| Objectives1.Ovarian cancer is one of the most common gynecological cancers.However,because of the lack of early specific symptoms,most cases are diagnosed at a more advanced disease stage.Ovarian cancer has become a serious threat to life and health of females with malignant tumors.Numerous epidemiological studies have focused on the influence of individual food types on the survival of patients with ovarian cancer.However,the findings arising from these studies are,to some extent,controversial and confusing.Therefore,the present study investigated a diverse array of food intake and ovarian cancer prognoses.The purpose of this study was to provide strong evidence for associations between the intake of different food types and survival outcomes in patients with ovarian cancer.2.Although food intake plays an important role in the development of ovarian cancer,dietary pattern analysis has emerged as a key method to assess the potentially complex interactions between specific foods.At present,there is limited evidence on the associations between dietary patterns and the survival of patients with ovarian cancer;furthermore,these results have poor applicability for the Chinese population.Therefore,this study investigated the effects of dietary patterns on the survival of Chinese patients with ovarian cancer and provided a theoretical basis for promoting the survival of ovarian cancer patients from the perspective of overall dietary patterns.3.The effect of inflammatory levels on ovarian cancer prognosis has been widely established,and numerous studies have confirmed that dietary intake can alter inflammatory levels in the body.However,the role of inflammation on the association between diet and the survival of patients with ovarian cancer has not been sufficiently explored.Thus,this study investigated the mediation effect of inflammatory markers in blood cells on the associations between dietary patterns and ovarian cancer survival,and constructed inflammatory dietary patterns in ovarian cancer patients by reduced rank regression.The results of this study can provide scientific evidence for exploring the potential mechanisms underlying the associations between dietary patterns and ovarian cancer survival.4.Dietary guidance in cancer patients has become an important method to improve the prognosis of cancer,but there are no dietary guidelines for ovarian cancer patients.The existing evidence on dietary indices and dietary patterns is poor in terms of reproducibility and generalization among different patients with ovarian cancer.Therefore,in this study,the characteristics of vegetable dietary patterns and inflammatory dietary patterns of ovarian cancer patients were integrated to construct the Ovarian Cancer Survival Promoting Dietary Index(OCPI),which was independent of correlations between different foods.The results of this study enriched the evidence on dietary research evidence for ovarian cancer patients and provided a theoretical basis and effective methods for improving the survival outcome of patients with ovarian cancer in terms of lowering inflammation.Methods1.Study populationThis study was based on The Follow-Up Study of Ovarian Cancer(OOPS),a prospective cohort study of newly diagnosed patients with ovarian cancer.We recruited patients for the baseline survey between January 2015 and December 2020 with a histologically confirmed diagnosis of ovarian cancer.Follow-up and medical treatment were conducted at the gynecological oncology ward at Shengjing Hospital of China Medical University.Participants were required to recall information related to dietary intake for the year prior to the diagnosis of ovarian cancer.We also collated a range of demographic,clinical,and lifestyle data.This study was approved by the Ethics Committee of Shengjing hospital of China Medical University(2015PS38K and 2020PS265K)and all participants provided written informed consent.2.Exposure measures(1)Based on the Chinese Food Composition Tables and 132-items food frequency questionnaire which including food consumption,cooking methods and dietary habits,we calculated the intake in grams per day for each food item for each patient and the nutrients intake.(2)Dietary patterns: The Chinese Healthy Eating Index(CHEI)and Dietary Inflammation Index(DII)were used to evaluate the prior dietary patterns of patients.This study applied factor analysis in order to generate major dietary patterns and factor loadings on all food items.Varimax rotation was applied for greater interpretability.After evaluation of eigenvalues and the scree test,main factors were determined.Food items with high factor loading were the main contributors to dietary pattern and representative of the character of each pattern.(3)Inflammation-related markers in blood cells: Venous blood samples were obtained from all participants after an overnight fast(at least 12 hours).Blood routine examination results within 30 days prior to the date of diagnosis of the user.If the patient has multiple test results within 30 days prior to diagnosis,the average value of multiple test results will be taken.Furthermore,this study calculated Neutrophil-to-Lymphocyte Ratio(NLR),Platelet-to-Lymphocyte Ratio(PLR),Monocyte-to-Lymphocyte Ratio(MLR),and Lymphocyte-to-Monocyte Ratio(LMR)based on the results of blood routine examination.(4)Inflammatory dietary pattern: The inflammatory dietary pattern was assessed using reduced rank regression,which is a statistical method determining linear functions of predictors(dietary intake)by maximizing the explained variation in responses.This study selected inflammation-related markers as response variables so the final derived dietary pattern could explain the inflammation status.Finally,the inflammatory dietary pattern score was obtained by adding the standardized intake multiplication factor load for each food.