Estrogen receptor, progesterone receptor, interleukin-6 and interleukin-8 are variable in breast cancer and benign stem/progenitor cell populations.

BACKGROUND: Estrogen receptor positive breast cancers have high recurrence rates despite tamoxifen therapy. Breast cancer stem/progenitor cells (BCSCs) initiate tumors, but expression of estrogen (ER) or progesterone receptors (PR) and response to tamoxifen is unknown. Interleukin-6 (IL-6) and interleukin-8 (IL-8) may influence tumor response to therapy but expression in BCSCs is also unknown. METHODS: BCSCs were isolated from breast cancer and benign surgical specimens based on CD49f/CD24 markers. CD44 was measured. Gene and protein expression of ER alpha, ER beta, PR, IL-6 and IL-8 were measured by proximity ligation assay and qRT-PCR. RESULTS: Gene expression was highly variable between patients. On average, BCSCs expressed 10-106 fold less ERα mRNA and 10-103 fold more ERß than tumors or benign stem/progenitor cells (SC). BCSC lin-CD49f-CD24-cells were the exception and expressed higher ERα mRNA. PR mRNA in BCSCs averaged 10-104 fold less than in tumors or benign tissue, but was similar to benign SCs. ERα and PR protein detection in BCSCs was lower than ER positive and similar to ER negative tumors. IL-8 mRNA was 10-104 higher than tumor and 102 fold higher than benign tissue. IL-6 mRNA levels were equivalent to benign and only higher than tumor in lin-CD49f-CD24-cells. IL-6 and IL-8 proteins showed overlapping levels of expressions among various tissues and cell populations. CONCLUSIONS: BCSCs and SCs demonstrate patient-specific variability of gene/protein expression. BCSC gene/protein expression may vary from that of other tumor cells, suggesting a mechanism by which hormone refractory disease may occur.

Fresh surgical specimens yield breast stem/progenitor cells and reveal their oncogenic abnormalities.

BACKGROUND: The process by which breast cancer stem cells arise is unknown. It may be that the benign stem cells in breast tissue are transformed into malignant stem cells through the acquisition of genetic abnormalities. In this study, we collected and compared benign and malignant breast stem/progenitor cells to determine whether specific genetic abnormalities occur in breast cancer stem/progenitor cells within the human body. METHODS: Fresh surgical specimens from benign and malignant breast tissues were obtained directly from the operating room and examined. Cells variably expressing stem cell-associated surface markers CD49f and CD24 were collected by fluorescence-activated cell sorting. The frequencies of these cells in benign and malignant breast tissues were ascertained. Oncogenetic mutation analyses were performed and expression of stem cell-associated genes was measured. RESULTS: The frequencies of stem/progenitor cells were similar between benign and malignant tissues. Stem cell-associated gene expression also was similar between benign and malignant stem cells. Genetic mutations in the PIK/AKT pathway were found in 73% of the tumors' stem cells, specifically within two subpopulations. No mutations were found in stem/progenitor cell subpopulations from benign breast tissue. CONCLUSIONS: The results of this study suggest that, following malignant transformation, breast cancer stem/progenitor cells retain their stem cell functions and relative frequencies. In addition, they develop malignant capabilities by acquiring mutations in genes critical for maintaining normal cellular metabolism and proliferation.

A prospective study of carcinoid crisis with no perioperative octreotide.

BACKGROUND: Carcinoid crises, defined as the sudden onset of hemodynamic instability in patients with neuroendocrine tumors undergoing operation, are associated with significantly increased risk of postoperative complications. Octreotide has been used prophylactically to reduce crisis rates as well as therapeutically to treat crises that still occur. However, studies using octreotide still report crisis rates of 3.4% to 35%, leading to the questioning of its efficacy. METHODS: Patients with neuroendocrine tumors undergoing operation between 2017 to 2020 with no perioperative octreotide were prospectively studied. Clinicopathologic data were compared by χ2 test for discrete variables and by Mann-Whitney U test for continuous variables. RESULTS: One hundred and seventy-one patients underwent 195 operations. Crisis was documented in 49 operations (25%), with a mean duration of 3 minutes. Crisis was more likely to occur in patients with small bowel primary tumors (P = .012), older age (P = .015), and carcinoid syndrome (P < .001). Those with crises were more likely to have major postoperative complications (P = .003). CONCLUSION: Completely eliminating perioperative octreotide resulted in neither increased rate nor duration compared with previous studies using octreotide. We conclude perioperative octreotide use may be safely stopped, owing to inefficacy, though the need for an effective medication is clear given continued higher rates of complications.

