Friday, July 23, 2021

Iris Publishers- Open access Journal of Archives in Neurology & Neuroscience | Is there still some reason for classic presentation of Amyotrophic Lateral Sclerosis described in the literature?

 


Authored by Marco Orsini*

Opinion

Obviously, a lot has changed regarding Amyotrophic Lateral Sclerosis (ALS). That old and exemplary definition made by Chacort, of a neurological disease, of a progressive, degenerative and inexorable character, with “isolated” depletion of the upper and lower motor neurons no longer seems so limited to words. ALS is already considered a systemic disease; not only because of new findings that circumvent motor manifestations, but because of genetic codes that signal a form of evolution of hereditary cases. Speaking of that 5-8 year survival after the onset of the first signs and symptoms, the increase in new technologies, associated with a different way of medicating and treating, changed the natural history of book chapters; even with the cruelty with which it strips and compromises patients in various topics related to their functional abilities. We are looking for a picture of Amyotrophic Lateral Sclerosis described in detail in the literature [1-2].

Charcot3, one of the best neurologists in the world, should “return” with his knowledge and unique clinical dissection of his cases, and to her the right to redescribe this new spectrum of presentation of ALS. We focus on what is known about ALS and where the research is going - from the small steps of extending longevity, improving therapies, conducting clinical trials and compiling population registries, to the global goals of establishing measures that protect against onset and finding the triggers for this neurodegenerative disorder [4]. In cases of hereditary ALS, much has become history with the advancement of molecular biology. In patients with ALS/FTD (Fronto-Temporal Dementia), for example, the neuroinflammation mechanism characterized by innate immune responses of tissue-resident glial cells is uniformly present in end-stage pathology. Human imaging studies and rodent models support that neuroinflammation begins at early stages of disease pathogenesis. In addition, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence of an auto-inflammatory state (humoral system) [5]. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage [6]. ALS has broad genetic and hypothesized environmental causes and phenotypic variability. And what about sporadic ALS cases? These are even more unpredictable. In clinical practice, diagnostic difficulties mostly arise with patients who present either with only upper motor neuron, or with only lower motor neuron signs. In addition, patients with ALS may also have other nonmotor findings, such as changes in sensitivity, cognition problems, dysautonomia. It may be difficult to distinguish ALS with clinically predominant lower motor neuron involvement from alternative diagnoses including spinal atrophies of adult onset, Kennedy’s disease, inclusion body myositis and motor neuropathies with conduction blocks 4-[7]. Although the degeneration predominantly affects the motor system, cognitive and behavioural symptoms have been described for over a century. In ALS, it is not possible to define a standard, nor to dare to scrutinize the survival of these patients. We have a certain medical rationality coupled with experience and dedication to the study of this merciless disease; but we still know little about its mysterious pathophysiological framework. We take advantage of and dedicate this opinion article to Professor Marcos RG de Freitas, neurologist, student and eternal apprentice of Professor Antonio Rodrigues de Mello.


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Thursday, July 22, 2021

Iris Publishers- Open access Journal of Yoga, Physical Therapy and Rehabilitation | Use of Yoga Practices for Young Children

 


Authored by  Beth Elenko*

Abstract

The purpose of this opinion paper is to present the use of yoga practices in young children, primarily those younger than age 3 years old. The benefits that are seen in older children are just as beneficial to the young child who is typically developing as well as for those who are at risk or developmentally delayed who participate in early intervention. Young children can use yoga strategies to promote motor, and sensory skills in the early years. Even if modified from typical yoga poses to enhance their skills in a fun and creative way. Applying these yoga practices with young children has limitedly been studied, and further research on the benefits and uses is still necessary. Programs that are developing need to increase the evidence to support their practices.

Keywords: Young child; Yoga; Early intervention; Motor; Sensory development

Abbreviations: EI= early intervention Early interventionists: occupational, physical therapists, speech language pathologists or special educators toddlers -typically referred to as children ages 1-3 years.

Introduction

Yoga practices in children have been steadily increasing over the years. A 2017 National Health Interview Survey (NHIS) done every 5 years found that the use of yoga has increased in percentage almost tenfold in children ages 4-17 years [1]. Yoga is used with notable benefits throughout the lifespan. In children, yoga can help improve many skills such as decreasing anxiety, emotional regulation, improving body awareness, concentration, strength, flexibility, and behaviors that affect them. Through yoga we can improve our physical bodies, learn to breathe, and begin to take care of our bodies [2-5]. Most of the benefits of yoga have been demonstrated for school age children, even those with special needs [6-8]. Yet, yoga for young children under the age of 3 years has been studied the least in the literature [8-11], The purpose of this opinion paper is to increase awareness of using yoga practices with younger children.

Younger children especially toddlers, ages 1–3-year-olds can practice modified yoga poses. At a young age, children imitate the movements and behavioral practices of their caregivers whether it be grandparents, parents, teachers or siblings. It is what they naturally do and how they learn their basic developmental skills. Yoga itself benefits not only mindfulness, and reduces stress but improves skills in motor, attention, and behavior [5]. The benefits are growing and outweigh the negatives if there are any, although in one study it has been reported that yoga may be harmful to young children due to their lack of development [8]. Yoga not only benefits typically developing children, but children with developmental disabilities who receive early intervention (EI) (services for children who are at risk for or have developmental delays from birth to the age of 3 years old). I would argue that simple yoga postures mimic motor skills and promote weight bearing and elongation of muscles in young children as they develop. This can not only be beneficial, but essential to their sensory motor development. There are some children whether developmentally delayed or who engage in sedentary play that can engage in this an alternative activity. One that promotes their motor learning through yoga and that could be transferred to their development of motor skills.