(5)OCPI: This simplified dietary score method by Matthias B.Schulze was used to calculated OCPI.It was calculated by summing the weighted standardized consumption of food items which was with high factor loadings on the vegetable dietary patterns(promoted survival of ovarian cancer patients)and inflammatory dietary pattern(increased risk of death of ovarian cancer patients).In the calculation process,food items with a factor loading> 0.50 in vegetable dietary pattern,food items with a factor loading<-0.08 in inflammatory dietary pattern,and food items with a factor loading> 0.2 in inflammatory dietary pattern were remained.(6)Other foundational exposure: Age at diagnosis,education level,household income level,menopause status,parity,physical activity level,smoking and drinking status,and diet changes were obtained according to the questionnaire.The height and weight of patients were measured by professionals according to national standards,and the Body Mass Index(BMI)was calculated.Histological type,histopathologic grade,International Federation of Gynecology and Obstetrics(FIGO)stage,and residual lesions were judged by professional doctors and recorded into the electronic medical record system of Shengjing Hospital.3.Outcome measuresFollow-up was available until the 31 st of March 2021 and the follow-up stage was conducted in both passive and active modes.The main outcome was death from any cause.4.Statistical analysis(1)Cox proportional hazards regression models were used to evaluate hazard ratios(HRs)and 95% confidence intervals(CIs)for the associations between dietary factors and the survival of ovarian cancer patients.The final adjusted model included age at diagnosis,(<55 or ≥55 years)and BMI(normal or abnormal),physical activity(<14.05 MET-hour/day or ≥14.05 MET-hour/day),education level(senior high school/technical secondary school/below or junior college/university/above),household income level(< 10000 yuan/month or≥10000 yuan/month),parity(≤ 1 or > 1),menopausal status(yes or no),smoking status(yes or no),drinking status(yes or no),total energy intake(kcal/day),histological type(serous or non-serous),FIGO stage(I–II or III–IV),histopathologic grade(well differentiated or moderate/ poorly differentiated),residual lesions(yes or no),dietary patterns(continuous),and dietary changes(yes or no).(2)Dietary factors were categorized by tertile or exposed/unexposed distribution,where the lowest tertile served as the unexposed or reference group;(3)A linear trend across increasing quartiles was tested using the median value of each tertile as a continuous variable;(4)Continuous variables were used to investigate the dose-response relationship between dietary factors and ovarian cancer survival;(5)Restricted cubic splines with three knots were used to express potentially non-linear associations between dietary factors and ovarian cancer survival;(6)Mediation analyses were applied to estimate whether inflammation-related markers play a mediating role in the association between dietary factors and ovarian cancer survival by difference method.The indirect effect,direct effect,and ratio of mediation effect and its95%CI were calculated.(7)We also carried out subgroup analyses according to age at diagnosis,BMI,physical activity,histological type of tumor,and FIGO stage of tumor.The interaction effects between dietary factors and demographic and clinical characteristics were tested by adding multiplicative terms in multivariable regression models;(8)Multiple sensitivity analyses were performed to check the robustness of the results in non-smoker,non-drinker,patients with poorly differentiated tumor,patients without residual lesions,and patients with more than one year survival time.Results1.Study population characteristicsUntil 31 March 2021,744 patients with ovarian cancer were enrolled in OOPS.We further excluded participants who not provided data on important covariate(n= 20),and those with implausible caloric intakes [the <2.5 or >97.5 percentiles(<570.93 and >3035.26kcal/day,respectively)](n= 36).Finally,dietary data were available for 688 patients with o ovarian cancer.During the median(interquartile)follow-up time of 37.57(24.70～50.17)months,a total of 125 deaths were reported from 688 patients.The surviving patients tended to have higher levels of education and better household income levels than the deceased patients.Patients with an advanced FIGO stage and larger residual lesions had a significantly worse survival(P<0.05).2.Association between the intake of different foods and ovarian cancer survivalUsing an adjusted model,a significantly increasing trend for ovarian cancer survival was observed with a high intake of total vegetables(HR,95% CI=0.56,0.32～0.99;P trend<0.05),dark vegetables(HR,95% CI=0.54,0.32～0.91;P trend=0.02),fish and seafood(HR,95% CI=0.59,0.35～0.99;P trend=0.03),fresh egg(dose-response relationship HR,95% CI=0.83,0.70～0.99),and tea(HR,95% CI=0.59,0.41～0.85).In addition,a significantly increasing trend for ovarian cancer survival was observed for a low intake of milk and dairy products(HR,95%CI=2.09,1.20-3.6;P trend=0.06),and processed red meat and poultry meat(HR,95% CI=1.65,1.11～2.45).Whole grain intake was associated with a U-shaped risk of death in ovarian cancer patients(P trend<0.01).3.Association between dietary patterns and ovarian cancer survival(1)Prior dietary patterns: After adjusting for confounding factors,patients in the highest tertile of CHEI scores had a better survival than those in the lowest tertile(HR,95% CI=0.56,0.35～0.90;P trend=0.02).There was a boundary significant association between a higher DII and worse ovarian cancer survival(dose-response relationship HR=1.15;95% CI=0.99,1.33),and there was significant association with non-drinkers.In non-drinkers,the highest tertile of the DII was related to worse survival when compared with the lowest tertile scores(HR,95%CI=2.11,1.06-4.21,P trend =0.03).