Abstract Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR) to identify differences in their ...glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of13 C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA) cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS) in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only) > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells), leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1) provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2) lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism.
Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to ...trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (
n
= 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg,
p
< 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years,
p
= 0.014) with lower LVEF before anthracycline (63 vs. 67 %,
p
< 0.0001) and trastuzumab (62 vs. 67 %,
p
< 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients.
B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their ...overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.
To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or ...persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible: patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle.
Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n = 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.
HIF-1α is overexpressed in many human cancers compared to normal tissues due to the interaction of a multiplicity of factors and pathways that reflect specific genetic alterations and extracellular ...stimuli. We developed two HIF-1α chimeric reporter systems, HIF-1α/FLuc and HIF-1α(ΔODDD)/FLuc, to investigate the tightly controlled level of HIF-1α protein in normal (NIH3T3 and HEK293) and glioma (U87) cells. These reporter systems provided an opportunity to investigate the degradation of HIF-1α in different cell lines, both in culture and in xenografts. Using immunofluorescence microscopy, we observed different patterns of subcellular localization of HIF-1α/FLuc fusion protein between normal cells and cancer cells; similar differences were observed for HIF-1α in non-transduced, wild-type cells. A dynamic cytoplasmic-nuclear exchange of the fusion protein and HIF-1α was observed in NIH3T3 and HEK293 cells under different conditions (normoxia, CoCl2 treatment and hypoxia). In contrast, U87 cells showed a more persistent nuclear localization pattern that was less affected by different growing conditions. Employing a kinetic model for protein degradation, we were able to distinguish two components of HIF-1α/FLuc protein degradation and quantify the half-life of HIF-1α fusion proteins. The rapid clearance component (t1/2 ∼4–6 min) was abolished by the hypoxia-mimetic CoCl2, MG132 treatment and deletion of ODD domain, and reflects the oxygen/VHL-dependent degradation pathway. The slow clearance component (t1/2 ∼200 min) is consistent with other unidentified non-oxygen/VHL-dependent degradation pathways. Overall, the continuous bioluminescence readout of HIF-1α/FLuc stabilization in vitro and in vivo will facilitate the development and validation of therapeutics that affect the stability and accumulation of HIF-1α.
The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality ...regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.
Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess ...the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery.
Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival PFS and overall survival OS). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables.
At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. K(trans) is volume transfer constant. In a stepwise Cox regression, skewness of K(trans) (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001).
Our study shows that skewness of K(trans) was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter K(trans) as a predictor of outcome in these patients.
Brain natriuretic peptide and risk of atrial fibrillation after thoracic surgery Amar, David, MD; Zhang, Hao, MD; Shi, Weiji, MS ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
11/2012, Letnik:
144, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Objectives Postoperative atrial fibrillation (POAF) complicating general thoracic surgery is a marker of increased morbidity and stroke risk. Our goal was to determine whether increased preoperative ...brain natriuretic peptide (BNP) levels are able to stratify patients by the risk of POAF. Methods Using a prospective database of 415 patients aged 60 years or older, who had undergone lung or esophageal surgery during a 1-year period, the preoperative clinical data, including BNP levels, were compared between patients who developed POAF lasting longer than 5 minutes during hospitalization and those who did not. Results POAF occurred in 65 (16%) of the 415 patients and was more frequent among patients who had undergone esophagectomy or anatomic lung resection (22% or 58 of 269) compared with those who did not (5% or 7 of 146; P < .0001). After esophagectomy or anatomic lung resection, 46 (34%) of the 135 patients with BNP levels greater than the median (≥30 pg/mL) developed POAF compared with only 12 (9%) of 134 patients with BNP levels less than 30 pg/mL ( P < .0001). The rates of POAF in patients undergoing other thoracic procedures were low and not associated with the BNP levels. Multivariate logistic regression analysis showed that in patients undergoing esophagectomy or anatomic lung resection, older age (5-year increments, odds ratio OR, 1.28; 95% confidence interval CI, 1.01-1.61; P = .04), male gender (OR, 2.61; 95% CI, 1.12-4.17; P = .02), and BNP level 30 pg/mL or greater (OR, 4.52; 95% CI, 2.19-9.32; P < .0001) were independent risk factors for POAF. The length of hospital stay was significantly increased in patients who developed POAF compared with those who did not ( P < .0001). Conclusions Among patients undergoing anatomic lung resection or esophagectomy, increased age, male gender, and preoperative BNP level of 30 pg/mL or greater were significant risk factors for the development of POAF. The identification of patients who are more likely to develop POAF will allow the development of trials assessing prevention strategies aimed at reducing this complication.
