Understanding Allergic Rhinitis and Non-Small Cell Cancer from

Pathology to Treating Practice with Case Reports

Yuxuan Jiang

1,#,* a

, Yu Li

2,# b

, Baiqing Sun

3,# c

and Yongli Zhang

4,* d

1

College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, U.S.A.

2

Faculty of Art & Science, University of Toronto-St. George, Toronto, ON M5S, Canada

3

Department of Pharmacy, Uppsala University, Uppsala, Uppsala, 75321, Sweden

4

Department of Critical Care Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China

#

These authors contributed equally to this paper

Keywords: Respiratory Diseases, Allergic Rhinitis, Non-Small Cell Lung Cancer.

Abstract: Recently, COVID-19 has caused a pandemic and received substantial medical attention worldwide.

Subsequently, we recognize the increasing public interest in not only antiviral treatments, but general

respiratory health. Respiratory diseases can take place by endogenous as well as exogenous causes.

Suffering from an unhealthy condition of the respiratory system, from annoying issues as seasonal allergic

rhinitis, all the way to lethal lung cancer brings loads of burden to not only an individual, but also the whole

society. Efficient care and treating practices thus require urgent improvement. Here we present a systematic

study from case reports for the comprehensive understanding of therapeutic options progress focused not

only the currently available, but also under development strategies for the summarised respiratory diseases

based on the pathophysiology understanding. To be specific, currently available treatment options for these

diseases, including pharmacological, immunogenic in according with oncogenic factors and relative

treatments for NSCLC, whose efficacy and side effects are well-characterized. We also discuss and envision

future treatment options that are underway of development, which may lead to advancements in both

potency and reduced adverse effects. Applications of technologies should also be considered promptly by

medical professionals.

1 INTRODUCTION

1

Cells in human bodies need oxygen to stay

functional and alive, inhalation of oxygen from the

atmosphere to the human body depends on the lungs

and the function of the respiratory system. Oxygen

first fills the alveoli and is delivered to each of the

organs through blood vessels. The respiratory

system has numerous functions in addition to gas

exchange, and it is a crucial site where the interior of

our body constantly ‘communicates’ to the extrinsic

environment. People cough and sneeze to protect

their airways from irritants that may cause diseases.

Aerobic organisms have developed numerous

defense mechanisms to protect the airway as they

a

https://orcid.org/0000-0002-2582-6808

b

https://orcid.org/0000-0002-4921-8831

c

https://orcid.org/0000-0001-7966-5627

d

https//orcid.org/0000-0002-4263-8382

evolve. However, respiratory illness remains the

leading cause of death and disability (Soriano 2020).

This main global burden should be thoroughly

studied to enhance the quality of human lives.

Upon understanding the significance of treating

respiratory diseases, we realize that various types of

respiratory diseases that affect different subsections

of the respiratory tract have been investigated in the

medical field. Our review will focus on respiratory

diseases that are highly prevalent and have

contributed heavily to the public health burden, such

as Allergic rhinitis (AR), and Non-Small Cell Lung

Cancer (NSCLC). We selected these diseases as

references for analysis, as they differ in pathogenesis

and treatment options, representing distinct

categories within the broad scope of respiratory

pathology. Until recently, potential therapeutic

targets for all three diseases have been identified.

Several treatment options for AR and NSCLC are

widely implemented in clinical practices, while

416

Jiang, Y., Li, Y., Sun, B. and Zhang, Y.

Understanding Allergic Rhinitis and Non-Small Cell Cancer from Pathology to Treating Practice with Case Reports.

DOI: 10.5220/0011213700003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 416-425

ISBN: 978-989-758-595-1

Copyright

c

optimizations and novel drugs are still being

explored.

In order to assist the public in the understanding

of respiratory diseases, here we provide a systematic

review of allergic rhinitis, COVID-19, and non-

small cell lung cancer from bench to bedsides. We

summarized the pathophysiology of each disease, as

well as research leading to target identification and

currently accepted treatment practices. Furthermore,

we discussed the ongoing research suggesting

potentially novel and more effective treatment

approaches with emphasis on drug development.

This paper is organized in three parts as each talks

about one disease, with an ordered sequence from

the upper to the lower respiratory tract.

2 ALLERGIC RHINITIS

Seasonal allergic rhinitis is caused by oversensitive

immune response to certain allergens in the

environment that are not generally considered

harmful, which mainly affects the upper respiratory

tract. The disease affects a large percentage of the

general population, which leads to a number of

complications that severely impacts patients’ quality

of life and leads to decreased productivity at the

workplace (Lamb 2006). Although allergic rhinitis is

not a particularly serious condition, treatments that

relieve symptoms still constitute a medical need.

The currently accepted therapeutic standards are

antihistamines, intranasal corticosteroids and

antileukotrienes, which target different mediators of

the immune response pathway (Emeryk 2019).

Recently, anticholinergic drugs have received

attention for their anti- inflammatory properties,

which are being repurposed as maintenance therapy

for AR and have gained FDA approval. Some

researchers have also proposed the activation of the

anti-inflammatory cholinergic pathway as a potential

therapeutic approach, which requires further

pharmacological and clinical investigation (Yamada

2018).

2.1 Pathology and Complication

Generally, allergic rhinitis (AR) is characterized by

oversensitive IgE-mediated immune response to

allergens and upper airway inflammation (Wheatley

2015). Symptoms include nasal itching, sneezing,

watery rhinorrhea, and nasal obstruction (Min 2010).

