Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas

Background

Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown.

Methods

RNAseq data from 515 LGG patients in the Cancer Genome Atlas (TCGA) were analyzed to compare the effect of expression of the 9 DNA repair genes located on chromosome arms 1p and 19q on progression free survival (PFS) and overall survival (OS) between patients who received chemotherapy and those who did not. Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line.

Results

The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n?=?175) than in tumors without the codeletion (n?=?337) (p?<?0.001). In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS. This difference between chemotherapy and non-chemotherapy groups in the association of gene expression with survival was not observed in non-DNA repair genes located on chromosome arms 1p and 19q. MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p?<?0.001).

Conclusions

Our results suggest that reduced expression of DNA repair genes on chromosome arms 1p and 19q may account for the increased chemosensitivity of LGGs with 1p19q codeletion.

     

Radiological characteristics based on isocitrate dehydrogenase mutations and 1p/19q codeletion in grade II and III gliomas

The radiological features of lower-grade gliomas (LGGs) classified according to isocitrate dehydrogenase (IDH) mutations and codeletion of chromosomal arms 1p and 19q (1p/19q codeletion) remain unclear. We aimed to systematically characterize the radiological features of molecularly classified LGGs using IDH and 1p/19q codeletion statuses. One hundred and one LGGs were re-classified into 36 tumors with IDH mutations (IDH-Mut), 35 tumors with IDH-Mut and 1p/19q codeletion (IDH-Mut/Codel), and 30 tumors with wildtype IDH (IDH-Wt). Calcification, heterogeneous signal intensity in T2-weighted images, and cortical invasion were significantly more frequent in IDH-Mut/Codel than in IDH-Mut and IDH-Wt tumors (calcification: 48.6 vs 5.6 and 6.7%, heterogeneity: 94.3 vs 33.3 and 50%, and cortical invasion: 94.3 vs 55.6 and 40.0%, respectively). A frontal location was significantly more frequent for IDH-Mut and IDH-Mut/Codel than for IDH-Wt tumors (52.8 and 71.4 vs 12.1%, respectively), and dense contrast-enhancement was significantly more frequent in IDH-Wt than in IDH-Mut and IDH-Mut/Codel tumors (50.0 vs 2.8 and 2.9%, respectively). In conclusion, IDH-Mut/Codel tumors were characterized by calcification, frontal location, heterogeneous signal intensity, and cortical invasion; IDH-Mut tumors differed from IDH-Wt tumors according to predominant frontal lobe location and less frequent dense enhancement patterns.     

Clinical value of chromosome arms 19q and 11p losses in low-grade gliomas

Background

Diffuse low-grade gliomas (LGGs) form a heterogeneous subgroup of gliomas in adults. Chromosome (chr) arms 1p/19q codeletion and IDH mutation have been shown to be closely associated with oligodendroglial phenotype and better prognosis. We sought to identify relevant biomarkers in non 1p/19q codeleted LGGs.

Methods

We characterized a retrospective series of 126 LGGs using genomic arrays, microsatellite analysis, IDH sequencing, MGMT promoter methylation assay, and p53 expression analysis.

Results

Our study confirms that 1p/19q codeletion, mutually exclusive with p53 overexpression, was associated with: (i) better prognosis, (ii) oligodendroglial phenotype, (iii) MGMT promoter methylation, and (iv) IDH mutation. Interestingly, 1p/19q codeleted tumors occur in older patients at diagnosis. Our study shows that non 1p/19q codeleted LGGs can be divided in 5 main genomic subgroups: (i) 11p loss, (ii) 19q loss (iii) 7 gain, (iv) 19 gain, and (v) unclassified. In non 1p/19q codeleted LGGs, we demonstrated that (i) 11p loss is associated with astrocytoma phenotype and has an independent negative prognostic value, and (ii) 19q loss diminished the favorable prognostic value of IDH mutation. Our findings were validated in an independent cohort of 98 LGGs.

Conclusion

Novel genomic entities and biomarkers have been identified in non 1p/19q codeleted LGGs. Our findings may help to stratify non 1p/19q codeleted LGGs, facilitating future individualization of treatment. Further prospective studies are warranted to support our findings.     

