PancreaticcancerPancreatic cancer (PC) asa fourth cause of cancer related mortality worldwide has extremely poorprognosis. A meta-analysis of 14 PC studies showed the 30% and 45% lower riskin subjects with history of any allergies and nasal allergies, respectively (43).Also, several studies have confirmed their finding, but only one studyestimated a non-significant decreased risk???? ???? (7, 44-47). Other review exploring 11published studies reported reduced risk of PC in respiratory allergy conditionssuch as allergies to plants or pollen or hay fever (48).Regarding skin allergies, two studies announced negative association but onlyone reached statistical significance(46, 47).In a study conducted on1297 PDAC cases and 1024 normal controls revealed that asthma was related withreduced risk of PDAC (OR=0.6, 95% (CI):0.

5-0.9) which consist with a result of meta-analysisof 10 case–control studies (OR=0.7, 95% CI 0.6- 0. 9).

Nasal allergies and associatedsymptoms were protective factor for PDAC (OR=0.7, 95% CI: 0.5-0.8 and OR= 0.6,95% CI: 0.5-0.8, respectively) which confirmed by a meta-analysis of nasalallergy studies (OR=0.

6, 95% (CI):0.5- 0.7) (49).Controversy, cohortstudies performed in different countries (36, 50, 51) reported no association between PCrisk and serum Ig E levels, history of Allergy, or skin prick tests. Theseinconclusive results may be attributed to young studied population and short followup, resulting to only a small number of cases; Furthermore, data were notadjust for potentially confounding factors.The underlying mechanismsof association between Allergy and PDAC risk are unclear.

It has been proposedthat hyperactive immune system involved in subjects with Allergy(10).Furthermore, susceptibility and severity of asthma and allergies are known tobe affected by genetic factors and interactions between gene and environment (52, 53). A study investigating SNP in 56allergy-associated candidate genes revealed that genetic variants may be relatedwith a fewer PC risk (54).Further researches are needed to clarify the role of genetics in theserelationships.

In addition, it has been found that cromolyn as an anti-allergicagent can suppress proliferation and propagation of human PC cells invitro and invivo(55).Colorectal CancerColorectal cancer (CRC)is another most common malignancies regarding to incidence and mortality (56). Studies reporting the associationof Allergy and digestive tract tumors have had different results (10).Allergywere described to be protective factors in a case–control studies on  CRC patients in Australia and Italy (57, 58). Although, these studies usedself-reported history of atopy and did not differ between different types ofallergies; so, it may be lead to misclassification. In contrast, cohort studiesdid not advocate the protective effect of atopy against CRC.

Another cohortstudy in California reported (RR=1; 95% CI: 0.7–1.3) for colon cancer and (RR=0.9;95% CI: 0.5–1.

4) for colon and rectum cancer (35, 59). Cohort studies investigatingassociation between AAC and CRCs was presented in table2.A meta-analysis of 16studies in 2009 found no association between Allergy and CRC risk (60).A study among colon and rectum cancer patients in Taiwan reported an inverse relationshipbetween allergic rhinitis and only rectum cancer (61).The Iowa Women’s Health study highlighted history of two or more atopicconditions correlated with a 42% decrement in CRC risk (62).

More recent cohort study among different iethnic population explained that Allergywere a protective effect against CRC among both men and women (RR = 0. 9, 95%CI: 0.8-0. 9) in all populations except Latinos. Also, Allergy cases had a 20% fewerCRC-related mortality(63).

The biological mechanismfor the correlation of Allergy with CRC is not understood but could be as aresult of antitumor functions of type I Ig E-mediated immune activity. Thiseffect leads to migration of immune cells such as eosinophils and mast cells tointestinal mucosa. Allergens can enter the body through respiratory system andthe digestive system, where mast cells and eosinophils are widespread (64).This can result to type I Ig E-mediated hypersensitivity reactions, due to the highactivation of eosinophils and mast cells and over response of T-helper celltype II.

Complexes of Ig E and cancer cell can degranulate mast cells which releasefactors to inhance permeability and inflammation (65).Eosinophil levels are speculated to have cytotoxic effects and antitumor activityon precancerous cells that drive from high proliferating tissues, such as thegut lining (62, 66, 67). Due to the high presence ofeosinophils and degranulation of mast cell in the respiratory mucosal lining ofasthmatic cases, leukocytes in the gut of subjects with atopic conditions ismore (68).Another theory, termed the prophylaxis hypothesis proposed that immuneresponses and inflammation in mucosal layer can cause to further rapidclearance of mutagenic stimulators (10).