The disease is caused by immune sensitization to a

large variety of inhaled allergens with either indoor

or outdoor origins, including pollen, dust mites, pets,

pests and mold (Wheatley 2015). From the

pathophysiologic perspective, dendritic cells present

characteristic peptide segments on the cell

membrane to form histocompatibility complex

(MHC) class I and II when exposed to allergens,

which signal the transformation of naive CD4+ T

cells to T-helper (Th2) cells. Allergen-specific Th2

cells secrete several Th2-type cytokines such as IL-

3, IL-4, IL-5 and IL-13. Among these cytokines that

are essential for inflammatory responses, IL-4 and

IL-13 promote allergen-specific IgE production by B

cells, which induces the proliferation of eosinophils,

macrophages, and mast cells. Mast cells release

several inflammatory mediators, including histamine

and leukotrienes, which are responsible for increased

nasal itching, vascular permeability, and mucus

hypersecretion (Min 2010, Small 2018, Meltzer

1997). This stage of allergic response constitutes the

early reaction (Min 2010). IL-3 and IL-5, on the

other hand, promotes eosinophil proliferation and

infiltration into the nasal mucosa, which secretes

pro-inflammatory mediators, cationic proteins, and

reactive oxygen species, directly contributing to

increased mucus production and airway constriction

(Antunes 2020). This process triggers the late

reaction, exhibiting nasal congestion, smooth muscle

hyperplasia and airway remodeling as chronic

symptoms (Figure 1) (Min 2010).

Although mild to moderate allergic rhinitis rarely

has serious complications, pharmacological therapy

is recommended by physicians due to the disease’s

significant impacts on patients’ quality of life and

association with secondary inflammatory

complications. AR contributes to unproductive time

at school or work, sleep apnea, and reduced

cognitive abilities, which results in indirect

economic loss comparable to that of mental

disorders and diabetes (Lamb 2006, Wheatley 2015).

Clinical reviews have suggested an increased risk for

several comorbidities if chronic AR is left untreated,

including conjunctivitis, sinusitis, and otitis media

with effusion (OTE) (Min 2010). Study results have

proposed that inflammation involved in AR results

in impaired ciliary function and sinus obstruction,

which creates an anaerobic environment favorable

for bacterial growth that eventually facilitates

middle ear infection and chronic OTE (Bergeron

2005). Other complications of AR, such as nasal

polyposis and adenoid hypertrophy, are suggested by

clinical evidence, although their association with

rhinitis has not been investigated thoroughly (Min

2010).

The association between allergic rhinitis and

asthma is especially pronounced due to their similar

Understanding Allergic Rhinitis and Non-Small Cell Cancer from Pathology to Treating Practice with Case Reports

417

disease pathophysiology. Clinical data has

confirmed that up to 40% of AR patients have

concomitant asthma, and 94% of asthma patients

have AR (Wheatley 2015). In AR patients without

asthma, eosinophil infiltration, lymphocyte number,

and increased IL-5 production in the bronchial

mucosa have been observed after antigen challenge

(Min 2010). It has been proposed that AR-induced

airway hyperresponsiveness contributes to an

increased risk of asthma through migration of IL-5

producing T cells to the bone marrow, which is

associated with an increase in progenitors that can

differentiate into eosinophils (Bergeron 2005).

Eosinophils in the lower airway contribute to airway

remodeling through the release of cytokines and

reactive oxygen species (ROS), which stimulates

mucus hyperproduction, eosinophil recruitment and

damage to the bronchial mucosa (Kudo 2013). Kudo

et al. also pointed out that cytokine and leukotriene

production lead to proliferation of airway smooth

muscle cells and deposition of extracellular matrix

by myofibroblasts (Kudo 2013). The confirmed

association between AR and allergic asthma

becomes the basis for identifying biological targets

that are involved in the pharmacological treatments

of both diseases.

Figure 1: Pathogenesis of allergic rhinitis. Allergen

binding activates the immune system’s intracellular

signaling pathway, releases inflammatory molecules and

causes chemotaxis of immune cells to the upper

respiratory tract tissue (Min 2010).

2.2 Treatments

2.2.1 Current Treatment Options

Several types of pharmacological treatments

available for allergic rhinitis include oral and

intranasal antihistamines, antileukotrienes,

decongestants, and intranasal corticosteroids. These

drugs have well- characterized pharmacokinetic and

pharmacodynamic profiles from clinical trials.

Although each drug class targets a different step in

the inflammatory response pathway, almost all are G

protein-coupled receptor antagonists, demonstrating

the selection of receptor proteins as excellent

therapeutic targets.

Antihistamines target the H1 histamine receptors,

which mainly mediate hypersensitive reactions and

allergic responses (Devillier 2008). At the periphery

level, antihistamines bind to H1 receptors and

stabilize their inactive form, inhibiting allergic

reactions induced by histamine binding (Devillier

2008). Synthesized by lipoxygenase from

arachidonic acid, cysteinyl leukotriene (Cys-LT) is a

class of lipid mediators that act as autocrine and

paracrine factors in eosinophils, which promote the

release of ROS, cationic proteins, and cytokines that

directly contribute to inflammation (Miyata 2020,

Kuehl Frederick 1980). Antileukotrienes inhibit the

effects of Cys-LT as Cys-LT receptor type 1

antagonists, thereby reducing the level of cytokines

and eosinophil chemotaxis to the site of

inflammation (Miyata 2020, Wilson 2004). Note that

dysfunction of arachidonic acid metabolism also

appears in allergic asthma patients, which indicates a

close association between rhinitis and asthma

treatments (Miyata 2020). Corticosteroids are

glucocorticoid receptor antagonists, which are

observed to inhibit the production of multiple

inflammatory mediators, including cytokines (IL-3,

IL-5, granulocyte-macrophage stimulating factor)

and arachidonic acid metabolites. Thus,

corticosteroids suppress T-cell activation, eosinophil

influx, cytokine release, mast cell count, and

histamine content, relieving inflammatory symptoms

effectively (Meltzer 1997). In summary,

antihistamines and antileukotrienes target the final

and intermediate steps, while corticosteroids have an

observable effect on multiple steps of the

inflammatory response pathway.

