MR imaging features associated with distant metastasis-free survival of patients with invasive breast cancer: a case–control study

Purpose

Preoperative breast magnetic resonance (MR) imaging features of primary breast cancers may have the potential to act as prognostic biomarkers by providing morphologic and kinetic features representing inter- or intra-tumor heterogeneity. Recent radiogenomic studies reveal that several radiologist-annotated image features are associated with genes or signal pathways involved in tumor progression, treatment resistance, and distant metastasis (DM). We investigate whether preoperative breast MR imaging features are associated with worse DM-free survival in patients with invasive breast cancer.

Methods

Of the 3536 patients with primary breast cancers who underwent preoperative MR imaging between 2003 and 2009, 147 patients with DM were identified and one-to-one matched with control patients (n = 147) without DM according to clinical–pathologic variables. Three radiologists independently reviewed the MR images of 294 patients, and the association of DM-free survival with MR imaging and clinical–pathologic features was assessed using Cox proportional hazard models.

Results

Of MR imaging features, rim enhancement (hazard ratio [HR], 1.83 [95% confidence interval, CI 1.29, 2.51]; p = 0.001) and peritumoral edema (HR, 1.48 [95% CI 1.03, 2.11]; p = 0.032) were the significant features associated with worse DM-free survival. The significant MR imaging features, however, were different between breast cancer subtypes and stages.

Conclusion

Preoperative breast MR imaging features of rim enhancement and peritumoral edema may be used as prognostic biomarkers that help predict DM risk in patients with breast cancer, thereby potentially enabling improved personalized treatment and monitoring strategies for individual patients.

     

Factors associated with a higher rate of distant failure after primary treatment for glioblastoma

Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5 % of patients and non-local in 34.5 %. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences.     

Spin-echo echo-planar perfusion prior to chemoradiation is a strong independent predictor of progression-free and overall survival in newly diagnosed glioblastoma

Spin-echo echo planar (EP) perfusion weighted imaging (SE-PWI) has been demonstrated to be more selective than gradient-echo EP PWI for blood volume in microvessels the size of glioma neocapillaries, but it has not been comprehensively studied in human clinical use. We assessed whether SE-PWI before and after initiating chemoradiation can stratify patients with respect to progression free survival (PFS) and overall survival (OS). Sixty-eight patients with newly diagnosed glioblastoma (mean age 58.3, 36 males) were included in analysis. SE EP cerebral blood volumes (SE-CBVs) in enhancing and nonenhancing tumor, normalized to contralateral normal appearing white matter (SE-nCBV), were assessed at baseline and after initial chemoradiation. SE-nCBV parameters predictive of PFS and OS were identified in univariate and multivariate Cox proportional hazards models. Multivariate analysis demonstrated that baseline tumor mean SE-nCBV was predictive of PFS (p = 0.038) and OS (p = 0.004). Within the patient sample, baseline tumor mean SE-nCBV <2.0 predicted longer patient PFS (median 47.0 weeks, p < 0.001) and OS (median 98.6 weeks, p = 0.003) compared with baseline mean SE-nCBV >2.0 (median PFS 25.3, median OS 56.0 weeks). Exploratory multi-group stratification demonstrated that very high (>4.0) tumor SE-nCBV was associated with worse patient OS than intermediate high (>2.0, <4.0) SE-nCBV (p = 0.025). Baseline mean SE-nCBV can stratify patients for PFS and OS prior to initiation of chemoradiation, which may help select patients who require closer surveillance. Our exploratory analysis indicates a magnitude-dependent relationship between baseline SE-nCBV and OS.     