Brain cancerSince early 1990s, manystudies reported that Allergy may be related with a lower risk of brain tumors (59, 69-73).In a case–control studyin Boston displayed an inverse association of glioblastoma with medications forany kind of allergies (RR= 0.6, 95% CI: 0.4–1.

0) (74).In a multicenter international case–control research recruited data among 1178 patientshistory of allergy was a protective factor (OR=0.4, 95% CI: 0.5–0. 7) for GM.

(75-78). Two case–control and three cohortstudies highlighted the protective effect of Allergy against GM (Table1)(22, 79, 80). It has been presented a lowerrisk of GM among people with a history of allergy (OR=0.5; 95% CI: 0.2–1.0) in Swedishtwins cohort and (HR=0.5; 95% CI: 0.1–1.

9) for high-grade GM in hospitaldischarges cohort (22).A meta-analysis published in 2009 disclosed that meningioma (a low-grade tumor)did not display inverse relationship with Allergy in adults (70).INTERPHONE is a largepopulation based case–control study performed among 13 country included 2103patients with different type of brain tumor, as well as  2520 normal controls. Finding of this studyindicated an significant inverse association between a history of any allergyand GM (OR = 0.7, 95 % CI: 0.6–0.9), acoustic neuroma (OR = 0.

6, 95 % CI:0.5–0.8), and meningioma (OR = 0.8, 95 % CI: 0.6–0.

9), but not parotid gland tumors (OR= 1.2, 95 % CI: 0.7–2.0) (81).

Thereare few reports about acoustic neuroma. Brenner et al. in a case–controlstudy of 96 cases and 799 controls reported a significant positive associationbetween a history of hay fever and acoustic neuroma (OR = 2.4, 95 % CI 1.

4–4.0),which was stronger with an older age at diagnosis or shorter disease duration (80).Two studies in adults noted an inverse relationship between prediagnostic IgElevels and GM risk (73, 82). Anotherpopulation-based case–control study (CEFALO), among children and adolescents in Denmark,Norway, Sweden, and Switzerland. There was no relationship between Allergy and alltype of brain tumor (OR=1.0; 95% CI: 0.

7–1.3). The risk of Allergy at presentand in the past were 0.8 and 1.2 (95% CI 0.5–1.1; 95% CI: 0.9–1.

7) respectively.Similarly, these results were repeated for GM (83). In contrast,results of two case–control studies among children with brain tumor wascompatible with the results of studies of adults (84, 85). They reported greater declines riskfor PNET/medulloblastoma than pilocytic astrocytoma or GM (84, 85).The older age-range ofparticipants in CEFALOstudy (7–19 years) compared with 0–14 years in the two other reports mightexplain some of controversies, as the distribution of brain cancer subtypes varybetween these studies. Moreover, the distribution of GM subtypes greatlydiffers from adults. The main type of adult GM is stage 4, and the rest arestage 3 or 2, but main GMs in children are stage 1 (pilocytic astrocytoma).This may explain the discrepancy between findings of studies with different agerange.

Lung cancer (LC)Almost allepidemiological studies indicated that people with a history of allergicdisease have a greater risk of LC. Five case–control studies among never-smokerreported risks of LC associated with asthma to be 1.1–2.7 (86-89). Santillan and colleagues analyzedresults of five case–control studies and estimated (RR=1.8, 95% CI: 1.3– 2.3)(90).

The analysis of the data from studies, which controlled for smoking historygave a pooled estimate of 1.7 (95% CI:1.3–2.2) (90).History of asthma among nonsmokers and smokers cases were 1.6 and 1.7 respectively(86).

Another study expressed a strong association between asthma and with higherrisk of LC only among men (91).Another population-based case–control study among Missouri woman found the asthmawas a non-significant risk factor (OR=1.2, 95% CI: 0.

8–2.1) in smokers andsignificant risk factor (OR=2.7, 95% CI: 1.4–5.4) in non-smokers (87).This finding is compatible with finding of study conducted among never-smokingwomen in five city areas of the USA with risk of 1.7 (95% CI: 1.

1–2.5) forhistory of asthma (88).A study in 98 female cases of small cell lung cancer (SCLC) and 204 controls reportedhistory of asthma related with statistically significant increased risk of LCafter adjustments (92).A study in China reported the increased risk of asthma (OR=2.

