Baicalein activates 5' adenosine monophosphate-activated protein kinase, inhibits the mammalian target of rapamycin, and exhibits antiproliferative effects in pancreatic neuroendocrine tumors in vitro and in vivo.

BACKGROUND: The mammalian target of rapamycin inhibition has been shown to prolong progression-free survival in patients with pancreatic neuroendocrine tumors. The natural compound baicalein indirectly inhibits the mammalian target of rapamycin, but it is unknown if baicalein exhibits such effects at physiologically achievable concentrations or exhibits synergy. METHODS: Pancreatic neuroendocrine tumor cell lines were cultured with baicalein, everolimus, and/or a synthetic 5' adenosine monophosphate-activated protein kinase activating agent alone and in combination. Cell viability assays and immunoblotting were performed. Female severe combined immunodeficient-beige mice were injected with BON-1 cells and treated with baicalein and COH-SR4 solutions via oral gavage. Tumor volumes were compared at 30 days. RESULTS: Immunoblotting revealed that treatment of baicalein induced 5' adenosine monophosphate-activated protein kinase activation and the mammalian target of rapamycin inhibition. Treatment with baicalein alone led to a significant decrease in the ratio of viable cells compared with controls at 72 hours at concentrations ≥5 µM (P = .021). The addition of COH-SR4 led to significantly greater effect on cell viability than with baicalein alone (P < .001, P < .001). The combination of baicalein with everolimus resulted in significantly lower cell viability than with everolimus alone (P = .005, P < .001). Tumor volume in vivo was significantly decreased with the combination of baicalein and COH-SR4 compared with controls (P = .003). CONCLUSION: Baicalein exhibits antiproliferative effects against pancreatic neuroendocrine tumor cell lines at doses ≥5 µM and demonstrates synergy.

Liver-Directed Therapy in Neuroendocrine Neoplasms Metastatic to Both Liver and Bone.

Bone metastases from gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) have been associated with poor prognosis, but it is unclear whether patients with concurrent bone metastases who receive liver-directed therapy (LDT) would derive survival benefit. The California Cancer Registry dataset, merged with data from the California Office of Statewide Health Planning and Development, was used to perform a retrospective study of GEPNENs metastatic to both liver and bone between 2000 and 2012. A total of 203 patients were identified. Of these, 14.8% underwent LDT after bone metastasis diagnosis, 22.1% received LDT prior to that diagnosis, and 63.1% never received LDT. The median overall survival from the time of bone metastasis diagnosis was significantly longer in those that received LDT after diagnosis when compared with those that never received LDT (p = 0.005) and was not significantly different from the median overall survival of those that had received LDT prior to diagnosis (p = 0.256). LDT may still be associated with improved survival even after a diagnosis of bone metastasis.

Outcomes of cytoreductive operations for peritoneal carcinomatosis with or without liver cytoreduction in patients with small bowel neuroendocrine tumors.

BACKGROUND: This study determines how much cytoreduction for small bowel neuroendocrine tumors with peritoneal carcinomatosis and liver metastases can be achieved and the corresponding survival benefits of different levels of clearance. METHODS: Records of patients with small bowel neuroendocrine tumors with peritoneal carcinomatosis were reviewed and scored using the Lyon Stage system. Kaplan-Meier survival was calculated and compared by log-rank analysis. RESULTS: Among 323 patients with small bowel neuroendocrine tumors identified, 98 (30%) had peritoneal carcinomatosis. At laparotomy, 82% had Lyon Stage ≥3 compared with 78% who had Lyon Stage ≤2 after debulking (P < .00001). Median overall survival for Lyon Stage = 0 was 132 months and 51 months for Lyon Stage ≥1 (P = .026). For incomplete clearance, overall survival was 76 months for Lyon Stage ≤1 compared with 32 months for Lyon Stage ≥3 (P = .037). Seventy-nine (81%) patients had liver metastases, and 57 underwent >70% liver metastases cytoreduction. Overall survival was 76 months for Lyon Stage ≤1 and >70% liver metastases cytoreduction, 38.5 months for Lyon Stage ≥3 and >70% liver metastases cytoreduction, 22 months for Lyon Stage ≤1 and liver metastases not cytoreduced, and 20 months for Lyon Stage ≥3 and liver metastases not cytoreduced (P = .018). CONCLUSION: A majority of patients with peritoneal carcinomatosis from small bowel neuroendocrine tumors can be cytoreduced. Best survival times are seen with complete clearance; however, there are improved survival times for Lyon Stage ≤1. In patients with liver metastases, best survival after cytoreduction is seen when both Lyon Stage ≤1 and liver metastases >70% are achieved.

