Adrenocortical Carcinoma

In the paper

“In the Michigan Endocrine Oncology Repository that contains data from >400 patients with a diagnosis of ACC, the mean stage at diagnosis is as follows: stage 1, 14%; stage 2, 45%; stage 3, 27%; and stage 4, 24% (T.E., unpublished results).”

What the sources say

• Not checked yetcites T.E., unpublished results

In the paper

“However, 3 times as many patients in the OA group had stage 3 disease and only 4 patients (11%) undergoing LA were found to have stage 3 disease, potentially introducing a bias toward more advanced disease in the OA group”

What the sources say

• Not checked yetcites [261] Brix, 2010, Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients, Eur Urol source

In the paper

“After LA, 30% had positive margins or intraoperative tumor spill compared with 16% of OA patients despite larger tumors and more stage 3 tumors.”

In the paper

“despite on average smaller tumors in the LA group (7.0 cm) compared with the OA group (12.3 cm), the LA group had a significantly earlier recurrence (9.2 vs 19.2 months).”

What the sources say

• Not checked yetcites [262] Miller, 2010, Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma, World J Surg source

In the paper

“In addition, University of Michigan data show the site of first metastasis can also be used to predict survival, with those having tumor recurrence in the peritoneum outside the tumor bed having the worst survival.”

In the paper

“A retrospective study from the University of Michigan reviewed 88 ACC patients, 17 of whom underwent LA, and 79% of the operations were performed at outside facilities, and no laparoscopic operations for ACC were performed at the University of Michigan, potentially introducing a referral bias (262).”

What the sources say

• Not checked yetcites [262] Miller, 2010, Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma, World J Surg source

In the paper

“The overall response to chemotherapeutic regimens is 30% and 50%, when counting stable disease as a response. However, the response is invariably transient and short-lived (6–18 months).”

In the paper

“The Surveillance, Epidemiology, and End Results (SEER) database provides an estimation of incidence of approximately 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States (4).”

What the sources say

• Not checked yetcites [4] Kebebew, 2006, Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?, World J Surg source

In the paper

“The median age of diagnosis is in the fifth to sixth decade, with the German ACC Registry reporting a median age at diagnosis of 46 years (9).”

What the sources say

• Not checked yetcites [9] Fassnacht, 2009, Clinical management of adrenocortical carcinoma, Best Pract Res Clin Endocrinol Metab source

In the paper

“The incidence is believed to be 1 to 2 per million per year, but valid data are lacking (3).”

What the sources say

• Not checked yetcites [3] Allolio, 2006, Clinical review: Adrenocortical carcinoma: clinical update, J Clin Endocrinol Metab source

In the paper

“In Southern Brazil, the incidence during childhood is 2.9 to 4.2 per million per year compared with an estimated incidence of 0.2 to 0.3 per million children per year worldwide (5).”

What the sources say

• Not checked yetcites [5] Pianovski, 2006, Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil, Pediatr Blood Cancer source

In the paper

“Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis.”

In the paper

“Adrenal tumors are very common, affecting 3% to 10% of the human population, and the majority are small benign nonfunctional adrenocortical adenomas (ACA) (1).”

What the sources say

• Not checked yetcites [1] Mansmann, 2004, The clinically inapparent adrenal mass: update in diagnosis and management, Endocr Rev source

In the paper

“Although data vary significantly, ACC comprises 5% to 15% of malignancies in BWS (43, 44).”

What the sources say

• Not checked yetcites [43] Lapunzina, 2005, Risk of tumorigenesis in overgrowth syndromes: a comprehensive review, Am J Med Genet C Semin Med Genet source
• Not checked yetcites [44] Wiedemann, 1983, Tumours and hemihypertrophy associated with Wiedemann-Beckwith syndrome, Eur J Pediatr source

In the paper

“Approximately 3% to 10% of LFS-associated cancers are ACCs, suggesting that germline TP53 mutations infer a significant relative risk increase (31, 32).”

What the sources say

• Not checked yetcites [31] Li, 1988, A cancer family syndrome in twenty-four kindreds, Cancer Res
• Not checked yetcites [32] Bougeard, 2008, Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families, J Med Genet source

In the paper

“A review of data from the 1986 National Mortality Followback Survey identified smoking in men and contraceptive use in women, especially before age 25 as risk factors (18).”

What the sources say

• Not checked yetcites [18] Hsing, 1996, Risk factors for adrenal cancer: an exploratory study, Int J Cancer source

In the paper

“This is in accordance with a median age of 46 years in a large single center series in France (10).”

What the sources say

• Not checked yetcites [10] Luton, 1990, Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy, N Engl J Med source

In the paper

“Most TP53 mutations affect the DNA binding and tetramerization domains (14).”

What the sources say

• Not checked yetcites [14] Wasserman, 2012, Towards an understanding of the role of p53 in adrenocortical carcinogenesis, Mol Cell Endocrinol source

In the paper

“Although it was initially believed that this mutation specifically predisposes to ACC development in childhood, it is now well recognized that this mutation causes other LFS-associated tumors as well as a Li Fraumeni-like syndrome in affected families (37).”

What the sources say

• Not checked yetcites [37] Custódio, 2012, Molecular epidemiology of adrenocortical tumors in southern Brazil, Mol Cell Endocrinol source

In the paper

“The fact that 1.3% of all childhood cancers are ACCs as opposed to 0.02% to 0.2% of adult cancers confirms a higher relative incidence early in life (12, 15–17).”

What the sources say

• Not checked yetcites [12] Wajchenberg, 2000, Adrenocortical carcinoma: clinical and laboratory observations, Cancer source
• Not checked yetcites [15] Schteingart, 2005, Management of patients with adrenal cancer: recommendations of an international consensus conference, Endocr Relat Cancer source
• Not checked yetcites [16] Crucitti, 1996, The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group, Surgery source
• Not checked yetcites [17] Michalkiewicz, 2004, Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry, J Clin Oncol source

In the paper

“The relative increase in incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in ∼50% to 80% of children with ACC (Table 1)(28–30).”