While there has been little research on benefits of yoga for young children [8-11], there is much to support the use and benefits of yoga practices on improving mindfulness of children especially in schools [1-5]. These same benefits can apply to younger children, and they go beyond mindfulness. In young children, primary development is occurring in the first years of life. Yoga can promote and enhance what is already naturally occurring, while simultaneously teaching the child an activity to promote mindfulness as they grow. Not only can this be done as a family activity, but it can also be done to enhance skills that may be delayed in young children under proper direction from early interventionists [7]. Early interventionists promote motor and sensory skills to optimize development in young children which yoga can simultaneously nurture.

Motor

Think about babies first movements against gravity during the first year of life. Babies push on their arms and lift their heads as early developmental skills. As they gain these skills and begin to be more active in their movements, they strengthen their core muscles as a stable base for their arms and legs to move more freely. By the time they are physically ready to walk and stable in these muscles, they can begin to imitate simple yoga poses. Many yoga poses encourage these basic movements in creative and fun ways for toddlers [11].

Even those toddlers that are developmentally delayed need to work on these skills and practice them in a variety of ways. This can be done by imitating animals or silly postures. While doing this, it allows them to imitate postures that enhance their movement capabilities. Thus, strengthening their core muscles in their trunk, head and neck as well as their extremities. Toddlers can work on postural control, muscles, and joint stability as they maintain these postures. Toddlers who need to work on increased upper body stability through weight bearing benefit from a fun and creative way as they imitate these simple and modified yoga poses. The practice and repetition in learning these motor skills and yoga integrate beautifully while building their endurance for movements which they can carry over into their daily routines. Many poses focus on balance and stability of posture. The young child’s participation helps them with their balance and learning of these movement skills. This full body movement brings together their use of hands and feet enhancing bilateral integration and midline orientation. Overall, a toddler’s motor development can be enhanced by creative and fun mechanisms using yoga poses and principles at an early age [11].

Sensory

As the young infant develops control motorically in different postures, other important sensory skills are developing simultaneously. They develop skills in their visual system as they gain control of their head and neck muscles and begin to move in space. As the child grows and experiences control in more movement, they develop proprioception, a sense of body awareness to know where they are in space, in relation to the world around them and feel the surfaces their body touches in their environment. Yoga can provide this sense of body awareness as they hold various yoga positions which are essential for their sensory motor development. Their vestibular or movement system is enhanced by various postural changes, and head position as they explore different postures. The visual, proprioceptive, and vestibular systems are fundamental systems to development of a young child.

Discussion

While yoga has been known to improve mindfulness and decrease stress in persons across the lifespan, its benefits for learning have yet to be explored in young children [11]. Specifically, with young children with special needs in EI. Children today are affected by trauma and other stressors of their social-emotional development that would benefit from coping strategies [12]. These can include behavioral, breathing, focus, and meditation. Learning these at a young age can inspire children to implement practices across their lifetime. Modifications of yoga postures can be done to meet the needs of differing abilities as well. Many poses can be modified for young children who may not have the complete control or achieved the skill needed to maintain the poses.

Conclusion

Applying yoga principles to young children needs further research and continued practice to identify the benefits and strategies that work best for their young developing bodies. There is no reason to think that the benefits children ages 4 and up receive would not benefit typically developing children under 4. Further application for children with developmental delays under three with modifications is necessary under the guidance of their occupational and physical therapists. As programs develop and utilize these yoga poses to emulate benefits for younger children, it is critical that we increase the evidence to support them.

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Wednesday, July 21, 2021

Iris Publishers- Open access Journal of Advances in Cancer Research & Clinical Imaging | A Simple Screening Test for Cancer

 


Authored by  AbulKalam M Shamsuddin*

Abstract

Comparative and correlative studies of the pathology and pathogenesis of colon cancer in animal models and human disease have resulted in conceptualization of ‘field effect” theory, and identification of a simple carbohydrate marker that is expressed early during carcinogenesis. This assimilated body of knowledge has resulted in development of a simple screening test for cancers of the lung, breast, colorectum, uterus, pancreas, and prostate. The marker galactose-N acetyl-galactosamine (Gal-GalNAc) is expressed in the cell surface and secreted glycoproteins of otherwise normal appearing tissues remote from cancer or precancerous lesions and is detected by enzymatic oxidation (10 minutes) followed by color reaction (1 minute). The high sensitivity, specificity, and cost-effectiveness of this point-of-care test makes it a great tool in our strategies for early detection, hence control of cancer. It would also reduce the number of unnecessary and expensive procedures, thereby decreasing the total national health-care cost to the societies and governments, globally.

Keywords: Screening test; Lung cancer; Breast cancer; Prostate cancer; Colon cancer; FOBT

Abbreviations: AOM: azoxymethane; FOBT: fecal occult blood test; Gal-GalNAc: galactose-N acetyl- galactosamine; GOS: galactose oxidase Schiff; MNNG: N-methyl-N’-nitro-N-nitroso-guanidine; NCI: National Cancer Institute; T-Ag or TF-Ag: Thomsen-Friedenreich antigen

Introduction

Regrettably, in 2020 approximately 10 million people were killed by cancer; now-a-days there is hardly a family that is not affected by cancer. Additionally, the healthcare cost, and loss of productivity owing to morbidity and poor quality of life, has been immensely draining to families, societies, and governments alike, everywhere. This scourge has been around for a very long time with no end in sight. As in SARS-Cov-2 now, in 1971 President Richard Nixon had declared ‘War on Cancer’ to combat this menace. Alas, 50 years later, conquering cancer remains an elusive goal despite progress in treatment, albeit modest. Again, akin to SARS-Cov-2, prevention is our best alternative. Cancer prevention includes (a) detection at the very early stage of the disease (secondary prevention) to reduce cancer mortality and increase the survival rate of patients; and (b) etiology prevention or primary prevention to reverse precancerous lesions or in situ carcinomas (a cancer that is still confined) to normal or stop them from progressing to invasive malignancies in populations at high risk – ‘nipping in the bud’. Thus, early detection is fundamental to prevention, and the key is to find the marker which is differentially expressed in highrisk tissues (cancer and precancer) but not in normal. Biomarker(s) meeting this criterion is/are logical choice for establishing accurate methods to detect cancers at infancy; it may also help in monitoring the efficacy of chemoprevention program by serving as intermediate endpoint marker [1].