Among these treatment options, intranasal

corticosteroids have been confirmed as the most

effective by several meta-analyses of randomized,

controlled clinical trials (Wilson 2004). Therefore,

corticosteroids, sometimes in combination with

antihistamines, are recommended by physicians as

the frontline treatment that controls symptoms of

moderate-to-severe allergic rhinitis (Wheatley 2015,

Min 2010, Small 2018). Antihistamines and

antileukotrienes are often prescribed as combined

treatment to control mild persistent allergic rhinitis,

but their potency is less than that of intranasal

corticosteroids (Rodrigo 2006, Ciprandi 2004). We

speculate that the enhanced potency of

corticosteroids can be attributed to its effect on

multiple steps of the inflammatory pathway, which

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

418

is yet to be confirmed by clinical evidence. Due to

the seasonal or perennial nature of allergic rhinitis,

regular administration of symptom-relieving

pharmacological agents during peak season is

usually relevant in the long term for patients with

allergic rhinitis.

In rare cases, allergen immunotherapy may be

applied to desensitize the immune response to

certain allergens systematically (Durham 2016).

Currently available methods include subcutaneous

immunotherapy (SCIT) and sublingual

immunotherapy (SLIT), which are differentiated

based on the routes of delivery (Durham 2016, Cox

2017). SCIT or SLIT requires at least 3 years of

administration, can be costly overall, and can result

in anaphylactic reaction 0.1% of SCIT injection

visits (Cox 2017). Therefore, immunotherapy is

recommended by physicians in limited cases only if

pharmacological therapies are not well-tolerated or

ineffective, which is relevant for only a small

fraction of patients (Wheatley 2015).

2.2.2 Novel Targets in Cholinergic Immune

System

Although corticosteroids are sufficiently potent and

have been the standard allergic rhinitis treatment for

years, recent reviews have discovered that

systematic long-term administration of

corticosteroids is associated with adverse effects on

the cardiovascular, gastrointestinal,

neuropsychiatric, endocrine, and immune systems

(Yasir 2020, Kummer 2006). Therefore, an incentive

was created to develop an alternative drug with

comparable potency. Recently, cholinergic receptor

antagonists, traditionally used as bronchodilators in

the treatment of asthma and chronic obstructive

pulmonary disease (COPD), have received attention

for their anti-inflammatory properties. Although the

use of anticholinergic drugs in allergic rhinitis

treatment is uncommon, several preclinical and

clinical studies have demonstrated their

effectiveness in AR treatment with an improved

safety profile (Pieper 2007, Wessler 2008, Li 2011).

The discovery of anticholinergic drugs as a new

treatment option started with an understanding of the

cholinergic signaling pathway of immune cells.

Traditional views have limited the function of

acetylcholine to the autonomic nervous system, yet

literature has demonstrated solid evidence on the

role of a non-neuronal cholinergic system that

regulates immune function (Verbout 2012).

Experimental results revealed that acetylcholine is

secreted by immune cells and acts as an autocrine

and paracrine factor for airway epithelial and

inflammatory cells (Kistemaker 2012). In the

cholinergic signaling pathway for the inflammatory

response, acetylcholine can be secreted into human

blood, which is transported by organic cation

transporters to the site of infection and signals

chemotaxis of immune cells. Acetylcholine is

detected by muscarinic cholinergic receptors, which

stimulates increased release of cytokines and

chemotactic factors that initiate inflammatory

response. Experiments with human cell lines and

mouse models indicated an effect on lymphocyte

proliferation and cytokine production when known

muscarinic receptor agonists, such as carbanol and

Oxo-M, were applied to stimulate acetylcholine

secretion (Verbout 2012). Collectively, laboratory

evidence supports that muscarinic receptor in this

system are viable drug targets for the attenuation of

an immune response.

Indeed, further research confirmed the

expression of muscarinic receptors (mChA) in

human lymphocytes and characterized the effect of

several muscarinic antagonists, validating M3-

subtype mChA as the target for a novel

immunosuppressant drug. Experimental evidence

suggested the expression of all five subtypes of

muscarinic receptors (M1-M5) in both mouse and

human lymphocytes, including T cells, B cells,

natural killer cells, and macrophages, through

radioligand binding and RT-PCR (Verbout 2012).

Furthermore, studies regarding human airway

epithelial cells confirmed the role of the cholinergic

system in airway remodeling that leads to

bronchoconstriction and mucus production, which

was effectively alleviated by anticholinergic drugs

(Kistemaker 2012, Wang 2019). However, it was

also discovered that there was variance by individual

in the levels of subtype mChA expressed: unlike M1

and M2, M3-M5 receptors are reliably expressed in

all subjects, with M3 being the most abundant

(Tayebati 2002). Therefore, although concerns were

raised regarding the specificity of mChA antagonists

as drugs, it was logical to explore M3 receptor

antagonists as potential drug molecules for

respiratory system inflammation (Jiang 2011). In

fact, several M3 receptor antagonist drugs of the

quaternary ammonium bromide class, such as

tiotropium and ipratropium, have been approved by

the FDA as intranasal sprays that relieve the

symptoms of severe allergic rhinitis (Albertson

2017).