What the sources say

• Not checked yetcites [28] Rodriguez-Galindo, 2005, Biology, clinical characteristics, and management of adrenocortical tumors in children, Pediatr Blood Cancer source
• Not checked yetcites [29] Varley, 1999, Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors, Am J Hum Genet source
• Not checked yetcites [30] Wagner, 1994, High frequency of germline p53 mutations in childhood adrenocortical cancer, J Natl Cancer Inst source

In the paper

“Interestingly, recent in vitro studies confirm growth-promoting effects of estrogen on the ACC cell line NCI-H295 (20).”

What the sources say

• Not checked yetcites [20] Sirianni, 2012, Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment, J Clin Endocrinol Metab source

In the paper

“In the adult as well as in the pediatric population, there is a predilection for the female gender (the ratio of female to male ranges from 1.5–2.5:1) (10, 17).”

What the sources say

• Not checked yetcites [10] Luton, 1990, Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy, N Engl J Med source
• Not checked yetcites [17] Michalkiewicz, 2004, Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry, J Clin Oncol source

In the paper

“Up to 25% of TP53 mutations occur de novo, and these patients lack a significant family history (34).”

What the sources say

• Not checked yetcites [34] Chompret, 2000, P53 germline mutations in childhood cancers and cancer risk for carrier individuals, Br J Cancer

In the paper

“The p.R337H mutation was initially considered not to be a result of common ancestry; however, recent analyses suggest a founder effect in most cases, although in some cases, de novo mutations may still exist (7, 39).”

What the sources say

• Not checked yetcites [7] Garritano, 2010, Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect, Hum Mutat source
• Not checked yetcites [39] Ribeiro, 2001, An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma, Proc Natl Acad Sci U S A source

In the paper

“The common sequelae of all these changes are an upregulation of IGF2 expression and a downregulation of the other two transcripts (41).”

What the sources say

• Not checked yetcites [41] Weksberg, 2005, Beckwith-Wiedemann syndrome, Am J Med Genet C Semin Med Genet source

In the paper

“A role of estrogens has also been suggested by the observation of a probable relative increase of diagnosis of ACC during pregnancy (10, 19).”

What the sources say

• Not checked yetcites [10] Luton, 1990, Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy, N Engl J Med source
• Not checked yetcites [19] Icard, 2001, Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group, World J Surg source

In the paper

“Analysis of the SEER database gives a slightly older mean age of 55 years (11).”

What the sources say

• Not checked yetcites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

In the paper

“Patients with Lynch syndrome have a significant increase in lifetime risk of cancer, specifically for the core malignancies, colorectal and endometrial cancer (57).”

What the sources say

• Not checked yetcites [57] Stoffel, 2009, Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome, Gastroenterology source

In the paper

“However, it has become clear over the last decade that patients with CAH commonly develop adrenal myelolipomas (77).”

What the sources say

• Not checked yetcites [77] Nermoen, 2011, High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency, Clin Endocrinol (Oxf) source

In the paper

“The vast majority of Lynch syndrome-associated colorectal cancers show loss of immunostaining for at least 1 of the gene products and are microsatellite unstable (59).”

What the sources say

• Not checked yetcites [59] Hampel, 2005, Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer), N Engl J Med source

In the paper

“Some cases of ACC in conjunction with congenital adrenal hyperplasia (CAH) have been described (75).”

What the sources say

• Not checked yetcites [75] Bauman, 1982, Virilizing adrenocortical carcinoma. Development in a patient with salt-losing congenital adrenal hyperplasia, JAMA source

In the paper

“However, tumor-associated hypoglycemia is a well-described phenomenon, historically termed Anderson's syndrome, which may be attributed to IGF-2–mediated hypoglycemia (79–81).”

What the sources say

• Not checked yetcites [79] Ishikura, 2010, Cushing's syndrome and big IGF-II associated hypoglycaemia in a patient with adrenocortical carcinoma, BMJ Case Rep source
• Not checked yetcites [80] Anderson, 1930, A tumor of the adrenal gland with fatal hypoglycemia, Am J Med Sci source
• Not checked yetcites [81] Rustin, 1983, Adrenocortical carcinoma with tumour-induced hypoglycaemia, J R Soc Med source

In the paper

“Recent analysis of a French multicenter registry determined that ∼10% of MEN1 patients have distinct adrenal tumors, and of these, up to 14% are malignant (48).”

What the sources say

• Not checked yetcites [48] Gatta-Cherifi, 2012, Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database, Eur J Endocrinol source

In the paper

“Most recently, ACC has also been reported in 2 cases of patients with Carney complex (73, 74).”

What the sources say

• Not checked yetcites [73] Anselmo, 2012, A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer, J Clin Endocrinol Metab source
• Not checked yetcites [74] Morin, 2012, Carney complex with adrenal cortical carcinoma, J Clin Endocrinol Metab source

In the paper

“Other rare paraneoplastic syndromes are hyperreninemic hyperaldosteronism, erythropoietin-associated polycythemia, and leukocytosis (caused by chemokine release from the tumor) (82–84).”

What the sources say

• Not checked yetcites [82] Yamanaka, 2000, A case of renin-producing adrenocortical cancer, Endocr J source
• Not checked yetcites [83] Oka, 1996, Erythropoietin-producing adrenocortical carcinoma, Urol Int source
• Not checked yetcites [84] Schteingart, 2001, Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome, J Clin Endocrinol Metab source

In the paper

“Screening has been proven cost-effective, and surveillance for colon cancer with regular colonoscopies significantly decreases morbidity and mortality in affected patients (60, 61).”

What the sources say

• Not checked yetcites [60] Dinh, 2011, Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population, Cancer Prev Res source
• Not checked yetcites [61] Järvinen, 2000, Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer, Gastroenterology source

In the paper

“Roughly 20% to 30% of ACCs are incidentally diagnosed by imaging procedures for unrelated medical issues (25).”

