Changes in total and acylated ghrelin levels during mitotane treatment in patients with adrenocortical carcinoma
Hanna Komarowska1, Marcin Ruciński2, Marta Fichna1, Barbara Bromińska1, Dariusz Iżycki3, Agata Czarnywojtek1, Marek Ruchała1
1 Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
2 Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland
3 Department of Cancer Immunology, Division of Medical Biotechnology, Poznan University of Medical Sciences, Poznań, Poland
KEY WORDS
acylated ghrelin, adrenocortical carcinoma, mitotane, side effects, total ghrelin
ABSTRACT
INTRODUCTION Adrenocortical carcinoma (ACC) is a highly aggressive cancer with poor prognosis. Mitotane is the only approved drug for ACC treatment. Tolerability and efficacy of mitotane is variable. There is evidence that ghrelin may affect cancer development and the occurrence of side effects.
OBJECTIVES We examined the differences in plasma ghrelin concentrations between patients with benign adrenal tumors and adrenal carcinoma. We also investigated the effect of mitotane treatment on circulating plasma ghrelin levels in patients with ACC. Additionally, we assessed the relationship between ghrelin concentrations, mitotane levels, and side effects of mitotane treatment.
PATIENTS AND METHODS We enrolled 26 patients with ACC and 42 controls with adrenocortical adenoma (ACA). Clinical and histopathologic features, hormonal secretion pattern, and plasma acylated and total ghrelin levels were measured in every patient. Serum mitotane levels, body mass index, and side ef- fects of mitotane treatment were estimated every 3 to 12 weeks during follow-up in patients with ACC. RESULTS There was no significant difference in total and acylated ghrelin concentrations between ACC and ACA groups before mitotane introduction in ACC. We observed that during mitotane treatment, both total and acylated ghrelin levels became elevated in ACC compared with ACA. A positive correlation was found between circulating mitotane levels and acylated ghrelin as well as the ratio of acylated to total ghrelin levels in all patients treated with mitotane. Higher ghrelin levels were associated with increased risk of side effects.
CONCLUSIONS Plasma ghrelin levels are changed during mitotane treatment. These changes may be connected with side effects of mitotane.
Correspondence to:
Hanna Komarowska, MD, PHD, Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, ul. Przybyszewskiego 49, 60-355 Poznań, Poland, phone: +4861 869 1330, email: hkomar@ump.edu.pl
Received: March 18, 2019.
Revision accepted: June 5, 2019. Published online: June 6, 2019. Pol Arch Intern Med. 2019; 129 (7-8): 469-475 doi:10.20452/pamw.14865 Copyright by Medycyna Praktyczna, Kraków 2019
INTRODUCTION Adrenal tumors are currently a relatively frequent disorder, affecting up to 4% to 10% of the population. A significant increase in their prevalence has been reported worldwide due to the wide availability of sensitive imag- ing techniques. Adrenal tumors comprise sever- al types of neoplasms with different clinical man- ifestation and prognosis. Typically, small benign and hormonally inactive lesions are diagnosed that do not require treatment.1
Adrenocortical carcinoma (ACC) is a rare and highly aggressive cancer. Its clinical symptoms de- pend mainly on hormonal activity of the tumor.