Fundamental to the success of prevention programs of any disease is the detection of the problems. It includes identification of people with existing disease and those who are at risk of developing the disease. Identification of people with cancer is relatively simple for most cancers because of signs and symptoms from the disease; the individual, now a patient seeks medical attention. Extensive work-up including a battery of diagnostic tests are performed and appropriate therapy is administered; regrettably, it is usually too late for many, if not for most as it does not prevent the disease. Hence the adage: an ounce of prevention is better than a pound of cure. For an effective prevention program, we must actively seek individuals with cancer or high risk thereof from an apparently healthy noncompliant population. This is done by separating i.e., screening individuals into groups with high and low probability of cancer with the help of rapid, simple, accurate, and inexpensive tests (screening tests). Implicit in the definition of screening is a promise that there is a benefit for those who participate; they will be followed with further diagnostic tests and future management of the problem. But a screening test is never intended to give the full diagnosis, hence the distinction from diagnostic tests [2]. An individual who is screening test positive will need to undergo diagnostic procedures to confirm the presence of the disease. Ideal screening tests should have a high sensitivity (proportion of diseased subjects who are test- positive) and specificity (proportion of non-diseased subjects who are testnegative), be simple and non- invasive or minimally invasive, easy to administer – therefore enjoying a high acceptability amongst populations and of course cost-effective. It would not be successful if it is shunned for discomfort, cultural, religious, or other reasons or just too expensive [2]. Currently, except for colon cancer, there are no true good screening tests for other cancers at early stages. Imaging technologies such as mammogram, chest X-ray, low dose CT etc. cannot detect early cancers, for a tumor must attain a minimum size before it can be ‘visible’ by these. And that is too late!

The Galactose Oxidase-Schiff Test

The Galactose Oxidase-Schiff Test is one such screening test that fits all the criteria of an ideal screening test as it is rapid, simple, non-invasive, easy to administer, and inexpensive. Its high accuracy has been consistently and reproducibly demonstrated independently by numerous investigators in three continents. That is not surprising because of extensive scientific research on carcinogenesis and operation of i) field-effect of carcinogens and ii) a marker differentially and specifically expressed during carcinogenesis, shared by both cancer and precancer, but not by normal or regenerating tissue.

Field-effect

I studied early detection of cancer using colon cancer as a model since 1975 at the University of Maryland School of Medicine as my PhD dissertation. The advantages of colon as a model include a) relatively easy access to samples, b) well known precancerous changes (polyps) and conditions e.g., ulcerative colitis, Crohn’s disease etc.; c) well developed animal models with d) well characterized steps of carcinogenesis viz. initiation → promotion → progression; etc. Both in vivo and in vitro carcinogenesis experiments with rats and mice were performed to see how colon cancer forms in them, and to identify the earliest recognizable changes by microscopy and histochemistry [3,4]. Colon tissue from rats and human were cultured in the Petri dishes and exposed to the carcinogens N-methyl-N’-nitro-N-nitroso- guanidine (MNNG) for rat colon [3], and fecapentaene-12 a suspected human carcinogen, for human colon explants [5]. The findings were correlated with in vivo animal models, and ultimately to the human disease [6]: what does the human colon near and far from the cancer look like (Figure 1)?

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It has been observed that the earliest recognizable change in the carcinogen-exposed tissue is an alteration in the composition of secreted mucus that persists through precancerous and cancerous tissues. The microscopic and histochemical changes in the human colon away from cancer are identical to those seen in the colons of rats (mouse colon is distinctly different from human or rat colon [7]) treated with the carcinogen azoxymethane in vivo, or MNNG for rat explants and fecapentaene-12 for human explants in vitro in Petri dishes. These changes are therefore the earliest evidence (or markers) of cancer formation – even before a cancer has formed. Using high iron diamine alcian blue technique, the mucus in the colon away from the cancer that looked normal by naked eye appears as blue (Figure 2, lower frame) as opposed to black in truly normal human colon without cancer, in the upper frame (Figure 2). Also note that the colonic glands or crypts in a cancer bearing colon appear distorted – changes identical to the rat carcinogenesis models. It was reasoned that because of the generalized effect of the carcinogen throughout the entire field of the large intestine, it is most likely that the tissue away from an obvious cancer would be abnormal – Field-Effect. The carcinogens in our environment such as the air we breathe, the food we eat etc. expose the entire lung or large bowel. Therefore, it is logical that their effect would be observed throughout the exposed field. While the vast majority of the cells will undergo DNA repair, and other host defense mechanisms such as NK cell will prevent them to progress to cancer, a few cells will be promoted and even fewer progressed to precancer and cancer who may share the same early changes as the rest of the exposed tissue in the field. (Figures 2,3).

irispublishers-openaccess-cancer-research-clinical-imaging

irispublishers-openaccess-cancer-research-clinical-imaging

Field-Effect phenomenon indicates that the entire field bears the brunt of the carcinogenic assault and expresses variable changes throughout. In the schematic drawing of the large intestine (Figure 3), it is depicted that irrespective of where a cancer or a precancerous polyp may be, areas of the otherwise normal appearing mucosa will show expression of the marker perhaps in a patchy manner (it is not practical to sample the entire large intestine to see if every millimeter has the change; hence this assumption of “patchy”). Rectum being a part of the large intestinal “field” and a convenient sampling site is therefore likely to show the same changes. Since digital rectal examination is a part of routine physical examination (though not practiced diligently by many primary care physicians now-a-days), it is simple and noninvasive. It also allows the physician to examine the prostate in males, and uterus, cervix, and adnexa in females. Samples from lungs such as coughed up sputum, nipple aspirate from breast, endocervical mucus, or prostatic secretion are likewise simple and noninvasive.

