Opium Use and Risk of Cancer

Kansainvälinen syöväntutkimuskeskus (International Agency for Research on Cancer, IARC) arvioi hiljattain oopiumin käytön syövän vaaraa lisääväksi ykkösluokan karsinogeeniksi, mutta tieto oopiumin käytön yhteydestä syöpäsairauksiin on yhä puutteellista. Hyödynsin väitöskirjassani Iranian Opium and Cancer (IROPICAN) -tutkimushankkeessa kymmenessä Iranin maakunnassa kerättyä tietoaineistoa. Tutkimukseni käsittelee pään ja kaulan alueen, virtsarakon ja suoliston syöpien yhteyttä oopiumin käyttöön. Tutkimukseni perustuu 633 histologisesti varmennettuun pään ja kaulan alueen levyepiteelikarsinoomaan, 717 virtsarakon syöpään ja 848 suolistosyöpään sairastuneen henkilön ja kaikille syöpälajeille yhteisten 3477 verrokkihenkilön tietoihin. Verrokkihenkilöt olivat sairaaloissa vierailleita henkilöitä, joilla ei ollut syöpää ja jotka eivät olleet syöpäpotilaiden sukulaisia eivätkä ystäviä. Tiedot kerättiin laajan haastattelulomakkeen avulla. Siinä kysyttiin opiumin käytön aloitusikää, käytön kestoa, tiheyttä, käytetyn opiumin määrää ja käyttötapaa. Lisäksi kysyttiin mahdollisista sekoittavista tekijöistä kuten tupakan, nuuskan ja vesipiipun käytöstä ja ravintotekijöistä. Vastausprosentti oli tutkimukseen valittujen syöpätapausten joukossa 99 % ja verrokkien joukossa 89 %. Tutkimuksen laadunvarmistus- ja pilottivaiheissa todettiin oopiuminkäyttötietojen raportoinnin olevan suhteelliseen luotettavaa: 70 prosentilla tapauksista ja 69 prosentilla verrokeista itse ilmoitettu tieto siitä, käyttääkö hän oopiumia vai ei, piti paikkansa. Tieto piti paikkansa peräti 96 prosentilla tapauksista ja 88 prosentilla verrokeista, jotka kertoivat käyttävänsä oopiumia säännöllisesti. Analyyseissä oopiumin vaikutusta kuvattiin ristitulosuhteilla (odds ratio, OR), jotka laskettiin logistisella regressiolla ja korjattiin sekoittajatekijöiden vaikutuksista. Oopiumin säännölliseen käyttöön liittyi suurentunut pään ja kaulan levyepiteelikarsinoomaan riski (OR: 3,8; 95 %:n luottamusväli: 3,0–4,8). Riski kasvoi, kun käyttötiheys ja -määrä lisääntyivät ja kesto piteni. Oopiumin säännöllisen käytön havaittiin lisäävän eniten kurkunpään syövän riskiä (OR: 6,6; 4,7–9,1). Oopiumin käytöllä ja tupakoinnilla oli merkittävä yhteisvaikutus pään ja kaulan levyepiteelikarsinooman riskiin: OR oli 8,2 (6,2–10,7) niillä, jotka sekä käyttivät oopiumia että polttivat savukkeita, verrattuna niihin, jotka eivät olleet koskaan tehneet kumpaakaan. Oopiumia säännöllisesti käyttävillä oli 3,5-kertainen (2,8–4,3) virtsarakkosyövän riski verrattuna niihin, jotka eivät olleet koskaan käyttäneet oopiumia. OR oli 4,8 (3,7– 6,3) tutkittavilla, jotka haastattelun aikaan käyttivät yhä oopiumia, mutta vain 1,5 (1,0–2,4) niillä, jotka olivat lopettaneet oopiumin käytön yli 10 vuotta ennen haastattelua. Henkilöillä, jotka käyttivät sekä raakaa oopiumia että oopiumimehua, OR oli 7,4 (4,1–13,3). Oopiumin ja tupakan yhteiskäyttö nosti riskin 7,7-kertaiseksi (6,0–9,7). Oopiumin säännöllisellä käytöllä ei havaittu olevan yleisesti ottaen yhteyttä suolistosyövän riskiin (OR: 0,9; 0,7–1,2). Silti oopiumin käyttö vähintään kaksi kertaa päivässä voi liittyä lisääntyneeseen suolistosyövän riskiin: OR oli 2,0 (1,1–3,8) verrattuna niihin, jotka eivät käytä oopiumia. Oopiumin säännöllisen käytön havaittiin olevan vahvasti yhteydessä lisääntyneeseen virtsarakkosyövän ja pään ja kaulan alueen levyepiteelikarsinooman riskiin, mutta varsin heikosti tai ei ollenkaan suolistosyövän riskiin. Opinnäytetyöhöni sisältyvät tutkimukset lisäävät ymmärrystä oopiumin käytön vaikutuksesta tutkittujen syöpälajien kehittymisriskiin ja toimivat pontimena alan tuleville tutkimuksille.The use of opium has been classified by the International Agency for Research on Cancer (IARC) as a carcinogenic to humans (Group 1 carcinogen), but there is still a lot that needs to be clarified regarding the association between opium use and cancer. To study this association further, I