Histopathologic diagnosis of ACC is based on Weiss criteria.2 ACC forms a very heterogenous group of tumors with different biology, overall survival, and prognosis.3 The stages of ACC range from I to IV. Complete surgical resection consti- tutes the first essential step of treatment. Mito- tane is a single drug approved for ACC treatment. It exerts antitumoral and antihormonal effects,4 and can be beneficial both as an adjuvant therapy and in metastatic spread. Its effect is maintained as long as the serum concentration of the drug remains between 14 and 20 mg/l; however, only about 40% to 50% of patients achieve serum
| Parameter | ACC (n = 26) | ACA (n = 42) | P value | |
|---|---|---|---|---|
| Age, y, median (Q1-Q3) | 57 (46-68) | 54 (44-63) | 0.36 | |
| Sex, n (%) | Female | 14 (53.85) | 20 (47.62) | 0.48 |
| Male | 12 (46.15) | 22 (52.38) | ||
| Tumor size, mm, median (Q1-Q3) | 125 (82-170) | 42 (30-57) | <0.001 | |
| Hormone secretion, n (%) | Glucocorticoids | 5 (19.23) | 7 (16.67) | – |
| Androgens | 2 (7.69) | – | – | |
| Glucocorticoids and androgens, n (%) | 4 (15.38) | – | – | |
| Aldosterone | NA | – | – | |
| Inactive, n (%) | 13 (50) | – | – | |
| ENSAT tumor stage, n (%) | II | 8 (30.77) | – | – |
| III | 2 (7.69) | – | – | |
| IV | 16 (61.54) | – | – | |
| Ki67 index, median (Q1-Q3) | 25 (8-36.25) | – | – | |
| BMI, kg/m2, median (Q1-Q3) | 23.87 (22.53-28.30) | 26.25 (23.83-31) | 0.14 | |
| Follow-up, mo, mean (SD) (min-max) | 10.63 (9.44) (1-36) | – | – | |
Abbreviations: ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma; BMI, body mass index; ENSAT, European Network for the Study of Adrenal Tumors; NA, not available
mitotane levels within the therapeutic range. Moreover, mitotane can be poorly tolerated, es- pecially due to severe neurotoxicity and gastroin- testinal problems.5,6 Furthermore, the efficacy of mitotane is limited. The median progression-free survival in advanced ACC on mitotane treatment is just about 2 months.7,8 On the other hand, ev- ery patient displays individual tolerability and ef- ficacy of the drug. We observed that mitotane dos- es and treatment time needed to achieve the ther- apeutic range were difficult to predict and varied between patients. Even if high doses of mitotane are given, serum concentrations above 14 mg/l are only reached in half of the patients, while in some patients, the minimum effective serum con- centration is not reached throughout the entire therapy. The reason for this remains unknown.9 Therefore, it is necessary to determine the fac- tors responsible for mitotane tolerance and ef- fectiveness. Such knowledge would help choose the most suitable treatment regimens and might indicate in which cases mitotane-based therapy would be beneficial.10
Currently, there is some evidence demonstrat- ing a significant role of ghrelin in cancer devel- opment. Higher serum ghrelin concentrations were found in patients with cancer compared with healthy controls.11 Additionally, ghrelin and its receptors are expressed in several types of tumors.12 It is suggested that ghrelin is a use- ful biomarker in some endocrine-related cancers. However, due to inconclusive findings, the role of ghrelin in cancer development is still unclear. The results of some studies show a stimulatory effect, while others demonstrate the inhibito- ry effect of ghrelin on tumor progression and proliferation.12,13
In the current study, we examined the differ- ences in plasma ghrelin concentrations between patients with benign adrenal tumors and ACC.
We also investigated the effect of mitotane treat- ment on circulating plasma ghrelin levels in pa- tients with ACC. Additionally, we assessed the re- lationship between ghrelin concentrations, mi- totane levels, and side effects of mitotane treat- ment. This topic has not been studied before.
PATIENTS AND METHODS The study protocol was approved by the local ethics committee (No. 255/15). A signed informed consent form was ob- tained from each enrolled patient.
Study patients A total of 26 patients with ACC were included in this prospective study. The in- clusion criteria were age above 18 years, histolog- ic diagnosis of ACC based on Weiss criteria, eligi- bility for treatment with mitotane, no other active malignancy, and no concomitant ACC treatment such as radiotherapy or chemotherapy. Adrenal- ectomy was performed in 16 patients. Advanced ACC not amenable to radical resection was diag- nosed in 10 cases.
Tumor size, tumor stage at diagnosis according to the European Network for the Study of Adre- nal Tumors classification,14 Weiss score, Ki67 pro- liferation index, presence of distant metastases, body mass index (BMI), and hormonal secretion pattern were evaluated in every patient at base- line (TABLE 1). Total and active ghrelin levels were estimated before and during mitotane treatment. Serum mitotane levels, BMI, and side effects of the mitotane treatment were estimated every 3 to 12 weeks during follow-up.
