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Martin Fassnacht - One of the best experts on this subject based on the ideXlab platform.

  • linsitinib osi 906 versus placebo for patients with locally advanced or metastatic Adrenocortical Carcinoma a double blind randomised phase 3 study
    Lancet Oncology, 2015
    Co-Authors: Martin Fassnacht, Eric Baudin, Harm R. Haak, Matthias Kroiss, Alfredo Berruti, Michael J Demeure, Jill Gilbert, David I Quinn, Elizabeth Hesseltine
    Abstract:

    Summary Background Adrenocortical Carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced Adrenocortical Carcinoma. Methods In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic Adrenocortical Carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for Adrenocortical Carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. Findings Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256–507] vs 356 days [249–556]; hazard ratio 0·94 [95% CI 0·61–1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. Interpretation Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in Adrenocortical Carcinoma. Funding Astellas.

  • update in Adrenocortical Carcinoma
    The Journal of Clinical Endocrinology and Metabolism, 2013
    Co-Authors: Martin Fassnacht, Matthias Kroiss, Bruno Allolio
    Abstract:

    Adrenocortical Carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant Adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the Adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.

  • combination chemotherapy in advanced Adrenocortical Carcinoma
    The New England Journal of Medicine, 2012
    Co-Authors: Martin Fassnacht, Massimo Terzolo, Eric Baudin, Harm R. Haak, Bruno Allolio, Alfredo Berruti, Staffan Welin, Carmen Schadebrittinger, Andre Lacroix, Barbara Jarzab
    Abstract:

    A b s t r ac t Background Adrenocortical Carcinoma is a rare cancer that has a poor response to cytotoxic treatment. Methods We randomly assigned 304 patients with advanced Adrenocortical Carcinoma to re ceive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. Results For first-line therapy, patients in the EDP–mitotane group had a significantly higher response rate than those in the streptozocin–mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P = 0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP–mitotane group and 2.2 months in the streptozocin–mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. Conclusions Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.)

  • contemporary management of Adrenocortical Carcinoma
    European Urology, 2011
    Co-Authors: Laurent Zini, Francesco Porpiglia, Martin Fassnacht
    Abstract:

    Abstract Context Adrenocortical Carcinoma (ACC) is a rare and typically aggressive malignancy. Available recommendations are based primarily on retrospective series or expert opinions, and only few prospective clinical studies have yet been published. Objective To combine the available evidence for diagnostic work-up and treatment of ACC to a contemporary recommendation on the management of this disease. Evidence acquisition We conducted a systematic literature search for studies conducted on humans and published in English using the Medline/PubMed database up to 31 January 2011. In addition, we screened published abstracts at meetings and several Web sites for recommendations on ACC management. Evidence synthesis In patients with suspected localised ACC, a thorough endocrine and imaging work-up is followed by complete (R0) resection of the tumour by an expert surgeon. In experienced hands, laparoscopic adrenalectomy is probably as effective and safe for localised and noninvasive ACC as open surgery. Most clinicians agree that mitotane should be used as adjuvant therapy in the majority of patients, as they have a high risk for recurrence. An international panel has suggested using tumour stage, resection status, and the proliferation marker Ki67 as guidance for or against adjuvant therapy. In patients with advanced disease at presentation or recurrence not amenable to complete resection, a surgical approach is frequently inadequate. In these cases, mitotane alone or in combination with cytotoxic drugs is the treatment of choice. The most promising regimens (etoposide, doxorubicin, cisplatin plus mitotane, and streptozotocin plus mitotane) are currently compared in an international phase 3 trial, and results should be available by the end of 2011. Several targeted therapies are under investigation and may lead to new treatment options. Management of endocrine manifestations with steroidogenesis inhibitors is required in patients suffering uncontrolled hormone excess. Conclusions Detailed recommendations are provided to guide the management of patients with ACC.

