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1.
Cancers (Basel) ; 14(2)2022 Jan 06.
Article in English | MEDLINE | ID: mdl-35053431

ABSTRACT

Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.

2.
Diagnostics (Basel) ; 11(7)2021 Jul 20.
Article in English | MEDLINE | ID: mdl-34359381

ABSTRACT

Since chronic inflammation is associated with ovarian cancer growth and progression, some clinical studies have assessed the association between the pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the prognosis of ovarian cancer. The purpose of this study was to assess the dynamic behavior of the NLR during the course of neoadjuvant chemotherapy (NACT) in patients with high grade serous (HGS) advanced epithelial ovarian cancer and assess its correlation with clinical response, progression free survival (PFS) and changes in other inflammatory indexes. We performed a prospective observational study on 161 patients who underwent NACT at the Department of Gynecologic Oncology, ARNAS G. Brotzu, Cagliari, between 2009 and 2019. NLR was evaluated before starting and after three cycles of NACT. Based on response after three cycles of NACT, patients were divided into two groups: responsive and non-responsive. The primary endpoint was to assess the predictive role of NLR by comparing the responsive and non-responsive patients at baseline and after three cycles of NACT. Secondary endpoints were (a) to correlate NLR with other inflammation markers (CRP, fibrinogen, ferritin, IL-6), albumin, and modified Glasgow Prognostic Score (mGPS) with NLR at baseline and after NACT; (b) to assess the association between NLR and PFS. We found that the NLR value at baseline was not associated with response to NACT, while a decrease in NLR after three cycles was correlated with a better response to NACT. Also, values of CRP, IL-6, ferritin, and mGPS after three cycles of NACT (but not at baseline) were significantly associated with clinical response. Moreover, we found that patients with a low NLR value after 3 cycles of NACT, but not at baseline, had a significantly higher PFS than patients with high NLR after 3 cycles of NACT. In conclusion, NLR change during treatment could serve as a predictive marker of response to NACT in patients with HGS advanced ovarian cancer. This allows for the early identification of non-responsive patients who will need treatment remodeling.

3.
Sci Rep ; 10(1): 6096, 2020 04 08.
Article in English | MEDLINE | ID: mdl-32269279

ABSTRACT

The identification of prognostic and predictive markers is crucial for choosing the most appropriate management method for ovarian cancer patients. We aimed to assess the prognostic role of tumor-associated macrophage (TAM) polarization in advanced ovarian cancer patients. We carried out a prospective observational study that included 140 consecutive patients with advanced-stage high-grade serous ovarian cancer as well as patients with other histotypes of ovarian cancer and patients with ovarian metastasis from other sites between June 2013 and December 2018. Patients were enrolled at the time of laparoscopic surgery before receiving any antineoplastic treatment. We found that patients with high-grade serous papillary ovarian cancers had a prevalence of M1 TAMs, a higher M1/M2 ratio, and a longer overall survival (OS) and progression-free survival (PFS) than other patients. Regression analysis confirmed that there was a significant positive association between the M1/M2 ratio and an improved OS, PFS and platinum-free interval (PFI), both in the entire population and in patients stratified according to tumor type and initial surgery. Kaplan-Meier analysis was performed after the patients were divided into 2 groups according to the median M1/M2 ratio and revealed that patients with a high M1/M2 ratio had a higher OS, PFS and PFI than those with a low M1/M2 ratio. In conclusion, the prognostic and predictive role of TAM polarization in the tumor microenvironment could be of great clinical relevance and may allow the early identification of patients who are likely to respond to therapy. Further studies in a larger prospective sample are warranted.


Subject(s)
Biomarkers, Tumor/immunology , Carcinoma/immunology , Macrophages/immunology , Ovarian Neoplasms/immunology , Carcinoma/pathology , Cell Differentiation , Cells, Cultured , Female , Humans , Macrophages/cytology , Ovarian Neoplasms/pathology , Survival Analysis , Tumor Microenvironment
4.
Front Physiol ; 9: 1294, 2018.
Article in English | MEDLINE | ID: mdl-30294279