The prevalence, operations, and outcomes of carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) is a sequela of carcinoid liver metastases (LM). The true prevalence of CHD is unknown due to infrequent screening by transthoracic echocardiography (TTE). Octreotide is believed to protect against new and recurrent CHD, but supporting data are scant. This study determined CHD prevalence and outcomes in patients screened by TTE and treated with octreotide. METHODS: Records of carcinoid patients from 2001 to 2021 were reviewed. Survival was estimated by Kaplan-Meyer curves and compared by log-rank. RESULTS: Among 282 patients screened by TTE, overall survival was lower in CHD (n = 40) versus non-CHD (n = 242) patients (p < 0.001). Despite octreotide therapy, 21 patients developed CHD. Among patients with inoperable LM, survival was lower in CHD patients without valve replacement (VR) (p < 0.001), but similar between CHD patients with VR and non-CHD patients. CHD patients with VR and hepatic cytoreduction had survival similar to CHD patients without VR. CONCLUSION: VR improves survival in CHD patients with inoperable LM. Hepatic cytoreduction after VR should be reserved for carefully selected cases. Our data do not support a protective effect of octreotide.

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.

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.

Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors.

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.

Characterizing the HER2/neu status and metastatic potential of breast cancer stem/progenitor cells.

INTRODUCTION: Treatment resistance, long latency, and high recurrence rates suggest that breast cancers arise from defective breast stem cells. HYPOTHESIS: Within cancers, subpopulations of cells will demonstrate differences in stem/progenitor potential, HER2/neu amplification, and gene expression. Related cells will be found in normal breast tissue. METHODS: ER-/PR-/HER2/neu + breast cancer cells were flow-sorted into subpopulations: (A) CD49f(+) CD24(-), (B) CD49f(+)CD24(+), (C) CD49f CD24(-), and (D) CD49f(-)CD24(+). Gel matrix cell invasion, fluorescence in situ hybridization (FISH) HER2/neu amplification, and qRT-PCR gene expression were measured in all groups. Cells from sorted groups were implanted into rat brains. Resultant tumors were analyzed by immunohistochemistry (IHC) and FISH. Normal breast tissue was examined by IHC. RESULTS: Tumor development varied among sorted groups (25-75%), but was highest in group A. Tumor cells were mostly CD49f(-)CD24(-), with variable fractions of other stem/progenitor cells. Tumors showed HER2/neu amplification, but fewer chromosome 17 per cell than inoculates. Group A tumors exhibited cells with normal chromosome 17 copy number and near normal HER2/neu amplification. Cell invasion was 61% higher in unsorted cells and 34-42% in sorted groups compared with controls. Sorted groups showed significantly different expression of development, proliferation, and invasion associated genes. In normal breast tissue, CD49f(+) cells were identified in CD14(+) CK19(-) basal epithelial layers of mammary glands; these were 95% CD24(+) and 60% CD44(+). CONCLUSIONS: Breast cancer stem/progenitor cell populations differ in tumor-initiating potential but are not solely responsible for metastasis. Cancer stem/progenitor cells are less polyploid than cancer cells in general and may not be HER2/neu amplified. In normal breast tissue, breast stem/progenitor cell-like populations are present.

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.

Expanded criteria for debulking of liver metastasis also apply to pancreatic neuroendocrine tumors.