The control group consisted of 42 patients with adrenocortical adenoma (ACA). In this group, BMI, hormonal secretion pattern, and plasma acylated and total ghrelin levels were measured.
Mitotane treatment Patients received mitotane once the diagnosis of ACC was confirmed by
an experienced pathologist. The therapy was in- troduced between 1 and 6 weeks after diagnosis. The initial dose was 2 g/d of mitotane and was ti- trated up to 6 g/d. The dose was reduced if unac- ceptable toxicity occurred or a patient refused fur- ther therapy.
All patients underwent regular follow-up vis- its (every 2-3 weeks at the beginning of treat- ment and then every 8-12 weeks after 3 months of treatment).
Adverse events All treatment-related side effects were recorded during the follow-up visits. The tox- icities were graded using the Common Termi- nology Criteria for Adverse Events, version 5.0.
Changes in total and acylated ghrelin levels as well as in the acylated-to-total ghrelin ratio were measured and correlated with mitotane levels and side effects. We chose the most common side ef- fects in our patients (vomiting, diarrhea, neu- rotoxicity from mitotane therapy). Differences in the concentration of acylated and total ghre- lin between patients with ACA and ACC were as- sessed. Subsequently, ACC patients were divided into groups according to their serum mitotane con- centrations. We used 14 mg/l as the cutoff value, because this concentration is considered a thresh- old for the therapeutic effect. The ghrelin level was also correlated with the occurrence of side effects.
Blood sampling Fasting plasma levels of total and acylated ghrelin as well as fasting serum lev- els of cortisol, dehydroepiandrosterone sulfate, adrenocorticotropic hormone, aldosterone, renin plasma activity, total cholesterol, triglycerides, and glucose were evaluated. Aprotinin was add- ed to samples collected for ghrelin assessment. Blood plasma was obtained through centrifu- gation and kept frozen at -70℃ until hormone assays. Ghrelin was measured by a radioimmu- noassay using a kit from Phoenix Pharmaceuti- cals (Cat. No. RK-031-30, Belmont, Massachu- setts, United States). The kit contained 125I-la- beled bioactive ghrelin as a tracer and rabbit polyclonal antibodies directed against the C-ter- minus of human ghrelin, which recognized both acylated and nonacylated forms of the peptide. Acylated ghrelin was measured by an enzyme- -linked immunosorbent assay using a kit from Sceti (Cat. No. 97 751, Tokyo, Japan). The mito- tane level was estimated by high-performance liquid chromatography. Other hormonal and glu- cose assays were performed by electrochemilu- minescence using electrochemiluminescence (Roche Diagnostics, Mannheim, Germany). To- tal cholesterol levels were measured by the en- zymatic colorimetric method, and triglycerides, by the enzymatic colorimetric method with glyc- erophosphate oxidase and 4-aminophenazon.
Statistical analysis All statistical analyses were carried out in the R programming language and software environment supported by the ggplot2 library for graph drawing. The values of total
and acylated ghrelin as well as the ratio of ac- ylated to total ghrelin depending on the mito- tane level in patients with ACC and ACA were displayed as a boxplot, where the median, inter- quartile range, minimum and maximum values, and outliers were presented. The Mann-Whitney test was used to determine whether the differ- ence between the studied groups was significant. The resulting P values were adjusted for multiple testing using the Benjamini-Hochberg correc- tion. The x2 test was used to compare descriptive characteristics between groups. Corrected P val- ues equal or lower than 0.05 were considered sig- nificant. Correlations of total ghrelin, acylated ghrelin, and the acylated-to-total ghrelin ratio with mitotane, BMI, Ki67, and tumor size were assessed using the Spearman rank-order corre- lation test. Individual results were presented as scatter plots. The association of total ghrelin, ac- ylated ghrelin, and the acylated-to-total ghrelin ratio with analyzed side effects observed during mitotane treatment was assessed using the tet- rachoric correlation coefficient calculation. First, data were transformed to dichotomous scale. In ACC patients, the values for total ghrelin, acylat- ed ghrelin, and the acylated-to-total ghrelin ratio were assigned to 2 categories: above and below the median (considered as a high and low level). Such data were divided between groups with or without the analyzed side effects. Obtained fre- quency tables were used to calculate the tetra- choric correlation coefficient by the R “polycor” package. Statistical significance was analyzed by the Fisher exact test for count data. The tet- rachoric correlation coefficient and significant- ly different P values were presented as a corre- lation matrix (FIGURE 1). For significant compar- isons, frequency tables with odds ratios were also presented in TABLE 2.