ABSTRACT

Cancer-related anemia (CRA) is a common sign occurring in more than 30% of cancer patients at diagnosis before the initiation of antineoplastic therapy. CRA has a relevant influence on survival, disease progression, treatment efficacy, and the patients' quality of life. It is more often detected in patients with advanced stage disease, where it represents a specific symptom of the neoplastic disease, as a consequence of chronic inflammation. In fact, CRA is characterized by biological and hematologic features that resemble those described in anemia associated to chronic inflammatory disease. Proinflammatory cytokine, mainly IL-6, which are released by both tumor and immune cells, play a pivotal action in CRA etiopathogenesis: they promote alterations in erythroid progenitor proliferation, erythropoietin (EPO) production, survival of circulating erythrocytes, iron balance, redox status, and energy metabolism, all of which can lead to anemia. The discovery of hepcidin allowed a greater knowledge of the relationships between immune cells, iron metabolism, and anemia in chronic inflammatory diseases. Additionally, chronic inflammation influences a compromised nutritional status, which in turn might induce or contribute to CRA. In the present review we examine the multifactorial pathogenesis of CRA discussing the main and novel mechanisms by which immune, nutritional, and metabolic components affect its onset and severity. Moreover, we analyze the status of the art and the perspective for the treatment of CRA. Notably, despite the high incidence and clinical relevance of CRA, controlled clinical studies testing the most appropriate treatment for CRA are scarce, and its management in clinical practice remains challenging. The present review may be useful to indicate the development of an effective approach based on a detailed assessment of all factors potentially involved in the pathogenesis of CRA. This mechanism-based approach is essential for clinicians to plan a safe, targeted, and successful therapy, thereby promoting a relevant amelioration of patients' quality of life.

6.
J Transl Med ; 14(1): 292, 2016 10 13.
Article in English | MEDLINE | ID: mdl-27737711

ABSTRACT

BACKGROUND: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population. METHODS: A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays. RESULTS: Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS). CONCLUSIONS: Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Colorectal Neoplasms/genetics , GTP Phosphohydrolases/genetics , Membrane Proteins/genetics , Mutation/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Adult , Aged , Aged, 80 and over , Female , Genetic Association Studies , Genetic Testing , Geography , Humans , Italy , Kaplan-Meier Estimate , Male , Middle Aged , Mutation Rate , Prognosis
7.
Future Oncol ; 11(19): 2697-2710, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26376740

ABSTRACT

The present review aimed at discussing the impact, pathogenesis and therapeutic approaches of muscle wasting, which is a major clinical feature of cancer-related cachexia syndrome. The pathogenesis of muscle wasting in cancer cachexia lies in a discrepancy between anabolic and catabolic pathways mediated by chronic inflammation. Effective interventions specifically aimed at hampering muscle loss and enhancing muscle function are still lacking. Promising agents include anti-inflammatory, orexigenic and anabolic drugs, alongside with nutritional supplements that influence the STAT3 and PI3K/Akt/mTOR pathways involved in muscle wasting. Personalized physical activity combined with pharmacological and nutritional support hold promise. A greater understanding of the pathogenetic processes of cancer cachexia-related muscle wasting will enable the development of an early and effective targeted mechanism-based multimodal approach.

8.
Expert Opin Pharmacother ; 16(14): 2163-77, 2015.
Article in English | MEDLINE | ID: mdl-26330024

ABSTRACT

INTRODUCTION: Cancer cachexia is a severe inflammatory metabolic syndrome accounting for fatigue, an impairment of normal activities and, eventually, death. The loss of muscle mass associated with body weight loss is the main feature of this syndrome. AREAS COVERED: The present review aims to describe the advances in the pharmacological approaches for cancer cachexia, highlighting the impact on weight loss, muscle wasting and related outcomes. EXPERT OPINION: Among the pharmacological agents, attention should yet be given to the currently most widely studied drugs, such as progestogens and NSAIDs. Emerging drugs, such as ghrelin and selective androgen receptor modulators, have obtained promising results in recent randomized clinical trials. Larger sample sizes and more robust data on the effectiveness of anti-cytokine agents are needed. Any pharmacological approach to counteract cancer cachexia should always be associated with an adequate caloric intake, obtained by diet or through enteral or parenteral supplementation, if indicated. Finally, we can currently state that a combined approach that simultaneously targets the fundamental pathways involved in the pathogenesis of cancer cachexia is likely to be the most effective in terms of improvements in body weight as well as muscle wasting, function, physical performance and quality of life.