0; 95% CI: 0.9 to 4.2)among nonsmokers even adjusting for smoking history (OR=2.1; 95% CI: 1.5 to 3.0)(89).In a case–control studyincluding 437 nonsmoking cases and 437 controls was revealed no significant associationamong nonsmokers, however a higher risk was found after adjusting for smokinghistory (OR=2.

1, 95% CI: 1.0–4.1)(93).In two studies in USA were not observed any association between history ofasthma and LC after adjusting age and smoking history (94, 95). It have been shown a %50 reducedrisk for LC among 217 case–control pairs women with asthma or hay fever fromthe Californian nested case–control study (96).

Similarly, prospective cohort studies displayed a higher risk of LC amongasthmatic patients. In a prospective study on a Finnish twin cohort, the riskof LC-mortality was higher in men with asthma (97).In a large ancient study covering 78000 participants, the risk of LC wasincreased (Standardized Incidence Ratio (SIR) = 1.3 in men and SIR = 1.7 inwomen) among asthmatic patients (98).In Swedish patients which hospitalized for asthma (99),the SIR was 1.6 (95% CI: 1.5–1.

7) during 8.5-years follow up.Esophageal and gastriccancerInconclusive results wereobtained from studies exploring esophageal and gastric cancer risk factors.

Ye etal. reported that higher risk of esophageal and gastric cancers in asthmaticpatients which may be due to the more gastro-esophageal reflux in thesepatients (100).Several case-control studies have reported inverse relationships betweenesophageal tumor and history of allergy (101-103). Kallen et al. reported a50% lower risk of stomach cancer mortality among asthmatics; but, cohortstudies reported no significant relationships(104).

Medullarythyroid carcinoma (MTC)The association betweena history of allergies andmedullarythyroid carcinoma (MTC) investigated in pooled analysis of 14 case-controlstudies. Results of 48 cancer patients and 240 controls showed a two-fold riskfor MTC in allergic disease. However, the positive association may as a resultof the release of vasoactive agents by the tumor leading allergic-like symptoms(105).Bladder cancer(BlC)An early case-controlstudy expressed that a history of atopic condition was associated to higherrisk of BlC in men, but with a lower risk in women (106).Other case-control studies have demonstrated positive relationships of havinghistory of asthma and either urothelial tumor (107)or BlC (108).Interestingly, risk of BlC increased in asthmatics with the glutathione S-transferase(GSTM1) or glutathione S-transferase (GSTT1) null genotypes. This finding was speculatedto be as a result of a lack of the detoxification of reactive asthma medicationintermediates by a deficiency of these enzymes (108).In cohort studies was reported no significant associations (59)or advanced risk for BlC in asthmatics patients only among men (98).

Rhabdomyosarcoma  Rhabdomyosarcoma (RMS)is a scarce and high malignant cancer of developing skeletal muscle which can happenanywhere in the body. Lupo et al in a case-control study of 322 RMScases and 322 controls found that allergies and hives were negatively relatedwith childhood RMS(OR = 0.6, 95% CI: 0.4–0.9) (109).Prostate cancer Prostate cancer (PrC)is one of most frequent malignancy in men and remains a main public healthproblem(110).

There are several studies exploring possible effect of systemic inflammationconditions on prostate carcinogenesis. In a study was assessed single-nucleotidepolymorphisms (SNP) between patients with PrC and normal controls revealed that4 genes (TLR1, TLR6, OAS1, and OAS2) participate in innate inflammationpathways were associated to higher risk of Prc (111).Also, it has been found that increased white blood cell count, as a marker ofsystemic inflammation, was significantly associated with advance PrC risk(112).Results from large-scale cohort study including 16,934 men which performed by Severiand coworker revealed a small increment in prostate cancer risk in asthmaticpatients compared to controls (HR: 1.

2; 95% CI: 1.05– 1.5) (113).Furthermore, the risk was further elevated in cases allocating antiasthmamedications such as inhaled glucocorticoids, systemic glucocorticoids, andbronchodilators.In a prospective questionnaire-basedcohort study reported that men with a history of asthma had a 30% low risk oflethal PrC (110).

In contrast, Zhao et al reported 86 of 1552 asthmatics were diagnosed PrCduring follow-up (35).In the large nationwide study, asthma was an independent risk factor for PrC andwas associated to a 136% higher risk after adjustment for possible confounding variables.Also, there was no direct relationship between history of glucocorticoids consumptionand PrC diagnosis. Glucocorticoids joined with mutated androgen receptors whichmay lead to development and progression of androgen-independent PrC (114).