RESULTS There were no significant differences between the ACC and ACA groups, except for tu- mor size. A comparison of clinical and biochem- ical characteristics of both groups are shown in TABLE 1.
There was no difference in total and acylated ghrelin concentrations between ACC and ACA groups (P = 0.34 and P = 0.47, respectively) before mitotane treatment in patients with ACC. How- ever, we found that total ghrelin levels were sig- nificantly higher in the whole group of ACC pa- tients (before and during mitotane treatment) than in patients with ACA (FIGURE 2).
We observed that during mitotane treatment, both total and acylated ghrelin levels became el- evated in the ACC group (both in patients who achieved and who did not achieve the therapeu- tic mitotane concentration) compared with ACA group. However, the difference was significant only in the group with therapeutic mitotane lev- els (FIGURE 2).
A positive correlation was found between the concentrations of circulating mitotane and acylated ghrelin levels as well as acylated-to-total
FIGURE 1 Correlation matrix showing a tetrachoric correlation coefficient for total ghrelin, acylated ghrelin, and the ratio of acylated to total ghrelin levels and selected side effects. Each cell in the table shows the correlation between 2 variables.
a Significant differences (P <0.05) Abbreviations: GGTP, -glutamyltransferase
Total ghrelin
Acylated ghrelin
Acylated/total ghrelin
1
| Adrenal insufficiency | 0.09 | 0.61ª | -0.07 | 0.8 |
|---|---|---|---|---|
| Elevated alanine aminotransferase | 0.16 | 0.08 | -0.07 | 0.6 0.4 |
| Elevated aspartate aminotransferase | 0.26 | 0.01 | 0.09 | 0.2 0 |
| Elevated alkaline phosphatase | 0.11 | -0.09 | -0.09 | -0.2 |
| High cholesterol | 0.19 | -0.05 | -0.52ª | -0.4 -0.6 |
| Elevated GGTP | 0.33 | -0.03 | -0.36 | -0.8 -1 |
| Adrenal insufficiency | ||
|---|---|---|
| Acylated ghrelin | No side effect - N (%) | With side effect - N (%) |
| Below median value - N | 39 (56) | 1 (11) |
| Above median value - N | 31 (44) | 8 (89) |
Odds ratio, 10.06 (95% CI, 1.19-84.834)
| High cholesterol | ||
|---|---|---|
| Acylated-to-total ghrelin ratio | No side effect - N (%) | With side effect - N (%) |
| Below median value - N | 27 (44) | 12 (80) |
| Above median value - N | 35 (56) | 3 (20) |
| Odds ratio, 0.19 (95% CI, 0.05-0.75) | ||
ghrelin ratio in all patients treated with mito- tane (FIGURE 3). In the group with mitotane lev- els of up to 14 mg/l, we observed a positive cor- relation of mitotane with acylated ghrelin levels and acylated-to-total ghrelin ratio, while a nega- tive correlation was found for mitotane and total ghrelin levels (FIGURE 3). In the group with the ther- apeutic concentration, only a correlation between mitotane and the acylated-to-total ghrelin ratio was detected.
Both acylated (P = 0.015; r = - 0.31) and to- tal ghrelin (P = 0.021; r = - 0.48) correlated with BMI. However, in our analysis, the change in ghre- lin concentrations was not related to the change in BMI in individual patient. Likewise, there was no correlation between ghrelin and tumor size or Ki67.