BACKGROUND: Recently, there has been a move toward decreasing the threshold for liver debulking for metastatic carcinoid tumors from 90% to 70%. The debulking threshold and factors that predict outcomes of liver debulking operations specifically among pancreatic neuroendocrine tumors are not well defined. METHODS: Records of patients with pancreatic neuroendocrine tumors undergoing liver debulking with a threshold of 70% from 2006 to 2016 were reviewed. Extrahepatic metastases and positive margins by enucleation were allowed. Liver progression-free survival and overall survival were calculated by the Kaplan-Meier method for various factors and compared by log-rank. Factors also were correlated with liver progression-free survival and overall survival by multivariate regression analyses. RESULTS: Forty-two patients underwent 44 operations, of which 24 resulted in 100% debulking, 12 resulted in ≥90% debulking, and 8 resulted in ≥70% debulking. Median liver progression-free survival was 11 months. The 5-year overall survival rate was 81%. There were no significant differences in outcome based on percent debulked. Only liver metastasis ≥5 cm correlated with liver progression-free survival and overall survival. CONCLUSION: Consideration should be given to expanding the criteria for liver debulking in pancreatic neuroendocrine tumors to include a new threshold of >70% debulking, intermediate grade tumors, positive margins, and extrahepatic metastases; these criteria yield results indistinguishable from complete resection. Using these expanded criteria will increase the number of patients eligible for an operation and maintain high survival rates.

Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival.

BACKGROUND: It is unclear whether there is a benefit to resection of primary gastrointestinal carcinoid neoplasm with hepatic metastases. We investigated whether primary tumor resection in this setting led to a significant difference in outcomes. METHODS: A retrospective review of patients with abdominal carcinoid neoplasms between 1995 and 2006 was performed. Data collected on patients with proven carcinoid liver metastases at initial diagnosis included whether the primary neoplasm was resected, time to progression of liver metastases, and status at last follow-up. Progression-free survival and survival were calculated by the method of Kaplan-Meier and compared by the log-rank test. RESULTS: There were 84 patients, 60 of whom had their primary neoplasm resected. The resected group had a greater median progression-free survival of 56 months, compared with 25 months for the primary nonresected group (P < .001). Median survival time for the resected group was longer at 159 months, compared with 47 months for the nonresected group (P < .001). CONCLUSIONS: Resection of the primary neoplasm is associated with better progression-free survival and overall survival in patients with abdominal carcinoid neoplasms. Therefore, localization and resection of the primary neoplasm should be considered, even among patients in whom the primary neoplasm is asymptomatic.

Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis.

BACKGROUND: Operations and anesthesia in carcinoid patients can provoke carcinoid crises, which can have serious sequelae, including death. Prophylactic octreotide is recommended to prevent crises. Recommended prophylaxis regimens vary from octreotide long-acting repeatable to preoperative bolus to continuous octreotide infusion; however, efficacy data are lacking. We have shown previously that crises correlated with major complications and that octreotide long-acting repeatable and preoperative bolus failed to prevent crises. This study examines the impact of continuous octreotide infusion. METHODS: A total of 127 patients (71% with liver metastases, 74% with carcinoid syndrome) who underwent 150 operations with continuous octreotide infusions were enrolled in this prospective case series. Our main outcome measures were the occurrence of intraoperative carcinoid crises and post-operative complications. RESULTS: Crises occurred at a rate of 30% as compared with 24% in our previous series, which examined the impact of preoperative octreotide bolus. Crises were significantly associated with the presence of hepatic metastases (P = .02) or history of carcinoid syndrome (P = .006), although neither was required for crises. Prompt vasopressor treatment shortened the mean duration of hypotension to 8.7 minutes, compared with 19 minutes in our prior series. Crises no longer correlated with major complications (P = .481) unless instability persisted for greater than 10 minutes (P = .011). CONCLUSION: Octreotide infusions do not prevent intraoperative crises. Patients without liver metastases or carcinoid syndrome can have intraoperative crises. Postoperative complications can be decreased by reducing the duration of crises. Further study is needed to determine how best to shorten hemodynamic instability during crises.

A Disease-Specific Hybrid Rotation Increases Opportunities for Deliberate Practice.