Evaluation of the prognosis for N2 status in patients with small bowel neuroendocrine tumors.

BACKGROUND: The 8th edition AJCC Staging for small bowel neuroendocrine tumors created a novel N2 classification. This study investigates if it is independently prognostic. METHODS: Records of patients from 2008 to 2019 were reviewed. Survival rates were estimated by Kaplan-Meier method and compared by log-rank. The Cox Proportional Hazards model was used to determine factors associated with overall survival (OS) via multivariate analysis. RESULTS: Among 300 patients, 225 were N2 and 60 were N1. No differences were seen in pathologic markers for N1 compared to N2. N2 were more likely to have liver metastases (LM) (p = 0.048) but rates of resectability were similar. Median OS for N1 with >70% liver cytoreduction was not yet reached compared to 121 months for N2 (p = 0.005). On multivariate analysis, LM was associated with shorter survival (p = 0.028), but nodal status was not. CONCLUSIONS: Unlike LM, N2 status is not independently prognostic, but a marker for aggressive LM.

Management of Metastatic GEPNETs.

The chief causes of death of patients with GEPNETs are liver failure from hepatic replacement by tumor in the majority and bowel obstruction in the remainder. Many patients are with liver metastases are actually eligible for hepatic cytoreductive operations, even if they have numerous bilobar metastases and extra-hepatic disease, provided that greater than 70% of the liver tumor volume can be removed. This can often be done by combinations of parenchyma-sparing enucleations, wedge resections and radio frequency ablations. Patients with higher liver tumor burden can be treated with intra-arterial therapies, such as embolization and chemoembolization. Patients with peritoneal carcinomatosis are recommended to undergo cytoreductive operations including peritoneal stripping and bowel resections. Consensus guidelines by experts recommend bisphosphonate therapy for patients with bone metastases, reserving surgical treatment for patients with mechanical issues and/or potential spinal cord compression. Radiation can be employed for isolated painful metastases. PRRT may be an emerging therapy for treatment of bone metastases.

Neuroendocrine metastases to the ovaries are significantly associated with small bowel neuroendocrine tumors and carcinomatosis.

INTRODUCTION: Neuroendocrine tumors (NETs) metastatic to the ovary are traditionally considered rare, but data are lacking. This study seeks to better characterize the prevalence and outcomes of patients with neuroendocrine ovarian metastases (NOM). METHODS: Women with well-differentiated lung and gastroenteropancreatic NETs 2007-2017 were identified by medical record query. Clinicopathologic data were reviewed among patients with and without NOM. RESULTS: Of 242 patients, 27 (11.2%) developed NOM. NOM developed in 24.8% of SBNET patients and 65.7% of patients with carcinomatosis and intact ovaries. 33.3% had associated small bowel obstructions; 11.1% had ureteral obstruction. NOM were not apparent on imaging in 29.6% nor visible intraoperatively in 8.3%. Five-year survival rate was 61.5%. Those who underwent oophorectomy had a lower rate of subsequent ureteral obstruction (p < 0.01). CONCLUSIONS: NOM are more prevalent than previously reported and associated with significant morbidity. Empiric oophorectomy may be considered for SBNET patients and strongly advised in carcinomatosis.

A prospective study of opioid use for postoperative pain management after breast operation.