Subject(s)
Cachexia/drug therapy , Neoplasms/complications , Amino Acids/therapeutic use , Body Weight/drug effects , Cachexia/etiology , Cachexia/physiopathology , Carnitine/therapeutic use , Clinical Trials as Topic , Cytokines/antagonists & inhibitors , Dietary Supplements , Drug Therapy, Combination , Eicosapentaenoic Acid/therapeutic use , Fatigue/etiology , Humans , Neoplasms/physiopathology , Progestins/therapeutic use , Quality of Life , Steroids/therapeutic use
10.
Nutrition ; 31(1): 239-43, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25466670

ABSTRACT

OBJECTIVES: Myelofibrosis (MF) is characterized by shortened survival and a greatly compromised quality of life. Weight loss and cachexia seem to be the most important factors influencing survival in patients with MF. The aim of this study was to assess the efficacy of an integrated supportive therapy in improving cachexia and MF-related symptoms. METHODS: We reported on a case of a patient with MF who presented with weight loss and cachexia associated with severe anemia, fatigue, fever, and bone pain. The circulating levels of inflammatory, oxidative stress parameters, hepcidin, and erythropoietin were evaluated and were above normal ranges. The patient was treated with a multitargeted approach specifically developed for cachexia including oral l-carnitine, celecoxib, curcumin, lactoferrin, and subcutaneous recombinant human erythropoietin (EPO)-α. RESULTS: Surprisingly, after 1 y, cachexia features improved, all MF symptoms were in remission, and inflammatory and oxidative stress parameters, hepcidin, and EPO were reduced. CONCLUSIONS: Because our protocol was targeted at inflammation and the metabolic state, its effectiveness may emphasize the role of inflammation in the pathogenesis of MF symptoms and demonstrates a need for the study of new integrated therapeutic strategies.


Subject(s)
Cachexia/drug therapy , Primary Myelofibrosis/drug therapy , Weight Loss , Anemia/drug therapy , Anemia/etiology , C-Reactive Protein/metabolism , Cachexia/blood , Cachexia/etiology , Carnitine/therapeutic use , Celecoxib/therapeutic use , Curcumin/therapeutic use , Erythropoietin/therapeutic use , Fatigue/drug therapy , Fatigue/etiology , Ferritins/blood , Fever/drug therapy , Fever/etiology , Hepcidins/blood , Humans , Interleukin-6/blood , Iron/blood , Lactoferrin/therapeutic use , Male , Middle Aged , Oxidative Stress/drug effects , Patient Compliance , Primary Myelofibrosis/blood , Primary Myelofibrosis/complications , Quality of Life , Reactive Oxygen Species/metabolism , Recombinant Proteins/therapeutic use , Treatment Outcome , Tumor Necrosis Factor-alpha/blood
11.
Haematologica ; 100(1): 124-32, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25239265

ABSTRACT

Anemia in oncology patients is often considered a side effect of cancer therapy; however, it may occur before any antineoplastic treatment (cancer-related anemia). This study was aimed to evaluate the prevalence of cancer-related anemia in a large cohort of oncology patients and whether inflammation and malnutrition were predictive of its development and severity. The present study included 888 patients with cancer at different sites between May 2011 and January 2014. Patients were assessed at diagnosis before any cancer treatment. The prevalence of anemia according to the main clinical factors (tumor site, stage and performance status) was analyzed. In each patient markers of inflammation, iron metabolism, malnutrition and oxidative stress as well as the modified Glasgow prognostic score, a combined index of malnutrition and inflammation, were assessed and their role in predicting hemoglobin level was evaluated. The percentage of anemic patients was 63% with the lowest hemoglobin levels being found in the patients with most advanced cancer and compromised performance status. Hemoglobin concentration differed by tumor site and was lowest in patients with ovarian cancer. Hemoglobin concentration was inversely correlated with inflammatory markers, hepcidin, ferritin, erythropoietin and reactive oxygen species, and positively correlated with leptin, albumin, cholesterol and antioxidant enzymes. In multivariate analysis, stage, interleukin-6 and leptin were independent predictors of hemoglobin concentration. Furthermore, hemoglobin was inversely dependent on modified Glasgow Prognostic Score. In conclusion, cancer-related anemia is a multifactorial problem with immune, nutritional and metabolic components that affect its severity. Only a detailed assessment of the pathogenesis of cancer-related anemia may enable clinicians to provide safe and effective individualized treatment.