(2)Posterior dietary pattern: Factor analysis revealed four major dietary patterns:vegetable pattern,animal offal and processed food pattern,fruits and sweets pattern,and scallions and garlic pattern.Furthermore,the highest tertile of the vegetable pattern scores was related to better survival when compared with the lowest tertile scores(HR,95%CI=0.50,0.28～0.87;P trend=0.02).Ovarian cancer patients with the highest adherence to the animal offal and processed food pattern was associated with a poorer survival than those with the lowest adherence after adjustment(HR,95%CI=1.57,0.96～2.55;P trend=0.04).There was no significant association between the other two dietary patterns and ovarian cancer survival.4.Mediation effect of inflammatory markers in common blood cells on the association between dietary patterns and ovarian cancer survivalThere were positive associations between lymphocyte count and LMR and ovarian cancer survival,and negative associations with NLR,PLR,and MLR on ovarian cancer survival.Moreover,there was a mediation effect for NLR on the association between CHEI and ovarian cancer survival;the mediation proportion(95% CI)was 13.80%(4.20%,36.70%)(P=0.03).Furthermore,there was a mediation effect of NLR,MLR and LMT on the association between the vegetable pattern and ovarian cancer survival;the mediation proportion(95% CI)was 9.00%(2.70%,25.80%)(P=0.04),12.30%(3.40%,36.10%)(P=0.04),and 12.80%(3.50%,37.40%)(P=0.03),respectively.Moreover,there was a mediation effect for PLR,MLR and LMT on the association with the scallions and garlic pattern on ovarian cancer survival;the mediation proportion was 28.70%(2.40%,86.60%)(P<0.05),34.80%(3.40%,88.90%)(P=0.02),and 37.40%(3.50%,90.80%)(P=0.02),respectively.5.Association between inflammatory dietary pattern and ovarian cancer survival(1)Inflammatory dietary pattern was characterized by high intakes of bread,coffee,pastries/cakes,deep-fried dough sticks and low intake ginger,celery,cauliflower/cauliflower.This dietary pattern explained 19.50% of the total variation of the response variable,accounted for 18.89% and 20.22% of the variance in NLR and MLR,respectively.(2)Compared with dead patients,adherence to inflammatory dietary pattern was worse in surviving patients(t=3.56,P<0.0001),mean± standard deviation were 0.22±0.62 and-0.06±0.71,respectively.Furthermore,patients in the highest tertile for inflammatory dietary pattern score had a 188% greater risk of death than those in the lowest tertile after adjustment(HR,95% CI= 2.88,1.65～5.04;P trend <0.001).6.Association between OCPI and ovarian cancer survival(1)OCPI was included 19 food items,which with a weight of +1 in it included garlic moss,white gourd,fungus,cauliflower,pumpkin,oilseed rape,kohlrabi/cabbage,eggplant,pakchoi,spinach,and celery.Food items with a weight of-1 in the OCPI included instant noodles,mushrooms,bananas,candies/preserved fruit,deep-fried dough sticks,pastries/cakes,coffee,and bread.Moreover,the OCPI score was consistent with the adherence and health effects of the vegetable pattern(P<0.0001)and inflammatory dietary pattern(P<0.0001)in patients with ovarian cancer.(2)Compared with dead patients,surviving patients had higher OCPI scores(t=38207.00,P<0.0001),median(quartile)were-2.11(-4.66,0.67)and-0.81(-3.86,3.64),respectively.Furthermore,patients in the highest tertile of OCPI scores had a 46% lower risk of death than those in the lowest tertile after adjustment(HR,95% CI= 0.54,0.33～0.87;P trend <0.01).Conclusions1.The consumption of total vegetables,dark vegetable,fish and seafood,fresh egg,and tea were protective factors for ovarian cancer survival.However,the intake of milk and dairy products,processed red meat and poultry meat,were adverse factors for ovarian cancer survival.The consumption of whole grain in the range of approximately 7 to 40 g/d was negatively associated with the risk of death.2.A higher CHEI score was associated with a lower risk of death in ovarian cancer patients,while a higher DII score was significantly associated with a higher risk of death in non-drinkers.Moreover,four dietary patterns were established;there was a positive association with the high vegetable pattern score for ovarian cancer survival,and high animal offal and processed foods pattern score for the risk of death.3.There was a mediation effect of NLR on association with the CHEI on ovarian cancer survival,and a mediation effect of NLR,MLR,and LMT on association with the vegetable pattern on ovarian cancer survival.An inflammatory pattern was identified in ovarian cancer patients.Moreover,the dietary pattern was associated with an increased risk of death in ovarian cancer;this was mediated by the levels of inflammation in the body.4.We found that the OCPI can fully reflect the comprehensive characteristics of real healthy dietary tendency and inflammatory risk diets.Furthermore,this score was found to be negatively correlated with the risk of death from ovarian cancer.OCPI provided evidence of dietary guidance for improving survival by reducing inflammation levels while considering healthy dietary habits in ovarian cancer. |
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