Author ' s response to reviews Title : The influence of taste disorders on dietary behaviors in patients with cancer under chemotherapy treatment

Remove ‘dietary nutrient’ consumption and replace with ‘food habits’ (since an FFQ was used). Insert ‘(sweet)’ after sucrose. Replace ‘perception’ threshold with ‘detection’ threshold. Corrections are done (Page 2, paragraph 1, line 7, 9, 11,12,13, 16, 17) Introduction Reference all background statements. Corrections are done, we added bibliography: 11. Sherry VW: Taste alterations among patients with cancer. Clinical journal of oncology nursing 2002, 6(2):73-77. 12. Barale K, Aker SN, Martinsen CS: Primary taste thresholds in children with leukemia undergoing marrow transplantation. JPEN J Parenter Enteral Nutr 1982, 6(4):287-290 13. Bartoshuk LM: Chemosensory alterations and cancer therapies. NCI Monogr 1990(9):179-184. 20. Epstein JB, Phillips N, Parry J, Epstein MS, Nevill T, Stevenson-Moore P: Quality of life, taste, olfactory and oral function following high-dose chemotherapy and allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2002, 30(11):785-792. 22. Halyard MY: Taste and smell alterations in cancer patients--real problems with few solutions. The journal of supportive oncology 2009, 7(2):68-69. 23. Rolls ET R: Basic Characteristics of Glutamates and Umami Sensing in the Oral Cavity and Gut. J Nutr 2000, 130:960S–965S. 25. Redda MG AS: Radiotherapy-induced taste impairment. Cancer treatment reviews 2006, 32:541-547. 41. Henkin RI, Schecter PJ, Friedewald WT, Demets DL, Raff M: A double blind study of the effects of zinc sulfate on taste and smell dysfunction. The American journal of the medical sciences 1976, 272(3):285-299. 42. Ripamonti C, Zecca E, Brunelli C, Fulfaro F, Villa S, Balzarini A, Bombardieri E, De Conno F: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 1998, 82(10):1938-1945 43. Stoll AL, Oepen G: Zinc salts for the treatment of olfactory and gustatory symptoms in psychiatric patients: a case series. The Journal of clinical psychiatry 1994, 55(7):309-311. 44. Fukasawa T, Orii T, Tanaka M, Suzuki N, Kanzaki Y: Relation between drug-induced taste disorder and chelating behavior with zinc ion; statistical approach to the drug-induced taste disorder, part II. Chemical & pharmaceutical bulletin 2008, 56(8):1177-1180. 45. Heyneman CA: Zinc deficiency and taste disorders. The Annals of pharmacotherapy 1996, 30(2):186-187. 46. Nakata Y, Hirashima T, Kondou Y, Tokuoka Y, Imazato H, Iwata K, Oomori Y, Yamato A, Shimizu S, Nagao S et al: Involvement of zinc in taste disturbance occurring during treatment for malignant tumor in the chest and the effects of polaprezinc oral disintegrating tablets (a retrospective study). Gan to kagaku ryoho 2008, 35(6):955-959 Method Sampling How were the sample/s recruited? We added more description about the samples recruited at Patients and methods section (Page 4, paragraph 2, line 1) “We conducted a crosssectional study of flavor test evaluations at the Oncology Center of a University hospital in Mexico City; our sample population consisted of 60 subjects who agreed to participate. They had no history of infections of the oral/nasal cavity, brain disease, acute respiratory illness or gastroesophageal reflux. Study participants included 30 subjects with a histological diagnosis of a malignant neoplasia (breast, lung, prostate, multiple myeloma and lymphoma) while in their second chemotherapy cycle. Subjects with central nervous system metastasis, gastrointestinal and head and neck cancer and oral, nasal disease or infections were excluded. We included 30 control-group subjects with no evidence of cancer. Eligible patients had biopsy proved diagnosis of cancer on clinical stages II and III with an Eastern Cooperative Group performance status (ECOG) of 0 or 1, with adequate hematologic, hepatic, and renal functions” Were the cancer and non-cancer groups matched in any way (eg demographically)? No, there are no matched analysis. But there are no differences in age, demographic and gender between cases and controls. What sort of cancer (also prognosis) did the patient group have? This is important as cancer of the head and neck or GI tract may have a direct influence on the outcome variables over and above that of the chemotherapy. We reviewed that point in patients and methods section. (Page 4, paragraph 2, line 6) “Study participants included 30 subjects with a histological diagnosis of a malignant neoplasia (breast, lung, prostate, multiple myeloma and lymphoma) while in their second chemotherapy cycle. Subjects with central nervous system metastasis, gastrointestinal and head and neck cancer and oral, nasal disease or infections were excluded”. Dietary assessment It is unclear if a dietary history was taken in addition to using an FFQ or were both used? More detail as to the structure, format and outcome measures of the FFQ is required. For this purpose we search for a validated FFQ in our population. The only validated FFQ is the one we used. Information about structure and format of this FFQ is detailed in Dietary history questionnaire (Page 5, paragraph 2, line 2) “Nutrients intake was evaluated using the “SNUT” program. This food frequency questionnaire (FFQ) was developed and validated for Mexican population by the National Institute of Public Health Mexico [28] SNUT is composed of a matrix listing 116 food items and 10 frequencies of consumption with specified size portion; the program also included information concerning the frequency of ingestion and the brand of vitamin supplements. SNUT software is useful to calculate daily intake of: calories, proteins, carbohydrates, saturated, polyunsaturated and monounsaturated fat; vitamins and zinc intake” Taste threshold assessment Where any tests carried out at baseline, before the chemotherapy? The aim of this study was to determine the existence of taste disorders in cancer patients treated with chemotherapy. Baseline