Subject(s)
Anemia/etiology , Biomarkers/analysis , Inflammation/physiopathology , Iron/metabolism , Neoplasms/blood , Neoplasms/complications , Nutritional Status , Adult , Aged , Anemia/diagnosis , Anemia/epidemiology , Case-Control Studies , Female , Follow-Up Studies , Hemoglobins/metabolism , Humans , Italy/epidemiology , Male , Middle Aged , Neoplasm Staging , Neoplasms/immunology , Oxidative Stress , Prevalence , Prognosis , Prospective Studies
12.
J Cell Mol Med ; 18(12): 2519-29, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25338520

ABSTRACT

Weight gain and obesity are among the most important risk factors for post-menopausal oestrogen-dependent breast cancer (EDBC). Weight gain is associated with oxidative stress, which in turn promotes breast cancer progression. We carried out a prospective study in 216 consecutive post-menopausal breast cancer patients aiming to examine the correlations between traditional prognostic factors (tumour size, T, nodal, N, grading, G, and metastasis status, M), and body mass index (BMI), leptin, pro-inflammatory cytokines (Interleukin, IL,-6 and tumour necrosis factor-alpha, TNF-α), and oxidative stress (reactive oxygen species, ROS, glutathione peroxidase, GPx, superoxide dismutase, SOD) among patients with oestrogen receptor (ER)+ and ER- breast cancers. Distribution of T, N and M categories did not differ between ER+ and ER- breast cancer patients. ER- patients showed a higher incidence of G3 tumours. Weight, BMI, leptin, IL-6 and ROS were higher in ER+ compared with ER- patients. Among ER+ patients, BMI, leptin, IL-6 and ROS correlated with T and M. Leptin, IL-6 and ROS were positively correlated also with N. Among ER- patients, BMI and leptin did not correlate with any of prognostic parameters, whereas a positive correlation between IL-6, ROS and M was found. Multivariate regression analysis showed that BMI, leptin, IL-6 and ROS were predictive for T, N and M in ER+ patients. Weight gain, inflammation and oxidative stress are involved in EDBC prognosis. Their modulation through antidiabetic, anti-inflammatory and antioxidants drugs combined with endocrine therapy may constitute a targeted approach in post-menopausal EDBC.


Subject(s)
Breast Neoplasms/blood , Inflammation Mediators/blood , Oxidative Stress , Postmenopause/blood , Aged , Body Mass Index , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Estrogens/metabolism , Female , Glutathione Peroxidase/blood , Humans , Interleukin-6/blood , Leptin/blood , Lymphatic Metastasis , Middle Aged , Multivariate Analysis , Neoplasm Staging , Postmenopause/metabolism , Prognosis , Prospective Studies , Reactive Oxygen Species/blood , Receptors, Estrogen/metabolism , Regression Analysis , Superoxide Dismutase/blood , Tumor Necrosis Factor-alpha/blood
13.
Oncol Lett ; 8(3): 1279-1282, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25120706

ABSTRACT

Adjuvant endocrine therapy is an integral component of care for endocrine-dependent breast cancer. The aim of this type of therapy is to counteract the production and the action of estrogens. The ovary is the primary site of estrogen production in premenopausal women, whereas, in postmenopausal women, the main source of estrogens is adipose tissue. Therefore, ovarian function suppression is an effective adjuvant strategy in premenopausal estrogen-dependent breast cancer. Similarly, the inhibition of estrogen action at the receptor site by tamoxifen has proven to be effective. To date, international consensus statements recommend tamoxifen (20 mg/day) for five years as the standard adjuvant endocrine therapy for premenopausal women. It should be noted that tamoxifen is a potent inducer of ovarian function and consequent hyperestrogenism in premenopausal women. In the present study, we report two cases of ovarian cyst formation with very high estrogen levels and endometrial hyperplasia during the administration of tamoxifen alone as adjuvant treatment for estrogen receptor-positive breast cancer in premenopausal women. These cases suggest that in young premenopausal patients with estrogen-dependent breast cancer, ovarian suppression is an essential prerequisite for an adjuvant endocrine therapy with tamoxifen. In this context, luteinizing hormone-releasing hormone agonist treatment by suppressing effective ovarian function may lead to a hypoestrogenic status that may positively impact breast cancer prognosis and prevent the effects of tamoxifen at the gynecological level. It is important to reconsider the action of tamoxifen on ovarian function and include these specific effects of tamoxifen in the informed consent of premenopausal patients who are candidates for tamoxifen alone as adjuvant endocrine treatment.