CD133 positive U87 glioblastoma cells-derived exosomal microRNAs in hypoxia- versus normoxia-microenviroment

Diffuse low-grade gliomas (DLGG) prognosis is variable, depending on several factors, including the isocitrate dehydrogenase (IDH) mutation and the 1p19q codeletion. A few studies suggested associations between these parameters and tumor radiological characteristics including topography. Our aim was analyzing the correlations between the IDH and 1p19q statuses and the tumor intracerebral distribution (at the lobar and voxel levels), volume, and borders. We conducted a retrospective, monocentric study on a consecutive series of 198 DLGG patients. The IDH and 1p19q statuses were recorded. The pre-treatment magnetic resonance FLAIR imagings were reviewed for determination of lobar topography, tumor volume, and characterisation of tumor borders (sharp or indistinct). We conducted a voxel-based lesion-symptom mapping analysis to investigate the correlations between the IDH and 1p19q statuses and topography at the voxel level. The IDH mutation and 1p19q statuses were correlated with the tumor topography defined using lobar anatomy (p?<?0.001 and p?=?0.004, respectively). Frontal tumors were more frequently IDH-mutant (87.1 vs. 57.4%) and 1p19q codeleted (45.2 vs. 17.0%) than temporo-insular lesions. At the voxel level, these associations were not found. Tumors with sharp borders were more frequently IDH-mutant (p?=?0.001) while tumors with indistinct borders were more frequently IDH wild-type and 1p19q non-codeleted (p?<?0.001). Larger tumors at diagnosis (possibly linked to a slower growth rate) were more frequently IDH-mutant (p?<?0.001). IDH wild-type, 1p19q non-codeleted temporo-insular tumors are distinct from IDH-mutant, 1p19q codeleted frontal tumors. Further studies are needed to determine whether the therapeutic strategy should be adapted to each pattern.     

Automatic segmentation of thoracic CT images using three deep learning models

PurposeDeep learning (DL) techniques are widely used in medical imaging and in particular for segmentation. Indeed, manual segmentation of organs at risk (OARs) is time-consuming and suffers from inter- and intra-observer segmentation variability. Image segmentation using DL has given very promising results. In this work, we present and compare the results of segmentation of OARs and a clinical target volume (CTV) in thoracic CT images using three DL models.Materials and methodsWe used CT images of 52 patients with breast cancer from a public dataset. Automatic segmentation of the lungs, the heart and a CTV was performed using three models based on the U-Net architecture. Three metrics were used to quantify and compare the segmentation results obtained with these models: the Dice similarity coefficient (DSC), the Jaccard coefficient (J) and the Hausdorff distance (HD).ResultsThe obtained values of DSC, J and HD were presented for each segmented organ and for the three models. Examples of automatic segmentation were presented and compared to the corresponding ground truth delineations. Our values were also compared to recent results obtained by other authors.ConclusionThe performance of three DL models was evaluated for the delineation of the lungs, the heart and a CTV. This study showed clearly that these 2D models based on the U-Net architecture can be used to delineate organs in CT images with a good performance compared to other models. Generally, the three models present similar performances. Using a dataset with more CT images, the three models should give better results.     

Comparative volumetric analysis of the extent of resection of molecularly and histologically distinct low grade gliomas and its role on survival

The authors investigate the role of extent of resection (EOR) and genetic markers on patient outcome and survival for LGGs. We conducted a retrospective cohort between 2005 and 2015, of 109 adult patients who underwent surgery for a LGG by a single surgeon. Volumetric computations of MRI studies were conducted to evaluate the EOR, and genetic markers (IDH1, 1p/19q co-deletion, and p53) were assessed and their effects on survival and neurological outcome were evaluated. The median EOR was 88.1%. Permanent postoperative neurological deficits were seen in 4.6% of patients. EOR was a significant predictor for both overall survival (OS) (hazard ratio [HR]?=?0.979, 95% CI 0.961–0.980, p?=?0.029) and progression free survival (PFS) (HR?=?0.982, 95% CI 0.968–0.997, p?=?0.018). Malignant progression free survival (MPFS) was predicted by the 1p/19q co-deletion (HR?=?0.148, 95% CI 0.019–1.148, p?=?0.048). Patients with EOR of 100% had a significantly better OS than EOR less than 90% (p?=?0.038). Patients with an EOR of at least 76% had a better OS than EOR less than 76% (p?=?0.025). Patients with an EOR of at least 71% had a better PFS than EOR less than 71% (p?=?0.030). Preoperative tumor volume was found to have significant association with EOR (R²?=?0.049, p?=?0.031). Increased EOR is associated with improved OS and PFS survival outcomes, while 1p/19q co-deletion provides improved MPFS. Understanding both surgical resections and molecular markers of the tumor are important for effective management of LGG patients.     