Prognostic paradox: brain damage around the glioblastoma resection cavity

Hyperintense lesions around the resection cavity on magnetic resonance diffusion-weighted imaging (MR-DWI) frequently appear after brain tumor surgery due to the damage of surrounding brain. The putative connection between the lesion and the prognosis for patients with glioblastoma (GBM) was explored. This retrospective study reviewed consecutive sixty-one patients with newly diagnosed GBM. Postoperative MRI was performed within 2 weeks after the initial surgery. We classified the cases into two groups depending on whether DWI hyperintense lesions were observed or not [DWI(+) group and DWI(?) group]. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. Forty-two patients were identified. The various extents of hyperintense lesions around the resection cavity were observed in 28/42 (66.7 %) cases. In the DWI(+) and DWI(?) groups, median PFS was 10.0 [95 % confidence interval (CI) 8.4–11.5] and 6.7 (95 % CI 4.9–8.5) months, respectively (p = 0.042), and median OS was 18.0 (95 % CI 12.2–23.8) and 17.0 (95 % CI 15.7–18.3) months, respectively (p = 0.254). On multivariate analysis, the presence of DWI hyperintense lesion was more likely to be an independent predictor for 6-month PFS (p = 0.019; HR, 0.038; 95 % CI 0.002–0.582). Tumor recurrence appeared outside the former DWI hyperintense lesion. Hyperintense lesions surrounding the resected GBM on MR-DWI might be a favorable prognostic factor in patients with GBM.     

Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study

The PRECISE study used convection enhanced delivery (CED) to infuse IL13-PE38QQR in patients with recurrent glioblastoma multiforme (GBM) and compared survival to Gliadel Wafers (GW). The objectives of this retrospective evaluation were to assess: (1) catheter positioning in relation to imaging features and (2) to examine the potential impact of catheter positioning, overall catheter placement and imaging features on long term clinical outcome in the PRECISE study. Catheter positioning and overall catheter placement were scored and used as a surrogate of adequate placement. Imaging studies obtained on day 43 and day 71 after resection were each retrospectively reviewed. Catheter positioning scores, catheter overall placement scores, local tumor control and imaging change scores were reviewed and correlated using Generalized Linear Mixed Models. Cox PH regression analysis was used to examine whether these imaging based variables predicted overall survival (OS) and progression free survival (PFS) after adjusting for age and KPS. Of 180 patients in the CED group, 20 patients did not undergo gross total resection. Of the remaining 160 patients only 53% of patients had fully conforming catheters in respect to overall placement and 51% had adequate catheter positioning scores. Better catheter positioning scores were not correlated with local tumor control (P = 0.61) or imaging change score (P = 0.86). OS and PFS were not correlated with catheter positioning score (OS: P = 0.53; PFS: P = 0.72 respectively), overall placement score (OS: P = 0.55; PFS: P = 0.35) or imaging changes on day 43 MRI (P = 0.88). Catheter positioning scores and overall catheter placement scores were not associated with clinical outcome in this large prospective trial.     

Identifying the survival subtypes of glioblastoma by quantitative volumetric analysis of MRI

This study was to project a powerful volumetric-related parameter on magnetic resonance imaging (MRI) for classifying patients with glioblastoma multiforme (GBM) into distinct subgroups objectively. The preoperative MRIs of 147 patients with primary GBM were analyzed. Volumetric-related parameters, including V1 (tumor volume), V2 (peritumoral T2/FLAIR hyperintense volume) and V2/V1 (the volume ratio), were estimated by an ellipsoid model. Log-rank analysis and Cox regression methods were used to compare Kaplan–Meier plots and identified prognostic parameters. Log-rank analysis revealed that V1 and V2 were correlated with survival, but the P value was marginally significant (P = 0.082, P = 0.091, for progression-free survival [PFS]; P = 0.120, P = 0.073, for overall survival [OS], respectively). V2/V1 was a potential prognostic factor for both PFS and OS (P < 0.001 and P < 0.001, respectively). Cox regression analysis documented that higher V2/V1 (ratio ≥ 7.0) was independent unfavorable prognostic factor. The odd ratio (OR) of higher V2/V1 was 2.662 (95 % confidence interval [CI], 1.782–3.975; P < 0.001) for PFS and 3.450 (95 % CI, 2.079–5.725; P < 0.001) for OS, respectively. The volumetric-related parameters of V1, V2 and V2/V1 were helpful for predicting the prognosis of patients with GBM. V2/V1 was a more comprehensive and systematic prognostic factor in GBM patient, especially for those with small tumor but large peritumoral T2 hyperintense or large tumor but small peritumoral T2 hyperintense.     