What the sources say

• Not checked yetcites [25] Fassnacht, 2010, Epidemiology of adrenocortical carcinoma

In the paper

“Recently, a systematic analysis has defined the prevalence of Lynch syndrome in patients with ACC to be ∼3%, comparable to the prevalence in colorectal and endometrial cancer, estimated at 2% to 5% (62).”

What the sources say

• Not checked yetcites [62] Raymond, 2013, Adrenocortical carcinoma is a Lynch syndrome-associated cancer, J Clin Oncol source

In the paper

“Most patients with cortisol-secreting tumors will have suppressed ACTH (<10 pg/mL) and increased cortisol on a spontaneous 8:00 am blood draw.”

In the paper

“Mineralocorticoid excess can be caused by either bilateral hyperplasia or ACA, and these lesions are usually small (<2 cm) (115).”

What the sources say

• Not checked yetcites [115] Funder, 2008, Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source

In the paper

“Concurrent androgen and cortisol production is evident in roughly half of all ACC patients with hormone excess.”

In the paper

“The most common metastatic sites are lung (40%–80%), liver (40%–90%), and bone (5%–20%) (92).”

What the sources say

• Not checked yetcites [92] Allolio, 2004, Management of adrenocortical carcinoma, Clin Endocrinol (Oxf) source

In the paper

“The risk for malignant adrenal tumors increases with tumor size, with the index of suspicion increasing for tumors >4 cm (sensitivity, 97%; specificity, 52%) and >6 cm (sensitivity, 91%; specificity, 80%) (89).”

What the sources say

• Not checked yetcites [89] Sturgeon, 2006, Risk assessment in 457 adrenal cortical carcinomas: how much does tumor size predict the likelihood of malignancy?, J Am Coll Surg source

In the paper

“Other sites, such as brain and skin, are much less affected by tumor spread (<5%).”

In the paper

“Although earlier studies found 49% of patients with metastatic disease (stage 4) at presentation, currently only 25% to 30% of patients present with metastatic disease (9, 13, 25).”

What the sources say

• Not checked yetcites [9] Fassnacht, 2009, Clinical management of adrenocortical carcinoma, Best Pract Res Clin Endocrinol Metab source
• Not checked yetcites [13] Wooten, 1993, Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature, Cancer source
• Not checked yetcites [25] Fassnacht, 2010, Epidemiology of adrenocortical carcinoma

In the paper

“A contralateral adrenal tumor can be found in ∼5% of patients, although it is difficult to differentiate this from metachronous or synchronous tumors.”

In the paper

“They are bilateral in 2% to 10% of cases (98, 99).”

What the sources say

• Not checked yetcites [98] Bharwani, 2011, Adrenocortical carcinoma: the range of appearances on CT and MRI, AJR Am J Roentgenol source
• Not checked yetcites [99] Dunnick, 1982, CT appearance of adrenal cortical carcinoma, J Comput Assist Tomogr source

In the paper

“Estrogen production occurs in 1% to 3% of male ACC patients, causing gynecomastia and testicular atrophy (through suppression of the gonadal axis).”

In the paper

“Only a minority of tumors are <6 cm (9%–14%), with only 3% presenting as lesions <4 cm (89, 90).”

What the sources say

• Not checked yetcites [89] Sturgeon, 2006, Risk assessment in 457 adrenal cortical carcinomas: how much does tumor size predict the likelihood of malignancy?, J Am Coll Surg source
• Not checked yetcites [90] Paton, 2006, Outcomes of adrenal cortical carcinoma in the United States, Surgery source

In the paper

“The hallmark of a biochemical evaluation is the measurement of steroid hormones produced by the tumor (Table 3 and Figure 2).”

What the sources say

• Not checked yetcites Table 3
• Not checked yetcites Figure 2

In the paper

“After initial resection, locoregional recurrence becomes a challenge with pelvic, peritoneal, or retroperitoneal metastases.”

In the paper

“Intensity of FDG uptake was found to be related to survival in patients with ACC, with a maximum SUV of >10 indicating poor prognosis (111).”

What the sources say

• Not checked yetcites [111] Mackie, 2006, Use of [18F]fluorodeoxyglucose positron emission tomography in evaluating locally recurrent and metastatic adrenocortical carcinoma, J Clin Endocrinol Metab source

In the paper

“In the hormonal evaluation of such lesions, a 1 mg DST is preferred because it has a greater specificity in diagnosing subclinical Cushing's syndrome (93).”

What the sources say

• Not checked yetcites [93] Nieman, 2008, The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

In the paper

“The second most commonly produced hormones in patients with ACC are adrenal androgens (40%–60% of hormone-secreting ACCs), causing rapid-onset male pattern baldness, hirsutism, virilization, and menstrual irregularities in women.”

In the paper

“One of the first genetic assessments with flow cytometry revealed aneuploidy (a genomic aberration consistently observed in most cancers) in 4 of 4 ACCs, yet only diploidy or tetraploidy in normal adrenal cortices and benign adrenal tumors (180).”

What the sources say

• Not checked yetcites [180] Klein, 1985, Flow cytometric determinations of ploidy and proliferation patterns of adrenal neoplasms: an adjunct to histological classification, J Urol source

In the paper

“ACCs with poor outcome were enriched for genes involved in cell cycle and proliferation, whereas ACCs in the better outcome group exhibited overexpression of genes involved in differentiation, metabolism, and intracellular transport.”

What the sources say

• Not checked yetcites [191] de Reyniès, 2009, Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival, J Clin Oncol source

In the paper

“Using accepted proliferation immunomarkers, such as Ki67, a general consensus has emerged that ACCs have a Ki67 labeling index >5%. Conversely, ACAs generally show a much lower index, although there is some overlap observed depending on the particular study.”