The side effects that occurred in patients treat- ed with mitotane are summarized in TABLE 3. The correlation of total ghrelin, acylated ghre- lin, and the acylated-to-total ghrelin ratio with side effects observed during mitotane treatment is shown in FIGURE 1. We found a significant corre- lation between acylated ghrelin and adrenal insuf- ficiency as well as between the acylated-to-total ghrelin ratio and increased cholesterol levels.
DISCUSSION Ghrelin levels are often elevated in patients with malignancies. However, in our study, we did not observe any changes in ghrelin concentrations between patients with ACC and those with benign adrenal tumors. Ghrelin was reported to affect the development and progres- sion of various types of cancer.11-13 In our previous study, we showed higher concentrations of ghre- lin in the ACC tissue compared with other adrenal tumors and healthy adrenal glands. We also dem- onstrated a positive effect of ghrelin on prolifer- ation and migration of ACC cell lines in vitro. In the current study, we did not observe any differenc- es in ghrelin levels between patients with ACC and ACA. We also found no correlation between tumor size and Ki67 index and circulating ghrelin levels. Hence, it seems that proliferation is not directly related to circulating ghrelin levels, but rather to its local expression level in the tissue. Literature review shows that the physiological concentration of total ghrelin in human serum ranges between 150 and 600 pg/ml.15,16 In fact, this is a lower con- centration than that used in most in vivo experi- ments. However, it is worth noting that expression
P = 0.04
50
Acylated ghrelin, pg/ml
40
30
20
10
0
ACA
ACC
P = 0.02
Total ghrelin, pg/ml
1000
500
0
1
ACA
ACC
| Adverse effect | Grade 1 | Grade 2 | Grade 3 | Total |
|---|---|---|---|---|
| Adrenal insufficiency | – | 9 (33.3) | – | 9 (33.3) |
| Hypothyroidism | 1 (3.7) | 1 (3.7) | – | 2 (7.4) |
| Diarrhea | 2 (7.4) | 2 (7.4) | – | 4 (14.8) |
| Nausea | 3 (11.1) | 1 (3.7) | – | 4 (14.8) |
| Vomiting | 1 (3.7) | – | – | 1 (3.7) |
| Fatigue | 2 (7.4) | – | – | 2 (7.4) |
| Elevated alanine aminotransferase | 13 (48.15) | 2 (33.3) | – | 15 (55.56) |
| Elevated aspartate aminotransferase | 15 (55.56) | 2 (7.4) | – | 17 (62.96) |
| Elevated alkaline phosphatase | 10 (37) | 2 (7.4) | – | 12 (44,4) |
| High cholesterol | 9 (33.3) | 3 (11.1) | 1 (3.7) | 13 (48.15) |
| Elevated GGTP | 4 (14.8) | 10 (37) | 7 (25.9) | 21 (77.8) |
| Dysarthria | 3 (11.1) | 2 (7.4) | – | 5 (18.5) |
Data are presented as number (percentage) of patients.
Abbreviations: see FIGURE 1
of ghrelin and its receptors occurs within the adre- nal gland. A number of previous papers indicated that both ghrelin and its receptors are expressed in adrenocortical parenchymal cells.13,17-19 There- fore, we assume that ghrelin produced by the ad- renal gland may also participate in the regulation of adrenal function in a para/autocrine manner. Local ghrelin concentrations within the adrenal glands alone may be higher than those in serum. The majority of studies showed no or a negative as- sociation of ghrelin with the risk and progression of cancer.11 Our research supports that the plasma ghrelin level does not affect the potential of ACC to grow and metastasize.
Elevated serum ghrelin levels in patients with malignant disease are usually explained by weight loss and cachexia.20 In our study, we showed a sig- nificant correlation between body weight and the concentration of total and acylated ghrelin in all patients, just as in the general population. Nonetheless, it should be noted that in the ACC group, we did not observe significant changes in body weight during treatment. Therefore, we
assume that our findings were not related with changes in BMI in our patients.