BACKGROUND: The opioid epidemic has necessitated increased attention to prescribing practices. This study seeks to prospectively quantify postoperative opioid use after breast operation. METHODS: Consecutive patients undergoing breast operation at a single institution in 2018 prospectively tracked each dose of medication and completed a survey of perceptions regarding their opioid prescription. RESULTS: Of 100 patients, 88 completed log, survey, or both. The tab quantity required to fulfill the needs of 80% of patients was: Partial mastectomy (PM) 3, PM with sentinel lymph node biopsy 6, PM with bilateral reduction 8, total mastectomy 34, and bilateral mastectomy 47. Of survey respondents, 51.2% felt they had been prescribed too much pain medication. Most (83.0%) had leftover tabs, and 67.9% indicated they kept them in their home. CONCLUSIONS: The majority of patients were overprescribed opioids after breast operation. A reduction could be achieved by targeting the needs of 80% of the population.

Β-Adrenergic agonist administration is not associated with secondary carcinoid crisis in patients with carcinoid tumor.

BACKGROUND: Patients with carcinoid tumors are at risk for profound intraoperative hypotension known as carcinoid crisis, which catecholamines are traditionally believed to trigger. However, data supporting this are lacking. METHODS: Anesthesia records were retrospectively reviewed for carcinoid patients treated with vasopressors. Hemodynamics for those with crisis were compared between those who received ß-adrenergic agonists (B-AA) versus those who did not. RESULTS: Among 293 consecutive operations, 58 were marked by 161 crises. There was no significant difference in the incidence of paradoxical hypotension with B-AA compared to non-B-AA (p = 0.242). The maximum percent decrease in mean arterial pressure following drug administration was significantly greater in those patients treated with non-B-AA than with B-AA (31.6% vs. 12.5%, p < 0.0001). There were no differences in crisis duration (p = 0.257) or postoperative complication rate (p = 0.896). CONCLUSIONS: ß-Adrenergic agonist use was not associated with paradoxical hypotension, prolonged carcinoid crisis, or postoperative complications in patients with intraoperative carcinoid crisis.

Surgical resection of breast cancers: Molecular analysis of cancer stem cells in residual disease.

BACKGROUND: Approximately 70% of breast cancer patients have residual disease after neoadjuvant chemotherapy. This study was designed to determine whether breast cancer cells with stemlike properties are present in residual disease after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The presence of breast cancer cells with stemlike properties with specific mutations may help explain the poor prognosis associated with residual disease. METHODS: A total of 68 breast cancer specimens were collected at the time of mastectomy or lumpectomy. A total of 44 were chemotherapy naïve and 24 were collected as residual disease after neoadjuvant chemotherapy. Tumor cells were collected by fluorescence-activated cell sorting, with breast cancer cells with stemlike properties specifically identified using breast stem cell associated antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast cancer cells with stemlike properties were analyzed for genetic mutations, including PIK3CA. RESULTS: Breast cancer cells with stemlike properties, demonstrating EpCAM-positive, CD44-positive, CD49f±, CD24± expression were present in chemotherapy-naïve tumors and residual disease. In both chemotherapy-naïve and residual disease specimens the highest frequency of PIK3CA mutations were detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were detected in all stages of breast cancer (35%), in both chemotherapy naïve (39%) and residual disease (29%) and in both estrogen receptor positive (41%) and negative tumors (14%) (P = ns). Various PIK3CA mutations were identified in chemotherapy-naïve specimens versus residual disease specimens in both patient-paired and unpaired breast cancers. CONCLUSION: Breast cancer cells with stemlike properties with mutations in PIK3CA were present in chemotherapy-naïve breast cancers and residual disease after neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy does not completely eradicate PIK3CA-defective breast cancer cells with stemlike properties. Although these findings may help explain the poor clinical outcomes in patients with residual disease, they also identify breast cancer cells with stemlike-property targets for therapies.

A prospective study of the pathophysiology of carcinoid crisis.

BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed.