Challenges and Opportunities in Leukemia
Christopher K. Williams, MD FRCPC
Abstract
The African environment has for millennia been dominated by rampant agents of infections, of which malaria is among the best known, virtually uncontrolled, and associated with lifelong human struggles, ameliorarated by measures as socioeconomicaly affordable. This has led to the emergence of a variety of genetic aberrations, some of which are deleterious, resulting in major disease dysparities, including benign ones like sickle cell disease, and malignancies like the leukaemias, lymphomas, and breast cancer. They include the reduced incidence and the absence of its peak in acute lymphoblastic leukaemia in the first quinquennium of Nigerian children, which is otherwise typically seen in the children of high-income countries. Conversely is the observation in acute myelogenous leukaemia, with its chloroma-associated variant and its incidence peaking in the second quinquennium. This epidemiology is akin to the recent observation of acute myelogenous leukemia among sickle cell disease patients among the people of African descent in California, USA. Chloroma-associated acute myelogenous leukemia, and Burkitt lymphoma are linked with low socioeconomic status, an epidemiological feature that is shared with triple negative breast cancer patients in West Africa and the women of African descent in the United States. While a role for the malaria-associated genetic aberration underlying the Duffy null genotype is confirmed in the diversity of the triple negative breast cancer in the women of West Africa and those of African descent in the United States, it is conceivable, but not yet established in acute myelogenous leukemia. The zoonosis-linked human T-cell lymphotropic virus type 1 infection is associated with at least 17% of non-BL-non-Hodgkin lymphoma in form of its sentinel disease, the adult T-lymphoma/leukemia, but unexpicably much lower than the 50-60% of other major endemic zones of Japan and the African descendants of the Caribeean. This report describes the clinical, laboratory, and epidemiological features of leukemia and lymphoma cases diagnosed between 1982 and 1984 in the city of Ibadan, Nigeria, some of the features of which are reminiscent of the observations of Ludwig Gross’s experiments on environmental influences, such as malnutrition and infections, on animal leukemogenesis. These events are the consequences of the primordial pressures that have shaped human genetics and pathophysiology. Evidence provided in this study, indicating association of increasing socioeconomic status with increasing frequency of the c-ALL subtype, is indicative of the prospects for leukemogenesis of acute lymphoblastic leukemia and its epidemiology in Nigerians. Some findings reported here indicate the influence of the African genetic ancestry in the etiology of acute myelogenous leukemia, while socioecomic status is linked to the etiology of childhood acute lymphoblastic leukemia, as well as a variant of chronic lymphocytic leukemia, and the chloroma-associated acute myelogenous leukemia. These observations are suggestive of the existence of pathways to etiological discoveries in the leukemias. Observations reviewed in this paper reflect examples of changes that have occurred over the past 200 years in the societal perception of health challenges among the new-found communities of colonial Africa and the Americas – from the reductionistic connotations such as in the “virgin-soil theory” – towards that of social determinants of health.
María Alejandra Deu
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
María Ceciclia Bertone
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Luisina Belén Peruzzo
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Carla Luciana Pennella
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Cristian Germán Sanchez La Rosa
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Myriam Ruth Guitter
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Elizabeth Melania Alfaro
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Pedro Zubizarreta
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
María Sara Felice
Pediatric Hematology Oncology Department, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires C1245, Argentina.
Abstract
Spinal cord compression (SCC) is an unusual manifestation of leukemias and lymphomas in children and defines an oncological emergency frequently unsuspected, being a cause of severe sequelae. Our aim was to analyze the characteristics of patients who presented signs or symptoms of spinal cord compression in early phases of malignant hematopoietic diseases. From November-1988 to July-2022, 3878 patients with leukemia and lymphoma were diagnosed. Of them, 36 children (0.92%) presented spinal cord compression signs/symptoms in early phases of their diagnosis: Acute Lymphoblastic Leukemia (n=18), Acute Myeloblastic Leukemia and Myeloid Sarcoma (n=7), Non-Hodgkin Lymphomas (n=9) and Hodgkin Lymphoma (n=2). Clinical characteristics, images and hematological findings, treatment strategies, results and sequelae were analyzed. Sex distribution was 3.5/1 (M/F) and the media age at diagnosis was 10 (range: 4.9-16.9) years. The most common symptoms were back pain (34/36), functional impotence (27/36) and sphincter compromise (10/36). The media time from symptom onset to diagnosis was 47,5 (range: 0-300) days. Magnetic resonance imaging was performed on 33 (92%) patients and showed epidural mass (n=16) or vertebral collapse (n=17) in all of them. Two patients received initial radiotherapy and 11 decompressive surgeries for the management of the urgency spinal cord compression. Bone marrow aspiration was the diagnostic procedure in 69% of cases. All patients received chemotherapy and 94% achieved complete remission. Severe sequelae were observed in 10 patients (paraplegia with neurogenic bladder and kyphoscoliosis). Leukemia and lymphoma should be considered as a differential diagnosis when spinal cord compression is suspected, and magnetic resonance imaging is the mandatory study to confirm this diagnosis as a matter of urgency. Bone marrow involvement was evident due to hematological alterations in 95% of cases allowing to guide the diagnosis and initiate treatment early to reduce sequelae.