In the paper

“High-grade ACCs are enriched for mutations of TP53 (14, 140–142) and/or CTNNB1 (143–149), and these mutations tend to be mutually exclusive (reviewed in Ref. 150).”

What the sources say

• Not checked yetcites [14] Wasserman, 2012, Towards an understanding of the role of p53 in adrenocortical carcinogenesis, Mol Cell Endocrinol source
• Not checked yetcites [140] Ohgaki, 1993, p53 mutations in sporadic adrenocortical tumors, Int J Cancer source
• Not checked yetcites [141] Lin, 1994, Mutations of the p53 gene in human functional adrenal neoplasms, J Clin Endocrinol Metab
• Not checked yetcites [142] Reincke, 1994, p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies, J Clin Endocrinol Metab
• Not checked yetcites [143] Heaton, 2012, Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin, Am J Pathol source
• Not checked yetcites [144] Berthon, 2012, Wnt/β-catenin signalling in adrenal physiology and tumour development, Mol Cell Endocrinol source
• Not checked yetcites [145] Leal, 2011, Wnt/β-catenin pathway deregulation in childhood adrenocortical tumors, J Clin Endocrinol Metab source
• Not checked yetcites [146] Gaujoux, 2011, β-Catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma, Clin Cancer Res source
• Not checked yetcites [147] El Wakil, 2011, The Wnt/β-catenin pathway in adrenocortical development and cancer, Mol Cell Endocrinol source
• Not checked yetcites [148] Masi, 2009, Investigation of BRAF and CTNNB1 activating mutations in adrenocortical tumors, J Endocrinol Invest source

In the paper

“Chromosome 17, specifically at 17p13, contains the well-known tumor suppressor gene TP53.”

In the paper

“Tumors with an abundance of these features (3 or more, as in the Weiss system) most often behave in a malignant fashion and can be classified as ACC, whereas tumors without these features (0–2 in the Weiss system) do not metastasize and can be classified as ACA.”

In the paper

“Most ACAs and all ACCs initiate from monoclonal cell populations, suggesting that mutation events lead to clonal expansion and ultimate progression to cancer (177, 178).”

What the sources say

• Not checked yetcites [177] Beuschlein, 1994, Clonal composition of human adrenocortical neoplasms, Cancer Res
• Not checked yetcites [178] Gicquel, 1994, Clonal analysis of human adrenocortical carcinomas and secreting adenomas, Clin Endocrinol (Oxf) source

In the paper

“Hypercortisolism in connection with ACC is due to autonomous cortisol secretion. The resultant ACTH-independent Cushing's syndrome is accompanied by a low ACTH level (<10 pg/mL).”

In the paper

“identified H19, PLAGL1, G0S2, and NDRG2 as silenced genes (188).”

What the sources say

• Not checked yetcites [188] Barreau, 2013, Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas, J Clin Endocrinol Metab source

In the paper

“However, the levels of DHEAS and testosterone are usually markedly higher in ACC, the onset of hormone excess symptoms is more pronounced, and most symptoms develop over a relatively short period of time (months).”

In the paper

“Giordano et al (192) determined that ACCs with high histological grade exhibited marked overexpression of cell cycle and functional aneuploidy genes, which correlated with decreased overall survival.”

What the sources say

• Not checked yetcites [192] Giordano, 2009, Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling, Clin Cancer Res source

In the paper

“The examination of 36 adrenocortical samples (10 normal tissues, 10 nonfunctional ACAs, 9 cortisol-secreting adenomas, and 7 ACCs) revealed differential expression of 22 miRNAs, with 14 miRNAs preferentially expressed in ACCs.”

What the sources say

• Not checked yetcites [197] Tömböl, 2009, Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis, Endocr Relat Cancer source

In the paper

“ACCs exhibit a large degree of intratumor heterogeneity, an unsurprising finding given their large size and the evolutionary nature of cancer progression.”

• Also stated in: § VI. Pathology · hedged

  “Taken together, these observations provide support for a clonal model in which ACC can exhibit step-wise progression from low- to high-grade carcinoma.”

In the paper

“Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503. Downregulated miRNAs included miR-214, miR-375, and miR-511 (197).”

What the sources say

• Not checked yetcites [197] Tömböl, 2009, Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis, Endocr Relat Cancer source

In the paper

“A number of studies have found that whereas ACAs have few regions of chromosomal losses and gains, ACCs exhibited complex chromosomal alterations.”

In the paper

“Unsupervised clustering of the samples according to miRNA expression resulted in clear differentiation of the tumors from the normal controls. Further differentiation between ACA and ACC could not be achieved.”

What the sources say

• Not checked yetcites [199] Doghman, 2010, Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors, Cancer Res source

In the paper

“TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs (140, 142, 202).”

What the sources say

• Not checked yetcites [140] Ohgaki, 1993, p53 mutations in sporadic adrenocortical tumors, Int J Cancer source
• Not checked yetcites [142] Reincke, 1994, p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies, J Clin Endocrinol Metab
• Not checked yetcites [202] Barzon, 2001, Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors, Eur J Endocrinol source

In the paper

“In this study, similar to the adult ACC study, miR-483 was found to be significantly upregulated in pediatric ACCs. However, a majority of the differentially expressed miRNAs were downregulated in ACCs, most notably miR-99a and miR-100.”

What the sources say

• Not checked yetcites [199] Doghman, 2010, Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors, Cancer Res source

In the paper

“the study identified a significant upregulation of miR-483 (diagnostic sensitivity of 80% and specificity of 100%) and downregulation of miR-195 and miR-335 in ACC (198).”

What the sources say

• Not checked yetcites [198] Soon, 2009, miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer, Clin Cancer Res source

In the paper

“High IGF2 expression levels in adrenal tumors, when analyzing malignant and benign tumors, are associated with a 5-fold increased risk for recurrence and a shorter disease-free survival (184, 191).”