used the data collected by the Iranian Opium and Cancer (IROPICAN) study in ten provinces of Iran. This study focuses on examining the association between opium use and cancers of the head and neck, bladder, colon, and rectum. The overall aim of this project is to evaluate the association between the consumption of opium and cancers of the head and neck, colorectum, and bladder. This dissertation utilized 633 histologically confirmed cancer cases of head and neck squamous cell carcinoma (HNSCC), 717 cases of bladder cancer (BC), 848 cases of colorectal cancer (CRC), and 3,477 common controls selected from hospital visitors who did not have cancer and were not relatives or friends of the cancer cases. The extensive questionnaire used in the study covered a variety of topics, including opium use (e.g., information on age at initiation, duration, frequency, typical amount, and route), as well as potential confounding factors such as tobacco use (e.g., cigarettes, nass, and waterpipe), and dietary factors. The response rate was 99% for the cancer cases and 89% for the controls. In the validation and pilot phases of the study, the reported opium use showed a reasonably good level of accuracy, with a sensitivity of 70% for cancer cases and 69% for controls. The study showed excellent reliability with intra-class correlation coefficients of 0.96 for ever opium use and 0.88 for regular opium use. Multivariable unconditional logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI). The ORs were adjusted for potential confounders for each cancer type. Regular opium use was associated with a highly increased risk of HNSCC (OR: 3.8, 95% CI: 3.0, 4.8). There was a strong dose–response relationship between opium use and HNSCC risk, with increasing risk seen with higher frequency and amount of use, and with longer duration. Regular opium use was found to significantly increase the risk of cancers of the pharynx OR 2.9, 95% CI: 1.4, 6.0), larynx (OR 6.6, 95% CI: 4.7, 9.1), and other sites within the head and neck region (OR: 6.0, 95% CI: 2.4, 14.7). There was a significant interaction between opium use and cigarette smoking affecting HNSCC risk, with an OR of 8.2 (95% CI: 6.2, 10.7) among those who used opium and smoked cigarettes at the same time compared to those who had never used anything, but the association with opium remained significant among individuals who had never used tobacco. Regular opium consumption was also associated with an increased risk of BC, with an OR of 3.5 (95% CI: 2.8, 4.3) compared to those who had never used opium. The risk of BC decreased to one-third among individuals who had stopped using opium more than ten years before the date of the interview, compared to those who still used opium. The risk of developing BC was found to be 4.8 (95% CI: 3.7, 6.3) among current opium users. However, for those who had stopped using opium more than 10 years prior to the interview, the risk of BC decreased to 1.5 (95% CI: 1.0, 2.4). The OR for individuals who used both crude opium (teriak) and opium juice was 7.4 (95% CI: 4.1, 13.3). There was a joint effect of opium and tobacco, with an OR of 7.7 (95% CI: 6.0, 9.7) for individuals who used both opium and tobacco. No association was found between regular opium consumption and the risk of CRC (OR 0.9, 95% CI: 0.7, 1.2) compared to individuals who never used opium. Still, the study suggests that opium use two or more times per day may be associated with an increased risk of CRC with an OR of 2.0 (95% CI: 1.1, 3.8) compared to non-users of opium. Regular opium use was found to be strongly associated with an increased risk of developing BC and HNSCC, but the link between regular opium use and CRC was weak. The studies included in my thesis will add to the understanding of the impact of opium use on the risk of developing cancer in the head and neck, bladder, colon, and rectum, and serve as a crucial background for future investigations in this field