Natalia Neparidze, MD
Yale University School of Medicine New Haven, CT
Krystal W. Lau, PhD
Flatiron Health, New York, NY
Xiaoliang Wang, PhD
Flatiron Health, New York, NY
Scott Huntington, MD, MPH
Yale University School of Medicine New Haven, CT
Omer Jamy, MD
University of Alabama at Birmingham, Birmingham, AL
Gregory S. Calip, PharmD, MPH, PhD
Flatiron Health, New York, NY
Harsh Shah, DO
University of Utah, Huntsman Cancer Center, Salt Lake City, UT
Deborah M. Stephens, DO
University of Utah, Huntsman Cancer Center, Salt Lake City, UT
Rebecca Miksad, MD, MPH
Flatiron Health, New York, NY
Ravi B. Parikh, MD, MPP
University of Pennsylvania, Philadelphia, PA
Samuel Takvorian, MD, MSHP
University of Pennsylvania, Philadelphia, PA
Gaurav Goyal, MD
University of Alabama at Birmingham, Birmingham, AL
Erlene Seymour, MD
Flatiron Health, New York, NY
Abstract
Background: The COVID-19 pandemic impacted healthcare visit trends, transitioning care to utilize telemedicine. We aimed to investigate if the uptake in telemedicine during pandemic was equitable across racial groups for patients with hematologic malignancies.
Methods: Using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database we analyzed patients with diagnosis of acute myelogenous leukemia (AML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) or multiple myeloma (MM). Patients were categorized into treatment types within lines of therapy: outpatient (oral therapy and outpatient infusions combined with oral therapy) vs. inpatient treatments (chemotherapy, cellular therapy). Monthly visit rates were calculated as the number of visits (telemedicine or in-person [in-clinic treatment administration, vitals, and/or labs]) per active patient per 30-day standardized month. We used time-series forecasting methods on pre-pandemic monthly visit rate data (March 2016 – February 2020) to estimate projected counterfactual monthly visit rates between March 2020 – February 2021.Telemedicine uptake was descriptively analyzed over time (t).
Results: We included 18,924 active patients (2,394 Black and 16,530 White) and 884,504 visits (117,673 Black and 766,831 White). 4,053 AML, 3,468 diffuse large B cell lymphoma, 1,943 follicular lymphoma, 2,151 mantle cell lymphoma, 5,926 chronic lymphocytic leukemia and 7,752 myeloma patients. Black patients had no significant reductions in in-person visit rates throughout the pandemic period compared to the projected rates. Conversely, White patients experienced an 18% (95% PI 9.9% – 25%) lower rate of in-person visits for outpatient therapy during the early pandemic (March – May 2020) (actual monthly visit rate 1.61; projected visit rate 2.0 [95% CI 1.8-2.2]). Telemedicine uptake was significantly higher for White patients compared with Black patients for all diseases and treatment categories between March 2020-February 2021 (t = 9.5, p < 0.01), AML inpatient (t = 2.4, p = 0.04), MM outpatient (Figure 3C) (t = 6.0, p < 0.01) and MM inpatient treatment categories (Figure 3D) (t = 2.3, p = 0.04).
Conclusions: White patients had significantly higher telemedicine uptake compared with Black patients for all treatment categories. These findings challenge healthcare systems to direct efforts toward reducing the gap in healthcare access.