14.
Gynecol Oncol ; 124(3): 417-25, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22198049

ABSTRACT

OBJECTIVES: Gynecological neoplastic disease progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, anemia, and immunodepression, which result in a cachexia syndrome and a marked decrease in patient quality of life (QoL). Therapeutic protocols associated with appropriate and effective psychological and social support systems are essential to counteract the symptoms of neoplastic disease in incurable patients. METHODS: A phase III randomized study was performed to establish the most effective and safest treatment to improve the key symptoms in advanced gynecological cancer patients, i.e., lean body mass (LBM), resting energy expenditure (REE), fatigue, and QoL. In addition, the impact of the treatment arms on the main metabolic and inflammatory parameters, including C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, reactive oxygen species (ROS), and glutathione peroxidase, was evaluated. The change in the Glasgow Prognostic Score (GPS) during treatment was also assessed. A total of 104 advanced-stage gynecological cancer patients were enrolled and randomly assigned to receive either megestrol acetate (MA) plus l-carnitine, celecoxib, and antioxidants (arm 1) or MA alone (arm 2). The treatment duration was 4 months. RESULTS: The combination arm was more effective than arm 2 with respect to LBM, REE, fatigue, and global QoL. As for the secondary efficacy endpoints, patient appetite increased, and ECOG PS decreased significantly in both arms. The inflammation and oxidative stress parameters IL-6, TNF-α, CRP, and ROS decreased significantly in arm 1, while no significant change was observed in arm 2. CONCLUSIONS: The combined treatment improved both immunometabolic alterations and patient QoL. Multimodality therapies for cachexia ideally should be introduced within a context of "best supportive care" that includes optimal symptom management and careful psychosocial counseling.


Subject(s)
Antioxidants/therapeutic use , Cachexia/drug therapy , Carnitine/therapeutic use , Genital Neoplasms, Female/drug therapy , Genital Neoplasms, Female/metabolism , Megestrol Acetate/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Antioxidants/adverse effects , Cachexia/metabolism , Cachexia/pathology , Carnitine/adverse effects , Celecoxib , Female , Genital Neoplasms, Female/pathology , Humans , Inflammation/metabolism , Inflammation/pathology , Megestrol Acetate/adverse effects , Middle Aged , Prospective Studies , Pyrazoles/adverse effects , Quality of Life , Sulfonamides/adverse effects , Treatment Outcome
15.
Oncologist ; 15(8): 894-902, 2010.
Article in English | MEDLINE | ID: mdl-20647390

ABSTRACT

Advanced-stage cancer patients often suffer from anemia that closely resembles the anemia of chronic inflammatory diseases characterized by specific changes in iron homeostasis and absorption. i.v. iron improves the efficacy of recombinant human erythropoietin (rHuEPO) in anemic cancer patients undergoing chemotherapy. We report the results of an open-label, randomized, prospective trial aimed at testing the efficacy and safety of treatment with oral lactoferrin versus i.v. iron, both combined with rHuEPO, for the treatment of anemia in a population of 148 advanced cancer patients undergoing chemotherapy. All patients received s.c. rHuEPO-beta, 30,000 UI once weekly for 12 weeks, and were randomly assigned to ferric gluconate (125 mg i.v. weekly) or lactoferrin (200 mg/day). Both arms showed a significant hemoglobin increase. No difference in the mean hemoglobin increase or the hematopoietic response, time to hematopoietic response, or mean change in serum iron, C-reactive protein, or erythrocyte sedimentation rate were observed between arms. In contrast, ferritin decreased in the lactoferrin arm whereas it increased in the i.v. iron arm. In conclusion, these results show similar efficacy for oral lactoferrin and for i.v. iron, combined with rHuEPO, for the treatment of anemia in advanced cancer patients undergoing chemotherapy.


Subject(s)
Anemia/drug therapy , Erythropoietin/therapeutic use , Ferric Compounds/administration & dosage , Lactoferrin/administration & dosage , Neoplasms/blood , Administration, Oral , Aged , Anemia/blood , Anemia/complications , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Erythropoietin/blood , Female , Hemoglobins/metabolism , Humans , Male , Neoplasms/drug therapy , Prospective Studies , Quality of Life , Recombinant Proteins , Treatment Outcome
16.
J Mol Med (Berl) ; 88(7): 677-86, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20339829