  • Adrenocortical Carcinoma a clinician s update
    Nature Reviews Endocrinology, 2011
    Co-Authors: Martin Fassnacht, Rossella Libe, Matthias Kroiss, Bruno Allolio
    Abstract:

    Adrenocortical Carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of β-catenin as key factors involved in the development of Adrenocortical Carcinoma. Most patients present with steroid hormone excess, for example Cushing syndrome or virilization, or abdominal mass effects, but a growing proportion of patients with Adrenocortical Carcinoma (currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeutic measures for Adrenocortical Carcinoma exists, but collaborative efforts, such as international conferences and networks, including the European Network for the Study of Adrenal Tumors (ENSAT), have substantially advanced the field. In patients with suspected Adrenocortical Carcinoma, a thorough endocrine and imaging work-up is recommended to guide the surgical approach aimed at complete resection of the tumor. To establish an adequate basis for treatment decisions, pathology reports include the Weiss score to assess malignancy, the resection status and the Ki67 index. As recurrence is frequent, close follow-up initially every 3 months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Results of a large phase III trial in advanced Adrenocortical Carcinoma are anticipated for 2011 and will hopefully establish a benchmark therapy. New targeted therapies, for example, IGF-1 receptor inhibitors, are under investigation and may soon improve current treatment options.

Gary D Hammer - One of the best experts on this subject based on the ideXlab platform.

  • longitudinal patterns of recurrence in patients with Adrenocortical Carcinoma
    Surgery, 2019
    Co-Authors: Jason A Glenn, Paul G Gauger, Gary D Hammer, Francis P Worden, Tobias Else, David T Hughes, Mark S Cohen, Shruti Jolly, Thomas J Giordano, Barbra S Miller
    Abstract:

    Background Patterns and prognostic implications of recurrent Adrenocortical Carcinoma are poorly understood. In this study, we aim to describe temporal and spatial patterns of Adrenocortical Carcinoma recurrence. Methods This is a retrospective review of 576 patients with Adrenocortical Carcinoma evaluated at a single institution. Clinicopathologic and follow-up data were collected longitudinally. Results A total of 354 patients underwent resection of stage I-III Adrenocortical Carcinoma. We found that 249 (70%) patients developed disease recurrence. The median recurrence-free interval after primary resection was 11 months. The most common sites of initial recurrence were lung and tumor bed. The shortest time to recurrence was associated with lung or multiple site metastases. We found that 142 of 249 patients developed one or more additional sites of recurrence (median 5 months), most commonly involving the lungs. A total of 20 patients developed a third site of recurrence. We found that 100 patients underwent one or more reoperations or metastasectomies and 79 recurred again after reoperation. Same organ or site recurrence was common after reoperation (67%). Although lung metastases occurred early, recurrences to the peritoneal cavity or to multiple sites were associated with worse survival. Metastasectomy beyond three total operations did not improve overall survival. Conclusion Survival varies according to site of recurrence and other clinicopathologic factors. Knowledge of patterns of recurrence may assist in anticipating disease course and lead to better informed selection of treatment.

  • adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with Adrenocortical Carcinoma
    The Journal of Clinical Endocrinology and Metabolism, 2014
    Co-Authors: Tobias Else, Barbra S Miller, Aaron Sabolch, Shruti Jolly, Andrew R Williams, Gary D Hammer
    Abstract:

    Context: Adrenocortical Carcinoma is a rare malignant endocrine neoplasia. Studies regarding outcome and prognostic factors rely on fairly small studies. Here we summarize the experience with patients with a diagnosis of Adrenocortical Carcinoma from a large tertiary referral center. Objective: The objective of the study was to identify prognostic factors in patients with Adrenocortical Carcinoma and evaluate adjuvant treatment strategies. Design: Patient data were collected in a retrospective single-center study. Epidemiological, patient, and tumor characteristics were analyzed for prognostic factors regarding overall and recurrence-free survival in Cox regression models (multivariable and univariable). Results: Three hundred ninety-one adult patients with the diagnosis of Adrenocortical Carcinoma were identified. Median overall survival was 35.2 months. Cortisol production [hazard ratio (HR) 1.4, HR 1.5], tumor stage (HR stage 3 of 2.1 and 2.1, HR stage 4 of 4.8), and tumor grade (HR 2.4 and 2.0) were i...

  • Adrenocortical Carcinoma is a lynch syndrome associated cancer
    Journal of Clinical Oncology, 2013
    Co-Authors: Victoria M Raymond, Gary D Hammer, Jessica Everett, Larissa V Furtado, Shanna L Gustafson, Chelsy R Jungbluth, Stephen B Gruber, Elena M Stoffel, Joel K Greenson, Thomas J Giordano
    Abstract:

    Purpose Adrenocortical Carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC.