Tiotropium was approved by the FDA in 2004 as

a bronchodilator in maintenance therapy for COPD,

and severe asthma when used in conjunction with

Understanding Allergic Rhinitis and Non-Small Cell Cancer from Pathology to Treating Practice with Case Reports

419

corticosteroids (Albertson 2017). Research has

demonstrated that tiotropium bromide blocks the M3

receptor and regulates apoptosis of immune and

airway epithelial cells, thus inhibiting eosinophil

infiltration and alleviating bronchoconstriction

(Pieper 2007). Recently, bencycloquidium bromide

(BCQB) was approved and became available on the

Chinese market. While tiotropium bromide is

designated for COPD or asthma treatment and

BCQB for allergic rhinitis, their mechanisms of

action are quite similar. Both drugs possess a

quaternary ammonium ion in a six-membered,

bridged ring, a benzene group, and a bromide ion,

indicating similar pharmacokinetic properties and

binding mechanism. To minimize toxicity, these

mChA receptor antagonist drugs were designed as

charged molecules in dosage forms to prevent the

crossing of biological membranes (Albertson 2017).

This similar structure is observed in several short-

acting and long-acting muscarinic receptor

antagonists that were approved by the FDA as

maintenance therapies in COPD and acute asthma.

The recent development of mChA receptor

antagonist drugs has recognized acetylcholine as a

pro- inflammatory signaling molecule, where drugs

were designed to inhibit the chemotactic and

proliferative effects of acetylcholine. However,

some researchers have raised opposing views,

suggesting that ACh released by the central nervous

system might confer anti-inflammatory protective

effects through a distinct neuroimmune pathway

(Grando 2015, Borovikova 2000). Experimental

evidence has proved that low levels of ACh can

inhibit histamine release, as well as activate α-7

nicotinic receptors that cause local anti-

inflammatory effects (Grando 2015). ACh released

by the efferent vagus nerve also reduces the level of

tumor necrosis factor (TNF), a pro-inflammatory

cytokine, and promotes the production of anti-

inflammatory cytokines (Borovikova 2000). Antunes

Table 1: Risk factors related to lung cancer (Darby 2005)..

Relative

R

isk factors ris

k

Relative

R

isk factors ris

k

Tobacco use or ex

p

osure Comorbidities

Current smoking 20

Human Immunodeficiency 2 to 11

virus infection

Former smoking 9

Chronic obstructive 2 to 3.1

p

ulmonary disease

Secondhand smoke 1.3 Tuberculosis

—

ex

p

osure Other

Environmental exposures

History of chest radiotherapy 5.9

Famil

y

histor

y

of lun

g

cancer 2

Asbestos 3 Histor

y

of chemothera

py

4.2

Radon 3 Older age

—

Other ex

p

osures

—

Air pollution

Arsenic

Berylliu

m

Beta-carotene in

g

estion

Chromiu

m

Nickel

Soot

et al. also discovered that neostigmine, an

acetylcholinesterase inhibitor, can reduce eosinophil

influx and increase antioxidant defense by

increasing the level of ACh in a BALB/c mice

model (Antunes 2020). Collectively, these studies

provide solid evidence for a cholinergic anti-

inflammatory pathway (CAP), which is worth

further investigation for the future discovery of

viable drug targets.

3 LUNG CANCER AND

NON-SMALL CELL LUNG

CANCER

Non-small cell lung cancer (NSCLC), accounting for

80% to 85% in lung cancer cases, has four main

subtypes which are adenocarcinoma, squamous cell

carcinoma and large cell carcinoma (Liu 2019).

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

420

Though these subtypes start from different lung

cells, they are all classified as NSCLC because of

the similar treatment and prognosis (Ettinger 2017).

Different from small-cell lung cancer (SCLC),

NSCLC tends to grow and spread slower, which is

more likely to be found before spread. For instance,

according to detect mutations in epidermal growth

factor receptor (EGFR), recent trials have suggested

that instead of chemotherapy, initial therapy with

tyrosine kinase inhibitors (TKIs) may be the best

choice for treating NSCLC (da Cunha Santos 2011).

In addition, the use of immune checkpoint inhibitors

(ICIs) has been successfully applied in clinical

cancer treatments (Fan 2017). ICIs targeting

programmed cell death protein 1 (PD-1) and

programmed cell death protein ligand 1 (PD-L1)

display apparent benefits for the treatment of

advanced NSCLC (Xia 2019). We also introduce

other treating options of lung cancer such as

chemotherapy and radiation together with their

perspectives.

3.1 Epidemiology

There are two types of lung cancer, micro-cell lung

cancer, and non-small cell lung cancer (NSCLC)

with the latter accounts for 85% of all lung cancer.

NSCLC tends to be the toxic infection in both

genders (Siegel 2019). Its mortality rate is rather

high when compared with three other most common

occurred cancer types (ie. colon, breast and pancreas

cancer). The life-threatening risk of NSCLC is more

obvious as more than a quarter of patients have died

within 12 months of diagnosis. Besides, the five-

year survival rate is only 17.8% (Kenfield 2008).