Estimating the annual frequency of synchronous brain metastasis in the United States 2010–2013: a population-based study

In this retrospective, IRB-exempt study, we analyzed data from 68 patients diagnosed with glioblastoma (GBM) in two institutions and investigated the relationship between tumor shape, quantified using algorithmic analysis of magnetic resonance images, and survival. Each patient’s Fluid Attenuated Inversion Recovery (FLAIR) abnormality and enhancing tumor were manually delineated, and tumor shape was analyzed by automatic computer algorithms. Five features were automatically extracted from the images to quantify the extent of irregularity in tumor shape in two and three dimensions. Univariate Cox proportional hazard regression analysis was performed to determine how prognostic each feature was of survival. Kaplan Meier analysis was performed to illustrate the prognostic value of each feature. To determine whether the proposed quantitative shape features have additional prognostic value compared with standard clinical features, we controlled for tumor volume, patient age, and Karnofsky Performance Score (KPS). The FLAIR-based bounding ellipsoid volume ratio (BEVR), a 3D complexity measure, was strongly prognostic of survival, with a hazard ratio of 0.36 (95% CI 0.20–0.65), and remained significant in regression analysis after controlling for other clinical factors (P?=?0.0061). Three enhancing-tumor based shape features were prognostic of survival independently of clinical factors: BEVR (P?=?0.0008), margin fluctuation (P?=?0.0013), and angular standard deviation (P?=?0.0078). Algorithmically assessed tumor shape is statistically significantly prognostic of survival for patients with GBM independently of patient age, KPS, and tumor volume. This shows promise for extending the utility of MR imaging in treatment of GBM patients.     

Gross total resection improves overall survival in children with choroid plexus carcinoma

Choroid plexus carcinoma (CPC) is a rare, malignant, primary brain tumor with a poor prognosis. While previous reports have shown benefits of aggressive surgery, very few large-scale studies have focused exclusively on the pediatric population, for whom the risks of aggressive surgery must be weighed carefully against the benefits. We performed a comprehensive systematic review of pediatric CPCs to test the effects of gross total resection (GTR) on overall survival (OS) and progression-free survival (PFS). A Pubmed search was performed to identify children with CPC who underwent surgical resection. Only disaggregated clinical cases in which extent of resection was confirmed by CT or MRI were included for analysis. Kaplan–Meier and multivariate Cox regression survival analyses were performed to determine the effects of extent of resection on OS and PFS. Disaggregated clinical data from a total of 102 pediatric CPC patients (age ≤18 years) with known extent of resection and overall survival were analyzed. GTR was significantly associated with better OS by Kaplan–Meier analysis (logrank p < 0.001). Multivariate Cox regression analysis adjusting for age, gender, tumor location (supratentorial vs. infratentorial), and type of adjuvant therapy (chemotherapy, radiation, and combined therapy), showed that GTR independently increased OS (p = 0.006). While GTR also improved PFS on Kaplan–Meier analysis (p = 0.027), the effect did not meet our criteria for significance in our multivariate Cox model (p = 0.120). GTR improved OS of pediatric CPC and is recommended if it can be safely performed.     

Multicenter imaging outcomes study of The Cancer Genome Atlas glioblastoma patient cohort: imaging predictors of overall and progression-free survival