The marker: gal-galnac

The observed mucin histochemical change has further been identified as due to a biochemical alteration in the cell surface and secreted glycoprotein – presence of the carbohydrate moiety D- galactose-ß-(1-3)-N-acetyl-D-galactosamine (Gal-GalNAc, also called Thomsen-Friedenreich antigen or T- Ag, or TF antigen, though it may be different). In normal cells, a terminal sialic acid blocks the T-Ag from being recognized by the lectin peanut agglutinin (PNA), or the enzyme galactose oxidase; in cancer and precancer owing to loss of the sialic acid it is now recognizable. D-galactose oxidase specifically oxidizes C-6 hydroxyl groups of D-galactopyranose and N-acetyl galactosamine residues of Gal-GalNAc, generating two vicinal aldehyde groups that react with basic fuchsin to give magenta/purple coloration. Thus, Gal- GalNAc can be visualized by a simple enzymatic reaction with galactose oxidase followed by Schiff’s reagent, resulting in the development of a simple test for early detection, initially of colorectal cancer [8] by using rectal mucus sample.

What is an Ideal Cancer Marker According to the National Cancer Institute (NCI)?

Kelloff et al of the Division of Cancer Control and Prevention (DCCP) at the National Cancer Institute [1] outlined six criteria for intermediate endpoint biomarkers of use in chemoprevention, and here is how Gal-GalNAc and STEDi live up to those expectations:

Is the intermediate biomarker differentially expressed in normal and high-risk tissue? YES!

Figure 4 shows the expression of Gal-GalNAc (magenta) in a colon cancer but, not by the normal human colon (Figure 5). The normal tissues were obtained from healthy normal people without any cancer. Note the absence of magenta color in the mucus of normal colonic goblet cells. Also note that the colonic glands or crypts in truly normal humans appear uniform test tube shaped as compared to the those in cancer-bearing colon or in rats treated with the carcinogen azoxymethane (see Figure 4-6).

irispublishers-openaccess-cancer-research-clinical-imaging

irispublishers-openaccess-cancer-research-clinical-imaging

irispublishers-openaccess-cancer-research-clinical-imaging

At what stage of carcinogenesis does the marker appear?

The earlier a reliable marker appears in the carcinogenic process, the greater is the chance for successful intervention. Answer: Gal-GalNAc is expressed very early during carcinogenesis. Not only the marker is expressed early during the carcinogenesis in rats in vivo (Figure 6 left panel) but also by human precancerous polyp (right panel appearing as purplish). The colors are slightly different owing to different batch of staining and tissue preparation. The mucus alteration is also observed in rat and human explants exposed to carcinogens in vitro [4,5]. Note the distorted appearance of the colonic glands as opposed to uniform test tube shaped ones in normal (Figures 5,6).

Does the marker and its assay provide acceptable sensitivity, specificity, and accuracy?

Answer: Both the marker [9,10] and the assay [11-14, Table I] enjoy 70-100% sensitivity and specificity. That it is not expressed by regenerating cells following wounding is an added evidence that Gal-GalNAc is carcinogenesis specific [10]. Please see the results on colon cancer in the following Table: results on other organ sites are provided after this: (Table 1)

Table 1: Performance Summary of GOS Test for Colorectal Cancer.

irispublishers-openaccess-cancer-research-clinical-imaging

The proof of field-Effect: Schematic diagram of the human large intestine depicting the location of the cancers detected by the rectal mucus test. That the “field-effect” phenomenon is operational is proved by the detection of cancers in the various segments of the colon remote from the rectum where the mucus was sampled from. Note that 4 of 5 cancers (80%) of the ascending (or the right) colon, 5 of 7 (71.4%) of the descending (or the left) colon and 29 of 33 (87.9%) of the sigmoid colon were detected in the two studies by Sakamoto et al [11,12] (Figure 7). The widely used current fecal occult blood test (FOBT) for colon cancer screening has been notoriously inaccurate; “Occult blood testing is, at best an imperfect approach to the screening of colorectal cancer” concluded Dr. Ahlquist [15]. And that is not surprising since blood is not a marker of cancer or precancer. A newer test combining FOBT and DNA in stool appears to have better sensitivity and specificity albeit at a very high price.

irispublishers-openaccess-cancer-research-clinical-imaging

Gal-GalNAc is a common tumor marker: The usefulness of the tumor marker Gal-GalNAc in differentiating the benign from the malignant and pre-malignant lesions of the prostate was tested [16] yielding similarly high sensitivity and specificity (vide infra). Having determined that the principle is practicable in colon and prostate, studies were conducted on other cancers. The expression of Gal-GalNAc determined in a total of 133 tissue samples from 81 cases of the carcinomas of the breast, ovary, pancreas, stomach, and endometrium and 52 cases of respective normal controls [17]. None of the 52 cases of normal tissues (except 15 cases of stomach) showed expression of Gal-GalNAc. In contrast, 100% of adenocarcinomas from the breast (19 of 19), ovary (15 of 15), and pancreas (6 of 6), and 94.1% of stomach (16 of 17) cancers, and 91.7% (11 of 12) of uterine adenocarcinomas expressed Gal- GalNAc. The normal epithelia and their secretions in the vicinity of the carcinoma (within the “field”) in the breast, bronchus, endometrium, and pancreatic duct also expressed Gal-GalNAc in contrast to normal tissues obtained from non-cancerous individuals, which were totally non-reactive. Thus, the tumor marker Gal- GalNAc recognized by galactose oxidase-Schiff sequence was highly expressed not only by a variety of adenocarcinomas but also by the apparently normal-appearing epithelia and their secretions in the vicinity of carcinomas confirming the operation of a field effect phenomenon by carcinogenic agent(s) in these organs as well, setting the stage for identification of the marker in these secretions for mass screening for these cancers too [17].

