Hormone-related Symptoms Research Articles

Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study

BackgroundRelugolix, an oral gonadotropin-releasing hormone receptor antagonist, demonstrated testosterone suppression to castrate levels in men with advanced prostate cancer (PCa) in the HERO study. Since advanced PCa and its treatments can impact patients’ daily life, it is imperative to understand the impact of systemic therapy on patient health-related quality of life (HRQOL). ObjectiveTo report the HRQOL for patients on relugolix compared with those on leuprolide in on-treatment and testosterone recovery periods of the HERO study. Design, setting, and participantsA phase 3 randomized controlled study was conducted in 934 patients with advanced PCa. InterventionPatients underwent 2:1 randomization and received relugolix 120 mg orally once daily or leuprolide 3-mo injections for 48 wk. Testosterone recovery was evaluated in a patient subset. Outcome measurements and statistical analysisHRQOL evaluations were based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) and the Prostate Cancer Module (EORTC QLQ-PR25) during treatment and testosterone recovery phases. In a post hoc analysis, predictors of HRQOL deterioration were evaluated. Results and limitationsNo statistically significant differences between the two groups were found in changes from baseline to the end of treatment in either the EORTC QLQ-C30 or the EORTC QLQ-PR25 instrument. During the testosterone recovery phase, hormonal treatment–related symptoms scores were lower for relugolix than for leuprolide, suggesting a lower burden of hormone-related symptoms associated with a treatment that has more rapid testosterone recovery after treatment cessation. Limitations include low patient numbers in the testosterone recovery group. ConclusionsOral relugolix is a therapeutic option with similar patient-reported HRQOL to leuprolide, providing an oral option for androgen deprivation therapy associated with a more rapid testosterone reduction. Patient summaryIn men with advanced prostate cancer, relugolix had similar health-related quality of life to leuprolide.

Adrenocortical Carcinoma: Clinical Presentation, Outcomes of Treatment and Survival Analysis from a 15-Year Experience

Background: Adrenocortical carcinoma (ACC) is a rare malignant tumor of adrenocortical origin, often with an unfavorable survival. The estimated incidence is 0.7 to 2 per million per year. Materials and Methods: The authors retrospectively reviewed all clinical data of the ACC patients that underwent surgical extirpation in the present study institution between January 2005 and December 2020. All demographic data, perioperative outcomes, survival, and predictive factors associated with mortality were analyzed. Results: Twenty-three patients were included in the present study. The median (IQR) age was 51 (38 to 61) with females predominant at 78.3%. The median (IQR) tumor size was 8.3 (5.3 to 14.8) cm. with the left side predominant at 65.2%. The most common presentation was hormone-related symptoms at 52.2% and isolated hypercortisolism at 34.8%, was the most common hormonal excess. Complete resection (R0) was achieved in 82.6% of the patients. Following the European Network for the Study of Adrenal Tumors (ENSAT) staging system, 52.2% of the patients were in stage 2. Adjuvant therapies such as radiation, mitotane, and chemotherapy, were required in 47.7% of the patients. Eight patients (34.8%) were death during the median follow up of 44 months. The estimated 1-, 2-, and 5-year overall survivals were 78.3%, 73.9%, and 65.2% respectively. The ENSAT stage 3 to 4 (HR 1.61, 95% CI 1.16 to 21.5, p=0.03), nodal metastasis (HR 2.11; 95% CI 1.36 to 50.26; p=0.02), distant metastasis (HR 1.75; 95% CI 1.16 to 28.62; p=0.03, and the neutrophil to lymphocyte ratio (NLR) of 5 or more (HR 2.66; 95% CI 1.74 to 116.81; p=0.01) were significant factors associated with disease mortality in univariate analysis. NLR of 5 or more was the only significant factor (HR 2.51, 95% CI 1.2 to 126.84; p=0.03) in multivariate analysis. Conclusion: ACC is a rare malignancy associated with aggressive behavior. Multidisciplinary approach with surgical removal is the mainstay of treatment. The high NLR of 5 or more is a significant factor associated with poor disease survival. Keywords: Adrenocortical carcinoma; Mitotane; Survival; Prognosis; Neutrophil to lymphocyte ratio