低级别胶质瘤的化疗

低级别胶质癌（low—grade gliomas，LGGs）的生物学特性及临床预后相差极大，如何治疗仍存在较大争议。根据目前循证医学的证据，手术及放疗在LGGs中的作用已基本肯定。化疗在LGGs中的应用虽已有20余年的历史，但资料大多来自于回顾性的非随机的临床研究。PCV及Temozolomide（TMZ）方案在复发进展或新诊断的患者中均显示有客观疗效，但随诊时间较短，远期生存情况如何还不清楚。正在进行的前瞻性随机对照临床研究旨在明确TMZ在LGGs中的作用以及1p/19q和MGMT状态对TMZ化疗的影响，研究的结果将帮助我们制定最佳治疗方案。尽管目前化疗在LGGs中确切的价值还不十分清楚．但正在成为一种有希望的治疗措施。     

Tumor growth dynamics in serially-imaged low-grade glioma patients

Background

Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing into aggressive and fatal high-grade gliomas.

Methods

We retrospectively identified LGG patients with numerous (≥?8) serial magnetic resonance imaging (MRI) studies. Tumor volumes were measured by manual segmentation on serial imaging to study the natural history and growth of the lesion. Patient demographic information, tumor characteristics, and histological data were collected from electronic medical records and paper charts.

Results

Out of 74 LGG patients, 10 patients (13.5%) were identified to meet the study criteria with number of MRIs acquired ranging from 8 to 18 (median, 11.5) over a median of 79.7 months (range 39.8–113.8 months). Tumor diameter increased at a median of 2.17 mm/year in a linear trajectory. Cox regression analysis revealed that initial tumor volume was an independent predictor of time to clinical intervention, and Mann–Whitney U test found that patients younger than 50 years old had significantly slower-growing tumors. Clinical intervention was more likely for tumors above a volume threshold of 73.6 mL.

Conclusion

We retrospectively analyzed the natural history of LGGs of patients managed at a single institution with numerous serial MRI scans. Comparisons of our cohort to the literature suggest that this is a subset of particularly slow-growing and low-risk tumors.

     

Comparison of human and automatic segmentations of kidneys from CT images

PURPOSE: A controlled observer study was conducted to compare a method for automatic image segmentation with conventional user-guided segmentation of right and left kidneys from planning computerized tomographic (CT) images. METHODS AND MATERIALS: Deformable shape models called m-reps were used to automatically segment right and left kidneys from 12 target CT images, and the results were compared with careful manual segmentations performed by two human experts. M-rep models were trained based on manual segmentations from a collection of images that did not include the targets. Segmentation using m-reps began with interactive initialization to position the kidney model over the target kidney in the image data. Fully automatic segmentation proceeded through two stages at successively smaller spatial scales. At the first stage, a global similarity transformation of the kidney model was computed to position the model closer to the target kidney. The similarity transformation was followed by large-scale deformations based on principal geodesic analysis (PGA). During the second stage, the medial atoms comprising the m-rep model were deformed one by one. This procedure was iterated until no changes were observed. The transformations and deformations at both stages were driven by optimizing an objective function with two terms. One term penalized the currently deformed m-rep by an amount proportional to its deviation from the mean m-rep derived from PGA of the training segmentations. The second term computed a model-to-image match term based on the goodness of match of the trained intensity template for the currently deformed m-rep with the corresponding intensity data in the target image. Human and m-rep segmentations were compared using quantitative metrics provided in a toolset called Valmet. Metrics reported in this article include (1) percent volume overlap; (2) mean surface distance between two segmentations; and (3) maximum surface separation (Hausdorff distance). RESULTS: Averaged over all kidneys the mean surface separation was 0.12 cm, the mean Hausdorff distance was 0.99 cm, and the mean volume overlap for human segmentations was 88.8%. Between human and m-rep segmentations the mean surface separation was 0.18-0.19 cm, the mean Hausdorff distance was 1.14-1.25 cm, and the mean volume overlap was 82-83%. CONCLUSIONS: Overall in this study, the best m-rep kidney segmentations were at least as good as careful manual slice-by-slice segmentations performed by two experienced humans, and the worst performance was no worse than typical segmentations from our clinical setting. The mean surface separations for human-m-rep segmentations were slightly larger than for human-human segmentations but still in the subvoxel range, and volume overlap and maximum surface separation were slightly better for human-human comparisons. These results were expected because of experimental factors that favored comparison of the human-human segmentations. In particular, m-rep agreement with humans appears to have been limited largely by fundamental differences between manual slice-by-slice and true three-dimensional segmentation, imaging artifacts, image voxel dimensions, and the use of an m-rep model that produced a smooth surface across the renal pelvis.     

Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF-2/FGFR-2 axis

The mechanisms by which mammary carcinomas acquire hormone independence are still unknown. To study the role of cancer-associated fibroblasts (CAF) in the acquisition of hormone-independence we used a hormone-dependent (HD) mouse mammary tumor and its hormone-independent (HI) variant, which grows in vivo without hormone supply. HI tumors express higher levels of FGFR-2 than HD tumors. In spite of their in vivo differences, both tumors have the same hormone requirement in primary cultures. We demonstrated that CAF from HI tumors (CAF-HI) growing in vitro, express higher levels of FGF-2 than HD counterparts (CAF-HD). FGF-2 activated the progesterone receptors (PR) in the tumor cells, thus increasing cell proliferation in both HI and HD tumors. CAF-HI induced a higher proliferative rate on the tumor cells and in PR activation than CAF-HD. The blockage of FGF-2 in the co-cultures or the genetic or pharmacological inhibition of FGFR-2 inhibited PR activation and tumor cell proliferation. Moreover, in vivo, the FGFR inhibitor decreased C4-HI tumor growth, whereas FGF-2 was able to stimulate C4-HD tumor growth as MPA. T47D human breast cancer cells were also stimulated by progestins, FGF-2 or CAF-HI, and this stimulation was abrogated by antiprogestins, suggesting that the murine C4-HI cells respond as the human T47D cells. In summary, this is the first study reporting differences between CAF from HD and HI tumors suggesting that CAF-HI actively participate in driving HI tumor growth.     

The fragile histidine triad gene: a molecular link between cigarette smoking and cervical cancer.

PURPOSE: Smoking is an epidemiologic risk factor for cervical cancer. The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered in 80% of tobacco-associated lung cancers. We hypothesized that reduced FHIT protein expression, homozygous deletions (HD) or hemizygous deletions (HemiD) and microsatellite alterations (MA) at the FHIT/FRA3B locus occur more commonly in cervical cancers of smokers than nonsmokers. EXPERIMENTAL DESIGN: Archival tissues of 58 patients with stage IA1 to IB2 squamous cell carcinoma of the cervix were identified. FHIT protein expression was studied with immunohistochemistry. Laser capture microdissection was used to isolate tumor and normal DNA. HD/HemiD of FHIT exons 4 and 5 were analyzed by monoplex real-time PCR. MA at FHIT/FRA3B were studied with multiplex nested PCR with three fluorescently labeled microsatellite markers (D3S1300, D3S1312, and D3S1480). RESULTS: Eighteen of 26 tumors from smokers (69%) and 13 of 32 nonsmokers (41%; P < 0.05) showed loss of FHIT protein expression. Thirty-seven stage IB tumors yielded sufficient DNA for analyses. HD or HemiD of both exons tested occurred in 8 of 17 smokers (47%) and 2 of 20 nonsmokers (10%; P < 0.05). MA at more than two sites were found in 11 of 17 tumors of smokers (65%) and 6 of 20 nonsmokers (30%; P < 0.05). Mean composite genomic FHIT alteration scores were significantly higher for tumors of smokers versus nonsmokers (0.67 versus 0.40; P < 0.02). CONCLUSION: Loss of FHIT expression, HD, HemiD, and MA at the FHIT/FRA3B locus occur significantly more commonly in cervical cancers of smokers. These findings suggest that the tumor suppressor gene FHIT may represent a molecular target in cigarette smoking-associated cervical carcinogenesis.     

Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma

Epilepsy is a common symptom in patients with glioblastoma (GB). 213 patients with GB from RedLANO follow-up registry were included. All patients underwent surgery, if feasible, followed by chemoradiation based on temozolomide (Stupp platform). Information was recorded regarding demographics, seizure timing, anti-epileptic drugs (AEDs), dosage, time to next seizure, total seizures in 6 months, and main side effects of AEDs. The relationship between epilepsy treatment and overall survival (OS) was evaluated. Mean age was 53 years old and 56.8% were male. Seventy-eight patients (37%) were treated with levetiracetam (LEV), 27% were given another AED and 36% did not require any AED. Choice of AED was not associated with age (p?=?0.67), performance status (p?=?0.24) or anatomic tumor site (p?=?0.34). Seizures and AED requirement were greater in those having primary GB (p?=?0.04). After starting an AED, the mean time until next crisis was 9.9 days (SD ±?6.3), which was shorter in those receiving LEV (p?=?0.03); mean number of seizures during the first 3 and 6 months were 2.9 and 4, respectively. Most patients treated with LEV (n?=?46) required less than two medication adjustments compared to those treated with other AEDs (p?=?0.02). Likewise, less patients exposed to LEV required a coadjuvant drug (p?=?0.04). Additionally, patients receiving LEV had significantly less adverse effects compared to patients treated with another AED. OS was significantly higher in the group treated with LEV compared to other AEDs (25.5 vs. 17.9 months; p?=?0.047). Patients treated with LEV had better seizure control and longer OS compared to other AEDs.     

Preoperative grading of supratentorial nonenhancing gliomas by high b-value diffusion-weighted 3 T magnetic resonance imaging

The purpose of this study was to determine the difference in discrimination between high- and low-grade supratentorial nonenhancing gliomas (HGGs and LGGs, respectively) when using apparent diffusion coefficient (ADC) values with high or standard b-value. Thirty-nine patients underwent conventional magnetic resonance imaging and diffusion-weighted imaging (DWI) with standard and high b-values (b?=?1000 and 3000 s/mm², respectively). Minimum, maximum, and mean ADC values (ADC_MIN, ADC_MAX, and ADC_MEAN, respectively) were measured from ADC maps with both b-values. Receiver operating curve analysis was used to determine the cutoff ADC values for distinguishing between nonenhancing HGGs and LGGs. ADC_MIN, ADC_MAX, and ADC_MEAN values for the nonenhancing HGGs were lower than those for LGGs. These differences were much larger when a high b-value was used (all P?<?0.0001) than when a standard b-value was used (P?=?0.0001, <0.0001, and <0.0001, respectively). Discriminant analysis indicated that the greatest likelihood for discriminating HGGs and LGGs when ADC_MEAN was obtained with a high b-value, with cutoff value of 0.814?×?10^?3 mm²/s. ADC values obtained with a high b-value can be useful for grading and surgical management of nonenhancing HGGs and LGGs. The lowest degree of overlap was obtained when ADC_MEAN was determined with a b-value of 3000 s/mm².     

Evaluation of a radiotherapy protocol based on INT0116 for completely resected gastric adenocarcinoma

PURPOSE: With the results of the INT0116 study, adjuvant radiochemotherapy has become the standard treatment after complete resection of gastric adenocarcinoma. However, the implementation of radiotherapy (RT) remains a concern. In response, consensus guidelines on RT technique have been published. Our objective was to measure the inter- and intraclinician variability in RT field delineation using conventional two- (2D) and three-dimensional (3D) techniques. METHODS AND MATERIALS: Between 1999 and 2003, five radiation oncologists (ROs) treated 45 patients with completely resected, gastric adenocarcinoma using postoperative radiochemotherapy (INT0116). Two cases were included in this study (Patient 1 had cardia and Patient 2 had antral disease). Standardized vignettes (with surgical and pathologic findings) and preoperative and postoperative imaging for each case were developed. Each RO designed AP-PA fields for each patient (2D planning) on two separate occasions. This was repeated using a 3D planning technique. RESULTS: Patient 1 had a mean field area of 250.2 cm(2) (SD 12.0) and 227.9 cm(2) (SD 26.5) using 2D and 3D planning, respectively (p = 0.03). The mean clinical target volume (CTV) volume was 468.3 cm(3) (SD 65.9). Patient 1 had a significantly greater inter- than intra-RO variation for the field area designed with 3D planning; however, no difference occurred with 2D planning or CTV contouring. Patient 2 had a mean field area of 234.8 cm(2) (SD 33.1) and 226.8 cm(2) (SD 19.3) using 2D and 3D planning, respectively (p = 0.5). The mean CTV was 729.4 cm(3) (SD 67.3). For Patient 2, the inter-RO variability was significantly greater than the intra-RO variability for the field area using both 2D and 3D planning, and no difference was seen for the CTV. Composite beam's-eye-view plots revealed that the superior, inferior, and right lateral borders proved to be most contentious. CONCLUSION: Despite published guidelines and a departmental protocol, significant variations in the RT field areas were seen among ROs for both 2D and 3D planning. However, in general, CTV contouring was reproducible. Because 3D-RT hinges on accurate target identification, caution should be exercised before migrating to 3D planning for postoperative gastric cancer.     