What the sources say

• Not checked yetcites [184] Gicquel, 2001, Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors, Cancer Res
• Not checked yetcites [191] de Reyniès, 2009, Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival, J Clin Oncol source

In the paper

“In the normal adrenal gland, the WNT/β-catenin signaling pathway plays a crucial role in both embryonic development and maintenance of the adrenal cortex (228).”

What the sources say

• Not checked yetcites [228] Kim, 2008, Targeted disruption of β-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex, Development source

In the paper

“MiR-99a and miR-100 are bioinformatically predicted to target the 3′-untranslated regions of IGF1R, RPTOR, and FRAP1 (mTOR) and were experimentally confirmed to target several components of the IGF-1 signaling pathway (199).”

What the sources say

• Not checked yetcites [199] Doghman, 2010, Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors, Cancer Res source

In the paper

“However, when the Apc-knockout mice were crossed with adrenal-specific Igf2 overexpression mice, early-onset adrenal nodular hyperplasia evolving to large tumors later in life (including an invasive cortical tumor similar to an ACC) was observed, suggesting that both pathways may have synergistic effects on adrenocortical tumorigenesis (143).”

What the sources say

• Not checked yetcites [143] Heaton, 2012, Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin, Am J Pathol source

In the paper

“LA has become the gold standard for resection of benign adrenal masses, and it has been shown to result in significantly lower morbidity, less pain, shorter hospital stays, and decreased overall time to recovery when compared with open adrenalectomy (OA).”

In the paper

“Two studies published by the M.D. Anderson Cancer Center reported a recurrence rate of 86% in the OA group (154 patients) and 100% in the LA group (6 patients) (251, 257).”

What the sources say

• Not checked yetcites [251] Gonzalez, 2005, Laparoscopic resection of adrenal cortical carcinoma: a cautionary note, Surgery source
• Not checked yetcites [257] Grubbs, 2010, Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane, Ann Surg Oncol source

In the paper

“In mice harboring incomplete β-catenin knockout (knockout of β-catenin in a subset of adrenocortical cells), although normal adrenal development occurred, at age 45 weeks postpartum, these mice exhibited thinned and disorganized adrenal cortex in the setting of increased apoptosis (228).”

What the sources say

• Not checked yetcites [228] Kim, 2008, Targeted disruption of β-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex, Development source

In the paper

“ACCs can invade through the tumor capsule and are frequently microscopically present at the surface of the gland.”

In the paper

“Currently, the only curative approach to ACC is complete tumor resection.”

In the paper

“An activating Ser45 β-catenin mutation as well as activated β-catenin signaling was also identified in the NCI-H295 ACC cell line (149).”

What the sources say

• Not checked yetcites [149] Tissier, 2005, Mutations of β-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors, Cancer Res source

In the paper

“However, in the United States, 45% of adrenalectomies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in National Cancer Institute-designated Cancer Centers, suboptimal treatment of a rare and aggressive disease requiring specialized knowledge of surgical technique (11).”

What the sources say

• Not checked yetcites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

In the paper

“A 1999 study reported median survival of 74 months (5-year survival, 57%) in those undergoing complete second resections vs a median survival of 16 months (5-year survival, 0%) in those undergoing incomplete second resection.”

What the sources say

• Not checked yetcites [266] Schulick, 1999, Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma, Ann Surg Oncol source

In the paper

“In dog adrenal glands, mitotane leads to cell death, most likely via necrosis, and is followed by the emergence of a dense inflammatory infiltrate (283).”

What the sources say

• Not checked yetcites [283] Schteingart, 1993, Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma, Cancer Chemother Pharmacol source

In the paper

“the use of LA in ACC leads to a shorter disease-free interval and a higher incidence of incomplete resections.”

In the paper

“The pharmacological mechanism by which mitotane exerts its adrenolytic effect is still not completely understood.”

In the paper

“These results closely correspond with the surgical outcomes from a variety of other solid malignancies, in which a survival benefit is often seen in patients after a complete resection with negative margins but not in those with positive margins (19, 91, 244, 267, 273–275).”

What the sources say

• Not checked yetcites [19] Icard, 2001, Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group, World J Surg source
• Not checked yetcites [91] Fassnacht, 2009, Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification, Cancer source
• Not checked yetcites [244] Gonzalez, 2007, Response to mitotane predicts outcome in patients with recurrent adrenal cortical carcinoma, Surgery source

In the paper

“However, until recently, conclusive data regarding the efficacy of both of these adjuvant treatment modalities had been missing, and adjuvant therapy remains a controversy.”

In the paper

“data from other studies note their influence on outcome, although subsequent recurrence is expected (267, 268).”

What the sources say

• Not checked yetcites [267] Bellantone, 1997, Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma, Surgery source
• Not checked yetcites [268] Jensen, 1991, Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy, Arch Surg source

In the paper

“In those with low-grade tumors, tempo of disease progression can be slower and lead to longer survival with resection of sites of recurrence or metastasis.”

In the paper

“an analysis of almost 4000 patients from the National Cancer Data Base, which found that 9% of ACC patients treated with surgery had microscopically positive margins (R1), whereas a further 10% had macroscopically positive margins (R2) (11).”

What the sources say

• Not checked yetcites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

In the paper

“A case-control study from the German ACC Registry Group reported no difference in overall or disease-free survival, tumor capsule violation, or peritoneal carcinomatosis among 117 patients undergoing OA and 35 patients undergoing LA for stage 1 to 3 ACCs less than 10 cm (261).”

What the sources say

• Not checked yetcites [261] Brix, 2010, Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients, Eur Urol source

In the paper

“patients with positive margins had a dismal prognosis compared with those with uninvolved margins; 5-year survival was 10% after R2 resection, 21% after R1, and 49% after R0 (11).”

What the sources say

• Not checked yetcites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

In the paper

“Furthermore, mitotane has recently been shown to inhibit 5α-reductase, reducing the generation of more potent androgens (299).”