Among NSCLC, lamellate cell carcinoma

accounts for 30%. It originates from the first

generation of lamellate cells in the airway epithelial

cells of the lungs. This subdivision is strongly

associated with smoking (Noguchi 1995). About

40% of tumorigenesis happening in the lung is in the

form of adenocarcinoma. Secretory epithelial is

consisted of type II alveolar cells, where are full of

mucus and other nutrients (Gavelli 2000). Morbidity

of adenocarcinoma is the highest among all the

cancer types happened in lung, but unlike lamellate

cell carcinoma, smoking has no obvious effect on its

morbidity (Stellman 1997), so as the age factors.

Results have shown that the use of filters to prevent

smoke from entering the lung had failed but caused

deeper penetration into the lung (Xu 2014). In this

scenario, the smoke becomes carcinogen, and

adenocarcinoma appears. Compared with other

forms of lung cancer, adenocarcinoma grows slowly

and is more likely to be early detected before

metastasis. Large cell cancer accounts for only 5-

10% of lung cancer. There is no obvious symptom

of this type of cancer or tumor growth and as a result

it is usually diagnosed by chance. Bigger cells

carcinomas usually start at the center of the lung and

occasionally causing lymph swellings and limbs

frigi (Whitrow 2003).

Table1 summarized the commonly reported risk

factors of lung cancer. One of the major factors that

cause the lung cancer is smoking. Increasing number

of cigarettes and daily consumption is highly related

with morbidity of lung cancer (Straif 2009). Non-

smokers, however, still have potential risk of

developing lung cancer with risk ratio ranging from

1.14 to 5.20 according to meta-analysis and general

evaluation. The underlying reason is that they live

with smokers (Stayner2008). According to the

American Surgeon General, living with smokers can

increase the risk of non-smoking lung cancer by 20-

30% (Hecht 1999). Radon, a natural cancer-causing

agent, is one of the leading causes of lung cancer,

with an estimated 21,000 deaths from lung cancer in

the United States (Darby 2005). Although Radon has

been in contact with miners sometimes, there is

growing concern that Radon's exposure to natural

gas from uranium deposits are increasing. A series

of randomized controlled trials from North America,

Europe, and China have shown a 2.7-fold increase in

the risk of lung cancer-related lung cancer per liter

(PC).

3.2 Treating Options

Asbestos is used in industry or manufacturing in

conjunction with an improvement in mesothelioma

and lung cancer. The link between asbestos fiber

levels has been found to be a strong indicator of lung

cancer mortality (Wang 2014). As a result, the US

government has implemented steps to decrease the

use of asbestos in marketable and organizational

programs. Additional experimental risk factors

associated with lung cancer comprise the use of

arsenic solvents, disclosure to beryllium and

beryllium oxide; Ingredients include, nickel alloys,

chromium alloys and chloroses ester (Hung 2008).

The disease is more common for the individuals in

the growing periods with effective strategies.

3.2.1 Visual Aided Operation

Patients in stages I, II and III of NSCLCs could have

surgery to remove the tumor if it is feasible for the

tumor as well as the patients. Medical imaging

Understanding Allergic Rhinitis and Non-Small Cell Cancer from Pathology to Treating Practice with Case Reports

421

detection and biopsies help surgeons to distinguish

the originality of tumorigenesis and identify the

patients’ condition in the tumor progression. Video-

enable surgery is now available in clinical practice

and is popular among surgeons. During the surgery,

a tiny camera wrapped in a box is placed in the body

of the patient. Since a large piece of paper does not

need to be cut, a sphere is removed through a piece

of paper [90]. The operation criteria are created on

the basis of achieving a scope that is associated with

a general aim of preventing cancer.

3.2.2 Chemotherapy

Approximately 40% of patients have been diagnosed

in stage IV in recent cases. The goal of treating these

patients is to save their lives and reduce the

incidence of disease-related complications. For the

fourth level NCC, which is Cytotoxic Combination

Chemotherapy, is the first line of treatment that can

affect histology, age and related conditions (PS).

According to the American Society of Clinical

Oncology, patients with 0 or 1 PM are treated with

platinum (cislatine or carbofolatin), pastazal,

gemetitabine, doxtaxil, vinorelbine, erythromycin or

modified. The results of four large randomized

controlled trials have been applied to study platinum

or carboplatin. The results of one of these studies

have shown that the effects of one unit are larger

than the other. The median overall recovery for these

patients was approximately 8-10 months. The

specific combination depends on the type and

frequency of toxic effects and must be determined

individually. However, patients with

adonacarcinoma may benefit from permethrin.

Cysteine is slightly more effective than platinum but

has been proved to induce more side effects. Data

from 2 PPS patients have shown that they only need

one drug, which is not usually platinum. For

chemotherapy, serious events should motivate

agents to change. In addition, if cancer occurs,

therapy should be discontinued when the disease

resolves after four treatment cycles, but the

treatment does not reduce the tumor. 3PS patients do

not routinely use cytotoxic chemotherapy because

the risk of adverse events greatly worsens their

quality of life. More supportive care is generally

recommended for these patients (Hung 2008).

3.2.3 Radiotherapy

Radiotherapy uses the most powerful poles to

damage DNA in cancer cells. This helps to control

or eliminate tumors in the body. Patients with NCCL

who have had chest surgery and are not eligible for

surgery may benefit from radiotherapy.