ABSTRACT

Obesity is considered the most important risk and prognostic factor for estrogen-dependent breast cancer in postmenopausal women. Adipokines, in particular leptin, are at the center of the etiopathogenetic mechanisms by which obesity and related metabolic disorders influence breast cancer risk and its prognosis. The present prospective observational study aims to investigate the relationship between body mass index (BMI), serum levels of leptin and proinflammatory cytokines, and breast cancer prognostic factors. In the study, 98 postmenopausal and 82 premenopausal patients with ER-positive breast cancer participated. During the same study period, 221 control subjects were simultaneously recruited. Women underwent baseline measurements pre-operatively, before any surgical and systemic treatments. Pathologic characteristics of tumors were abstracted from pathology reports. Leptin and proinflammatory cytokines were assayed in stored fasting blood specimens. In postmenopausal breast cancer patients, BMI, leptin, and interleukin-6 significantly correlated with pathological tumor classification (pT) and TNM stage. Multivariate regression analysis showed that BMI and leptin, but not interleukin-6, were independent predictive variables of pT and TNM stage. Our results seem to suggest a twofold role of leptin in the etiopathogenesis of postmenopausal estrogen-positive breast cancer. Indeed, leptin reflects the total amount of fat mass, which correlates to aromatase activity and subsequent estrogens levels. Further studies are warranted to clarify the role of leptin and interleukin-6 in breast carcinogenesis and identify new therapeutic options, beyond the use of aromatase inhibitors, acting selectively on adipokine-driven pathways.


Subject(s)
Body Mass Index , Breast Neoplasms/blood , Breast Neoplasms/pathology , Leptin/blood , Postmenopause , Adult , Aged , Aged, 80 and over , Breast Neoplasms/diagnosis , Breast Neoplasms/immunology , Female , Humans , Interleukin-6/blood , Interleukin-6/immunology , Middle Aged , Premenopause , Prognosis , Prospective Studies , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology , Young Adult
17.
Nutrition ; 24(4): 305-13, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18262758

ABSTRACT

OBJECTIVE: In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS: All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS: By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION: The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.


Subject(s)
Antioxidants/administration & dosage , Cachexia/therapy , Dietary Supplements , Nutritional Support/methods , Oxidative Stress/drug effects , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/pharmacology , Appetite Stimulants/pharmacology , Ascorbic Acid/administration & dosage , Basal Metabolism/drug effects , Basal Metabolism/physiology , Cachexia/etiology , Carnitine/pharmacology , Exercise/physiology , Fatigue/prevention & control , Female , Humans , Interleukin-6/biosynthesis , Male , Medroxyprogesterone Acetate/pharmacology , Megestrol Acetate/pharmacology , Middle Aged , Muscle Proteins/biosynthesis , Neoplasms/complications , Oxidative Stress/physiology , Treatment Outcome , Tumor Necrosis Factor-alpha/blood , Vitamin A/administration & dosage , Vitamin E/administration & dosage
20.
Cancer Epidemiol Biomarkers Prev ; 15(5): 1030-4, 2006 May.
Article in English | MEDLINE | ID: mdl-16702388

ABSTRACT

PURPOSE: To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants, and drugs, all given orally, in a population of advanced cancer patients with cancer-related anorexia/cachexia and oxidative stress. PATIENTS AND METHODS: An open early-phase II study was designed according to the Simon two-stage design. The integrated treatment consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d alpha-lipoic acid + 2.7 g/d carbocysteine lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with 2 cans per day (n-3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2 inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated: (a) clinical (Eastern Cooperative Oncology Group performance status); (b) nutritional [lean body mass (LBM), appetite, and resting energy expenditure]; (c) laboratory [proinflammatory cytokines and leptin, reactive oxygen species (ROS) and antioxidant enzymes]; (d) quality of life (European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF). RESULTS: From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha, and a negative relationship worthy of note was only found between LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D(VAS), and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were "responders" or "high responders." The minimum required was 21; therefore, the treatment was effective and more importantly was shown to be safe. CONCLUSION: The efficacy and safety of the treatment have been shown by the study; therefore, a randomized phase III study is warranted.


Subject(s)
Anorexia/diet therapy , Cachexia/diet therapy , Dietary Supplements , Neoplasms/complications , Nutritional Support/methods , Adult , Aged , Anorexia/etiology , Ascorbic Acid/administration & dosage , Cachexia/etiology , Carbocysteine/administration & dosage , Celecoxib , Docosahexaenoic Acids/administration & dosage , Female , Humans , Linear Models , Male , Medroxyprogesterone/administration & dosage , Middle Aged , Oxidative Stress , Pyrazoles/administration & dosage , Statistics, Nonparametric , Sulfonamides/administration & dosage , Thioctic Acid/administration & dosage , Treatment Outcome , Vitamin A/administration & dosage , Vitamin E/administration & dosage
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