BackgroundDespite an aggressive therapeutic approach, the prognosis for most patients with glioblastoma (GBM) remains poor. The aim of this study was to determine the significance of preoperative MRI variables, both quantitative and qualitative, with regard to overall and progression-free survival in GBM.MethodsWe retrospectively identified 94 untreated GBM patients from the Cancer Imaging Archive who had pretreatment MRI and corresponding patient outcomes and clinical information in The Cancer Genome Atlas. Qualitative imaging assessments were based on the Visually Accessible Rembrandt Images feature-set criteria. Volumetric parameters were obtained of the specific tumor components: contrast enhancement, necrosis, and edema/invasion. Cox regression was used to assess prognostic and survival significance of each image.ResultsUnivariable Cox regression analysis demonstrated 10 imaging features and 2 clinical variables to be significantly associated with overall survival. Multivariable Cox regression analysis showed that tumor-enhancing volume (P = .03) and eloquent brain involvement (P < .001) were independent prognostic indicators of overall survival. In the multivariable Cox analysis of the volumetric features, the edema/invasion volume of more than 85 000 mm³ and the proportion of enhancing tumor were significantly correlated with higher mortality (Ps = .004 and .003, respectively).ConclusionsPreoperative MRI parameters have a significant prognostic role in predicting survival in patients with GBM, thus making them useful for patient stratification and endpoint biomarkers in clinical trials.     

Patterns of failure after radiosurgery to two different target volumes of enhancing lesions with and without FLAIR abnormalities in recurrent glioblastoma multiforme

Glioblastoma multiforme (GBM) invades beyond enhancing boundaries, and tumor cells are believed to exist in edematous peritumoral regions. We hypothesize that the concomitant treatment of both enhancing and FLAIR abnormalities on MRI by fractionated radiosurgery (FRS) would reduce local and regional recurrence. The purpose of this study was to demonstrate patterns of failure after FRS with simultaneous differential doses to two different target volumes of contrast enhancing lesions with/without FLAIR abnormality in recurrent GBM. Fifty-three patients with recurrent GBM were treated with FRS between 2008 and 2012. FRS was offered for the patients who had progressive tumors after the initial surgical resection followed by chemoradiation, and second-line chemotherapy. Radiosurgery Regimen A was 32 Gy (8 Gy × 4 treatments) to the contrast enhancing lesion only. Regimen B was 32 Gy (8 Gy × 4) to the contrast enhancing lesion and 24 Gy (6 Gy × 4) to the FLAIR abnormality delivered concomitantly. The study endpoint was radiographic failure on MRI at 2 months after FRS. Median survival after FRS was 7.5 months, and median progression-free survival after FRS was 4 months. Overall 82.4 % (42/51 lesions) recurred during follow-up. The local and regional failure rate was significantly lower in Regimen B (52 %) than in Regimen A (86.7 %) (p = 0.003). No sign of tumor progression in 10 % of Regimen A versus 28.6 % of Regimen B was shown during followup (p = 0.04). Instead, distant failure rate was higher in Regimen B. In conclusions, FRS was found to be a safe and effective salvage therapy for recurrent GBM. FRS to both contrast enhancing and FLAIR abnormalities appeared to improve local tumor control, and reduce regional tumor progression.     

The butterfly effect on glioblastoma: is volumetric extent of resection more effective than biopsy for these tumors?

A subset of patients with glioblastoma (GBM) have butterfly GBM (bGBM) that involve both cerebral hemispheres by crossing the corpus callosum. The prognoses, as well as the effectiveness of surgery and adjuvant therapy, are unclear because studies are few and limited. The goals of this study were to: (1) determine if bGBM have worse outcomes than patients with non-bGBM, (2) determine if surgery is more effective than biopsy, and (3) identify factors independently associated with improved outcomes for these patients. Adult patients who underwent surgery for a newly diagnosed primary GBM at an academic tertiary-care institution between 2007 and 2012 were retrospectively reviewed and tumors were volumetrically measured. Of the 336 patients with newly diagnosed GBM who were operated on, 48 (14 %) presented with bGBM, where 29 (60 %) and 19 (40 %) underwent surgical resection and biopsy, respectively. In multivariate analysis, a bGBM was independently associated with poorer survival [HR (95 % CI) 1.848 (1.250–2.685), p < 0.003]. In matched-pair analysis, patients who underwent surgical resection had improved median survival than biopsy patients (7.0 vs. 3.5 months, p = 0.03). In multivariate analysis, increasing percent resection [HR (95 % CI) 0.987 (0.977–0.997), p = 0.01], radiation [HR (95 % CI) 0.431 (0.225–0.812), p = 0.009], and temozolomide [HR (95 % CI) 0.413 (0.212–0. 784), p = 0.007] were each independently associated with prolonged survival among patients with bGBM. This present study shows that while patients with bGBM have poorer prognoses compared to non-bGBM, these patients can also benefit from aggressive treatments including debulking surgery, maximal safe surgical resection, temozolomide chemotherapy, and radiation therapy.     