Radiotherapy may be part of pain relief to improve

the quality of life for patients who do not respond to

surgery or chemotherapy. There are no nearby

lymph nodes for the first NCs with small nodes in

the lungs. Patients are treated with a procedure

called SBRT. This method uses advanced

coordination systems to accurately identify the

tumor and ensure the correct placement of the

tracking device. This allows for stronger and more

focused radiation therapy (Sher 2008). For NCN,

compared with the effectiveness of radiotherapy

with photons, protons, and carbon ions, SBRT

presented a 2-year overall life expectancy, low cost,

and high patient comfort in meta-analysis. In the

next stage study, environmental controls were

significantly higher in patients who did not receive

treatment at SBRT Level 1 NSCC in 70 untreated

patients receiving SBR (Hwang 2003). However,

with NCC, a non-pharmaceutical NC, patients

conducted a three-pronged multidisciplinary study of

SBRT toxicity and efficacy. Of the 55 patients

evaluated, SBRT patients had a 55.8% survival rate

in three years. In these studies, SBRT has been

found to provide surgical treatment for day-to-day

disease- related illnesses to environmental control

and results among certain scope of patients.

3.2.4 Targeting Specific Biomarkers

It helps to improve patient survival by targeting

appropriate molecular targets in private drug tumors

in the NSCLC. Besides, biomarker tests often regard

the quicker and effective way of occupying various

instances needed to maximize the achievement of

the epidermal role. There are agents that have been

successfully targeted in epidermal development

factor receptor (EGFR) mutations and in the

restoration of anaphylactic lymphoma kinase (ALK).

Through genetic testing, ROS1 and RET gene

mutations, MT amplification, and other molecular

changes in B-RAF, HER2, and K-RAS genes may

be targeted for future treatments.

3.2.5 Activating Epidermal Growth Factor

Receptor (EGFR) Gene

When EGFR is activated, it is a cellular tyrosine

kinase receptor that can activate pathways associated

with cell growth and proliferation. This gene carries

to a larger extent the distribution of the factors that

determine the mutation rate of the receptor factor. In

cancer, EGFR mutations continuously trigger

uncontrolled cell division. EGFR gene mutation: 10–

15%

of lung cancer adenocarcinoma of European

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

422

Table 2: Clinical and disease features of patients with EGFR gene (Muscat 1997).

Characteristics Mutation arm (N = 50) Wild-type arm (N = 50) P value

Age, y

0.419

Mean 57.3 59.1

Standard deviation 11.6 10.5

Sex, No. (%)

0.016

Male 18(36.0) 30(60.0)

Female 32(64.0) 20(40.0)

Smoking history, No. (%)

0.043

Smoker 16(32.0) 26(52.0)

Never smoker 34(68.0) 24(48.0)

Histologic type, No. (%)

0.131

ADC 49(98.0) 44(88.0)

SCC 1(2.0) 4(8.0)

Others 0(0) 2(4.0)

Disease stage, No. (%)

0.603

IB 8(16.0) 10(20.0)

IV 42(84.0) 40(80.0)

EGFR-TKI treatment, No.

(%)

ND

No 3(6.0) 26(52.0)

Yes 47(94.0) 24(48.0)

First-line 29(58.0) 5(10.0)

Second-line 15(30.0) 13(26.0)

Third-line or greater

3(6.0) 6(12.0)

and Asian origin, especially in non-smokers and in

women. Although these behaviors are common,

mutation testing is important for patients using

targeted tyrosine kinase inhibitor therapy (Muscat

1997). The risk of exposure to EGFR tyrosine kinase

inhibitors is usually these models encode the EGFR

kinase domain segment. Approximately 90% of

these mutations are due to 19 abrasions and a

mutation of L858R point 21, which corresponds to a

70% response rate for patients receiving erlotinib or

gefitinib treatment.

4 CONCLUSIONS

This paper presents the pathophysiology, current and

prospective treating options for allergic rhinitis (AR)

and non-small cell lung cancer (NSCLC), which

represents certain types of respiratory diseases and

affects distinct regions in the respiratory tract.

Allergic rhinitis is characterized by oversensitive

inflammatory response to an environmental factor

while NSCLC is caused by genetic mutation in the

lung tissue. Medical treatments are available for AR,

from which many target G-protein coupled receptors

and inhibit cell signaling events in the pathogenesis

pathways. With the improved understanding of

pathophysiology, we may find a better option for

treating NSCLC instead of current treatment options

such as operation, chemotherapy, and radiotherapy

to reduce adverse events and improve quality of life

for patients. To enhance the potency and minimize

side effects of treatments, ongoing medical research

on allergic rhinitis and NSCLC have identified novel

therapeutic targets. New drugs differ in action

mechanism as well as novel targets have been

developed and identified. For allergic rhinitis, the

acetylcholine-mediated cholinergic immune system

has been explored for its role in generating

inflammatory response, and several drugs

(tiotropium, ipratropium, bencycloquidium bromide)

targeting muscarinic receptors have been developed

to inhibit the pro- inflammatory effect of

acetylcholine. Future treatments for NSCLC may

emphasize on finding a kinase inhibitor which

functions by blocking a key enzyme or activating

EGFR gene. Recent studies found targeting specific

biomarkers and activating EGFR have been known

as future treatment options of NSCLC. However,

these treatment options may need more future

research to address drug resistance therefore

improve the outcomes in NSCLC patients.

Understanding Allergic Rhinitis and Non-Small Cell Cancer from Pathology to Treating Practice with Case Reports

423

REFERENCES

Albertson, T.E., et al., Muscarinic antagonists in early

stage clinical development for the treatment of asthma.

Expert Opinion on Investigational Drugs, 2017. 26(1):

p. 35-49.