  • resection of Adrenocortical Carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy
    Surgery, 2012
    Co-Authors: Barbra S Miller, Paul G Gauger, Gary D Hammer, Gerard M Doherty
    Abstract:

    Background Controversy surrounds the use of laparoscopy for resection of Adrenocortical Carcinoma. We evaluated the hypothesis that outcome is equivalent in patients undergoing laparoscopic adrenalectomy versus open adrenalectomy. Methods This is a retrospective review of 217 patients (156 patients with stage I–III cancer) with Adrenocortical Carcinoma referred to a single institution between 2005 and 2011. Outcome and operative data were assessed for the subset undergoing resection with curative intent. Student t and Fisher exact tests and the Kaplan–Meier method were used to compare data ( P ≤ .05 was considered statistically significant). Results One hundred fifty-six patients (64% female; median age, 47 years [range, 18–80]; median follow-up, 26.5 months [range, 1–188]) were identified. Forty-six patients underwent laparoscopic adrenalectomy, and 110 underwent open adrenalectomy. Twenty-seven percent of laparoscopic adrenalectomy patients had stage III cancer. After laparoscopic adrenalectomy, 30% had positive margins or intraoperative tumor spill compared to 16% of the open adrenalectomy patients ( P = .04). Overall survival for patients with stage II cancer was longer in those undergoing open adrenalectomy ( P  = .002). Time to visible tumor bed recurrence or peritoneal recurrence in stage II patients was shorter in laparoscopic adrenalectomy patients ( P = .002). Conclusion Open adrenalectomy is superior to laparoscopic adrenalectomy for Adrenocortical Carcinoma based on completeness of resection, site and timing of initial tumor recurrence, and survival in stage II patients. Intraoperative evaluation is insensitive for the detection of stage III tumors.

  • worsening central sarcopenia and increasing intra abdominal fat correlate with decreased survival in patients with Adrenocortical Carcinoma
    World Journal of Surgery, 2012
    Co-Authors: Barbra S Miller, Paul G Gauger, Gary D Hammer, Kathleen M Ignatoski, Stephanie Daignault, Ceit Lindland, Megan Doherty, Stewart C Wang, Gerard M Doherty
    Abstract:

    Background Accurate prediction of survival from Adrenocortical Carcinoma (ACC) is difficult and current staging models are unreliable. Central sarcopenia as part of the cachexia syndrome is a marker of frailty and predicts mortality. This study seeks to confirm that psoas muscle density (PMD), lean psoas muscle area (LPMA), lumbar skeletal muscle index (LSMI), and intra-abdominal (IA) or subcutaneous fat (SC) can be used in combination to more accurately predict survival in ACC patients.

Bruno Allolio - One of the best experts on this subject based on the ideXlab platform.

  • update in Adrenocortical Carcinoma
    The Journal of Clinical Endocrinology and Metabolism, 2013
    Co-Authors: Martin Fassnacht, Matthias Kroiss, Bruno Allolio
    Abstract:

    Adrenocortical Carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant Adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the Adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.

  • comparison of two mitotane starting dose regimens in patients with advanced Adrenocortical Carcinoma
    The Journal of Clinical Endocrinology and Metabolism, 2013
    Co-Authors: Tm Kerkhofs, Massimo Terzolo, Eric Baudin, Bruno Allolio, Sophie Leboulleux, Britt Skogseid, Rita Chadarevian, Hh Mueller, Franco Mantero, Hr Haak
    Abstract:

    Context:Mitotane is the only approved drug for treatment of Adrenocortical Carcinoma(ACC). Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been comp ...

  • combination chemotherapy in advanced Adrenocortical Carcinoma
    The New England Journal of Medicine, 2012
    Co-Authors: Martin Fassnacht, Massimo Terzolo, Eric Baudin, Harm R. Haak, Bruno Allolio, Alfredo Berruti, Staffan Welin, Carmen Schadebrittinger, Andre Lacroix, Barbara Jarzab
    Abstract:

    A b s t r ac t Background Adrenocortical Carcinoma is a rare cancer that has a poor response to cytotoxic treatment. Methods We randomly assigned 304 patients with advanced Adrenocortical Carcinoma to re ceive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. Results For first-line therapy, patients in the EDP–mitotane group had a significantly higher response rate than those in the streptozocin–mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P = 0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP–mitotane group and 2.2 months in the streptozocin–mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. Conclusions Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.)

  • Adrenocortical Carcinoma a clinician s update
    Nature Reviews Endocrinology, 2011
    Co-Authors: Martin Fassnacht, Rossella Libe, Matthias Kroiss, Bruno Allolio
    Abstract:

    Adrenocortical Carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of β-catenin as key factors involved in the development of Adrenocortical Carcinoma. Most patients present with steroid hormone excess, for example Cushing syndrome or virilization, or abdominal mass effects, but a growing proportion of patients with Adrenocortical Carcinoma (currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeutic measures for Adrenocortical Carcinoma exists, but collaborative efforts, such as international conferences and networks, including the European Network for the Study of Adrenal Tumors (ENSAT), have substantially advanced the field. In patients with suspected Adrenocortical Carcinoma, a thorough endocrine and imaging work-up is recommended to guide the surgical approach aimed at complete resection of the tumor. To establish an adequate basis for treatment decisions, pathology reports include the Weiss score to assess malignancy, the resection status and the Ki67 index. As recurrence is frequent, close follow-up initially every 3 months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Results of a large phase III trial in advanced Adrenocortical Carcinoma are anticipated for 2011 and will hopefully establish a benchmark therapy. New targeted therapies, for example, IGF-1 receptor inhibitors, are under investigation and may soon improve current treatment options.

  • adjuvant therapy in patients with Adrenocortical Carcinoma a position of an international panel
    Journal of Clinical Oncology, 2010
    Co-Authors: Alfredo Berruti, Martin Fassnacht, Eric Baudin, Harm R. Haak, Gary D Hammer, Bruno Allolio, Sophie Leboulleux, Britt Skogseid, Massimo Terzolo
    Abstract:

    Adjuvant therapy in patients with Adrenocortical Carcinoma : a position of an international panel

Massimo Terzolo - One of the best experts on this subject based on the ideXlab platform.

  • decision making for Adrenocortical Carcinoma surgical systemic and endocrine management options
    Expert Review of Anticancer Therapy, 2018
    Co-Authors: Soraya Puglisi, Alfredo Berruti, Paola Perotti, Deborah Cosentini, Elisa Roca, Vittoria Basile, Massimo Terzolo
    Abstract:

    ABSTRACTIntroduction: Adrenocortical Carcinoma (ACC) is a rare tumor characterized by poor prognosis in most cases. Moreover, in most cases ACC produces an excess of adrenal steroid hormones with r...

  • validation of the prognostic role of the helsinki score in 225 cases of Adrenocortical Carcinoma
    Human Pathology, 2017
    Co-Authors: Eleonora Duregon, Massimo Terzolo, Barbara Zaggia, Alfredo Berruti, Rocco Cappellesso, Valeria Maffeis, Laura Ventura, Ambrogio Fassina, Marco Volante, Mauro Papotti
    Abstract:

    Adrenocortical Carcinoma patient prognosis is extremely variable and poorly predictable. The newly introduced Helsinki Score is the first so far proposed diagnostic and prognostic system based on the combined evaluation of morphological (mitoses and necrosis) and immunohistochemical (Ki-67) parameters. The aim of the study was to validate the prognostic role of the Helsinki Score for Adrenocortical Carcinoma characterization. Thus, 225 Adrenocortical Carcinomas were reclassified using the Weiss Score and the Helsinki Score (3× mitotic count + 5 × necrosis + Ki-67 index). At univariate analysis, statistically significant prognostic values were observed at the log-rank test for mitotic count (cutoff values: <6 and ≥55; P<.0001), Ki-67 (cutoff values: <20 and ≥50; P<.0001), Weiss Score (cutoff values: <5 and ≥8; P<.0001), Helsinki Score (cutoff values: <13 and ≥19; P<.0001), histological variant (conventional versus oncocytic; P=.009), necrosis (P=.001), and stage (P=.005). Cox multivariate analysis using a backward stepwise selection method retained only Helsinki Score and Weiss Score as predictors of poor prognosis (P<.0001 and P=.0005, respectively). Helsinki Score (with a threshold of 28.5 points; area under the curve [AUC]=0.729, 95% confidence interval=0.66-0.79) and Ki-67 (with a threshold of 20.5%; AUC=0.727, 95% confidence interval=0.66-0.79) showed the best and equivalent AUCs predicting disease-related deaths determined using receiver operating characteristic statistics. In conclusion, the Helsinki Score is a valuable system to predict prognosis in Adrenocortical Carcinoma, outperforming the currently established prognostic parameters.