The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma

Forkhead box protein 3 (Foxp3) is known as a specific marker for regulatory T cells which contribute to immunosuppression in tumor microenvironment. However, existing studies regarding clinical significance of Foxp3+ tumor-infiltrating lymphocytes (TILs) in glioblastoma (GBM) remained discrepant. In this study, we aimed to explore whether this subtype of TILs correlated with prognosis in patients with GBM. Foxp3+ TILs as well as CD8+ ones were detected by immunohistochemistry on paraffin-embedded tumor samples from 62 patients. Staining for p53, MGMT and Ki-67 were also performed. The correlation of TIL subtypes with clinicopathologic features were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method and compared using log-rank test. Independent prognostic factors for PFS and OS were determined through univariate and multivariate analysis. Significant correlation was found between Foxp3 and CD8 expression (P = 0.003), but not between TIL subtypes and clinicopathologic characteristics. Patients with higher density of Foxp3+ TILs showed relatively shorter PFS (P < 0.001) and OS (P = 0.003) whereas patients with higher density of CD8+ TILs obtained no significant differences in survival. Survival analysis based on molecular classifications further clarified these predictive values. Univariate and multivariate analysis revealed that frequency of Foxp3+ TILs was probably associated with both PFS (P = 0.002) and OS (P = 0.003). In conclusion, the results suggest that Foxp3 positive infiltrates could provide an independent predictive factor in GBM.     

Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab

While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Baseline and 3–6 week post-treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Baseline ADC_L/ADC_M within nonenhancing T2/FLAIR volume (> or ≤0.64) can stratify OS (HR = 2.24, p = 0.002) and PFS (HR = 1.90, p = 0.005). %ADC_H within enhancing T1+C volume (> or ≤25 %) can also stratify OS (HR = 0.59, p = 0.034) and PFS (HR = 0.56, p = 0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR = 0.17, p < 0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADC_H within T1+C volume alone (1.3) or ADC_L/ADC_M within T2/FLAIR alone (1.86). ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma.     

The immunohistochemical expression of c-Met is an independent predictor of survival in patients with glioblastoma multiforme

Background and aims

Because the outcome of glioblastoma multiforme (GBM) remains dismal, there is an urgent need for a better molecular characterization of this malignancy. The aim of this prospective study was to investigate the prognostic impact of the expression of c-mesenchymal-epithelial transition (c-Met) a receptor tyrosine kinase implicated in expression growth, survival, motility/migration, and invasion in GMB patients managed according to the established diagnostic and therapeutic protocols.

Methods

Between May 2003 and March 2011, a total of 69 patients (33 males and 36 females; mean age: 52.2 ± 12.9 years, age range: 23–81 years) referred to our Department for the surgical removal of GBM were evaluated immunohistochemically for c-Met expression. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures.

Results

Compared with c-Met? subjects (n = 38), c-Met+ subjects (n = 31) had both a significantly lower OS (15.3 ± 2.3 vs. 22.6 ± 2.5 months, respectively, p < 0.01) and PFS (12.3 ± 2.1 vs. 19.1 ± 2.6 months, respectively, p < 0.05). After allowance for potential confounders, multivariate Cox regression analysis identified c-Met+ as an independent predictor of both OS (hazard ratio = 1.7; 95 % confidence interval = 1.2–1.9, p < 0.01) and PFS (hazard ratio = 1.6; 95 % confidence interval = 1.1–2.3, p < 0.05).

Conclusions

Our findings suggest that c-Met immunohistochemical expression is an independent predictor of outcomes in patients with GBM treated by standard of care.     