Antunes, G.L., et al., Cholinergic anti-inflammatory

pathway confers airway protection against oxidative

damage and attenuates inflammation in an allergic

asthma model. Journal of Cellular Physiology, 2020.

235(2): p. 1838-1849.

Bergeron, C. and Q. Hamid, Relationship between Asthma

and Rhinitis: Epidemiologic, Pathophysiologic, and

Therapeutic Aspects. Allergy, Asthma & Clinical

Immunology, 2005. 1(2): p. 81.

Borovikova, L.V., et al., Vagus nerve stimulation

attenuates the systemic inflammatory response to

endotoxin. Nature, 2000. 405(6785): p. 458-462.

Ciprandi, G., et al., Antihistamines added to an

antileukotriene in treating seasonal allergic rhinitis:

histamine and leukotriene antagonism. Eur Ann

Allergy Clin Immunol, 2004. 36(2): p. 67-70, 72.

Cox, L.S., Sublingual Immunotherapy for Allergic

Rhinitis: Is 2-Year Treatment Sufficient for Long-term

Benefit? JAMA, 2017. 317(6): p. 591-593.

da Cunha Santos, G., F.A. Shepherd, and M.S. Tsao,

EGFR Mutations and Lung Cancer. Annual Review of

Pathology: Mechanisms of Disease, 2011. 6(1): p. 49-

69.

Darby, S., et al., Radon in homes and risk of lung cancer:

collaborative analysis of individual data from 13

European case-control studies. BMJ, 2005. 330(7485):

p. 223.

Devillier, P., N. Roche, and C. Faisy, Clinical

Pharmacokinetics and Pharmacodynamics of

Desloratadine, Fexofenadine and Levocetirizine.

Clinical Pharmacokinetics, 2008. 47(4): p. 217- 230.

Durham, S.R. and M. Penagos, Sublingual or

subcutaneous immunotherapy for allergic rhinitis?

Journal of Allergy and Clinical Immunology, 2016.

137(2): p. 339-349.e10.

Emeryk, A., J. Emeryk-Maksymiuk, and K. Janeczek,

New guidelines for the treatment of seasonal allergic

rhinitis. Advances in Dermatology and

Allergology/Postępy Dermatologii i Alergologii, 2019.

36(3): p. 255-260.

Ettinger, D.S., et al., Non-Small Cell Lung Cancer,

Version 5.2017, NCCN Clinical Practice Guidelines in

Oncology. J Natl Compr Canc Netw, 2017. 15(4): p.

504-535.

Fan, Y. and W. Mao, Immune checkpoint inhibitors in

lung cancer: current status and future directions.

Chinese Clinical Oncology; Vol 6, No 2 (April 2017):

Chinese Clinical Oncology, 2017.

Gavelli, G. and E. Giampalma, Sensitivity and specificity

of chest x-ray screening for lung cancer. Cancer, 2000.

89(S11): p. 2453-2456.

Grando, S.A., et al., Recent progress in revealing the

biological and medical significance of the non-

neuronal cholinergic system. International

Immunopharmacology, 2015. 29(1): p. 1-7.

Hecht, S.S., Tobacco Smoke Carcinogens and Lung

Cancer. JNCI: Journal of the National Cancer Institute,

1999. 91(14): p. 1194-1210.

Hung, R.J., et al., A susceptibility locus for lung cancer

maps to nicotinic acetylcholine receptor subunit genes

on 15q25. Nature, 2008. 452(7187): p. 633-637.

Hwang, S.-J., et al., Lung cancer risk in germline p53

mutation carriers: association between an inherited

cancer predisposition, cigarette smoking, and cancer

risk. Human Genetics, 2003. 113(3): p. 238-243.

Jiang, J.-X., et al., Characterization of bencycloquidium

bromide, a novel muscarinic M3 receptor antagonist in

guinea pig airways. European Journal of

Pharmacology, 2011. 655(1): p. 74-82.

Kenfield, S.A., et al., Comparison of aspects of smoking

among the four histological types of lung cancer.

Tobacco Control, 2008. 17(3): p. 198.

Kistemaker, L.E.M., et al., Regulation of airway

inflammation and remodeling by muscarinic receptors:

Perspectives on anticholinergic therapy in asthma and

COPD. Life Sciences, 2012. 91(21): p. 1126-1133.

Kudo, M., Y. Ishigatsubo, and I. Aoki, Pathology of

asthma. Frontiers in Microbiology, 2013. 4: p. 263.

Kuehl Frederick, A. and W. Egan Robert, Prostaglandins,

Arachidonic Acid, and Inflammation. Science, 1980.

210(4473): p. 978-984.

Kummer, W., et al., Role of acetylcholine and polyspecific

cation transporters in serotonin- induced

bronchoconstriction in the mouse. Respiratory

Research, 2006. 7(1): p. 65.

Lamb, C.E., et al., Economic impact of workplace

productivity losses due to allergic rhinitis compared

with select medical conditions in the United States

from an employer perspective. Current Medical

Research and Opinion, 2006. 22(6): p. 1203-1210.

Li, J., et al., Subchronic toxicity and toxicokinetics of

long-term intranasal administration of

bencycloquidium bromide: A 91-day study in dogs.

Regulatory Toxicology and Pharmacology, 2011.

59(2): p. 343-352.

Liu, J.-C., et al., A Review on the Antitumor Activity of

Various Nitrogenous-based Heterocyclic Compounds

as NSCLC Inhibitors. Mini-Reviews in Medicinal

Chemistry, 2019. 19(18): p. 1517- 1530.

