demographics, clinical manifestations, blood counts, FAB and WHO subtypes, immunophenotyping and cytogenetic risk groups will also be tabulated and analysed.

Statistical analysis

Descriptive data will be presented in the form of frequency and valid percent for qualitative variables, mean and standard deviation (X ^ SD) for quantitative variables. Comparative studies between qualitative variables will be done by chi-square test. Comparative studies between groups will be performed using Mann–Whitney’s and Kruskal–Wallis tests for non-parametric variables. T-Test and one-way ANOVA will be used for parametric variables. The software used in the analysis will be SPSS version 24.

Dissemination

The study protocol will be presented at Maharashtra Association of Pathologists and Microbiologists Conference MAPCON 2023 (6–8^th October). The study results abstract will be presented at a regional pathology congress in 2024. Further, the results of this study will be published in a peer reviewed journal.

Study status

The study is currently recruiting. The recruitment was initiated in June 2023.

Conclusions

The results of this study will demonstrate the clinico-pathological patterns of acute/chronic leukemias and multiple myeloma within central India. Additionally, this study will provide insights on the tailoring of the various diagnostic techniques used in this study based upon their diagnostic efficiency, cost, turnaround time and on disease type and subtype. Furthermore, the results of this study may potentially be hypotheses generating on the concerned disease pathological features and their relationship with one-year clinical outcomes.

Data availability

No data are associated with this article.

References

1. Prakash S, Ramamurthi, Gopalan R, et al.: Leukaemias at Pondicherry. Indian J. Cancer. 1981 Mar; 18(1): 1–6. PubMed Abstract
2. Varghese PR, Elayidom NB, Joseph CD, et al.: Epidemiological observations on leukaemia in Kerala (A study of 1016 cases over three years). Ind. J. Haematol. 1984; 2: 15–17.
3. Salkar AB, Patrikar A, Bothale K, et al.: Clinicohematological evaluation of leukemias in a tertiary care hospital. IOSR-JDMS. 2014; 13: 126–134. Publisher Full Text
4. Engel-Nitz NM, Eckert B, Song R, et al.: Diagnostic testing managed by hematopathology specialty and other laboratories: costs and patient diagnostic outcomes. BMC Clin. Pathol. 2014 Apr 27; 14: 17. PubMed Abstract | Publisher Full Text | Free Full Text
5. Kulothungan V, Sathishkumar K, Leburu S, et al.: Burden of cancers in India - estimates of cancer crude incidence, YLLs, YLDs and DALYs for 2021 and 2025 based on National Cancer Registry Program. BMC Cancer. 2022 May 11; 22(1): 527. Publisher Full Text
6. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19; 127(20): 2391–2405. Publisher Full Text
7. Bain BJ, Estcourt L: FAB Classification of Leukaemia.Brenner, editor. Encyclopedia of Genetics. 2nd ed.New York: Elsevier; 2013; pp 5–7. Publisher Full Text
8. Mathur P, Sathishkumar K, Chaturvedi M, et al.: Cancer Statistics, 2020: Report From National Cancer Registry Programme, India. JCO Glob. Oncol. 2020; 6: 1063–1075. Publisher Full Text

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Version 1

VERSION 1 PUBLISHED 05 Oct 2023

Author details Author details

¹ Department of Pathology, Jawaharlal Nehru Medical College and Hospital, Datta Meghe Institute of Higher Education & Research, Sawangi, Wardha, Maharashtra, 442005, India

Priya Chatterjee
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Kishore Hiwale
Roles: Conceptualization, Methodology, Writing – Review & Editing

Sunita Vagha
Roles: Conceptualization, Methodology, Writing – Review & Editing

Snehlata Hingway
Roles: Conceptualization, Methodology, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (1)

version 1

Published: 05 Oct 2023, 12:1269

https://doi.org/10.12688/f1000research.138519.1

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© 2023 Chatterjee P et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Chatterjee P, Hiwale K, Vagha S and Hingway S. A study protocol for clinico-pathological diagnosis of hematological malignancies in a tertiary care hospital in central India [version 1; peer review: awaiting peer review]. F1000Research 2023, 12:1269 (https://doi.org/10.12688/f1000research.138519.1)

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[1] 1. Prakash S, Ramamurthi, Gopalan R, et al.: Leukaemias at Pondicherry. Indian J. Cancer. 1981 Mar; 18(1): 1–6. PubMed Abstract

[2] 2. Varghese PR, Elayidom NB, Joseph CD, et al.: Epidemiological observations on leukaemia in Kerala (A study of 1016 cases over three years). Ind. J. Haematol. 1984; 2: 15–17.

[3] 3. Salkar AB, Patrikar A, Bothale K, et al.: Clinicohematological evaluation of leukemias in a tertiary care hospital. IOSR-JDMS. 2014; 13: 126–134. Publisher Full Text

[4] 4. Engel-Nitz NM, Eckert B, Song R, et al.: Diagnostic testing managed by hematopathology specialty and other laboratories: costs and patient diagnostic outcomes. BMC Clin. Pathol. 2014 Apr 27; 14: 17. PubMed Abstract | Publisher Full Text | Free Full Text

[5] 5. Kulothungan V, Sathishkumar K, Leburu S, et al.: Burden of cancers in India - estimates of cancer crude incidence, YLLs, YLDs and DALYs for 2021 and 2025 based on National Cancer Registry Program. BMC Cancer. 2022 May 11; 22(1): 527. Publisher Full Text

[6] 6. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19; 127(20): 2391–2405. Publisher Full Text

[7] 7. Bain BJ, Estcourt L: FAB Classification of Leukaemia.Brenner, editor. Encyclopedia of Genetics. 2nd ed.New York: Elsevier; 2013; pp 5–7. Publisher Full Text

[8] 8. Mathur P, Sathishkumar K, Chaturvedi M, et al.: Cancer Statistics, 2020: Report From National Cancer Registry Programme, India. JCO Glob. Oncol. 2020; 6: 1063–1075. Publisher Full Text

A study protocol for clinico-pathological diagnosis of hematological malignancies in a tertiary care hospital in central India

Abstract

Keywords

Introduction

Protocol

Ethics statement

Study design and setting

Patient selection

Sample size calculation

Study procedure

Table 1. Clinical case history proforma.

Objectives

Statistical analysis

Dissemination

Study status

Conclusions

Data availability

References

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Open Peer Review

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Open Peer Review

Reviewer Status

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