What the sources say

• Not checked yetcites [299] Chortis, 2013, Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement, J Clin Endocrinol Metab source

In the paper

“Roughly 40% of mitotane is absorbed from the GI tract, and a significant amount is distributed to fatty tissues.”

In the paper

“In addition, most studies were single-center studies, often including only a relatively small number of patients.”

In the paper

“Subsequently, suramin has been tested in 2 studies where it led to an overall response rate of ∼20%. However, treatment had a narrow therapeutic range and serious side effects (312, 313).”

What the sources say

• Not checked yetcites [312] Arlt, 1994, Suramin in adrenocortical cancer: limited efficacy and serious toxicity, Clin Endocrinol (Oxf) source
• Not checked yetcites [313] LaRocca, 1991, Use of suramin in treatment of prostatic carcinoma refractory to conventional hormonal manipulation, Urol Clin North Am source

In the paper

“It has been determined that this is not a laboratory artifact because mitotane does not interfere with thyroid hormone measurements (300).”

What the sources say

• Not checked yetcites [300] Zatelli, 2010, Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model, Endocrinology source

In the paper

“Initial studies in the 1970s and 1980s evaluated single-compound regimens with minor success and a response rate ranging from 10% to 20%.”

In the paper

“Other drugs regularly used in combination with mitotane, such as platinum-based cytotoxic drugs, doxorubicin, and etoposide are also metabolized by CYP3A4, potentially reducing their antineoplastic effect.”

In the paper

“Doses greater than 20 g regularly result in neurological side effects, which are reversible with normalization of plasma levels (288).”

What the sources say

• Not checked yetcites [288] Terzolo, 2010, Mitotane

In the paper

“All studies have been retrospective and uncontrolled, and it is the general experience that a subgroup of patients shows a very slow disease progress, possibly confounding interpretation of these results.”

In the paper

“However, all studies are retrospective, and older studies lack the advantage of cross-sectional imaging.”

In the paper

“In ex vivo adrenal perfusion experiments, it was shown that mitotane can be extracted in the adrenal gland and further metabolized (284).”

What the sources say

• Not checked yetcites [284] Martz, 1980, Metabolism and covalent binding of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p,'-DDD). Correlation between adrenocorticolytic activity and metabolic activation by adrenocortical mitochondria, Drug Metab Dispos source

In the paper

“Alkaline phosphatase and γ-glutamyl transferase (GGT) can increase significantly and the rise is usually of no clinical significance, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) show only mild elevation.”

In the paper

“A low-dose loading protocol has also been described, probably leading to fewer side effects, the same efficacy, and increased patient compliance.”

In the paper

“Adrenal insufficiency occurs invariably and is treated preemptively.”

In the paper

“Occasionally, mitotane may affect mineralocorticoid synthesis and replacement therapy with fludrocortisone therapy may become necessary.”

In the paper

“Neurological side effects are dependent on plasma mitotane levels and usually do not occur until blood levels rise higher than 20 mg/L.”

In the paper

“Suramin, a compound used traditionally for the treatment of sleeping sickness, had been found to induce adrenal insufficiency in humans and to have adrenolytic activity in animal experiments, where it led to inflammatory changes of the adrenal cortex (310, 311).”

What the sources say

• Not checked yetcites [310] Feuillan, 1987, Effects of suramin on the function and structure of the adrenal cortex in the cynomolgus monkey, J Clin Endocrinol Metab source
• Not checked yetcites [311] Kaplan, 1987, Lack of response to suramin in patients with AIDS and AIDS-related complex, Am J Med source

In the paper

“Common drugs metabolized by this enzyme are statins, opiates, benzodiazepines, warfarin, and some antibiotics (for a complete list see Ref. 301).”

What the sources say

• Not checked yetcites [301] Kroiss, 2011, Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma, Clin Endocrinol (Oxf) source

In the paper

“With regard to fetal health, data are conflicting. Although there is a clear theoretical concern for disorders of sexual development in the developing fetus, there is little supporting evidence.”

In the paper

“Even after discontinuation of mitotane therapy, CYP3A4 induction and mitotane levels persist up to several months.”

In the paper

“Most studies, including a large retrospective analysis, have defined the therapeutic mitotane level to be 14 to 20 mg/L (296).”

What the sources say

• Not checked yetcites [296] Hermsen, 2011, Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study, J Clin Endocrinol Metab source

In the paper

“Side effects are mainly GI, neurological, and metabolic/endocrinological in nature and can usually be managed when mild (Table 8).”

In the paper

“The interpretation of early studies is difficult due to different study populations, ranging from microscopically remaining tumor to advanced pretreated metastasized disease. Responses are defined differently in these studies”

In the paper

“An initial study suggested a response rate of 14%, but the results of repeat studies are pending (314).”

What the sources say

• Not checked yetcites [314] Flack, 1993, Oral gossypol in the treatment of metastatic adrenal cancer, J Clin Endocrinol Metab

In the paper

“After a usual daily dose of 5 to 15 g/d, plasma levels range between 0 and 90 mg/L.”

In the paper

“In 1 case, an abortion was performed and minor abnormalities of the morphology of the adrenal gland were described (308).”

What the sources say

• Not checked yetcites [308] Leiba, 1989, The protracted effect of o,p'-DDD in Cushing's disease and its impact on adrenal morphogenesis of young human embryo, Ann Endocrinol

In the paper

“On the molecular level, RRM1 expression has been found to be inversely correlated with mitotane response. Low RRM1 expression was a predictor of response to mitotane therapy with prolonged tumor-free survival (298).”

What the sources say

• Not checked yetcites [298] Volante, 2012, Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer, Clin Cancer Res source

In the paper

“Major endocrine abnormalities result from the effect of mitotane on steroid hormone biosynthesis. Three main mechanisms lead to adrenal insufficiency and decreased bioavailability of cortisol: 1) inhibition of steroid hormone biosynthesis at the level of CYP11B1 and CYP11A1, 2) induction of CYP3A4 and increased 6β-hydroxylation of cortisol, and 3) induction of cortisol binding globulin (CBG).”