\u2018I thought I had fibroids, and now I don\u2019t\u2019: a mixed method study on health-related quality of life in uterine sarcoma patients

BackgroundUterine sarcomas are rare subtypes of primary urogenital tumours and need tailored treatment. This study aimed to examine the impact of diagnosis and treatment on health-related quality of life (HRQoL) in patients with uterine sarcoma and measures available to assess HRQoL in this group.MethodsThirteen patients with uterine sarcoma and 23 health care professionals were purposively sampled from sarcoma reference centers and participated in a semi-structured interview exploring HRQoL. Patients were also asked to review the EORTC QLQ-C30 and EORTC QLQ-EN24 for relevance. Data were analysed using thematic analysis and descriptive statistics.ResultsThe most commonly reported physical health issues were related to sexual dysfunction and urological symptoms. Hormone-related issues and gastrointestinal symptoms were also identified. Cancer-generic issues such as functional problems, fatigue, pain, and treatment-related adverse effects were also reported. Regarding mental health, fears (about having sex, of recurrence, or of death), altered body-image, and dealing with lacking knowledge regarding sarcoma had an impact on HRQoL. Social health issues were related to the impact on relationships with others, limitations in undertaking activities, loss of independence, changes in work or study capacity, and financial difficulties. Most of the items of the EORTC QLQ-C30 and EORTC QLQ-EN24 questionnaires were rated as relevant. Questions about lack of knowledge about sarcoma, shock of diagnosis, and menopausal symptoms were lacking from existing measures.ConclusionsUterine sarcoma patients experience a variety of concerns covering the physical, mental, and social domains of HRQoL that are in the main EORTC instruments, but not all of them. Combining cancer-generic, location- and sarcoma-specific items is recommended to assess HRQoL in this patient group.Trial registration NCT04071704.

Symptom trajectories and influencing factors of prostate cancer following radical prostatectomy in Chinese patients.

Patients following radical prostatectomy will encounter various symptoms that may vary depending on the recovery of surgery and the use of adjuvant treatments. However, few studies have used the scale developed for prostate cancer to longitudinally assess the course of symptoms in Chinese patients. This study aimed to identify the symptom trajectories and the influencing factors in the prostate cancer patients of our area. A prospective observational study was conducted, and 155 patients with prostate cancer from 3 hospitals in Shanghai were recruited. Demographic and disease-related information was collected during the hospitalization. Further information on symptoms, adjuvant treatment, and functional exercise was collected across 4 time points. Growth mixture modeling was used to identify the trajectory patterns of symptoms, and logistic regression was used to determine the predictors. A total of 143 patients completed the investigation of all points, with a lost-to-follow-up rate of 7.7%. Urinary incontinence, urinary tract irritation, sexual dysfunction, pelvic pain, and hormone related symptoms all had group heterogeneity, and the number of latent category trajectories obtained was 4, 3, 3, 4, and 3 respectively. There were differences in demographic, disease, and treatment-related information between the groups. Patients with prostate cancer have different symptom levels across different periods after radical prostatectomy. Medical staff can predict these changes based on the initial level of symptoms and related factors such as age, prostate volume, medical comorbidities, drug of adjuvant treatment to clarify the critical points, populations, and symptoms that require monitoring during follow-up.

Understanding the Management and Treatment of Well-Differentiated Pancreatic Neuroendocrine Tumors: A Clinician's Guide to a Complex Illness.

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms that arise in the neuroendocrine cells of the pancreas. Although their clinical presentations differ depending on cell type, most are indolent, whereas others cause noteworthy hormone-related symptoms. The increasing incidence of PanNETs, attributed to improved diagnostic modalities, demonstrates advances in current standard of care. However, given the heterogeneity of these tumors, treatment decisions can become complex and an individualized approach is often required. Surgical intervention has remained the mainstay for localized tumors, whereas systemic therapies remain viable options for patients with unresectable or metastatic disease. Liver-directed therapies such as radiofrequency ablation and hepatic arterial embolization have also become available adjunct therapies for patients with liver-predominant metastases. Despite the increase in the armamentarium of treatment options for patients with PanNETs, data regarding the ideal sequence of treatment, especially systemic treatments, are currently lacking. Ongoing clinical trials are aimed at addressing this knowledge gap in addition to developing the next generation of novel therapeutics.