Dhanya Mohan
Amna Khalifa Alhadari
Dileep Kumar
Sima Abdolla Nejad
Rahaf Mohamad Wardeh
Department of Internal Medicine, Dubai hospital, Dubai, United Arab Emirates
Batool Khan
Dubai Medical College for Girls, Dubai, United Arab Emirates
Madheeha Mahmood
Dubai Medical College for Girls, Dubai, United Arab Emirates
Zuha Fathima
Dubai Medical College for Girls, Dubai, United Arab Emirates
Mohammed Railey
Department of Neprology, Dubai hospital, Dubai, United Arab Emirates
Abstract
Cryoglobulinemic vasculitis presents with systemic vasculitis including vasculitic rash, fever, peripheral neuropathy, and, in rare cases renal involvement. This could be secondary to infections like hepatitis C, malignancies like myeloma, Non Hodgkin’s lymphoma and chronic lymphocytic leukemia. We encountered a patient who presented with fever, anemia, purpuric skin rash and acute kidney injury due to acute glomerulonephritis with nephritic picture and fluid overload that required hemodialysis.Investigations revealed hemolytic anemia, cryoglobulinemia, proliferative glomerulonephritis with Ig M intra-capillary deposits and hyaline thrombi. Bone marrow biopsy clinched the diagnosis of Chronic lymphocytic B cell lymphoma with CD 20 positivity. Treatment was instituted with Rituximab and Bendamustine. Plasmapheresis was done for hyperviscosity syndrome. With treatment, hemodialysis could be discontinued after 10 weeks and renal functions recovered partially with serum creatinine settling at 1.5 mg/dl. We present this case to highlight the presentation of chronic lymphocytic leukemia with cryoglobulinemic vasculitis that presented with purpura and rapidly progressive renal failure that required dialysis.
Richard L. Momparler
Département de pharmacologie-physiologie, Université de Montréal; Centre de recherche, Service d’hématologie-oncologie, CHU Sainte-Justine, Montreal, Quebec H3T 1C5, Canada
Sylvie Côté
Centre de recherche, Service d’hématologie-oncologie, CHU Sainte-Justine, Montreal, Quebec H3T 1C5, Canada
Louise F. Momparler
Centre de recherche, Service d’hématologie-oncologie, CHU Sainte-Justine, Montreal, Quebec H3T 1C5, Canada
Abstract
Complete eradication of leukemic stem cells (LSCs) in patients with acute myeloid leukemia (AML) is required for curative therapy. Epigenetic alterations that involve gene-silencing by DNA methylation by DNMT1, methylation of H3K27 by EZH2 histone methyltransferase (HMT) and methylation of H3K9 by G9a HMT may play a major role in the development of AML. The major action of these epigenetic alterations is the silencing of the genes that program differentiation of AML cells. Inhibitors of DNA and histone methylation have the potential to reverse this block in differentiation. If tumor suppressor genes (TSGs) contain two gene-silencing markers, such as DNA methylation and H3K27me3, they may not be fully reactivated with only an inhibitor of DNA methylation, such as 5-aza-2’-deoxycytidine (5-AZA-CdR), but may also require an inhibitor of EZH2. In support of this model is the synergistic antileukemic action as shown by a colony assay on AML cells using 5-AZA-CdR in combination with 3-deazaneplanocin A (DZNep), a potent inhibitor of EZH2. A similar type of interaction can occur when TSGs are silenced by DNA methylation and the G9a methylation of H3K9me2, a second gene-silencing marker. Treatment of these AML cells with 5-AZA-CdR and BIX01294, an inhibitor of G9a, also results in a synergistic antileukemic action. Leukemic cells that contain 3 different gene-silencing markers: DNA methylation, H3K27me3 and H3K9me2 may require 3 different inhibitors for maximal antineoplastic activity. This result was observed when the AML cells were treated in with 5-AZA-CdR, DZNep and BIX01294. The aim of this study was to demonstrate that epigenetic agents that target DNA and histone methylation have remarkable antineoplastic activity against myeloid leukemia cells. The second aim was to propose a dose-schedule for these epigenetic agents that can be evaluated in a clinical trial in patients with advanced AML for its potential to eradicate LSCs. One of the most sensitive targets for chemotherapeutic intervention in LSCs is the block in differentiation due to gene-silencing by DNA and histone methylation. Epigenetic agents that have the potential to reverse this block merit clinical investigation with high priority.