Although, there is inadequate document to establish this theory associated toprostate carcinogenesis.In a large,population-based case-cohort study including 4124 cases with asthma and8248 full-matched healthy control subjects, asthma was significantly associatedwith prostate cancer (OR= 2.4; 95% CI: 1.2–4.6; P = 0.011) and its independentrisk factors were age and hypertension (115).Head and neckcancer (HNC)Head and neck cancer(HNC) (tumors of the oral cavity, larynx oropharynx, and hypopharynx) is thefifth most frequent cancer worldwide. A meta-analysis of 14 studies showed an protectiveeffect of allergy symptoms for HNC (OR=0.

8, 95 % CI: 0.6–0.9) (116).In contrast, cohort studies showed that higher serum IgE levels were relatedwith an higher risk of HNC (117).In a cohort study with 14,849 participants subjects with positive tests forserum specific IgE for inhalant allergens had higher risk of HNC (OR=1.7, 95 %CI: 1.

0–3.1). In other cohort including 37747 subjects, high IgE levels was linkedwith an higher risk of oral and pharyngeal cancer (OR=1.4, 95 % CI:1.0–1.8) (26).Recently, Liao et alreported that elevated serum total IgE levels was related with a significantly 1.7-foldhigher HNC.

Symptomatic allergy was related with a significantly 40% decrementof HNC risk. Notably, asymptomatic atopic cases had a higher risk of HNC thansubjects with normal serum IgE level and no allergy symptoms(118).Squamous cell carcinoma (SCC) and earlyonset basal cell carcinoma (BCC)There are limited dataabout the contribution of atopic and allergic conditions in the etiology ofkeratinocyte tumors. In 2003, Twin Cohort study reported that females with ahistory of AD prone to be more likely to affect a basal cell carcinoma (BCC), butit was non-significant (OR=1.8, 95% CI:0.

8–3.9) (119).A Danish nationwide cohort study reported that increased risk of both squamouscell carcinoma (SCC) and BCC among subjects who had a history of AD (120).

Results from a nested case–control study of skin cancer patients demonstrated thatcases who developed a new primary cutaneous SCC had higher prediagnostic IgElevels than controls who did not (121).Similarly, a higher risk of SCC was reported in asthmatics subjects comparedwith non-asthmatics subjects (Table2) (122).Other studies presented positive (122),negative (20, 61, 104, 123), and null association between BCCand SCC and allergic condition (20, 123, 124). In a population-basedcase–control study including 375 early onset BCC patients and 251 controls, aswell as 254 SCC patients and 432 controls, an overall inverse association wasreported between an allergic conditions and risks of early onset BCC but not SCC.Interestingly, reduced risks of either early onset BCC or SCC related to atopichistory was noticed only in women (125).

Although, almost all studies was discussed above had limited data aboutpossible modifying factors, for instance age at onset, type of allergy and itsseverity, as well type of medications. Cervical Cancer(CC)Cervicalcancer (CC) is a malignant cancer of the cervix with nearly 277,000 newdiagnosed cases and 266,000 deaths annually (126). A case-control study among USA individuals reportedthat an odds of history of any allergy was 0.7 (95 % CI: 0.6 to 0.9) forsquamous cell SCC.

Also, they estimated the risk of CC related with SNPs in thechromosome 5 cytokine cluster genes(127).DiscussionDespite the hesitantresults, the currently available data from case-control and cohort studies indicatethat Allergy is related with a lower risk of cancer. Further research shouldfocus on a more carefully defined atopy status and manifestation of differentatopic diseases, to advance our understanding of the role that allergies mightplay in the risk of developing cancer.  Prophylaxis hypothesis may be the moreprobably explain the inverse association between Allergy and certain cancers.Actually, relationship between cancer risk and allergy symptoms was morecommonly highlighted in malignancies of tissues or organs which interface theexternal environment such as gastrointestinal cancers than others such asbreast and prostate tumors.Many of previousreports above collected data of allergy symptoms retrospectively; so recallbias is plausible. Also, study participants may mistake non-allergic symptomsand over-estimated the allergy symptoms.

Additionally, an ongoing chemoradiotherapymay influence the manifestation of Allergy (128),which could affect recall when subjects declaring history of atopic diseases. The involvements ofallergic inflammatory pathways in growth and development of cancer provide anopportunity for further evaluation and consideration. Moreover, establishmentof the genetic mechanisms behind the association between Allergy and cancersmight allow a novel insight to development of primary prevention and promisingapproach for effective treatments for cancer patients.

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