Glioblastoma with oligodendroglial component represents a subgroup of glioblastoma with high prevalence of IDH1 mutation and association with younger age

Glioblastoma with an oligodendroglial component (GBMO) is recognized as a subgroup of glioblastoma (GBM); however, the molecular and clinicopathological characteristics of GBMO are obscure. We evaluated the methylation status of MGMT, IDH1/2 mutation, deletions of 1p and 19q and expression of IDH1, p53, p16, CD151, and galectin3 proteins in 42 GBMOs (32 primary and 10 secondary tumors). Our aims were to correlate our molecular findings with clinicopathologic features, and to compare molecular-to-clinical correlations in the 42 GBMOs with the corresponding correlations in 45 GBMs. GBMO was subdivided into two subgroups according to the predominant cell component comprising >50 % of tumors: the astrocytic predominant type (GBMO-A) and oligodendroglioma predominant type (GBMO-O). Methylation of MGMT, IDH1/2 mutation, and co-deletion of 1p and 19q were found in 31.0, 26.2, and 17.9 % of patients with GBMO, respectively. Clinicopathological and molecular characteristics did not differ significantly between GBMO-A and GBMO-O. However, patients with GBMO-O experienced better outcomes than patients with GBMO-A (p = 0.007). On multivariate analysis the predominant cell type was an independent prognostic factor in overall survival [hazard ratio 4.2 (95 % confidence interval 1.4–12.8), p = 0.011]. When compared to patients with classic GBM, those with GBMO were younger (49.21 vs. 57.47, p = 0.003) and more frequently had tumors with IDH1 mutation (23.8 vs. 4.4 %, p = 0.009). Survival was similar in patients with GBMO and with classic GBM. Based on these results, GBMO may represent a subgroup of GBM that is associated with IDH1 mutation and younger age, although similar to classic GBM in prognosis.     

Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma

We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.     

Up-regulation of miR-9 expression as a poor prognostic biomarker in patients with non-small cell lung cancer

Purpose

Emerging evidences indicate that dysregulated microRNAs are implicated in cancer tumorigenesis and progression. MicroRNA-9 (miR-9) has various expression patterns in diverse human cancers. However, its clinical significance in human non-small cell lung cancer has not yet been elucidated. In the present study, we detected the expression of miR-9 in non-small cell lung cancer and adjacent noncancerous tissues and explored its relationships with clinicopathological characteristics and prognosis.

Methods

Expression levels of miR-9 in 116 pairs of non-small cell lung cancer and adjacent normal tissues were detected by real-time quantitative RT-PCR assay. To determine its prognostic value, overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan–Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis.

Results

MiR-9 expression in non-small cell lung cancer tissues was significantly higher than that in adjacent normal tissues (p = 0.001), and its up-regulation was significantly correlated to advanced tumor–node–metastasis (TNM) stage (p < 0.001), tumor size (p = 0.013), and lymph node metastasis (p = 0.001). Furthermore, Kaplan–Meier analysis demonstrated that high miR-9 expression clearly predicted poorer PFS (p < 0.001) and OS (p < 0.001). In the multivariate analysis, increased miR-9 expression was an independent prognostic factor for both PFS (p = 0.002) and OS (p = 0.013).

Conclusions

MiR-9 was up-regulated in non-small cell lung cancer tissues and correlated with adverse clinical features and unfavorable survival, indicating that miR-9 might be involved in non-small lung cancer progression and could serve as a promising biomarker for further risk stratification in the treatment of this cancer.     

Phosphorylated CXCR4 expression has a positive prognostic impact in colorectal cancer

Background

The CXCL12-CXCR4 chemokine axis plays an important role in cell trafficking as well as in tumor progression. In colorectal cancer (CRC), the chemokine receptor CXCR4 has been shown to be an unfavorable prognostic factor in some studies, however, the role of its activated (phosphorylated) form, pCXCR4, has not yet been evaluated. Here, we aimed to investigate the prognostic value of CXCR4 and pCXCR4 in a large cohort of CRC patients.

Patients and methods

A tissue microarray (TMA) of 684 patient specimens of primary CRCs was analyzed by immunohistochemistry (IHC) for the expression of CXCR4 and pCXCR4 by tumor cells and tumor-infiltrating immune cells (TICs).