  • practical treatment using mitotane for Adrenocortical Carcinoma
    Current Opinion in Endocrinology Diabetes and Obesity, 2014
    Co-Authors: Massimo Terzolo, Barbara Zaggia, Barbara Allasino, Silvia De Francia
    Abstract:

    PURPOSE OF REVIEW Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced Adrenocortical Carcinoma. RECENT FINDINGS Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences. SUMMARY Mitotane concentration of 14-20  mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced Adrenocortical Carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.

  • comparative diagnostic and prognostic performances of the hematoxylin eosin and phospho histone h3 mitotic count and ki 67 index in Adrenocortical Carcinoma
    Modern Pathology, 2014
    Co-Authors: Eleonora Duregon, Massimo Terzolo, Laura Ventura, Marco Volante, Luca Molinaro, Luisella Righi, Stefania Bolla, Anna Sapino, Mauro Papotti
    Abstract:

    Comparative diagnostic and prognostic performances of the hematoxylin-eosin and phospho-histone H3 mitotic count and Ki-67 index in Adrenocortical Carcinoma

  • comparison of two mitotane starting dose regimens in patients with advanced Adrenocortical Carcinoma
    The Journal of Clinical Endocrinology and Metabolism, 2013
    Co-Authors: Tm Kerkhofs, Massimo Terzolo, Eric Baudin, Bruno Allolio, Sophie Leboulleux, Britt Skogseid, Rita Chadarevian, Hh Mueller, Franco Mantero, Hr Haak
    Abstract:

    Context:Mitotane is the only approved drug for treatment of Adrenocortical Carcinoma(ACC). Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been comp ...

Tracy S Wang - One of the best experts on this subject based on the ideXlab platform.

  • cumulative gras score as a predictor of survival after resection for Adrenocortical Carcinoma analysis from the u s Adrenocortical Carcinoma database
    Annals of Surgical Oncology, 2021
    Co-Authors: Thuy B Tran, Lauren M Postlewait, Shishir K Maithel, Paula Marincola Smith, Jason D Prescott, Timothy M Pawlik, Jordan J Baechle, Carmen C Solorzano, Tracy S Wang
    Abstract:

    Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy, and many prognostic factors that influence survival remain undefined. Individually, the GRAS (Grade, Resection status, Age, and Symptoms of hormone hypersecretion) parameters have demonstrated their prognostic value in ACC. This study aimed to assess the value of a cumulative GRAS score as a prognostic indicator after ACC resection. A retrospective cohort study of adult patients who underwent surgical resection for ACC between 1993 and 2014 was performed using the United States Adrenocortical Carcinoma Group (US-ACCG) database. A sum GRAS score was calculated for each patient by adding one point each when the criteria were met for tumor grade (Weiss criteria ≥ 3 or Ki67 ≥ 20%), resection status (micro- or macroscopically positive margin), age (≥ 50 years), and preoperative symptoms of hormone hypersecretion (present). Overall survival (OS) and disease-free survival (DFS) by cumulative GRAS score were analyzed by the Kaplan–Meier method and log-rank test. Of the 265 patients in the US-ACCG database, 243 (92%) had sufficient data available to calculate a cumulative GRAS score and were included in this analysis. The 265 patients comprised 23 patients (10%) with a GRAS of 0, 52 patients (21%) with a GRAS of 1, 92 patients (38%) with a GRAS of 2, 63 patients (26%) with a GRAS of 3, and 13 patients (5%) with a GRAS of 4. An increasing GRAS score was associated with shortened OS (p < 0.01) and DFS (p < 0.01) after index resection. In this retrospective analysis, the cumulative GRAS score effectively stratified OS and DFS after index resection for ACC. Further prospective analysis is required to validate the cumulative GRAS score as a prognostic indicator for clinical use.