Our results suggest that changes in ghrelin lev- els between ACC and ACA patients are connect- ed with mitotane treatment. We found that in patients with ACC with therapeutic serum mito- tane concentrations, both acylated and total ghre- lin levels were higher than in those with ACA. Thus, the difference in ghrelin concentrations between these 2 groups might be explained by an increase in ghrelin concentrations caused by mitotane treatment.
We demonstrated a correlation between ghre- lin and mitotane even in patients who had not reached the therapeutic mitotane levels. This might be attributed to the observed side effects. In this group, as the concentrations of mitotane and acylated ghrelin increased, the level of total ghrelin decreased. Those alterations led to a de- crease in unacylated ghrelin. In the group with circulating therapeutic mitotane level, there was no such correlation. After reaching the therapeu- tic concentration, the situation stabilized and no further changes in the ghrelin concentration were observed. During mitotane therapy in ACC pa- tients, the most common adverse effects observed mainly at the beginning of treatment were diar- rhea and vomiting. The changes in ghrelin levels in this period might have been associated with these disturbances. A similar relationship was described by Malik et al.21 They demonstrated that cancer-associated dyspepsia may influence ghrelin levels. They examined the effects of cispl- atin treatment in the rat and found an increased proportion of acylated ghrelin in serum. In con- trast, Hiura et al22 showed that total ghrelin lev- els decreased after chemotherapy with cisplatin. They found that the degree of ghrelin level reduc- tion correlated with adverse events, especially an- orexia and severe nausea in patients with esoph- ageal cancer. It was even proposed that these pa- tients should be treated with ghrelin or its ago- nists to prevent side effects. Still, total ghrelin decreased only in the first days after chemother- apy with cisplatin, to return to normal on day 8 after drug administration. The authors did not investigate changes in the concentration of acyl- ated and unacylated ghrelin. Yanagimoto et al23 reported a negative correlation between acylated
Total ghrelin
Acylated ghrelin
Acylated/total ghrelin
30
rs =- 0.3
rs = 0.36
rs = 0.33
All samples
P = 0.048
P = 0.003
P = 0.01
20
10
0
10
20
30
40
rs = 0.35
rs = 0.44
Mitotane <14 mg/l
12
P = 0.02
P = 0.004
8
4
00
0
500
1000
30
rs = 0.4
Mitotane ≥14 mg/l
P = 0.04
25
20
15
0
0.05
0.10
0.15
ghrelin and creatinine in patients treated with cisplatin. The authors hypothesized that elevat- ed levels of acylated ghrelin may be associated with a lower risk of acute renal failure. They con- cluded that ghrelin may have a protective effect on kidney function.
Common side effects of mitotane other than diarrhea and vomiting are elevated levels of liver enzymes. Adrenal insufficiency and hypothyreo- sis resulting from treatment are substituted with exogenous hormones. The most serious complica- tions are neurologic disorders that require dose reduction, or even interruptions in therapy. We observed that the ghrelin concentration was par- ticularly high in patients with side effects of mi- totane. However, we were only able to demon- strate a significant relationship between acylat- ed ghrelin levels and adrenal insufficiency as well as between acylated-to-total ghrelin ratio and cholesterol levels (FIGURE 1). Possibly, the lack of associations between the ghrelin level and oth- er adverse effects results from the moderate in- tensity of the latter and a rapid intervention in the form of inclusion of anti-sickness and anti- -diarrheal drugs.
