Indoleamine 2,3-Dioxygenase-1 Expression in Adrenocortical Carcinoma.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO-1) is overexpressed in many human carcinomas and a successful target for therapy in mouse models. Prognosis of patients with advanced adrenocortical carcinoma (ACC) is poor due to the lack of effective treatments, and new therapies are therefore needed. Herein, we investigate whether IDO-1 is expressed in human ACC tissues. METHODS: 53 tissue samples from patients with ACC, adrenal adenoma (AA), adrenocortical tumors (ACTs), and normal adrenal were identified. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded slides for IDO-1. Samples were scored for cytoplasmic staining as per intensity and the percent of positive cells and for stromal staining by percent of positive cells. Tumor characteristics, PD-L1, PDL-2, and CD-8+ T-lymphocyte expression were also determined. RESULTS: Samples from 32 ACC, 3 ACT, 15 AA, and 3 normal adrenal were analyzed. IDO-1 was expressed in tumor tissue in 22 of 32 ACC samples, compared with 8 of 15 AA sample (P = 0.344). IDO-1 expression was significantly increased in stromal tissue of ACC samples (16 of 33), compared with AA samples (0 of 15) (P = 0.001). IDO-1 expression in ACC and AA samples was associated with PD-L2 expression (P = 0.034). IDO-1 expression in ACC stromal tissue was associated with CD8+ T-lymphocyte infiltration (P = 0.028). CONCLUSIONS: IDO-1 is expressed in a majority of ACC samples. Its expression in tumor tissue is associated with PD-L2 expression, and expression in stroma is associated with CD8+ cell infiltration. IDO-1 inhibition, alone or in combination with PD-1 inhibition, could therefore be an interesting target in treatment of ACC.

Should 68Ga-DOTATATE PET/CT be Performed Routinely in Patients with Neuroendocrine Tumors Before Surgical Resection?

BACKGROUND: The only potential cure for neuroendocrine tumors (NETs) is operative resection, which may also offer a survival benefit for advanced disease. We aimed to assess the role of 68Ga-DOTATATE PET/CT in preoperative planning and compared its performance to CT with IV contrast and MRI with Eovist®, for abdominal NETs. METHODS: Records of patients who underwent 68Ga-DOTATATE PET/CT in addition to MRI with Eovist® and/or CT with IV contrast were retrospectively evaluated. The effect of imaging findings on surgical management and characteristics of detected lesions were analyzed. Descriptive statistics were used. RESULTS: Of 21 patients who underwent 68Ga-DOTATATE PET/CT prior to surgical resection, five (24%) had a change in surgical management due to findings. In three patients, 68Ga-DOTATATE PET/CT identified the primary tumor. In two patients, 68Ga-DOTATATE PET/CT helped clarify equivocal hepatic lesions seen on MRI with Eovist®. MRI with Eovist® had the highest number of lesions found (median 13, versus 9 on CT and 9.5 on 68Ga-DOTATATE PET/CT). DOTATATE-avid lesions were on average larger than lesions seen only on MRI with Eovist® (1.6 cm versus 0.6 cm, p = 0.0002). The optimal cutoff point for detection by 68Ga-DOTATATE PET/CT was a size of 0.95 cm, with a sensitivity of 56% and specificity of 98%. CONCLUSIONS: Preoperative 68Ga-DOTATATE PET/CT is useful only in a subset of patients undergoing surgical resection for NETs. MRI with Eovist® is superior at identifying liver metastases when compared to 68Ga-DOTATATE PET/CT and should therefore be used routinely before hepatic cytoreduction of NETs.

Understanding Opioid Prescribing Practices of Resident Physicians.

BACKGROUND: To compare opioid prescribing practices of resident physicians across a variety of surgical and nonsurgical specialties; to identify factors which influence prescribing practices; and to examine resident utilization of best practice supplemental resources. METHODS: An anonymous survey which assessed prescribing practices was completed by residents from one of several different subspecialties, including internal medicine, obstetrics and gynecology, general surgery, neurosurgery, orthopedic surgery, and urology. Fisher's exact test assessed differences in prescribing practices between specialties. RESULTS: Only 35% of residents reported receiving formal training in safe opioid prescribing. Overall, the most frequently reported influences on prescribing practices were the use of standardized order sets for specific procedures, attending preference, and patient's history of prescribed opioids. Resident physicians significantly underutilize best practice supplemental resources, such as counseling patients on pain expectations prior to prescribing opioid medication; contacting established pain specialists; screening patients for opioid abuse; referring to the Prescription Monitoring Program; and counseling patients on safe disposal of unused pills (P < .001). DISCUSSION: The incorporation of comprehensive prescribing education into resident training and the utilization of standardized order sets can promote safe opioid prescribing.