Progesteron receptor expression in insulin producing cells of neuroendocrine neoplasms

Progesterone receptor (PgR) inhibits cell proliferation in pancreatic neuroendocrine neoplasms (PanNEN). In non-neoplastic pancreas, loss of PgR induces β-cell proliferation and insulin production. However, detailed association between PgR and insulin producing PanNENs is poorly understood. Insulin, proinsulin, and PgR were immunolocalized in 82 PanNENs (54 non-functioning PanNENs: NF-PanNENs and 28 insulinomas). The status of immunoreactivity was compared to the clinicopathological factors of the patients. Immunoreactivity was also confirmed by employing the double-immunohistochemistry. These results were also compared with those in non-neoplastic Langerhans islets. PgR immunoreactivity was significantly higher in insulinomas than that in NF-PanNENs (p < 0.001). Insulin and proinsulin immunoreactivity was also detected in 20 (37 %) of (single cell) insulin positive NFs (Inspos-NF-PanNEN), in which PgR expression was higher than in insulin negative NF-PanNENs (Insneg-NF-PanNEN, p = 0.03). The ratio of PgR-insulin double positive cells to overall insulin positive cells, as well as PgR-proinsulin double positive cells to proinsulin positive cells, was detected to the same degree in insulinoma (PgR-insulin 70 %, PgR-proinsulin 66 %), Inspos-NF-PanNENs (PgR-insulin 65 %, PgR-proinsulin 68 %) and normal islet (PgR-insulin 80 %, PgR-proinsulin 72 %). PgR and insulin expressing cells colocalize in tumor cells of the PanNENs regardless of the hormone-related symptoms of the patients. Inhibitory effect of PgR on tumor cells might be associated with the favourable clinical outcome of insulinoma patients.

Percutaneous Laser Ablation of Liver Metastases from Neuroendocrine Neoplasm. A Retrospective Study for Safety and Effectiveness.

To retrospectively assess safety and efficacy of laser ablation (LA) of multiple liver metastases (LM) from neuroendocrine neoplasms (NEN). Twenty-one patients with NEN and at least 3 LM ≤ 4cm in diameter underwent ultrasonography-guided LA. Up to seven LM were ablated in a single session; if the number of LM exceeded seven, the remaining LM were ablated in further LA sessions with a time interval of 3-4 weeks. LA was performed according to the multifiber technique. The patients underwent contrast-enhanced CT 1 month after LA, and were subsequently monitored every 3 months for the first 2 years and then every 6 months. In total, 189 LM were treated in 21 patients (mean 9 ± 8.2, median 6) in 41 LA sessions (range 1-5). The diameter of LM ranged from 5 to 35mm (median 19mm, mean 17.9 ± 6.4mm). One grade 4 complication occurred (0.53%): a bowel perforation managed by surgery. Technical efficacy was 100%, primary efficacy rate 94.7%, and secondary efficacy rate 100%. Complete relief of hormone-related symptoms was obtained in all the 13 symptomatic patients. Median follow-up was 39months (range 12-99). 1-, 2-, 3-, and 5-year survival rates were 95%, 86%, 66%, and 40%, respectively. Overall survival resulted higher for patients with Ki-67 expression ≤ 7% than for those with Ki-67 > 7% (p = 0.0347). LA is a promising and safe technique to treat LM from NEN. A longer follow-up should provide definitive information on the long-term efficacy of this liver-directed therapy. Retrospective study, local non-random sample, level 3.

Embolotherapy for Neuroendocrine Tumors

The most frequent solid organ involved in metastatic neuroendocrine tumors (NET) is the liver. Hepatic metastases occur during the lifetime of 46% to 93% of patients with NETs. Intra-arterial embolotherapies are palliative and should be used for patients with unresectable disease not amenable to resection or ablation. The most widely accepted indications for liver embololization for NET metastases are progression of unresectable hepatic metastases threatening liver function and palliation of hormone-related symptoms uncontrolled by somatostatin analogues. This article will discuss patient selection and administration of all embolotherapies currently used for palliation of neuroendocrine liver metastases.