Our observations remain in line with those reported for other types of cancer. It seems that changes in ghrelin levels in patients during che- motherapy are associated with side effects. More- over, some side effects seem to be correlated with an increase in ghrelin levels, while others, with reduced ghrelin levels. It is possible because ghre- lin exerts various physiologic effects. However, the role of acylated and unacylated ghrelin has not been fully explained. Unacylated ghrelin
(80%-90% of ghrelin in the bloodstream) used to be considered as inactive. However, recent data suggest that both ghrelin forms may actually ex- ert biological functions. For example, they influ- ence the cardiovascular system, adipogenesis, and cell proliferation. It was proved by Lear et al24 that in cardiomyocytes, des-G binds to specific recep- tors and has effects on glucose and medium-chain fatty acid uptake that are distinct from those of ghrelin. A cardioprotective effect of unacylated ghrelin in reperfusion process has recently been demonstrated.25 Unacylated ghrelin was also re- ported to promote adipogenesis.26 Dallak et al27 demonstrated that acylated and unacylated forms of ghrelin have a reverse effect on the develop- ment of insulin resistance and hepatic steatosis. Thus, some actions are shared by both unacylat- ed and acylated forms, while others appear to be opposite.28 The reverse alterations in both circu- lating ghrelin forms in patients during mitotane therapy may suggest that their implications for chemotherapy-related disturbances may be dif- ferent. Studies have shown that ghrelin may be a potential therapeutic agent for cachexia associ- ated with cancer. Different mechanisms of ghre- lin action in cancer-induced cachexia have been proposed. Nevertheless, the evidence is not suf- ficient to support or contradict the use of ghre- lin in those patients.20 In this context, it seems reasonable to evaluate the levels of both plasma ghrelin forms. Perhaps the assessment of the ra- tio of acylated to total ghrelin or acylated to non- acylated ghrelin might be a more useful tool with regard to clinical outcomes.
In conclusion, we postulate that circulat- ing ghrelin levels do not influence adrenocorti- cal cancer cell proliferation. Higher ghrelin lev- els in patients with ACC are probably connect- ed with mitotane treatment and its side effects. Further studies are warranted to explain the role of acylated and unacylated ghrelin. It is possible that changes in the ratio of acylated to unacylat- ed ghrelin are more important than changes in the level of total ghrelin.
ARTICLE INFORMATION
CONTRIBUTION STATEMENT HK conceived the concept of the study, interpreted data, and wrote the article. HK, M. Ruciński, and MF contrib- uted to the design of the research. HK, BB, MR, AC, and M. Ruchata were involved in data collection. HK, M. Ruciński, and DI analyzed the data. HK, M. Ruciński, MF, BB, DI, AC, and M. Ruchała drafted the article or revised it critically for important intellectual content. All authors edited and approved the final version of the manuscript.
CONFLICT OF INTEREST None declared.
OPEN ACCESS This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Inter- national License (CC BY-NC-SA 4.0), allowing third parties to copy and re- distribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited, distrib- uted under the same license, and used for noncommercial purposes only. For commercial use, please contact the journal office at pamw@mp.pl.
HOW TO CITE Komarowska H, Rucinski M, Fichna M, et al. Changes in total and acylated ghrelin levels during mitotane treatment in patients with adrenocortical carcinoma. Pol Arch Intern Med. 2019; 129: 469-475. doi: 10.20452/pamw.14865
REFERENCES
1 Cyrańska-Chyrek E, Grzymisławska M, Ruchała M. Diagnostic pitfalls of adrenal incidentaloma. Endokrynol Pol. 2017; 68: 360-377.
2 Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinico- pathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002; 26: 1612-1619.
3 Nowak KM, Samsel R, Cichocki A, et al. Prognostic factors in adreno- cortical carcinoma: data from a large Polish series. Pol Arch Intern Med. 2018; 128: 371-378.
4 Paragliola RM, Torino F, Papi G, et al. Role of mitotane in adrenocortical carcinoma - review and state of the art. Eur Endocrinol. 2018; 14: 62-66.
5 Maiter D, Bex M, Vroonen L, et al. Efficacy and safety of mitotane in the treatment of adrenocortical carcinoma: a retrospective study in 34 Bel- gian patients. Ann Endocrinol (Paris). 2016; 77: 578-585.
6 Berruti A, Grisanti S, Pulzer A, et al. Long-term outcomes of adjuvant mi- totane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab. 2017; 102: 1358-1365.
7 Fassnacht M, Terzolo M, Allolio B, et al. Combination chemother- apy in advanced adrenocortical carcinoma. N Engl J Med. 2012; 366: 2189-2197.
8 Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007; 356: 2372-2380.