We have shown previously that either echocardiographic indices of diastolic dysfunction or increased preoperative brain natriuretic peptide (BNP) predict postoperative atrial fibrillation (POAF). ...Because these 2 predictors of POAF have not been evaluated together, our goal was to further elucidate their concurrent role in patients undergoing noncardiac thoracic surgery.
We retrospectively identified 191 patients who had a preoperative transthoracic echocardiogram and serum BNP level collected as part of routine care before major lung or esophageal resection. Clinical and echocardiographic data were compared between patients who did or did not develop POAF (>5 minutes), and prognostic factors for POAF were identified.
Univariate associations with POAF (41 of 191; 22% patients) included older age (P = .04), male sex (P = .01), hypertension (P = .03), increased body mass index (P = .01), and prolonged transmitral flow deceleration time (P < .0001), whereas BNP was not statistically significant (P = .07). Stepwise logistic regression analysis showed that both increasing transmitral flow deceleration time (continuous data log base 2 transformed; odds ratio, 16.05; 95% confidence interval, 3.74-68.96; P = .0002) and left atrial diastolic volume index (continuous data log base 2 transformed; odds ratio, 3.29; 95% confidence interval, 1.22-8.91; P = .02) were independent risk factors of POAF (area under the receiver operating characteristic curve = 0.73). There was no significant interaction between BNP and the 2 independent variables (P = .60, and P = .90), respectively.
In a cohort of patients who had echocardiography and BNP measurements before undergoing major thoracic surgery, this study showed that when evaluated together greater preoperative left atrial diastolic volume index and transmitral flow deceleration time but not BNP levels were independent predictors for POAF.
To assess the direct costs of three surgical approaches in uterine cancer and the cost-effectiveness of incorporating robot-assisted surgery.
A cost system that allocates the actual cost of resources ...used to treat each patient, as opposed to borrowing cost data from a billing system, was used to determine direct costs for patients who underwent surgery for uterine cancer from 2009 to 2010. These costs included all aspects of surgical care up to 6 months after discharge. Total amortized direct costs included the capital cost of three dual-console robotic platforms with 5 years of service contracts. Nonamortized costs were also calculated (excluded capital costs). Modeling was performed to estimate the mean cost of surgical care for patients presenting with endometrial cancer from 2007 to 2010.
Of 436 cases (132 laparoscopic, 262 robotic, 42 laparotomy), total mean amortized direct costs per case were $20,489 (laparoscopy), $23,646 (robot), and $24,642 (laparotomy) (P<.05 robot compared with laparoscopy; P=.6 robot compared with laparotomy). Total nonamortized costs per case were $20,289, $20,467, and $24,433, respectively (P=.9 robot compared with laparoscopy; P=.03 robot compared with laparotomy). The planned surgical approach in 2007 was laparoscopy, 68%; robot, 8%; and laparotomy, 24% compared with 26%, 64%, and 9%, respectively, in 2010 (P<.001). The modeled mean amortized direct costs per case were $21,738 in 2007 and $22,678 in 2010 (+$940). Nonamortized costs were $21,298 in 2007 and $20,573 in 2010 (-$725).
Laparoscopy is least expensive when including capital acquisition costs. Laparoscopy and robotic surgery are comparable if upfront costs are excluded. There is cost neutralization with the robot when it helps decrease laparotomy rates.
PDF