In the paper

“At least 6 pregnancies with conception during or shortly after mitotane therapy have been reported. Four children were born evidently healthy, and no birth defects were encountered (305–307).”

What the sources say

• Not checked yetcites [305] Baszko-Błaszyk, 2011, Pregnancy in a patient with adrenocortical carcinoma during treatment with Mitotane - a case report, Endokrynologia Polska
• Not checked yetcites [306] Coonrod, 1995, Virilizing adrenal carcinoma in a woman of reproductive age: a case presentation and literature review, Am J Obstet Gynecol source
• Not checked yetcites [307] Kojori, 2011, Normal adrenal function in an infant following a pregnancy complicated by maternal adrenal cortical carcinoma and mitotane exposure, J Pediatr Endocrinol Metab source

In the paper

“The GI side effects (nausea and diarrhea) are most commonly dependent on the actual dose in contact with the lumen of the GI tract. These effects are rarely dose limiting and can be attenuated by distributing the mitotane amount into 3 or 4 daily doses.”

In the paper

“Mitotane induces SHBG and increases total testosterone but decreases the bioavailable fraction.”

In the paper

“One interpretation is that the changes are due to partial central hypothyroidism. This is further backed up by experiments in cell lines, where mitotane directly induces apoptosis in thyrotrope cells (300).”

What the sources say

• Not checked yetcites [300] Zatelli, 2010, Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model, Endocrinology source

In the paper

“There is a general concern that pregnancy may lead to increased likelihood of relapse and increased tumor growth. However, supporting evidence is minimal.”

In the paper

“A recent case report analyzed blood levels in a 21-week gestation normally developed fetus from a pregnancy terminated for ACC recurrence (309). In this study, amnion fluid and cord blood levels of mitotane were undetectable, arguing that there may be minimal exposure to the fetus.”

What the sources say

• Not checked yetcites [309] Tripto-Shkolnik, 2013, Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature, J Clin Endocrinol Metab source

In the paper

“Some trials report an occasional complete remission, but these are rare events (294).”

What the sources say

• Not checked yetcites [294] Boven, 1984, Complete response of metastasized adrenal cortical carcinoma with o,p'-DDD. Case report and literature review, Cancer source

In the paper

“Aminoglutethimide is an inhibitor of CYP11A1 and CYP11B1 and was initially introduced as an antiepileptic medication (322, 323).”

What the sources say

• Not checked yetcites [322] Santen, 1977, Adrenal suppression with aminoglutethimide. I. Differential effects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hydrocortisone, J Clin Endocrinol Metab source
• Not checked yetcites [323] Schteingart, 1967, Effects of aminoglutethimide upon adrenal function and cortisol metabolism in Cushing's syndrome, J Clin Endocrinol Metab source

In the paper

“The phase 3 trial GALACCTIC compared OSI906, a small-molecule inhibitor of IGF-1R and insulin receptor, in patients with stage 4 disease in a placebo-controlled fashion, with two-thirds receiving study drug and one-third receiving placebo.”

In the paper

“Ketoconazole inhibits CYP17A1, CYP11A1, and to some extent CYP11B1 (320).”

What the sources say

• Not checked yetcites [320] Auchus, 2010, Pharmacotherapy for hormone excess in adrenocortical carcinoma

In the paper

“based on the knowledge that children with BWS have higher levels of IGF-2 and that IGF2 is the most highly expressed gene in sporadic ACCs when compared with ACAs or normal tissues.”

In the paper

“Although this study established EDPM as an efficacious therapy, it also underscored the limitations of chemotherapy for ACC.”

In the paper

“Due to the inhibition of CYP11B1, a relative increase in adrenal androgens may occur, possibly worsening symptoms related to hyperandrogenemia.”

What the sources say

• Not checked yetcites [321] Hartzband, 1988, Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone, J Endocrinol Invest source

In the paper

“All study patients received concurrent mitotane therapy and with the recent finding of increased metabolism of other drugs due to CYP3A4 induction (eg, affecting cisplatin metabolism), there is criticism regarding whether chemotherapy without mitotane may be more successful.”

In the paper

“This has resulted in improved outcomes in a number of different cancers (2, 342–350).”

What the sources say

• Not checked yetcites [2] Viani, 2009, Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials, Int J Radiat Oncol Biol Phys source
• Not checked yetcites [342] Arriagada, 1996, Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group, J Clin Oncol source
• Not checked yetcites [343] Blichert-Toft, 1992, Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group, J Natl Cancer Inst
• Not checked yetcites [344] Fisher, 2002, Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer, N Engl J Med source
• Not checked yetcites [345] Johansen, 2008, Extended radical mastectomy versus simple mastectomy followed by radiotherapy in primary breast cancer. A fifty-year follow-up to the Copenhagen Breast Cancer randomised study, Acta Oncol source
• Not checked yetcites [346] Kuban, 2008, Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer, Int J Radiat Oncol Biol Phys source
• Not checked yetcites [347] Poggi, 2003, Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial, Cancer source
• Not checked yetcites [348] van Dongen, 2000, Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial, J Natl Cancer Inst source
• Not checked yetcites [349] Veronesi, 2002, Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer, N Engl J Med source
• Not checked yetcites [350] Zietman, 2005, Comparison of Conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial, JAMA source

In the paper

“To establish a gold standard of cytotoxic chemotherapy for ACC, a recent phase 3 trial (FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment) compared the most promising regimens (etoposide, doxorubicin, cislatin, mitotane [EDPM] vs streptozotocin, mitotane). This study confirmed the efficacy of chemotherapy and proved the superiority”

In the paper

“Interestingly, concomitant mitotane treatment negatively affected patient response, and sunitinib and mitotane levels were anticorrelated.”