Embolotherapy for Neuroendocrine Tumors

AbstractThe most frequent solid organ involved in metastatic neuroendocrine tumors (NET) is the liver. Hepatic metastases occur during the lifetime of 46% to 93% of patients with NETs. Intra-arterial embolotherapies are palliative and should be used for patients with unresectable disease not amenable to resection or ablation. The most widely accepted indications for liver embololization for NET metastases are progression of unresectable hepatic metastases threatening liver function and palliation of hormone-related symptoms uncontrolled by somatostatin analogues. This article will discuss patient selection and administration of all embolotherapies currently used for palliation of neuroendocrine liver metastases.

Prognosis of Malignant Pheochromocytoma and Paraganglioma (MAPP-Prono Study): A European Network for the Study of Adrenal Tumors Retrospective Study

Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival (OS) in MPP patients. Retrospective multicenter study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. One hundred sixty-nine patients from 18 European centers were included. Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases. Metastatic sites included bone (64%), lymph node (40%), lung (29%), and liver (26%); mean time between initial and malignancy diagnosis was 43 months (range, 0 to 614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines less than fivefold the upper limits of the normal range, and low proliferative index. In multivariate analysis, hypersecretion [hazard ratio 3.02 (1.65 to 5.55); P = 0.0004] was identified as an independent significant prognostic factor of worst OS. Our results do not confirm SDHB mutations as a major prognostic parameter in MPP and suggest additional key molecular events involved in MPP tumor progression. Aside from SDHB mutation, the biology of aggressive MPP remains to be understood.

Clinical and molecular prognostic factors in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare cancer, with an incidence less than 0.7-1.5 per 1 million people per year, with a poor prognosis. The overall survival (OS) depends on the ENSAT stage: in particular in metastatic ACC the OS varies from 10 to 20 months, with a 5-year survival around 10%. ACC has a different behavior, probably due to a different biology. For this reason, a careful prognostic classification is mandatory, in order to stratify the patients and propose a specific management. Prognostic factors can be divides in three groups: clinical factors (tumor stage, age, hormone-related symptoms), pathological factors (Weiss Score, mitotic count, Ki-67, SF-1 and AVA2, P53, beta-catenin immunohistochemistry, resection status), molecular factors (chromosomal aberrations, methylation profile, altered gene expression and miRNA expression, gene mutations). The best way to stratify ACC patients and propose the best therapeutic option is to combine clinical, pathological and molecular factors. Individualizing patients' prognosis and tumor biology appears as a necessary step for personalized medicine. In addition to tumor stage and tumor grade, the genomic classification may precise the risk stratification and thus help defining therapeutic strategy.

Prognostic factors for death after surgery for small intestinal neuroendocrine tumours.

BackgroundNeuroendocrine tumours of the small intestine (SI‐NETs) are rare gastrointestinal neoplasms with an annual incidence of about one per 100 000. Patients with apparently similar tumours have variable outcomes. The aim of this study was to identify postoperative prognostic factors identifiable after initial surgery.MethodsThis was a nested case–control study of patients with SI‐NETs who were treated between 1961 and 2001. Data were retrieved from the Swedish Cancer Registry. Patients who died from the SI‐NET and corresponding controls (who outlived cases by at least 1 month), matched by age at diagnosis and calendar period, were included. Sex, postoperative symptoms, postoperative 5‐hydroxyindoleacetic acid (5‐HIAA) values, European Neuroendocrine Tumor Society (ENETS) stage, insufficiency of the tricuspid valve, radical secondary surgery and secondary malignancy were studied as potential prognostic factors.ResultsIn total, 1122 patients were included (561 cases, 561 controls). Postoperative factors of prognostic importance included hormone‐related symptoms, stage IV disease, raised levels of 5‐HIAA, insufficiency of the tricuspid valve, secondary surgery not being macroscopically radical and a second malignancy.ConclusionStage and symptomatic disease are important prognostic factors in SI‐NET.

Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1–2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactoside-binding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs.

460P - Elevated levels of 5-HIAA and CgA in patients with PanNETs from the CLARINET Study

Background: While carcinoids frequently synthesize, and secrete serotonin into the circulation, and 5-HIAA is a common biomarker in the carcinoids, measurement of 5-HIAA in non-carcinoid PanNET patients (i.e. no hormone-related symptoms or nonfunctional) is not routinely recommended by international guidelines. The incidence of serotonin-producing PanNETs may be underestimated, with potential impact on clinical outcome when serotonin levels remain elevated. We sought to characterize 5-HIAA and CgA levels in PanNET patients who participated in the large placebo-controlled phase III CLARINET Study. Methods: Evaluable data available for urinary 5-HIAA and serum CgA for patients with PanNET in CLARINET study were analyzed. Urinary 5-HIAA and Serum CgA were assessed at baseline and every 12 weeks thereafter through Week 96. Changes in urinary 5-HIAA and serum CgA levels were calculated using a non-parametric Wilcoxon 2-sample test. Biochemical response for urinary 5-HIAA or serum CgA was defined as baseline >upper limit of normal (ULN, 41.6 µmol/d 5-HIAA; 98.1 µg/L CgA) and ≥50% decrease from baseline or a decrease to a value ≤ULN on study. Results: 91/204 patients in CLARINET had PanNETs. Evaluable data for urinary 5-HIAA and serum CgA concentrations were available in 79 and 88 patients, respectively. A substantial number of patients with PanNET had elevated (>ULN) urinary 5-HIAA levels (21/79; 27%) and/or serum CgA (63/88; 72%). Among the 21 PNET patients with baseline 5-HIAA >ULN, biochemical response was achieved in 85% (11/13) lanreotide-treated patients compared with 63% (5/8) in patients on placebo at the last available value (p = 0.33). Among patients with baseline CgA >ULN, biochemical response was achieved in 66% (19/29) of lanreotide vs. 18% (6/34) of placebo-treated patients (p = 0.0002). Limited sample sizes precluded robust analysis for statistically significant differences in the lanreotide vs. the placebo group among patients with elevated biomarkers at baseline and biochemical response. Conclusions: The percentage of patients with elevated urinary 5-HIAA was unexpected. The concept of PanNET and secretion of serotonin may need to be redefined. The potential of 5-HIAA and CgA as biomarkers of response and follow-up in nonfunctioning PanNET is alluring, but requires further study. Data from additional prospective studies are needed to impact clinical practice guidelines. Clinical trial identification: NCT00353496 Legal entity responsible for the study: Ipsen Biopharmaceuticals Funding: Ipsen Biopharmaceuticals r A.T. Phan: Consultant/Advisor: Ipsen, Novartis; speakers’ bureau: Celgene, Genentech, Eli Lilly, Ipsen, Novartis; research support: Incyte, Ipsen, Lexicon, Novartis, Sanofi. E.M. Wolin: Consultant/Advisor: Celgene, Ipsen, Novartis, Pfizer; research support: Ipsen (Inst), Novartis (Inst), Pfizer (Inst). N. Liyanage: Employee of Ipsen. B. Mirakhur: Employee of Ipsen Biopharmaceuticals. S. Pitman Lowenthal: Employee of Ipsen Biopharmaceuticals. A. Vinik: Const/Advisor: Isis, Merck, Neurometrix, Pamlab, Pfizer; speakers bureau: Merck, Pamlab; research support: BMS, Celgene, Eli Lilly, Medivation, Newlink Genetics, Novartis, Pharmaceutical Research Associates, Polaris, PRA International, Tercica, XBiotech. G.A. Fisher, Jr: Consultant/Advisor: Genentech, Ipsen; research support: BMS, Celgene, Lilly, Ipsen, Medivation, Newlink Genetics, Novartis, Pharmaceutical Research Associates, Polaris, PRA International, Tercica, XBiotech; stock ownership: Seattle Genetics. M. Pavel: Consultant/Advisor: Ipsen, Lexicon, Novartis, Pfizer; research support: Novartis.

Quality-of-life findings in patients with midgut neuroendocrine tumors: Results of the NETTER-1 phase III trial.