Abstract
Background: Several studies of the health problems incurred by flight attendants flying during the smoking years concluded that they suffered elevated rates of chronic bronchitis, heart disease, skin cancer, breast cancer, melanoma, reproductive cancers, middle ear infections, hearing loss, asthma, pneumonia, chronic obstructive pulmonary disease, various pulmonary function abnormalities, plus depression and anxiety.
Aims: Systematic review of secondhand smoke risks to flight attendants, exemplified using a specific case involving a deceased flight attendant who suffered from a multiplicity of tobacco-smoke-related diseases, including asthma, breast cancer, carotid artery stenosis, cataracts, cervical cancer, chronic obstructive pulmonary disease, coronary artery disease, laryngeal cancer, pneumonia and chronic myeloid leukemia. The decedent died in 2014 at age 68, losing an estimated 18.5 years of life expectancy.
Methods: Pharmacokinetic modeling was used for the first time to estimate the risk from secondhand smoke for flight attendants on typical passenger aircraft flown by the decedent during an 18 year period ending in 1988.
Results: Based on in-flight cotinine dosimetry measured in an Air Canada study, typical flight attendants would have inhaled a dose-equivalent of fine particle air pollution exceeding the “Air Pollution Emergency” levels of the U.S. Environmental Protection Agency’s Air Quality Index. The secondhand smoke cotinine dose for typical flight attendants in aircraft cabins is estimated to have been 6-fold that of the average US worker and 14-fold that of the average person. Thus, ventilation systems massively failed to control secondhand smoke air pollution in aircraft cabins, and led to extreme exposures. The decedent’s estimated lifetime cancer risk from secondhand smoke was 18 times U.S. OSHA’s Significant Risk of Material Impairment of Health level of 1 per 1000 per working lifetime.
Conclusions: In-flight exposure to toxic and carcinogenic tobacco smoke in smoky passenger cabins was the major risk factor leading to the decedent’s multiple smoking-related diseases, and her premature death. This has implications for the extant and future health of the cohort of surviving flight attendants exposed to secondhand smoke on aircraft during the 20th Century Era.
Evelim Leal de Freitas Dantas Gomes, Dr
São Paulo University USP
Carolina Cristina Santos Camargo
Ibirapuera University
Debora Nunes Prata Anjos
Ibirapuera University
Etiene Farah Teixeira de Carvalho
FacPhysio
Abstract
Onco-hematological diseases are serious conditions and often require aggressive treatment that can lead to systemic complications, consequently affecting musculoskeletal functions as well as physical and functional capacity. Respiratory complications can lead to a greater frequency of hospitalizations and immobility, creating a cycle of sedentarism as well as an increase in morbidity and mortality. The goal of physical therapy in such cases is to restore compromised functions in affected children and adolescents and ensure the performance of activities of daily living and better development.The aim of this review was to bring to light the dysfunctions promoted by onco-hematological diseases of childhood in order to understand the best way to approach the treatment for this population.In this review, the functional alterations of sickle cell anemia, leukemia and bone marrow transplantation were addressed, as well as the interventions used by physiotherapy for the treatment.
Ying Xiong
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Yanping Xie
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Zhongyu Zhu
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Ibeawuchi Oparaocha
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Oxana Sleesareva
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Boro Dropulić
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Rimas J. Orentas
Caring Cross, 910 Clopper Rd., Suite 200 S, Gaithersburg, MD 20878 USA
Abstract
The creation of autologous gene-modified cell products, such as CAR-T cells (chimeric antigen receptor T cells) has met with clinical success but has been severely restricted by cost, availability, and current commercial models of central manufacturing. Moreover, the inability to produce CAR-T cells at reasonable cost in all but the largest centers slow innovation. CAR-T cells are unique in that these ex vivo expanded effector T cell populations express activation receptors comprised of immunoglobulin-like binders, or other immune ligands, bypassing the restriction of expanding and appropriately activating effector cells that arise by recombination of V-D-J genetic elements. However, the use of a single binding moiety to recognize leukemia target cells has selected for the generation of escape mutants, or for cryptic clones to expand that were not initially detected upon diagnostic work-up. To meet this challenge, we have engineered both B cell malignancy-specific and HIV surface antigen-specific CAR-T cells that express multiple binding moieties, thereby reducing the chance of immune escape. The creation of a therapeutic CAR-T cell population also requires a complex set of procedures that includes procurement of a large number of patient T cells, most often by leukapheresis, activation of the T cell population using matrix-associated antibodies targeting the T cell receptor and an immune co-receptor, a gene vector to permanently transduce T cells, and a bioreactor that can accommodate the expansion of the engineered cell population to numbers suitable for infusion. This complex set of procedures, combined with the current central processing model, has led to a complex chain of custody and expensive temperature-controlled shipping requirements. We present here a model whereby production of CAR-T cells at the point of care, using simplified cell procurement, purification, and expansion, can reduce the time and expense of CAR-T cell generation, with the aim to expand the use of these therapies in both the majority world, and in managed care or publicly funded systems. The CAR-T populations produced in this point-of-care ready process are highly active, viable, and have preferred CAR-T phenotypic characteristics associated with clinical efficacy.