What the sources say

• Not checked yetcites [304] Kroiss, 2012, Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial, J Clin Endocrinol Metab source

In the paper

“The response rate was 20% and 50%, when stable disease was included. However, the median progression-free survival, again, was short with a median of 5 months (and even 2 months in the streptozotocin, mitotane group).”

In the paper

“For example, 2 early reports state that radiotherapy is ineffective, but they offer no details regarding patient or treatment characteristics (266, 339).”

What the sources say

• Not checked yetcites [266] Schulick, 1999, Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma, Ann Surg Oncol source
• Not checked yetcites [339] Cohn, 1986, Adrenocortical carcinoma, Surgery

In the paper

“Although traditionally considered ineffective for ACC (327–331), radiotherapy has been shown in several recent series to offer a significant improvement in disease control in both the adjuvant and palliative settings (247, 332–337), although such an improvement has not been universally demonstrated (338).”

What the sources say

• Not checked yetcites [247] Sabolch, 2011, Adjuvant and definitive radiotherapy for adrenocortical carcinoma, Int J Radiat Oncol Biol Phys source
• Not checked yetcites [332] Fassnacht, 2006, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma, J Clin Endocrinol Metab source
• Not checked yetcites [333] Hermsen, 2010, Response to radiation therapy in adrenocortical carcinoma, J Endocrinol Invest source
• Not checked yetcites [334] Markoe, 1991, Radiation therapy for adjunctive treatment of adrenal cortical carcinoma, Am J Clin Oncol source
• Not checked yetcites [335] Percarpio, 1976, Radiation therapy of adrenal cortical carcinoma, Acta Radiol Ther Phys Biol source
• Not checked yetcites [336] Polat, 2009, Radiotherapy in adrenocortical carcinoma, Cancer source
• Not checked yetcites [337] Magee, 1987, Adrenal cortical carcinoma: survival after radiotherapy, Clin Radiol source
• Not checked yetcites [338] Habra, 2013, A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma, J Clin Endocrinol Metab source

In the paper

“Eight of 14 patients had stable disease as their best response. However, after 7 cycles (∼6 months), all patients showed disease progression.”

What the sources say

• Not checked yetcites [316] Haluska, 2010, Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma, Cancer Chemother Pharmacol source

In the paper

“Although the initial trial design was to compare mitotane plus IMCA12 vs mitotane alone, a first phase of this trial enrolled 19 patients to mitotane and IMCA12 to assess toxicity. However, due to the lack of overall response and recruitment difficulties, the trial was terminated early (G.D.H., unpublished results).”

What the sources say

• Not checked yetcites G.D.H., unpublished results

In the paper

“Steady infusion can be safe because doses used are only 1/10 of the anesthetic dose (2–3 vs 20–30 mg/h).”

In the paper

“Drugs targeting the IGF-1R system are currently being tried in phase 1 and phase 2 trials in several tumor entities (315).”

What the sources say

• Not checked yetcites [315] Arnaldez, 2012, Targeting the insulin growth factor receptor 1, Hematol Oncol Clin North Am source

In the paper

“More specifically, although Habra et al (338) found a local recurrence rate of 44% for such patients, Fassnacht et al (332) showed a 14% local failure rate and Sabolch et al (247) found a 20% rate.”

What the sources say

• Not checked yetcites [338] Habra, 2013, A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma, J Clin Endocrinol Metab source
• Not checked yetcites [332] Fassnacht, 2006, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma, J Clin Endocrinol Metab source
• Not checked yetcites [247] Sabolch, 2011, Adjuvant and definitive radiotherapy for adrenocortical carcinoma, Int J Radiat Oncol Biol Phys source

In the paper

“Adrenal tumors, including ACC, have a tendency to undergo hemorrhage and might lead to bleeding complications (356).”

What the sources say

• Not checked yetcites [356] Thacker, 2009, Embolization of nonliver visceral tumors, Semin Intervent Radiol source

In the paper

“In the largest series to date, 103 lesions in 29 patients were treated with response in 21% of patients and stabilization in 62% (357).”

What the sources say

• Not checked yetcites [357] de Baere, 2010, Predictive factors for hypertrophy of the future remnant liver after selective portal vein embolization, Ann Surg Oncol source

In the paper

“Although treatment of metastasis is fairly safe, caution is demanded when treating primary adrenal tumors.”

What the sources say

• Not checked yetcites [356] Thacker, 2009, Embolization of nonliver visceral tumors, Semin Intervent Radiol source

In the paper

“ACC has a well-documented propensity for lymphatic dissemination (11, 91, 351), with involved nodal disease in approximately 15% to 27% of patients at the time of surgery (11, 91).”

What the sources say

• Not checked yetcites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source
• Not checked yetcites [91] Fassnacht, 2009, Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification, Cancer source
• Not checked yetcites [351] King, 1979, Adrenal cortical carcinoma: a clinical and pathologic study of 49 cases, Cancer source

In the paper

“Although it is difficult to determine from retrospective series the reasons for such discordant outcomes, the patients reported on by Habra et al (338) were treated outside of an academic center and might not have benefited from the multidisciplinary approach that such centers offer, particularly for rare cancers.”

What the sources say

• Not checked yetcites [338] Habra, 2013, A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma, J Clin Endocrinol Metab source

In the paper

“Although radiotherapy did not improve survival, it did significantly improve local control: at 5 years, local recurrence-free survival was 86% in the group that received radiation compared with 11% in those that did not (332).”

What the sources say

• Not checked yetcites [332] Fassnacht, 2006, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma, J Clin Endocrinol Metab source

In the paper

“Predictors of response were a size of <3 cm and high lipidol uptake.”

What the sources say

• Not checked yetcites [357] de Baere, 2010, Predictive factors for hypertrophy of the future remnant liver after selective portal vein embolization, Ann Surg Oncol source