New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials

Background

In a previous study, the European Organisation for Research and Treatment of Cancer (EORTC) reported a scoring system to predict survival of patients with low-grade gliomas (LGGs). A major issue in the diagnosis of brain tumors is the lack of agreement among pathologists. New models in patients with LGGs diagnosed by central pathology review are needed.

Methods

Data from 339 EORTC patients with LGGs diagnosed by central pathology review were used to develop new prognostic models for progression-free survival (PFS) and overall survival (OS). Data from 450 patients with centrally diagnosed LGGs recruited into 2 large studies conducted by North American cooperative groups were used to validate the models.

Results

Both PFS and OS were negatively influenced by the presence of baseline neurological deficits, a shorter time since first symptoms (<30 wk), an astrocytic tumor type, and tumors larger than 5 cm in diameter. Early irradiation improved PFS but not OS. Three risk groups have been identified (low, intermediate, and high) and validated.

Conclusions

We have developed new prognostic models in a more homogeneous LGG population diagnosed by central pathology review. This population better fits with modern practice, where patients are enrolled in clinical trials based on central or panel pathology review. We could validate the models in a large, external, and independent dataset. The models can divide LGG patients into 3 risk groups and provide reliable individual survival predictions. Inclusion of other clinical and molecular factors might still improve models’ predictions.     

Helical intensity-modulated Radiotherapy of the Pelvic Lymph Nodes with Integrated Boost to the Prostate Bed - Initial Results of the PLATIN 3 Trial

Background

Mitogen-activated protein kinase kinase kinase3 (MAP3K3/MEKK3) was identified to be differentially expressed in esophageal squamous cell carcinoma (ESCC) using cDNA microarrays by our laboratory. Here in we determined the clinical significance of MEKK3 in ESCC.

Methods

Immunohistochemical analysis of MEKK3 expression was carried out in archived tissue sections from 93 ESCCs, 47 histologically normal and 61 dysplastic esophageal tissues and correlated with clinicopathological parameters and disease prognosis over up to 7.5 years for ESCC patients.

Results

MEKK3 expression was significantly increased in esophageal dysplasia and ESCC in comparison with normal mucosa (p_trend?<?0.001). Kaplan Meier survival analysis showed significantly reduced median disease free survival median DFS?=?10 months in patients with MEKK3 positive ESCCs compared to patients with no immunopositivity (median DFS?=?19 months, p?=?0.04). ESCC patients with MEKK3 positive and lymph node positive tumors had median DFS?=?9 months, as compared to median DFS?=?21 months in patients who did not show the alterations (p?=?0.01). In multivariate Cox regression analysis, combination of MEKK3 overexpression and node positivity [p?=?0.015, hazard ratio (HR)?=?2.082, 95% CI?=?1.154 - 3.756] emerged as important predictor of reduced disease free survival and poor prognosticator for ESCC patients.

Conclusions

Alterations in MEKK3 expression occur in early stages of development of ESCC and are sustained during disease progression; MEKK3 in combination with lymph node positivity has the potential to serve as adverse prognosticator in ESCC.     

Rapid development of tamoxifen-stimulated mutant p53 breast tumors (T47D) in athymic mice.