IMPORTANCE: Incorporating deliberate practice (DP) into residency curricula may optimize education. DP includes educationally protected time, continuous expert feedback, and a focus on a limited number of technical skills. It is strongly associated with mastery level learning. OBJECTIVE: Determine if a multidisciplinary breast rotation (MDB) increases DP opportunities. DESIGN: Beginning in 2010, interns completed the 4-week MDB. Three days a week were spent in surgery and surgical clinic. Half-days were in breast radiology, pathology, medical oncology, and didactics. The MDB was retrospectively compared with a traditional community rotation (TCR) and a university surgical oncology service (USOS) using rotation feedback and resident operative volume. Data are presented as mean ± standard deviation. SETTING: Oregon Health and Science University in Portland, Oregon; an academic tertiary care general surgery residency program. PARTICIPANTS: General surgery residents at Oregon Health and Science University participating in either the MDB, TCR or USOS. RESULTS: A total of 31 interns rated the opportunity to perform procedures significantly higher for MDB than TCR or USOS (4.6 ± 0.6 vs 4.2 ± 0.9 and 4.1 ± 1.0, p < 0.05). MDB was rated higher than TCR on quality of faculty teaching and educational materials (4.5 ± 0.7 vs 4.1 ± 0.9 and 4.0 ± 1.2 vs 3.5 ± 1.0, p < 0.05). Interns operated more on the MDB than on the USOS and were more focused on breast resections, lymph node dissections, and port placements than on the traditional surgical rotation or USOS. CONCLUSIONS: The MDB incorporates multidisciplinary care into a unique, disease-specific, and educationally focused rotation. It is highly rated and affords a greater opportunity for DP than either the USOS or TCR. DP is strongly associated with mastery learning and this novel rotation structure could maximize intern education in the era of limited work hours.

Gene expression signatures of breast cancer stem and progenitor cells do not exhibit features of Warburg metabolism.

INTRODUCTION: Cancers are believed to adapt to continual changes in glucose and oxygen availability by relying almost exclusively on glycolytic metabolism for energy (i.e. the Warburg effect). The process by which breast cancers sustain growth in avascular tissue is thought to be mediated via aberrant hypoxia response with ensuing shifts in glycolytic metabolism. Given their role in initiating and perpetuating tumors, we sought to determine whether breast cancer stem and progenitor cells play an instrumental role in this adaptive metabolic response. METHODS: Breast cancer stem/progenitor cells were isolated from invasive ductal carcinomas, and benign stem cells (SC) were isolated from reduction mammoplasty tissues. Relative expression of 33 genes involved in hypoxia and glucose metabolism was evaluated in flow cytometrically isolated stem and progenitor cell populations. Significance between cohorts and cell populations was determined using Student's 2-tailed t test. RESULTS: While benign stem/progenitor cells exhibited few significant inter-group differences in expression of genes involved in hypoxia regulation or glucose metabolism, breast cancer stem/progenitor cells demonstrated significant inter-group variability. Breast cancer stem/progenitor cells adapted to microenvironments through changes in stem cell numbers and transcription of glycolytic genes. One of four breast cancer stem/progenitor cells subpopulations exhibited an aerobic glycolysis gene expression signature. This subpopulation comprises the majority of the tumor and therefore best reflects invasive ductal carcinoma tumor biology. Although PI3K/AKT mutations are associated with increased proliferation of breast cancer cells, mutations in breast cancer stem/progenitor cells subpopulations did not correlate with changes in metabolic gene expression. CONCLUSIONS: The adaptive capacity of breast cancer stem/progenitor cells may enable tumors to survive variable conditions encountered during progressive stages of cancer growth.

Expanded criteria for carcinoid liver debulking: Maintaining survival and increasing the number of eligible patients.

BACKGROUND: Cytoreduction of carcinoid liver metastases typically aims for ≥ 90% debulking in patients without extrahepatic disease. Data on the impact of less-restrictive resection criteria and other clinical and tumor-specific factors on outcomes are limited. METHODS: Records of carcinoid patients undergoing liver debulking from 2007 to 2011 were reviewed. Debulking threshold was 70%, extrahepatic disease did not preclude cytoreduction, and positive margins were allowed. Kaplan-Meier liver progression-free (PFS) and disease-specific (DSS) survival were calculated and compared by log-rank analysis and statistical significance of differences in distributions of factors between patient groups was determined by chi-squared analysis. RESULTS: Fifty-two patients were identified. Complete resection of intrahepatic and extrahepatic gross disease was achieved in 12 patients. All primaries reviewed were low grade, but one third of patients had at least one intermediate-grade metastasis. Fifteen patients (29%) had liver progression; median PFS was 72 months. Five-year DSS was 90%, with all deaths from liver failure. Only age was an important prognostic factor for PFS and DSS. Five-year DSS for patients <50 years was 73% and was 97% for patients 50 or older (P = .03). CONCLUSION: The use of expanded criteria for debulking resulted in 90% 5-year DSS. Although younger age portends a poorer prognosis, the favorable PFS and DSS justify also using expanded criteria in this subgroup.