Studies on lung cancer: Twelve of 12 pulmonary adenocarcinomas expressed Gal-GalNAc. The bronchial tissue away from the cancer were available in 4 cases, all of whom also expressed the marker both in the epithelial lining cells as well as in the secreted mucus [17]. Coughed-up sputum therefore can be used to screen people for cancers of the lungs. Indeed, three clinical studies on lung cancer were performed on coughed up sputum [18-20]. Lai et al [18] reported the results of their study on sputum specimens from 116 healthy persons; and 216 cases of benign and malignant lung diseases were tested for the marker Gal-GalNAc. The result showed that 165 of the 182 patients (90.7% sensitivity) with lung cancer, confirmed by cytology and histology, had positive results, whereas 22 of 116 (19.0%) healthy controls were positive (81.0% specificity, Table 2). In 28 cases of patients whose sputum cytology showed various degrees of dysplasia-a precancerous condition that progresses to cancer, 21 were found Gal-GalNAc positive, of which 15 patients were identified to have lung cancer on further work-up! Thus, the concept of “false positive” as generally used does not apply to Gal-GalNAc and the GOS Test since they take the precancerous lesions and early cancers into consideration. In addition, three cases of early lung cancer in this study were also positive, supporting the fact that Gal-GalNAc is expressed at an earlier stage in the malignant process of the lung as well. The studies by Cox & Miller [19] and Miller et al [20] had smaller sample size and showed sensitivities of 64.7 – 88% and specificities of 77.8 – 93.6%. The test revealed 20 of 23 lung cancers among 76 patients. The other 53 patients were either healthy or had benign lung disease such as bronchitis. Even more germane to the issue of prevention is the fact that 13 of 15 cancers detected were early stage (Stage I and II). Of note is that a tumor must attain a minimum size before it can be detected by imaging techniques. And that is late! (Figures 8,9) (Table 2).

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irispublishers-openaccess-cancer-research-clinical-imaging

Table 2: Lung Cancer study.

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Breast cancer study: Gal-GalNAc is also expressed by the normal-looking breast tissue away from an obvious cancer by way of the field-effect phenomenon [17]. The marker was positive in 19 of 19 histological specimens of breast cancer giving it a 100% sensitivity. More importantly, and germane to our screening, the ducts away from the cancers and close to the nipple also express the marker both in the cells as well as in the secretions in the ducts. Thus, the nipple aspirate from a breast harboring a cancer should express the marker. Kumar et al [21] demonstrated that Gal-GalNAc (or TF antigen) is differentially expressed in nipple aspirate, albeit using a different technique – monoclonal anti- TF antibody. Nineteen of 25 cancer patients and none of the 25 healthy controls were positive yielding a 100% specificity and 76% sensitivity. The relatively low sensitivity of the test in nipple aspirate as opposed to tissue expression may be due to the use of different techniques for identifying the marker – galactose oxidase Schiff’s v monoclonal anti-TF antibody. Chagpar et al [22] also reported the utility of using nipple aspirate and Gal-GalNAc in screening for breast cancer. They investigated 23 women with biopsy confirmed, unilateral stage I or II breast cancer. They took samples (nipple aspirate by way of a suction cup attached to a syringe) from both breasts prior to surgery. Most, but not all the women were able to provide large enough fluid samples that could then be evaluated. Based on the resulting color of the test strips one could differentiate between a healthy and cancerous breast (Figures 10,11).

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irispublishers-openaccess-cancer-research-clinical-imaging

irispublishers-openaccess-cancer-research-clinical-imaging

Prostate cancer study: The current screening test-PSA is inaccurate primarily because it is non-specific; its level goes up in benign conditions as well. The marker Gal-GalNAc is differentially and specifically expressed in prostate has also been observed in histological sections taken from 65 cases of adenocarcinoma [16]. While none of the 35 benign prostates and 11 foci of adenosis expressed Gal-GalNAc (100% specificity), 62 (95.4% sensitivity) of 65 adenocarcinomas expressed the marker. That the expression of the marker is not non-specific (meeting the NCI’s criteria #3) has been demonstrated by the absence in 25 samples of benign prostatic hyperplasia (BPH) and 11 of adenosis, neither of which are precancerous, nor were the normal prostates (10 samples) giving the marker a specificity of 100%. Notably, foci of prostatic intraepithelial neoplasia when present in some of the cancer specimens were also positive (Figure 12), demonstrating the useful of this marker in identifying early cancers [16]. As for colon, lungs, and breast, testing prostatic massage secretion or seminal fluid with GOS test should yield similar results (Figure 12).