Modelling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion

We have developed a mathematical framework for describing a bispecific monoclonal antibody interaction with two independent membrane-bound targets that are expressed on the same cell surface. The bispecific antibody in solution binds either of the two targets first, and then cross-links with the second one whilst on the cell surface, subject to rate-limiting lateral diffusion step within the lifetime of the monovalently engaged antibody-antigen complex. At experimental densities, only a small fraction of the free targets is expected to lie within the reach of the antibody binding sites at any time. Using ordinary differential equation and Monte Carlo simulation-based models, we validated this approach against an independently published anti-CD4/CD70 DuetMab experimental data set. As a result of dimensional reduction, the cell surface reaction is expected to be so rapid that, in agreement with the experimental data, no monovalently bound bispecific antibody binary complexes accumulate until cross-linking is complete. The dissociation of the bispecific antibody from the ternary cross-linked complex is expected to be significantly slower than that from either of the monovalently bound variants. We estimate that the effective affinity of the bivalently bound bispecific antibody is enhanced for about four orders of magnitude over that of the monovalently bound species. This avidity enhancement allows for the highly specific binding of anti-CD4/CD70 DuetMab to the cells that are positive for both target antigens over those that express only one or the other We suggest that the lateral diffusion of target antigens in the cell membrane also plays a key role in the avidity effect of natural antibodies and other bivalent ligands in their interactions with their respective cell surface receptors

Adherence to low-carbohydrate diet in relation to gastric cancer : Findings from a case-control study in Iran

This study examined the association between adherence to low carbohydrate diet (LCD) and risk of gastric cancer (GC). This hospital-based case-control study was conducted in Iran Cancer Institute, Tehran, Iran between 2010 and 2012. Totally, 178 patients with GC and 276 apparently healthy controls participated in this study. Cases were histo-pathologically confirmed GC patients aged ≥40 years diagnosed with GC in the last year. Dietary intakes were assessed using a validated 146-item Diet History Questionnaire. We computed the LCD score trough the protocol explained by Halton. Patients with GC were older (60.8 vs. 53.2 years, P < 0.001) and more likely to be male (74.2 vs. 63.8%, P = 0.02), married (97.8 vs. 86.6%, P < 0.001) and illiterate (62.4% vs. 26.1%, P < 0.001) than controls. Before adjusting for covariates, adherence to LCD-diet was not associated with risk of GC [odds ratio (OR) 1.31; 95% confidence interval (CI) 0.82-2.09 for highest vs. lowest tertile; Ptrend< 0.26]. Adjustments for several potential confounders including H-pylori infection and BMI, participants in the highest tertile of LCD score were 7% more likely to have GC than those in the lowest tertile; however, it was not statistically significant (OR 1.07; 95% CI 0.59-1.95 for highest vs. lowest tertile; Ptrend< 0.79). No significant association was also seen between adherence to animal- or vegetable-based LCD diet and risk of GC. In conclusion, we failed to find any evidence on the association between consumption of LCD and odds of GC. Further studies, in particular of prospective design, are required to confirm these findings.acceptedVersionPeer reviewe

Human Papillomavirus and Risk of Head and Neck SquamousCell Carcinoma in Iran

Human papillomavirus (HPV) causes a subset of head and neck squamous cell carcinoma (HNSCC). Knowledge of determinants of α-, β-, and γ-HPVs types in the oral cavity is required for a better understanding of HNSCC development. Oral rinse samples of 498 HNSCC cases and 242 controls from the IROPICAN study—a large multicenter case-control study in Iran—were screened for 21 α-HPV, 46 β-HPVs, and 52 γ-HPVs using bead-based HPV genotyping assays. α-HPVs were detected only in 1.2% of the patients and 2.9% of the controls from which HPV16 was the most prevalent type among participants. β-HPVs were detected in 43.8% of the patients and 38.6% of the controls where the lip and oral cavity (45.5%) had the highest positivity. Values for γ-HPV prevalence in patients and controls were 26.1% and 24.7%, respectively. The highest percentage of γ-HPV positivity was found in the larynx (30.4%). Concerning the β genus, HPV23 and HPV38 were the most prevalent types among the patients and controls, respectively. For the γ genus, SD2 in cases and HPV134 in controls were the most prevalent types. Overall, detection of α-HPVs (aOR, 0.40; 95% CI = 0.1 to 1.2; P = 0.11), β-HPVs (aOR, 1.9; 95% CI = 0.9 to 1.6; P = 0.29), and γ-HPVs infections (aOR, 1.04; 95% CI = 0.7 to 1.5; P = 0.83) was not associated with the HNSCC development. Our data did not suggest an HPV-related etiology for HNSCC pathogenesis. Nonetheless, this study provides novel insights into the diversity of β-, and γ-HPVs in different HNSCC anatomical subsites