MCF-7 cells are used routinely to study tamoxifen-stimulated drug resistance in vivo. However, unlike MCF-7 cells, T47D cells express mutant p53 protein and lose the estrogen receptor (ER) during long-term estrogen deprivation in vitro [Pink et al., Br. J. Cancer, 74: 1227-1236, 1996 (erratum, Br. J. Cancer, 75: 1557, 1997)]. As a result, T47D tumors may respond differently from MCF-7 tumors to long-term tamoxifen treatment. Ovariectomized athymic mice were given injections bilaterally with T47D cells (5 x 10(5)) into the mammary fat pads. A rapidly growing estradiol responsive tumor (T47D:E2) was established and 0.5 mg of tamoxifen given daily blocked estrogen-stimulated growth. In subsequent experiments, low doses of tamoxifen (0.17 mg or 0.5 mg) did not produce tamoxifen-stimulated tumors at 14 weeks, whereas high-dose tamoxifen (1.5 mg) consistently produced tamoxifen-stimulated tumors (T47D:Tam; 17 tumors/20 sites) at 8 weeks. In contrast, 1.5 mg of tamoxifen produced tamoxifen-stimulated MCF-7 tumors (MCF-7: Tam2) at a slower rate (20 weeks) and less consistently (14 tumors/26 sites). When the T47D:Tam tumor was passaged, it grew maximally with either 1.5 mg of tamoxifen or a 1-cm estradiol (premenopausal levels) capsule, and similar results were obtained with MCF-7:Tam2 tumors. Interestingly, when T47D:Tam tumors were treated with the 0.5 mg of tamoxifen, tumors grew only to 50% maximum. All of the tumors originating from MCF-7 and T47D cells expressed ER at similar levels; therefore, tamoxifen did not select for an ER-negative tumor. In conclusion, we have shown that tamoxifen-stimulated T47D p53 mutant tumors can be developed rapidly with high-dose therapy (1.5 mg daily). The results from this model provide new opportunities to investigate the rapid development of drug resistance to adjuvant tamoxifen in patients with mutant p53 breast tumors.     

Brain tumor target volume determination for radiation treatment planning through automated MRI segmentation

PURPOSE: To assess the effectiveness of two automated magnetic resonance imaging (MRI) segmentation methods in determining the gross tumor volume (GTV) of brain tumors for use in radiation therapy treatment planning. METHODS AND MATERIALS: Two automated MRI tumor segmentation methods (supervised k-nearest neighbors [kNN] and automatic knowledge-guided [KG]) were evaluated for their potential as "cyber colleagues." This required an initial determination of the accuracy and variability of radiation oncologists engaged in the manual definition of the GTV in MRI registered with computed tomography images for 11 glioma patients. Three sets of contours were defined for each of these patients by three radiation oncologists. These outlines were compared directly to establish inter- and intraoperator variability among the radiation oncologists. A novel, probabilistic measurement of accuracy was introduced to compare the level of agreement among the automated MRI segmentations. The accuracy was determined by comparing the volumes obtained by the automated segmentation methods with the weighted average volumes prepared by the radiation oncologists. RESULTS: Intra- and inter-operator variability in outlining was found to be an average of 20% +/- 15% and 28% +/- 12%, respectively. Lowest intraoperator variability was found for the physician who spent the most time producing the contours. The average accuracy of the kNN segmentation method was 56% +/- 6% for all 11 cases, whereas that of the KG method was 52% +/- 7% for 7 of the 11 cases when compared with the physician contours. For the areas of the contours where the oncologists were in substantial agreement (i.e., the center of the tumor volume), the accuracy of kNN and KG was 75% and 72%, respectively. The automated segmentation methods were found to be least accurate in outlining at the edges of the tumor volume. CONCLUSIONS: The kNN method was able to segment all cases, whereas the KG method was limited to enhancing tumors and gliomas with clear enhancing edges and no cystic formation. Both methods undersegment the tumor volume when compared with the radiation oncologists and performed within the variability of the contouring performed by experienced radiation oncologists based on the same data.     

The impact of changes in radiographic sarcopenia on overall survival in older adults undergoing different treatment pathways for pancreatic cancer

Objective

Sarcopenia is associated with poor outcomes in patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC). However, few studies have assessed changes in sarcopenia during multimodality therapy or its effect on overall survival (OS).