Uterine cancer: Currently there are no screening tests for uterine cancers except for maybe the Pap smear wherein a uterine cancer could be detected by chance; but it is usually advanced when the cancer cells shed from endometrium are detected in Pap smear. Expression of Gal-GalNAc with high sensitivity (91.7%) was observed in 12 cases of uterine endometrial adenocarcinoma [17]. In all three cases where endocervical tissues was available, the endocervical mucus was positive for Gal- GalNAc. The photomicrograph (Figure 13) shows histological section of endocervix of a patient with endometrial adenocarcinoma; magenta coloration of the mucus in the endocervical glands and in endocervix is evident. Again, this supports the Field-Effect of carcinogenesis. More importantly, this makes it a simple, convenient, and non-invasive method of screening for endometrial adenocarcinoma while a gynecologist routinely collects samples for Pap smear (Figure13).

irispublishers-openaccess-cancer-research-clinical-imaging

irispublishers-openaccess-cancer-research-clinical-imaging

Pancreatic cancer: Pancreatic cancer is one of the deadliest of all cancers, primarily because of its silent inception; and owing to its location, signs and symptoms do not show till very late. All 6 of 6 cases of adenocarcinoma of pancreas were positive for Gal- GalNAc, and the normal ducts away from the cancers also showed positive reaction [17]. Thus, GOS test could be performed on fluid samples including pancreatic juice obtained during ERCP (endoscopic retrograde cholangiopancreatography) thereby providing additional value to the screening of the cancer. Figure 14 shows an adenocarcinoma of the pancreas with magenta color in the cancerous ducts and glands. (Figure14).

How easily can the marker be measured?

Answer: GOS test for detection of the marker is non-invasive done on mucus sample obtained during routine digital rectal examination, coughed-up sputum, nipple aspirate, prostatic massage secretion, endocervical mucus etc., and the entire assay period is ~15 min. This is the only point-of-care test for breast, lung, colon, prostate, and uterus; the results are available before the individual is ready to leave the doctor’s office. The test sample is placed on a special paper and reacted with galactose oxidase for 10 minutes, rinsed with distilled water, reacted with Schiff’s basic fuchsin for 1 minute, washed with tap water and dried. A pinkmagenta- purple color is positive, no color is negative (Figure 15). Positive indicates the presence of the marker Gal-GalNAc which is correlated with the presence of precancer, precancer or a high-risk thereof (Figure15).

irispublishers-openaccess-cancer-research-clinical-imaging

irispublishers-openaccess-cancer-research-clinical-imaging

Note: Though desirable, quantitative evaluation of the color reaction is neither practical nor meaningful as studies have shown no correlation between the intensity of color and the underlying disease.

Can the marker be modulated by chemo preventive agents?

Answer: YES! Sakamoto et al. [23] and Yang & Shamsuddin [24] have demonstrated that; indeed Gal-GalNAc expression can be suppressed by the chemo preventive agent IP6 [25,26]. Figure 16 shows that HT-29 human colon cancer cells express the marker Gal- GalNAc (magenta color in mucus of cells in left panel). Following IP6 treatment, HT-29 cells terminally differentiate and produce mucin, yet not Gal-GalNAc, akin to normal goblet cells (right panel showing a differentiated HT-29 cell that has a mucus vacuole yet not expressing the marker [23,24]. Clinical studies are needed to validate this, but that would take a very long time. In this regard of particular importance is the study on colon cancer by Vucenik et al [13] where 32 of 53 (60%) samples collected from patients after tumor resection showed persistence of the biochemical change; 5 out of these 32 (16%) post-operative cases with positive GOS Test had tumor recurrence within a year. Thus, persistently positive test may serve as a predictor of tumor recurrence (Figure16).

Does modulation of the intermediate biomarker correlate with a decrease in cancer rate?

This would require a long time-years if not decades, and additional resources.

In conclusion, GOS test is a point-of-care screening test that is very simple, rapid, non-invasive, and inexpensive yet accurate for identifying asymptomatic people who may be at high risk of cancer or precancer of the lung, breast, colon, pancreas, prostate, and uterus. It is based on robust scientific background; researched and validated over three decades in >20 independent clinical studies in North America, Europe, and Asia. It exploits a disaccharide marker expressed early during carcinogenesis that persists in precancer and cancer and, satisfies all the practical rigid criteria set forth by NCI for an ideal marker. Given the fact that cancers of the lungs, breast, colon, prostate, and uterus comprise the most cancers, it is in the interest of public health that they are identified at a very early stage, or even before they are formed. The sooner it is used, the more lives could be saved from these cancers.

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Tuesday, July 20, 2021

Iris Publishers- Open access Journal of Pediatrics & Neonatal Care | Prevalence of Different Types of Leukemia and Associated Factors among Children with Leukemia in Children’s Cancer Units at Al-Kuwait Hospital, Sana’a City: A Cross-Sectional Study

 


Authored by Hassan A Al- Shamahy*


Introduction

Leukemia is the most common type of cancer in childhood, accounting for 25 percent of all cancers that occur before the age of 20. There are two main types of childhood leukemia - acute lymphocytic leukemia (ALL), which accounts for about three quarters of leukemia, and acute myeloid leukemia (AML) accounting for most of the rest of the leukemia cases. ALL is a disease that affects about three quarters of leukemia. The hematopoietic tissue in the bone marrow is characterized by the overproduction of immature lymphocytes (a type of white blood cell). ALL occurs at all ages, from birth to adulthood, but the incidence peaks between 2 and 6 years of age. In the United States, there is a majority of white and male children and young adults with ALL. Improvements in treatment have led to remarkable gains in survival, estimated at 79 percent at 5 years. Acute myeloid leukemia is a cancer of the myeloid white blood cell line that occurs at all ages from childhood. The outcome for AML is poorer than for ALL, with a 5-year survival rate of 41 percent [1,2]. The precise cause of leukemia is not up till now obvious. Nevertheless, a lot of factors, mainly genetics, genetic mutations, epigenetic lesions, ionizing radiation, other chemical and occupational contacts, curative drugs, smoking and some viral agents, have been concerned in the development of leukemia [3-8]. Commonly 2 types of classification systems are used for leukemia: (the Franco-American and British classification system (FAB), which relies on morphology and cytochemical staining to identify specific types of leukemia, and the World Health Organization (WHO) that reviews classification information, cytomorphology, cell chemistry, immune profiling, cytogenetics and clinical features to identify and classify clinically significant disease entities [9,10]. Lymphoma malignancies correspond to a heterogeneous group of illnesses separated into four classes established on tumor cell maturity and disease distribution such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), lymphoma malignancies, plasma cell tumors and hairy cell leukemia [11].