Maurizio Martellini
Scientific Director of Theranosti Centre Srl
Ka-Ngo Leung
Berkion Technology LLC
Giuseppe Gherardi
Theranosti Centre Srl
Lidia Falzone
Theranosti Centre Srl
Abstract
Alpha-particle emitting radioisotope Actinium225 (225Ac) is of great interest for use in Targeted Alpha Therapy (TAT) treatments of e.g., brain tumors, bladder cancer, neuroendocrine tumors and leukemia. A suitable 225 Ac radioligand is also potentially resolutive for the treatment of advanced and metastatic Castration-Resistant Prostate Cancers (mCRPCs). The mCRPC has a mean survival rate of 9-36 months and encompasses a heterogeneous ample range of molecular cancer behavior with a high risk of progression.
Global demand for the 225 Ac has spurred several production efforts including extraction from 233U, high energy protons or photon irradiation of 226Ra or spallation of 232Th by, at least, 100 MeV protons. Instead of using accelerators systems such as cyclotrons or LINACs, a Compact Neutron Generator (CNG) system has been developed. A 400kV-10 mA DC (D_7Li) CNG potentially able to produce substantial amount of 225Ac with low 227Ac impurities is here presented. Exploiting the high flux of 10 and 13 MeV energy neutrons generated by the (D_7Li) reactions to bombard a thin target layer of 226Ra, 225Ra/225Ac is produced via the 226Ra(n,2n)225Ra nuclear reaction. By irradiating a 5 mm thick 226Ra layer for 100 hours, about 11-13 mCi of 225Ac can be produced – corresponding to the TAT treatment of about 65 oncological patients – with an estimated 227Ac contamination of about one percent, which is below the acceptable limit for clinical use. This 225Ac production scheme by a suitable CNG should allow to adopt a local/regional approach avoiding the shipment costs of 225Ac.
The aim of this paper is to inform the production chain of radioisotopes to be used in medical field and the medical community involved in the application of radiopharmaceuticals for the cure of cancer, that a new technology based on Compact Neutron Generators (CNG) is in a R&D phase and will allow to produce the necessary quantity of radioisotopes for clinical and research purpose. This will be essential in treatment advanced metastatic cancer as for instance the metastatic Castration – Resistant Prostate Cancer.
Abstract
Successful cancer evolution (CE) relies on the sequential molecular and functional events including 1) telomere; 2) sub-telomere; 3) epigenetic; 4-6) hit-episodes; 7) an innovative cell cycle machinery, as the multi-phase, and 8) chromosomal abnormalities. In this regard, eight available, fundamental/evolutionary and strategic key information (Evolutionary- ID) presented.
Telomere length (TL), has the fundamental role in cancer development, with serious challenges in the clinical managements. Breast cancer and brain tumor are an unresolved problem in Science and Medicine. Besides, an early and translatable diagnostic- prognostic-predictive platform, by considering the targets-ID, is required. Diverse TL in two cases affected with astrocytoma with grade IV, revealed to be 12500 and 15000 bp in tumor, and 10000 and 9000 bp at genomic level. Interestingly, TL is declined in the lymph node, i.e., occurrence of evolution.