9 Kroiss M, Plonné D, Kendi S, et al. Association of mitotane with chylomi- crons and serum lipoproteins: practical implications for treatment of adreno- cortical carcinoma. Eur J Endocrinol. 2016; 174: 343-353.
10 Faillot S, Assie G. ENDOCRINE TUMOURS: The genomics of adrenocor- tical tumors. Eur J Endocrinol. 2016; 174: R249-R265.
11 Sever S, White DL, Garcia JM. Is there an effect of ghrelin/ghrelin analogs on cancer? A systematic review. Endocr Relat Cancer. 2016; 23: R393-R409.
12 Lin TC, Hsiao M. Ghrelin and cancer progression. Biochim Biophys Acta. 2017; 1868: 51-57.
13 Komarowska H, Rucinski M, Tyczewska M, et al. Ghrelin as a potential molecular marker of adrenal carcinogenesis: In vivo and in vitro evidence. Clin Endocrinol (Oxf). 2018; 89: 36-45.
14 Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal inciden- talomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016; 175: G1-G34.CZ
15 Komarowska H, Stangierski A, Warmuz-Stangierska I, et al. Differences in the psychological and hormonal presentation of lean and obese patients with polycystic ovary syndrome. Neuro Endocrinol Lett. 2013; 34: 669-674.
16 Kosowicz J, Baumann-Antczak A, Zamysłowska H, Sowiński J. Tech- nological difficulties in ghrelin and obestatin assays. Endokrynol Pol. 2011; 62: 336-339.
17 Barzon L, Pacenti M, Masi G, et al. Loss of growth hormone secreta- gogue receptor 1a and overexpression of type 1b receptor transcripts in hu- man adrenocortical tumors. Oncology. 2005; 68: 414-421.
18 Ueberberg B, Unger N, Sheu SY, et al. Differential expression of ghre- lin and its receptor (GHS-R1a) in various adrenal tumors and normal adrenal gland. Horm Metab Res. 2008; 40: 181-188.
19 Ueberberg B, Unger N, Saeger W, et al. Expression of ghrelin and its receptor in human tissues. Horm Metab Res Horm Stoffwechselforschung Horm Metab. 2009; 41: 814-821.
20 Khatib MN, Shankar AH, Kirubakaran R, et al. Ghrelin for the manage- ment of cachexia associated with cancer. Cochrane Database Syst Rev. 2018; 2: CD012229.
21 Malik NM, Moore GBT, Kaur R, et al. Adaptive upregulation of gas- tric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia. Regul Pept. 2008; 148: 33-38.CZ
22 Hiura Y, Takiguchi S, Yamamoto K, et al. Fall in plasma ghrelin concen- trations after cisplatin-based chemotherapy in esophageal cancer patients. Int J Clin Oncol. 2012; 17: 316-323.
23 Yanagimoto Y, Takiguchi S, Miyazaki Y, et al. Plasma ghrelin levels as a predictor of adverse renal events due to cisplatin-based chemotherapy in patients with esophageal cancer. Jpn J Clin Oncol. 2016; 46: 421-426.
24 Lear PV, Iglesias MJ, Feijóo-Bandín S, et al. Des-acyl ghrelin has spe- cific binding sites and different metabolic effects from ghrelin in cardiomyo- cytes. Endocrinology. 2010; 151: 3286-3298.
25 Harisseh R, Pillot B, Gharib A, et al. Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore. Basic Res Cardiol. 2017; 112: 4.
26 Hopkins AL, Nelson TAS, Guschina IA, et al. Unacylated ghrelin pro- motes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation. Sci Rep. 2017; 7: 45 541. CZ
27 Dallak MA. Acylated ghrelin induces but deacylated ghrelin prevents hepatic steatosis and insulin resistance in lean rats: effects on DAG/PKC/ JNK pathway. Biomed Pharmacother. 2018; 105: 299-311.
28 Chen W, Enriori P. Ghrelin: a journey from GH secretagogue to regulator of metabolism. Transl Gastrointest Cancer. 2015; 4: 14-27.