Globally Leukemia involved 200,676 males and 151,289 females (with ASR 5.6 and 3.6, respectively). There were 46,449 males and 35,880 females diagnosed in 2012 with leukemia in Europe. In Australia, Asia and the USA about 233,451 residents were diagnosed with leukemia by 2017. In contrast, in Africa by 2012, it has a rate of incidence equal to 23,928 cases (ASR 3.0 per 100,000) [12-14]. Leukemia was the most common type of cancer among children (including 29% of 3,707 cancer cases in children, and acute leukemia counting 89% (91% of which were ALL and 9% AML) of all cases of leukemia in children [15].

In developing countries, the influence of leukemia is massive attributable to premature death of children, loss of parents, failure of productivity due to disability, and high medical costs affecting the social, economic and health well-being of the population [16- 18]. While leukemia is treated very well in the developed world, there is little evidence of the current state of the disease in Yemen in general and in the study area in particular. On the other hand, in Yemen as is the case in most Arab countries, there are few specialized epidemiological records devoted to this area, and for this reason it is important to encourage, update, build and continue to present studies on childhood leukemia with the goal of achieving greater impact on public health, with early diagnosis and appropriate treatment aimed at enhancing survival and minimizing potential consequences. According to the limited Yemeni Cancer Studies, the most common types of cancer among Yemeni children and adults were leukemia (33.1%), lymphoma (31.5%), central nervous system tumors (7.2%), and bone tumors (5.2%) [19- 21]. This cross-sectional study aims to determine the prevalence of different types of leukemia and the associated factors among children with leukemia in the pediatric cancer units of Al-Kuwait Hospital, Sana’a City.

Patients and Method

A cross-sectional study was conducted on children with leukemia who were treated selectively in the pediatric leukemia units of Al-Kuwait University Hospital in Sana’a. Group diagnostics and histopathological diagnoses were formed in line with the French, American and British classifications of leukemia in children in the pediatric leukemia units, over a period of 5 years from January 1, 2014 to December 31, 2018. Factors associated with become infected with leukemia that were studied included ages, sex, and outcomes. The association of death and recovery with different age groups and leukemia types was also studied through rates and calculation of OR, CI, X2 and p values through probability tables (2x2 tables).

Statistical Analysis

Data were recorded using appropriate descriptive statistics (including frequency, mean, and standard deviation). The odds ratio (OR) was used to determine the strength of the association between two events, such as leukemia, age, gender, and residence. The association between death, age, and type of leukemia. In addition to calculating the relationship between cure, age of patients, and types of leukemia. The two events in the current study were independent if and only if OR was equal to 1. For sample constraints of odds ratio in small numbers (less than 5), Fisher’s exact test was used as an alternative estimator for the association between events in the current study.

Ethical Approval

Ethical approval was obtained from the Medical Research & Ethics Committee of the Faculty of Medicine and Health Sciences, Sana’a University. All data, including patient identification were kept confidential.

Results

Table 1 shows the age and gender distribution of children with childhood leukemia in Sana’a, Yemen. The mean ± SD age of all cases was 6.44 ± 3.7 years. Most of the cases were in the age group 1-5 years (50%), followed by the age group 6-10 years (32.1%), while only 17.9% of the cases were in the age group 11-15 years (disease decreases with increasing age). As for gender, most of the cases were males (66.7%), while the percentage of females was 33.3% (male to female ratio = 2-1). Table 2 shows leukemia outcomes among children suffering from childhood leukemia in Sana’a, Yemen. The cure rate was 40.7% while the death rate was 15 cases (6.2%), all of them male (male mortality rate = 9.3%). The relapse rate was 2%. The rest of the cases were in maintenance therapy (31.5%), induction therapy (15.4%), and consolidation (post-remission therapy) for 4.3% of cases. Table 3 shows the age-group association of death among children with childhood leukemia in Sana’a, Yemen. The highest mortality occurred in the 6-10 year age group (8/78; 10.2%), with an associated OR = 2.6, CI = 1-7.4, X2 = 3.4, p = 0.06. However, the low mortality rate was 3.3% in the 1-5 year group, without association (OR = 0.34, p = 0.06). Also, in the 11--15 yearold group, the death rate was 6.8% roughly similar to the overall death rate (6.1%).

Table 1:Age and gender distribution of children with childhood leukemia in Sana’a, Yemen.

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Table 2:Leukemia outcomes among children suffering from childhood leukemia in Sana’a, Yemen.

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Table 3:The association of death with age groups among children suffering from childhood leukemia in Sana’a, Yemen.

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Table 4 shows the type of leukemia association of death among children with childhood leukemia in Sana’a, Yemen. Acute lymphoblastic leukemia was the most common, accounting for 78.7% of the total, while the other types were less common, with acute myelogenous leukemia count of 15.6%, chronic myelogenous leukemia at 4.5% and Juvenile myelomonocytic leukemia only at 1.2. %. The highest mortality occurred in the AML (4/38; 10.5%), with an associated OR = 2.1, CI = 0.6 – 6.9, X2 = 1.5, p = 0.22. However, the mortality rate was 5.7% in the ALL patients, without association (OR = 0.72, p = 0.6).There was no death occurred in CML and JCM cases (0%). Table 5 shows the age-group association of cure among children with childhood leukemia in Sana’a, Yemen. The cure rates were roughly similar in the different age groups. It is ranged from 38.5% in 1-5 year group to 43.2% in 11-15 year group. Table 6 shows the type of leukemia association of cure among children with childhood leukemia in Sana’a, Yemen. The highest cure rate occurred in the JCM (2/3; 66%), with an associated OR = 2.9, CI = 0.2 – 33, X2 = 0.8, p = 0.3. The second high cure rate occurred in the CML (7/11; 63.6%), with an associated OR = 2.6, CI = 0.7 – 9.4, X2 = 2.5, p = 0.11. However, the cure rate was 23.6% in the AML patients, without association (OR = 0.4, p = 0.02). The cure rate was 42.2% in the ALL patients, with association (OR = 1.4, p = 0.3).