Sub-telomeres (STs) through the cellular journey, are the neighboring destination at genomic and somatic level. The evolutionary pattern of STs has not been, routinely, decoded to the personalized clinical managements. The ST–sequences, are diversely predisposed to variety of environmental factors and play influential role in healthy individuals and the patients. An early detection is available by analysis of the ST- hybridized signals in the biopsy of auxiliary lymph nodes (ALN), and/or by circulating tumor cells (CTCs) into the blood stream. Diverse pattern of signal frequency and intensity in individual chromosomes at both somatic (ALN) and genomic (lymphocytes) levels were remarkable. The most common involved targets included chromosomes 5 and 9, 16 and 19; with diverse intensity at p and q chromosomal arms respectively. These findings have the predisposing, and an initial influence through the patients’ course of disease.
ST- signals, by providing the STs-ID, offer periodical and predictive, indices in cancer screening and therapy.
Furthermore, the complementary, cell cycle protein expression (PE) including Ki67, cyclin D1, and cyclin E, accelerates an early clinical management through the period of disease based on the CTCs.
Epigenetics is the next molecular destination by focusing on the genomic/somatic index, as an evolutionary Epigenetics-ID with its impact on the cancer management. The target panel is Ataxia Telangiectasia mutated gene (ATM) as the molecular marker and an initiator of different cancers.
ATM has remarkable roles, including: 1) in DNA double strand break (DSB), 2) to initiate different types of neoplastic disorders, including cancer, and 3), polymorphism, D1853N as a peridisposing marker by initiating the hit process. The influential characteristics include: family history of neoplastic disorders through the pedigree, the key role of ATM promoter methylation, cooperation of ATM/Rb protein expression, D1853N- marker, telomere length (TL) and the clinico-pathological characteristics in different types of brain tumors, and the environmental factors. Interestingly, TL has an independent influence on the progressive cancer evolution. An early detection by CTCs based on the D1853N/Sub-TL/Cell cycle checkpoints based on the PE assay and molecular test facilitate an early detection and therapy, based on the personalized approach.
By highlighting the preventive insight in Medicine, a brief record on the “Methylation in Chorionic villus samples (CVS)” with aim of an early detective strategy is provided. All nine CVS samples were methylated for the MCPH1 gene. An early detection is possible either through CV sampling or by the circulating CV cells in the maternal blood.
Evolutionary Hit includes: presence of D1853N polymorphism of ATM, as the hit-initiator through an evolutionary and progressive molecular based sequential alterations led to discovery of three-hit hypothesis in a patient affected with astrocytoma. More hits include five, and eight- hit hypotheses in primary breast cancer patients. Such platforms are considered as the individualized model in cancer. The pedigrees and details at the molecular follow-up studies and functional alteration at protein level are available in the provided sections.
Novel strategy of Cell cycle phases in breast cancer is the major intersection for cancer therapy.
The novel cell cycle hypothesis (CCH) highlights the mosaic based of dual and/or multi-phases, as minor clones at single cell level in the breast cancer (BC) -patients, escorted by the normal cell population. Such mosaicism provided an archetypal, unique diagnostic and therapeutic model, by applying different mosaic patterns (MPs) as well as “G1/S, S/G2 and G1/S/G2, and accompanied by normal phases, as a sole including G1, S, and G2 at the single cells level.
Diagnosis is based on the mode of signal copy numbers (SCN) and the related PE. Interestingly MPs were also unmasked in patients with chronic myelogeneous leukemia and other solid tumors.
Finally, the predisposing/predictive/prognostic/preventive square provides an innovate CDKs inhibitor-based therapy in BC and other cancers.
Personalized base cancer therapy is the confusing procedure and requires the pedigree-based data, personalized, evolutionary based information including molecular and functional at both genomic and somatic, at single cell level. The target territories comprise cell cycle phases, proteins, Telomere length, telomerase, sub-telomere, and Epigenetics. The aim is directing the cell cycle fundamental forces back to normal, by performing:
1) Applying personalized, single cell-based approach, at molecular, functional level, pedigree analysis, and balancing the micro-/macro-environmental factors, including nutrition.
2) Satisfactory high single cell enumeration based on the FISH and protein expression assays;
3) Decoding the required dosage and combined therapeutic regimens accordingly,
4) Unmasking the cell cycle combined (mosaic) phases including different Cyclins; and
5) Bilateral cooperation between Pharmacology, Medicine, and Cancer Genetics/cell biology.
Let’s combine the evolutionary based strategy by translating the personalized data at molecular/ Functional/ Informative, and pedigree-based level to the personalized therapy.