348 Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with 177Lu-DOTATATE (177Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the 177Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on 177Lu arm vs. 15% on Oct, and worsened in 18% of patients on 177Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on 177Lu vs. 23% on Oct, and worsened in 19% of patients on 177Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with 177Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with 177Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of 177Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239.

Surgical Treatment of Malignant Pheochromocytoma and Paraganglioma: Retrospective Case Series.

Pheochromocytoma and paraganglioma (PPGL) are rare neoplasms; about 10% are malignant. Literature regarding possible benefit from resection is extremely limited. A 20year review of all patients undergoing surgery for malignant PPGL at the Mayo Clinic Rochester Campus between 1994 and June 2014 was performed. We identified 34 patients undergoing surgery for malignant PPGL. Median follow up was 6 and 5years survival was 90% (median 11years). Complete resection (R0) was achieved in 14 patients (41%). Median disease-free survival was 4.6years for patients with R0 resection (up to 12years). Only eight patients (23%) were disease-free on last follow up. Elevated preoperative fractionated metanephrines or catecholamines were documented in 23 patients (68%); these normalized in 13 of 23 patients (56%) postoperatively-with symptom relief in 15 of 18 preoperatively symptomatic patients (79%). Among 23 patients with hormone-producing tumors, significant reduction in number of antihypertensive medications was also noted postoperatively; 11 patients have remained off all antihypertensives, 6 required 1 medication, 1 required 2, while 5 required full blockade with phenoxybenzamine and a beta-adrenergic blocker. Surgery plays a significant role in the management of selected malignant PPGL. Resection can be effective in normalizing or significantly reducing levels of catecholamines and metanephrines, and can improve hormone-related symptoms and hypertension. Surgical resection, either complete or incomplete, is associated with durable survival despite a high rate of tumor recurrence.

Prognostic factors in stage III–IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study

BackgroundThe clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. Patients and methodsPatients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 ‘before surgery’; model 2 ‘post-surgery’. ResultsFour hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥20%, P = 0.06) in model 2. ConclusionThe mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

Role of somatostatin analogues in the treatment of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare epithelial neoplasms with neuroendocrine differentiation that most commonly originate in the lungs and gastrointestinal tract. Many patients have advanced disease not amenable to surgery or local management. Some tumors also secrete amines, such as serotonin, that lead to syndromes of hormone excess, such as diarrhea and flushing. Thus, management of patients with NETs often requires a dual approach, including hormone symptom management and systemic tumor control. Somatostatin analogues have long been a mainstay of managing the hormone-related symptoms, and increasing evidence also supports their use for tumor control in patients with well-differentiated NETs. This article reviews the role of somatostatin analogues in the treatment of NETs.

Somatostatin Analogs Therapy in Gastroenteropancreatic Neuroendocrine Tumors: Current Aspects and New Perspectives

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors that present many clinical features secreting peptides and neuroamines that cause distinct clinical syndromes such as carcinoid syndrome. However most of them are clinically silent until late presentation with mass effects. Surgical resection is the first line treatment for a patient with a GEP-NET while in metastatic disease multiple therapeutic approaches are possible. GEP-NETs are able to express somatostatin receptors (SSTRs) bounded by somatostatin (SST) or its synthetic analogs, although the subtypes and number of SSTRs expressed are very variable. In particular, SST analogs are used frequently to control hormone-related symptoms while their anti-neoplastic activity seems to result prevalently in tumor stabilization. Patients who fail to respond or cease to respond to standard SST analogs treatment seem to have a response to higher doses of these drugs. For this reason, the use of higher doses of SST analogs will probably improve the clinical management of these patients.

Update on surgical treatment of pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential (neurendocrine tumors PNETs) or overt (neuroendocrine carcinomas PNECs) malignant, but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimally-invasive approaches which should be tailored to the individual patient. Generally, surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs, indications for tumor resection are much wider than for pancreatic adenocarcinoma, in many cases due to the relatively benign tumor biology. Thus, patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands, even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However, poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly single-center series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable, ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review, we summarize recent advances in the surgical treatment of PNENs.