Table 4:The prevalence and association of death with type of leukemia among children suffering from childhood leukemia in Sana’a, Yemen.

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Table 5:The association of cure with age groups among children suffering from childhood leukemia in Sana’a, Yemen.

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Table 6:The association of cure with type of leukemia among children suffering from childhood leukemia in Sana’a, Yemen.

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Discussion

Information of the prevalence of leukemia in a population may envisage pathogenic hypotheses for disease control and aid in the effective management of leukemia and other malignant hematomas. In developing countries, and especially in Yemen, there is little information about the burden and patterns of haematological malignancies, especially leukemia. In the current study, with regard to gender, most of the cases were male (66.7%) while the percentage of females was 33.3% (male to female ratio = 2:1). This finding differs from that reported in Africa where the ratio of males to females is roughly equal, although females dominate slightly (1: 1.06) [22], but similar to that reported from the United States where the American Cancer Society estimates for leukemia in 2021, about 5,690 new cases, 3,000 in males and 2,690 in females [23]. The current results of different leukemia prevalence rates among gender are in line with the facts that the prevalence of leukemia must be varies according to gender due to the biological factors [11,15,24,25].

Leukemia may appear at all ages, from newborns to the elderly, but the distinctive forms have different age distributions [26]. In the current study, the mean age of ± SD for all cases was 6.44 ± 3.7 years and most of the cases were in the age group 1-5 years (50%), followed by the age group 6-10 years (32.1%), while only 17.9% of the cases were in the age group 11-15 years (Table 1). This is similar to what has been reported elsewhere for pediatric leukemia where the mean age ± SD of pediatric leukemia cases was 6.0 years with a peak incidence at 6-10 years [2,12,14]. This differs from the leukemia hypothesis with age in which older children may develop leukemia more frequently than younger children due to advancing age, as many environmental exposures to carcinogens, irradiation, and malignant mutations due to clonal expansion occur more often [27,28]. However, most of the younger children in the current study could be explained by the fact that prenatal and early life exposure is thought to be important determinants of childhood leukemia. Several mechanisms have been identified through which external and internal factors can influence the risk of developing leukemia in children. Exposure to a carcinogen or toxic substance early in a female’s life may cause permanent damage. Since no new oocytes are formed after birth and their maturation begins during pregnancy, the exposure that occurs during this critical time can be of great importance. During pregnancy, exposure to agents such as ionizing radiation may act directly while others may act indirectly by transporting the placenta. On the other hand, offspring may be exposed after birth to environmental exposure, either directly or indirectly [29]. Since most of the children are from rural areas, they may have been exposed to various environmental exposures during their stay with their parents who are farmers.

Environmental factors, even though not well articulated, influence the chance of developing leukemia. In this study, the highest proportion of 68.9% out of the total of 244 patients diagnosed with leukemia was observed among rural residents (p < 0.05). In Yemen, rural residents’ lifestyle is based on agricultural activities such as farming and plantations agriculture; especially Gat, fruits and vegetables plantation are the major practice around the study area, thus this may lead to the repeated use of chemicals such as pesticides, herbicides, and fertilizers for agricultural activities which will result in genetic mutations conferring leukemia [30].

Leukemia types were determined using the FAB classification method [10,11], Wright-stained morphological examination, and cytochemical staining with Sudan black B staining to differentiate the cell lineage. In this study, acute lymphocytic leukemia was the most common, accounting for 78.7% of the total, while the other types were less common, with acute myelogenous leukemia count of 15.6%, chronic myeloid leukemia 4.5%, and juvenile myeloid leukemia at only 1.2%. This result was consistent with results from Ethiopia, Nepal, and Pakistan [22,31], while it was contradictory with a study from Albania [32]. In the current study, the highest mortality occurred in the 6-10 year age group (8/78; 10.2%), with an associated OR = 2.6, CI = 1-7.4, X2 = 3.4, p = 0.06. However, the low mortality rate was 3.3% in the 1-5 year group, without correlation (OR = 0.34, p = 0.06). These results are consistent with the American Cancer Society’s fact that most cases of leukemia occur in young children, but most deaths occur in older children. Very young children may perform better than older children due to differences in the nature of leukemia in children, differences in treatment (often young children’s bodies can handle aggressive treatment better than older children), or a combination of these [23]. The highest mortality occurred in AML (4/38; 10.5%), cure rate = 23.6%. However, the mortality rate was 5.7% in ALL patients, with cure rate = 42.2%. These results are in line with findings by the Leukemia and Lymphoma Society of the USA where the 5-year survival rate for children and adolescents under the age of 15 years diagnosed with ALL was 91.8% in the United States between 2007 and 2013. While the survival rate for children under 15 years of age with AML was only 66.4% for the same period [33].

Conclusion

ALL is the most common type of leukemia in Sana’a city; and males and young children are affected the most by leukemia. In the current study there was an association between leukemia and younger age group, with males. There was an association between high mortality and the 6-10 year age group, with AML. Also, there was no association between ages and cure rate, but a high cure rate occurred with JCM and CML. More comprehensive investigations of relevant factors and predictors are needed with more modern diagnostic methods and investigate correlation factors with the treatment protocols used.


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