Patterns of Nutrient Intake in Relation to Gastric Cancer : A Case Control Study

Gastric Cancer (GC) is the most common cancer among Iranian men. We conducted a case-control study to investigate the association between patterns of nutrient intake and the risk of GC in Iran. We enrolled 178 GC patients and 271 controls matched for age and sex. We collected dietary intakes using a validated diet history questionnaire. We performed factor analysis on 28 nutrients using multivariate logistic regression models on tertiles of factor scores and estimated odds ratios (OR) and 95% confidence intervals (95% CI). We identified three nutrient patterns. The first pattern included pantothenic acid, riboflavin, zinc, animal protein, and calcium. Selenium, thiamin, carbohydrate, vegetable protein, niacin and low intake of vitamin E loaded the second pattern, and the third pattern was abundant in fiber, carotene, vitamin C and A. We found no significant association between GC and any of the dietary patterns. However, in the first patterns, men in the highest tertile had significantly higher odds of GC than the lowest (OR = 2.15, 95% CI: 1.13–4.09, p trend = 0.02). A dietary pattern loaded by animal products may increase the risk of GC among Iranian men. Larger studies are required to approve these findings in overall and in different subgroups. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1931697.acceptedVersionPeer reviewe

Association between gastric cancer and the intake of different types of iron and meats

Background: Heme and non-heme irons are two forms of iron in the diet. Few studies have evaluated the association between heme iron intake and the risk of gastric cancer (GC). We aimed to investigate the association between heme, non-heme and total iron intake and risk of GC in Iran. Methods: In a hospital-based case–control study, nutritionists interviewed 178 pathologically confirmed GC patients and 276 controls using a valid Diet History Questionnaire. Multiple logistic regression model was used to estimate Odds Ratios (OR) and 95% Confidence Intervals (CIs) for iron intake and risk of GC. Results: Subjects in the highest tertile of total iron intake were 46% less likely to get GC than those in the lowest (OR = 0.54, 95% CI: 0.32–0.92), however, the associations were not significant for intake of heme and non-heme iron. The risk of GC in the highest tertile of total meat intake was 2.51 times higher than the lowest. We found significant associations between GC and chicken (OR = 2.95; 95% CI: 1.66–5.22) and fish intake (OR = 1.89; 95% CI: 1.09–3.27), However, we found no associations between the risk of GC and intake of red meat, salted fish, and liver. Conclusion: Total iron intake was associated with a lower risk of GC which could be partly due to the high prevalence of anemia in Iran. Although, we could not find any significant association between the risk of GC and the intake of heme and non-hem iron among the Iranian population.publishedVersionPeer reviewe

Determinants of waterpipe smoking in Iranian adults : results from the IROPICAN study

INTRODUCTION: Waterpipe smoking has become increasingly popular in Western countries, particularly among young individuals. This study aims to identify the factors influencing waterpipe smoking by focusing on consumption patterns. METHODS: We utilized data from a multicenter case-control study (IROPICAN) conducted in Iran. Multivariate logistic regression estimated the adjusted odds ratio and 95% confidence intervals as a measure of association between waterpipe smoking and different factors. RESULTS: Among 3,477 subjects were included, 11.8% were waterpipe smokers. Most of 50 years (85%). Around 59% of occasional users started it before 30 years old. Low education, low SES, alcohol consumption, cigarette smoking, secondhand smoke exposure, and opium use were associated with waterpipe smoking. Stratified analysis by frequency pattern showed an association between occasional smoking with age 0.97 (0.96-0.98), university degree 0.36 (0.17-0.76), urban dwellers 1.40 (1.06-1.86) and between high SES and daily smoking 0.34 (0.17-0.69). CONCLUSION: Our results offer valuable information to policymakers for developing waterpipe smoking control measures. The occasional waterpipe smoking results may be generalized to the younger people in Western countries.Peer reviewe