Operative resection in early stage pancreatic neuroendocrine tumors in the United States: Are we over- or undertreating patients?

BACKGROUND: Many current guidelines recommend nonoperative management for pancreatic neuroendocrine tumors <2 cm. The objective of this study was to evaluate the utilization and outcomes of resection for these pancreatic neuroendocrine tumors in the United States. METHODS: Using the National Cancer Database (2004-2014), 3,243 cases of T1 (≤2.0 cm) pancreatic neuroendocrine tumors were identified. Additional patient and tumor characteristics were examined. Multivariate models were used to identify factors that predicted resection and to assess patient survival after resection. RESULTS: 75% of pancreatic neuroendocrine tumors measuring 0 to 1.0 cm and 80% of pancreatic neuroendocrine tumors measuring >1.0 and ≤2.0 cm were resected. Eighty-four pancreatic neuroendocrine tumors were functional, of which 82% were resected. Variables influencing resection included positive lymph nodes, tumor in body or tail of pancreas, well or moderately differentiated tumors, and resection at academic medical centers (odds ratio 1.5-4.9). When controlling for other variables, patients with pancreatic neuroendocrine tumors 1 to 2 cm who underwent resection had a prolonged 5-year survival rate (hazard ratio 0.51, confidence interval 0.34-0.75) when compared with those who did not undergo resection. This survival benefit of resection was not found for pancreatic neuroendocrine tumors 0 to 1 cm (hazard ratio = 0.63, confidence interval 0.36-1.11). CONCLUSIONS: Contrary to many current recommendations, most patients with pancreatic neuroendocrine tumors ≤2.0 cm undergo surgical resection in the United States. A survival benefit was found for resection of pancreatic neuroendocrine tumors 1 to 2 cm, suggesting that current recommendations should perhaps be revised.

Risk factors associated with positive resection margins in patients with adrenocortical carcinoma.

BACKGROUND: Positive resection margins are associated with worse survival after surgery for adrenocortical carcinoma (ACC). We aimed to identify risk factors for positive margins post-resection. METHODS: The NCDB was queried for ACC patients from 2006 to 2015. Patients with positive versus negative resection margins post-surgery were compared using Chi-square tests. Survival based on adjuvant treatment was assessed using Kaplan-Meier curves. RESULTS: 1,973 patients with ACC were identified, 217 (11.0%) with positive margins. Multivariable analysis identified extra-adrenal extension (HR 4.92, p < 0.001), lymph node metastases (HR 2.64, p = 0.001), and distant metastases (HR 1.53, p = 0.03) as risk factors for positive margins. No significant difference in margin status existed between patients who had an open versus minimally invasive procedure (p = 0.6). Positive margin patients receiving adjuvant radiation (p = 0.007) or combined chemo-radiation (p = 0.001) had the longest survival. CONCLUSION: No modifiable risk factors were identified, but patients with positive margins receiving adjuvant radiation or chemo-radiation had the longest survival.

Primary Tumor Site Affects Survival in Patients with Gastroenteropancreatic and Neuroendocrine Liver Metastases.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are commonly present with metastatic disease, and the liver is the most frequent metastatic site. Herein, we studied whether primary tumor site affects survival in patients with GEP-NETs and liver metastases (NELM). As a secondary endpoint, we studied whether extrahepatic disease and surgical resection impact survival in this patient population. METHODS: Patients with NELM diagnosed from 2006 to 2014 were identified from the National Cancer Database. Kaplan-Meier curves and nested Cox proportional hazards were used to assess variables associated with survival. RESULTS: 2947 patients with well- or moderately differentiated GEP-NETs and NELM met the inclusion criteria for this study. Patients with small bowel NETs survived the longest of all GEP-NETs with NELM (median not reached). Rectal and gastric NETs with NELM had the shortest survival (median 31 months). Patients with extrahepatic metastases who underwent any operation survived longer than those managed nonoperatively (median survival 38.7 months vs. 18.6 months, p = 0.01). On multivariable analysis, operations on the primary tumor and distant metastatic site (HR 0.23-0.43 vs. no surgery), treatment at an academic/research hospital, Charlson comorbidity index of 0, no extrahepatic metastases, and younger age were associated with prolonged survival (p < 0.01). CONCLUSIONS: Primary tumor site affects survival in patients with GEP-NETs and NELM. Surgical resection seems beneficial for all GEP-NETs with NELM, even in the presence of extrahepatic metastases.