  • features of synchronous versus metachronous metastasectomy in adrenal cortical Carcinoma analysis from the us Adrenocortical Carcinoma database
    Surgery, 2020
    Co-Authors: Katherine M Prendergast, Thuy B Tran, Lauren M Postlewait, Tracy S Wang, Shishir K Maithel, Paula Marincola Smith, Jason D Prescott, Timothy M Pawlik, Jason A Glenn, Ioannis Hatzaras
    Abstract:

    Abstract Background Adrenocortical Carcinoma is a rare, aggressive cancer. We compared features of patients who underwent synchronous versus metachronous metastasectomy. Methods Adult patients who underwent resection for metastatic Adrenocortical Carcinoma from 1993 to 2014 at 13 institutions of the US Adrenocortical Carcinoma group were analyzed retrospectively. Patients were categorized as synchronous if they underwent metastasectomy at the index adrenalectomy or metachronous if they underwent resection after recurrence of the disease. Factors associated with overall survival were assessed by univariate analysis. Results In the study, 84 patients with Adrenocortical Carcinoma underwent metastasectomy; 26 (31%) were synchronous and 58 (69%) were metachronous. Demographics were similar between groups. The synchronous group had more T4 tumors at the index resection (42 vs 3%, P 001). The metachronous group had prolonged median survival after the index resection (86.3 vs 17.3 months, P 001) and metastasectomy (36.9 vs 17.3 months, P  = .007). Synchronous patients with R0 resections had improved survival compared to patients with R1/2 resections ( P  = .008). Margin status at metachronous metastasectomy was not associated with survival ( P = . 452). Conclusion Select patients with metastatic Adrenocortical Carcinoma may benefit from metastasectomy. Patients with metachronous metastasectomy have a more durable survival benefit than those undergoing synchronous metastasectomy. This study highlights need for future studies examining differences in tumor biology that could explain outcome disparities in these distinct patient populations.

  • curative surgical resection of Adrenocortical Carcinoma determining long term outcome based on conditional disease free probability
    Annals of Surgery, 2017
    Co-Authors: Georgios A Margonis, Thuy B Tran, Lauren M Postlewait, Tracy S Wang, Ioannis Hatzaras, Rivfka Shenoy, Shishir K Maithel, Jason D Prescott, Jason A Glenn, John E Phay
    Abstract:

    Objective:To evaluate conditional disease-free survival (CDFS) for patients who underwent curative intent surgery for Adrenocortical Carcinoma (ACC).Background:ACC is a rare but aggressive tumor. Survival estimates are usually reported as survival from the time of surgery. CDFS estimates may be more

  • lymphadenectomy for Adrenocortical Carcinoma is there a therapeutic benefit
    Annals of Surgical Oncology, 2016
    Co-Authors: Jon M Gerry, Thuy B Tran, Lauren M Postlewait, Tracy S Wang, John E Phay, Kara Keplinger, Shishir K Maithel, Jason D Prescott, Jason A Glenn, Ryan C Fields
    Abstract:

    Background Lymph node metastasis is an established predictor of poor outcome for Adrenocortical Carcinoma (ACC); however, routine lymphadenectomy during surgical resection of ACC is not widely performed and its therapeutic role remains unclear.

  • outcomes after resection of cortisol secreting Adrenocortical Carcinoma
    American Journal of Surgery, 2016
    Co-Authors: Georgios A Margonis, Thuy B Tran, Lauren M Postlewait, Tracy S Wang, Ioannis Hatzaras, Rivfka Shenoy, Shishir K Maithel, Jason A Glenn, Yuhree Kim, John E Phay
    Abstract:

    Abstract Background We sought to define the impact of cortisol-secreting status on outcomes after surgical resection of Adrenocortical Carcinoma (ACC). Methods The U.S ACC group database was queried to identify patients who underwent ACC resection between 1993 and 2014. The short-term and long-term outcomes were assessed. Results The incidence of all functional and cortisol-secreting tumors was 40.6% and 22.6%, respectively. On multivariable analysis, cortisol secretion remained associated with an increased risk of postoperative complications (odds ratio=2.25, 95 % confidence interval=1.04 to 4.88; P = .04). At a median follow-up of 17.6 months, 118 patients (50.4%) had developed a recurrence. On multivariable analysis, after adjusting for patient and disease-related factors cortisol secretion independently predicted shorter recurrence-free survival (Hazard ratio=2.05, 95% confidence interval=1.16 to 3.60; P = .01). Conclusions Cortisol secretion was associated with an increased risk of postoperative morbidity. Recurrence remains high among patients with ACC after surgery; cortisol secretion was independently associated with a shorter recurrence-free survival. Tailoring postoperative surveillance of ACC patients based on their cortisol secreting status may be important.