Vitamins and Stomach Cancer : A Hospital Based Case-Control Study in Iran

Background: This study investigated the association between vitamins intakes and risk of gastric cancer (GC) among Iranian population. Methods: In this hospital-based case-control study, 178 pathologically confirmed GC patients and 276 healthy controls were interviewed to answer a valid diet history questionnaire. Unconditional logistic regression, in which potential confounders were taken into account, was applied to determine the association of vitamin intakes and odds of GC in total population and in stratums of body mass index (BMI), helicobacter pylori (H-pylori) infection, and smoking. Results: GC was directly associated with vitamin D (OR 1.59; CI 95% 1.07, 2.36) and cobalamin (OR 1.25; CI 95% 1.08, 1.44). Thiamin (OR 0.50; 95%CI 0.30, 0.83), pantothenic acid (OR 0.71; 95%CI 0.58, 0.87), folate (OR 0.99; 95%CI 0.99, 0.99) and vitamin E (OR 0.98; 95%CI 0.96, 0.99) were inversely associated with GC. In 231 H-pylori infected participants, consumption of thiamin (OR 0.3; 95% CI 0.59, 0.86), pyridoxine (OR 0.52; 95%CI 0.31, 0.85), and folate (OR 0.99; 95%CI 0.99, 0.99) reduced GC risk. In H-pylori negative participants, only vitamin E (OR 0.96; 95%CI 0.93, 0.99) reduced the risk and vitamin D (OR 1.99; 95%CI 1.18, 3.36), riboflavin (OR 1.91; 95%CI 1.37, 2.66), pantothenic acid (OR 1.34; 95%CI 1.13, 1.64), biotin (OR 1.03; 95%CI 1.01, 1.05), and cobalamin (OR 1.36; 95%CI 1.13, 1.64) increased the risk. In BMI stratums, only vitamin D (OR 1.81; 95%CI 1.07, 3.08) was associated with the risk of GC among normal weight participants. Vitamin E was associated with lower risk of GC in ever smokers (OR 0.97; 95%CI 0.95, 0.99) and thiamin (OR 0.41; 95%CI 0.19, 0.86) and niacin (OR 0.93; 95%CI 0.87, 0.99) were associated with lower risk in never smokers. Positive associations were observed by increasing vitamin D (OR 2.08; 95%CI 1.12, 3.85) and cobalamin (OR 1.33; 95%CI 1.08, 1.65) in never smokers. Conclusion: This study provided support for a possible protective effect of vitamin E, thiamin, pantothenic acid, and folate on GC risk. Vitamin D and cobalamin intake increased the risk.publishedVersionPeer reviewe

Opium use and risk of bladder cancer: a multi-centre case-referent study in Iran

Background Bladder cancer (BC) is the 10th most common type of cancer worldwide and the fourth most common type of cancer in Iran. Opium use is considered as one of the risk factors for BC. We aim to assess the association between various parameters of opium use, which in Iran is mainly ingested or smoked in various forms, and the risk of BC. Method In this multi-centre case-referent study in Iran, 717 BC cases and 3477 referents were recruited to the study from May 2017 until July 2020. Detailed histories of opium use (duration, amount, frequency) and potential confounders were collected by trained interviewers. Multivariable unconditional logistic regression models were used to measure adjusted odds ratio (OR) and 95% confidence intervals (CI). The ORs were adjusted for age, gender, place of residence and pack-years of cigarette smoking. Results Regular opium consumption was associated with an increased risk of BC (OR 3.5, 95% CI: 2.8, 4.3) compared with subjects who never used opium. Compared with continuous users, the risk decreased to one-third for those who stopped opium more than 10 years ago. The adjusted OR for those who used both crude opium (teriak) and opium juice was 7.4 (95% CI: 4.1, 13.3). There was a joint effect of opium and tobacco (OR for users of both opium and tobacco 7.7, 95% CI: 6.0, 9.7). Conclusions Regular opium use is associated with an approximately 4-fold risk for BC. The OR decreases along with the increasing time since stopping opium use

Geographic distribution and time trends of water-pipe use among Iranian youth and teenage students : A meta-analysis and systematic review

Water-pipe tobacco smoking is harmful to health, yet its rate of prevalence remains uncertain. Recent evidence has shown that the prevalence of water-pipe smoking among students is higher than in the general population. In this study, a systematic review of related literature on water-pipe use was conducted, and for this purpose, 76 articles were examined in the study. In this vein, geographic distribution and time trends of water-pipe consumption in Iran were considered. The results of this study showed that lifetime, last-year, and last-month prevalence of water-pipe smoking use among Iranian students were 28.78 (25.07–32.49), 20.84 (16.01–25.66), and 16.36 (11.86–20.85), respectively. The results also showed a wide variation by the region and sex in Iran. This study has shown the importance of addressing public prevention and alerting programs in schools and universities.acceptedVersionPeer reviewe