Resection of primary tumor may prolong survival in metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Patients with gastroenteropancreatic neuroendocrine tumors often present with stage IV disease. Primary tumor resection in these patients remains controversial. Herein, we studied the impact of primary tumor removal, identified variables associated with prolonged survival for each neuroendocrine tumor subtype, and determined factors that influence surgeons to perform primary tumor resection. METHODS: Patients with metastatic gastroenteropancreatic neuroendocrine tumors diagnosed from 2004 to 2014 were identified from the National Cancer Database. Nested Cox proportional hazards and logistic regression models were used to assess variables associated with survival and primary resection. RESULTS: A total of 14,510 patients met inclusion criteria. On multivariable analysis, resection of the primary tumor and grade 1 or 2 tumors was associated with prolonged survival in all subtypes (P < .001). Organ-specific variables associated with prolonged survival in patients undergoing primary tumor resection included the following: low grade for all organs; young age for pancreatic, small intestinal, colonic, and rectal neuroendocrine tumor; tumor size for colonic and rectal neuroendocrine tumor; and tumor location for colonic neuroendocrine tumor. Low tumor grade was found to be significantly associated with removal of the primary tumor across all organs. CONCLUSION: This study is the first suggesting that primary tumor resection is associated with prolonged survival for all gastro-entero-pancreatic NETs. Additional variables related to survival for each NET subtype were identified and might help select patients who benefit from primary tumor removal.

68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) changes management in a majority of patients with neuroendocrine tumors.

BACKGROUND: 68Gallium-DOTATATE positron emission tomography-computed tomography (PET CT) has shown superior accuracy in detecting grade 1 and 2 neuroendocrine tumors over previous imaging modalities and was recently included in National Comprehensive Cancer Network guidelines. It remains unclear which patients benefit most from this imaging modality. We therefore reviewed our initial experience with 68Gallium-DOTATATE PET CT to evaluate its usefulness in diagnosing, staging, and surveilling neuroendocrine tumors. METHODS: Records of patients who underwent 68Gallium-DOTATATE PET CT from March to December 2017 were prospectively evaluated. The primary endpoint was whether 68Gallium-DOTATATE PET CT changes treatment in patients with neuroendocrine tumors. Descriptive statistics, Fisher exact tests, and nested logistic regressions were conducted. RESULTS: A total of 50 consecutive patients were included. Of these, 41 patients (82%) had a biopsy-proven neuroendocrine tumor at the time of imaging. The remaining 9 patients (18%) had symptoms or biochemistry suggestive of a neuroendocrine tumor with negative cross-sectional imaging. 68Gallium-DOTATATE PET CT changed management in 33 patients (66%). There were 24 patients with intermodality changes in management and 9 patients with intramodality changes in management. Patients with scans performed for staging had a higher likelihood of a change in management (P = .006). CONCLUSION: Performing 68Gallium-DOTATATE PET CT should be considered for staging and surveillance of neuroendocrine tumors because it is frequently associated with changes in management.

National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress?

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. METHODS: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created. RESULTS: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). CONCLUSIONS: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.

Expression of programmed death ligand 1 and 2 in adrenocortical cancer tissues: An exploratory study.

BACKGROUND: Inhibition of the interaction of programmed death 1 with programmed death ligand 1 and 2 has been used successfully for treatment of multiple advanced cancers, but expression has not been studied in adrenocortical carcinoma. In this study, we investigated programmed death ligand 1 and 2 expression in adrenocortical carcinoma to determine the potential usefulness of checkpoint inhibitors in these malignant neoplasms. METHODS: A total of 56 tissue samples from patients with adrenocortical carcinoma (34) and benign adrenal tissues (22) were identified. Immunohistochemistry was performed for programmed death ligand 1, programmed death ligand 2, and CD8 and scored for membranous staining on adrenal and stromal tissue according to the immunoreactive score and absolute percentage, respectively. Descriptive statistics, a Mann-Whitney U test, and Fisher exact tests were calculated. RESULTS: In total, 15 adrenocortical carcinoma (44%) stained positive for programmed death ligand 2 and 1 adrenocortical carcinoma for programmed death ligand 1 (P = .03). Adrenocortical carcinoma samples were more likely to express programmed death ligand 2 on tumor cells or in stromal tissues than benign samples (OR = 2.3, P = .03). There was no relationship between programmed death ligand 2 and CD8 expression (P = .08). There were also no relationships between programmed death ligand 2 or CD8 expression and tumor characteristics. CONCLUSION: Programmed death ligand 2, but not programmed death ligand 1, is expressed commonly in adrenocortical carcinoma samples. The utility of certain checkpoint inhibitors should, therefore, be evaluated in further studies.