Meltzer, E.O., The pharmacological basis for the treatment

of perennial allergic rhinitis and non- allergic rhinitis

with topical corticosteroids. Allergy, 1997. 52(s36): p.

33-40.

Min, Y.-G., The Pathophysiology, Diagnosis and

Treatment of Allergic Rhinitis. Allergy Asthma

Immunol Res, 2010. 2(2): p. 65-76.

Miyata, J., et al., Cysteinyl leukotriene metabolism of

human eosinophils in allergic disease. Allergology

International, 2020. 69(1): p. 28-34.

Muscat, J.E., et al., Cigarette smoking and large cell

carcinoma of the lung. Cancer Epidemiology

Biomarkers &amp; Prevention, 1997. 6(7): p.

477.

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

424

Noguchi, M., et al., Small adenocarcinoma of the lung.

Histologic characteristics and prognosis. Cancer,

1995. 75(12): p. 2844-2852.

Pieper, M.P., N.I. Chaudhary, and J.E. Park,

Acetylcholine-induced proliferation of fibroblasts and

myofibroblasts in vitro is inhibited by tiotropium

bromide. Life Sciences, 2007. 80(24): p. 2270-2273.

Rodrigo, G.J. and A. Yañez, The role of antileukotriene

therapy in seasonal allergic rhinitis: a systematic

review of randomized trials. Annals of Allergy,

Asthma & Immunology, 2006. 96(6): p. 779-786.

Sher, T., G.K. Dy, and A.A. Adjei, Small Cell Lung

Cancer. Mayo Clinic Proceedings, 2008. 83(3): p. 355-

367.

Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics,

2019. CA: A Cancer Journal for Clinicians, 2019.

69(1): p. 7-34.

Small, P., P.K. Keith, and H. Kim, Allergic rhinitis.

Allergy, Asthma & Clinical Immunology, 2018. 14(2):

p. 51.

Soriano, J.B., et al., Prevalence and attributable health

burden of chronic respiratory diseases,

1990–2017: a systematic analysis for the

Global Burden of Disease Study 2017. The Lancet

Respiratory Medicine, 2020. 8(6): p. 585-596.

Stellman, S.D., et al., Impact of Filter Cigarette Smoking

on Lung Cancer Histology. Preventive Medicine,

1997. 26(4): p. 451-456.

Stayner, L., et al., An epidemiological study of the role of

chrysotile asbestos fibre dimensions in determining

respiratory disease risk in exposed workers.

Occupational and Environmental Medicine, 2008.

65(9): p. 613.

Straif, K., et al., A review of human carcinogens—

Part C: metals, arsenic, dusts, and fibres. The Lancet

Oncology, 2009. 10(5): p. 453-454.

Tayebati, S.K., et al., Muscarinic cholinergic receptor

subtypes in the hippocampus of aged rats.

Mechanisms of Ageing and Development, 2002.

123(5): p. 521-528.

Verbout, N.G. and D.B. Jacoby, Muscarinic Receptor

Agonists and Antagonists: Effects on Inflammation

and Immunity, in Muscarinic Receptors, A.D. Fryer,

A. Christopoulos, and N.M. Nathanson, Editors. 2012,

Springer Berlin Heidelberg: Berlin, Heidelberg. p.

403-427.

Wang, J., et al., Effect of Tiotropium Bromide on Airway

Inflammation and Programmed Cell Death 5 in a

Mouse Model of Ovalbumin-Induced Allergic

Asthma. Canadian Respiratory Journal, 2019. 2019: p.

6462171.

Wang, Y., et al., Rare variants of large effect in BRCA2

and CHEK2 affect risk of lung cancer. Nature

Genetics, 2014. 46(7): p. 736-741.

Wessler, I. and C.J. Kirkpatrick, Acetylcholine beyond

neurons: the non-neuronal cholinergic system in

humans. British Journal of Pharmacology, 2008.

154(8): p. 1558-1571.

Wheatley, L.M. and A. Togias, Allergic Rhinitis. New

England Journal of Medicine, 2015. 372(5): p. 456-

463.

Whitrow, M.J., et al., Environmental exposure to

carcinogens causing lung cancer: Epidemiological

evidence from the medical literature. Respirology,

2003. 8(4): p. 513-521.

Wilson, A.M., P.M. O'Byrne, and K. Parameswaran,

Leukotriene receptor antagonists for allergic rhinitis: a

systematic review and meta-analysis. The American

Journal of Medicine, 2004. 116(5): p. 338-344.

Xia, L., Y. Liu, and Y. Wang, PD-1/PD-L1 Blockade

Therapy in Advanced Non-Small-Cell Lung Cancer:

Current Status and Future Directions. The Oncologist,

2019. 24(S1): p. S31-S41.

Xu, B., R. Chetty, and B. Perez-Ordoñez, Neuroendocrine

Neoplasms of the Head and Neck: Some Suggestions

for the New WHO Classification of Head and Neck

Tumors. Head and Neck Pathology, 2014. 8(1): p. 24-

32.

Yamada, M. and M. Ichinose, The cholinergic anti-

inflammatory pathway: an innovative treatment

strategy for respiratory diseases and their

comorbidities. Current Opinion in Pharmacology,

2018. 40: p. 18-25.

Yasir, M., et al., Corticosteroid Adverse Effects. 2020:

StatPearls Publishing, Treasure Island (FL).

Understanding Allergic Rhinitis and Non-Small Cell Cancer from Pathology to Treating Practice with Case Reports

425