Results

The combined high expression of CXCR4 and pCXCR4 showed a favorable 5-year overall survival rate (68%; 95%CI = 59–76%) compared to tumors showing a high expression of CXCR4 only (48%; 95%CI = 41–54%). High expression of pCXCR4 was significantly associated with a favorable prognosis in a test and validation group (p = 0.015 and p = 0.0001). Moreover, we found that CRCs with a high density of pCXCR4+ tumor-infiltrating immune cells (TICs) also showed a favorable prognosis in a test and validation group (p = 0.054 and p = 0.004). Univariate Cox regression analysis for TICs revealed that a high density of pCXCR4+ TICs was a favorable prognostic marker for overall survival (HR = 0.97,95%CI = 0.96–1.00; p = 0.01). In multivariate Cox regression survival analyses a high expression of pCXCR4 in tumor cells lost its association with a better overall survival (HR = 0.99; 95%CI = 0.99–1.00, p = 0.098).

Conclusion

Our results show that high densities of CXCR4 and pCXCR4 positive TICs are favorable prognostic factors in CRC.

     

Effects of adjuvant chemotherapy and radiation on overall survival in children with choroid plexus carcinoma

Choroid plexus carcinoma (CPCs) is a rare, malignant, primary brain tumor with a poor prognosis. Currently, there is no consensus on the use of adjuvant therapy, and few large-scale studies focus exclusively on the pediatric population. We performed a comprehensive systematic review of pediatric CPCs to determine the effects of various adjuvant therapy modalities on overall survival (OS). A literature search was performed to identify studies reporting children with CPC who underwent surgical resection. Only patients who had clearly received adjuvant therapy, or were described as not selected for adjuvant therapy were analyzed in our comparison groups. Kaplan–Meier and multivariate Cox regression survival analyses were performed to determine the effects of different types of adjuvant therapies on OS. A total of 135 children (age ≤ 18 years) with CPC who had known adjuvant therapy status and OS were identified from 53 articles. Kaplan–Meier analysis showed that while adjuvant therapy overall improved OS (p = 0.001), different modes of adjuvant therapies had varying effects on OS (p = 0.034). Specifically, combined chemo-radiotherapy as well as chemotherapy alone improved OS (p = 0.001), but radiation did not (p = 0.129). Multivariate Cox proportional hazard model adjusting for confounding factors showed that combined therapy was associated with better OS compared to chemotherapy alone (HR: 0.291, p = 0.027). Both chemotherapy alone and combined chemo-radiation improved OS independent of age, gender, tumor location and extent of resection, while radiation alone did not.     

Defining prognostic factors of survival after external beam radiotherapy treatment of hepatocellular carcinoma with lymph node metastases

Purpose

To identify independent predictors of survival in patients with lymph node (LN) metastases from hepatocellular carcinoma (HCC) after external beam radiotherapy (EBRT).

Methods

There were 191 patients with LN metastases from HCC received EBRT enrolled in the study cohort. EBRT was designed to focus on the LNs and a median dose of 50 Gy (range 40–60 Gy) was delivered. Treatment response was assessed by the WHO response criteria. Factors such as demographic data, tumor characteristics, and treatment modalities were determined before EBRT. Predictors of survival were identified by univariate and multivariate analysis.

Results

The median survival was 8.0 months for all patients. Factors including Child-Pugh status (p = 0.009), intrahepatic tumor control (p = 0.015), LN location (p = 0.015), and response to EBRT (p < 0.001) were significant prognostic factors predicting for survival by multivariate analysis. The objective regression rate (ORR), which is the sum of complete and partial response rates, was as high as 79.1 %. As determined by multivariate analysis, the factors of LN location near liver (p = 0.002), smaller LN size (p = 0.021), and higher EBRT dose (p < 0.001) were associated with higher ORR values.

Conclusion

This study provides detailed information about survival outcomes and prognostic factors. Child-Pugh B value, uncontrolled intrahepatic tumor, LN location far from liver, and no response to EBRT are the unfavorable independent predictors.