taste were not made in this first study. As said in discussion (Page 10, paragraph 4, line 1) “Methodological weaknesses of this research include: Variability in cancer types and chemotherapy drugs used; and the absence of basal taste disorder evaluation before chemotherapy treatment, and for establishing a causal association between chemotherapy and taste disorders. Continuing research is required to develop an understanding of the nature, frequency, severity, and duration of taste alterations and their significance in food consumption and malnutrition in patients with cancer under chemotherapy treatment. Only three threshold concentrations were used. Was this method sensitive enough? In taste and evaluation section is corrected the mistake, there was not 3 but 5 concentration threshold. (Page 5, paragraph 3, line 1) “Five concentrations were dissolved in distilled water from each of the three taste study substances, including sucrose (3.5-15.5 μmol/ml), urea (91-115 μmol/ml) , and sodium glutamate (0.3-2.7 μmol/ml)”. What is meant by ‘hedonic responses’ and how were they measured? We discarded information about hedonic responses in order to avoid confusion in results. Data Analysis Specify which variables were analysed by which method? We completed Data analysis section (Page 6, paragraph 2, line 1) “Student t test was employed for continuous variables, the Mann-Whitney U test and Fisher’s exact test was employed for non-parametric variables, while the chi square test was utilized for nominal variables. All statistical analyses were carried out with SPSS/PC v. 15.0 program software (SPSS, Inc., Chicago, IL, USA)”. Results That ‘some subjects had no perception or recognition threshold at any concentration’ suggests a floor effect and a major methodological flaw (see above)! Unami taste is difficult to recognize and to be described. People are not used to identify this new flavor as the basic ones (bitter, sweet, salty and acid). This is why some subjects had no perception or recognition threshold at any concentration (we added this paragraph in discussion) (Page 8, paragraph 3, line 1) “This novel substance is difficult to recognize and to be described; people mentioned it as a different unrecognizable flavor, different from water, and were not able to identify this new perception as a basic taste one. This is why some subjects had no detection or recognition threshold at any concentration.”. We also eliminated table that used to be number 3 that describe this differences. Where there any baseline dietary or sensory measures taken prior to chemotherapy? The aim of this study was to determine the existence of taste disorders in cancer patients treated with chemotherapy. Baseline taste were not made in this first study. As said in discussion more studies are required to determine the cause of this disorders, in whom baseline characteristics are going to be important. Strange that there were no differences in dietary intakes at baseline, unless these measures were taken prior to chemotherapy? In studied population there were no statistical differences between cases and controls in calories and nutriments intake, this could be secondary to the good performance status in included patients (ECOG 0-1) and the exclusion of gastrointestinal cancer. Nutriments and calories patients intake is affected by taste disorders as showed in tables 4 and 5. This concludes that taste disorders are important adverse factors for diet consumption. This explanation was added to discussion section . (Page 9, paragraph 3, line1) “Calories and nutrient intake did not show statistical differences between cases and controls in our studied population, this could be due to a good performance status in included patients (ECOG 0-1) and the exclusion of individuals with gastrointestinal cancer”. .” Tables need more information as to when (what stage in the research process) the data were collected. Tables 2, 3, 4, 5 and 6: What test/s were used? Corrections are done. (Pages 15-20) Discussion Explore the significance of lower zinc intake among the cancer group? We added a possible explanation in discussion section (Page 10, paragraph 2, line 1) “Zinc deficiency have been associated in some studies with taste Zinc deficiency has been associated with taste disorders in some experiences [41-46], but other studies have not confirmed this findings [47, 48]. A possible explanation has been described: Drugs that cause hypogeusia have a sulfhydryl group in their structures; this component is known to bind and chelate heavy metal ions like zinc [16]. In the present study, zinc consumption was not significantly different between cases and controls. However, cases with higher sweet RT exhibited significantly less zinc consumption than patients with lower thresholds; these data might suggest some relationship between high sweet RT and low zinc intake”. Was the cancer the problem or the chemotherapy? The aim of this study was to determine the existence of a relationship between energy and nutrient consumption with chemosensory changes in cancer patients under chemotherapy treatment, so, it doesn’t answer that question. More prospective studies are needed including basal information about taste disorders and same information after chemotherapy. The methodological weaknesses of the research do not appear to be addressed in the discussion. We included in discussion (Page 10, paragraph 4, line1) “Methodological weaknesses of this research include: Variability in cancer types and chemotherapy drugs used; and the absence of basal taste disorder evaluation before chemotherapy treatment, and for establishing a causal association between chemotherapy and taste disorders. Continuing research is required to develop better understanding of the nature, frequency, severity, and duration of taste alterations and their significance in food consumption and malnutrition in those patients with cancer under chemotherapy”.