A Systematic Review of PET Textural Analysis and Radiomics in Cancer.

BACKGROUND: Although many works have supported the utility of PET radiomics, several authors have raised concerns over the robustness and replicability of the results. This study aimed to perform a systematic review on the topic of PET radiomics and the used methodologies. METHODS: PubMed was searched up to 15 October 2020. Original research articles based on human data specifying at least one tumor type and PET image were included, excluding those that apply only first-order statistics and those including fewer than 20 patients. Each publication, cancer type, objective and several methodological parameters (number of patients and features, validation approach, among other things) were extracted. RESULTS: A total of 290 studies were included. Lung (28%) and head and neck (24%) were the most studied cancers. The most common objective was prognosis/treatment response (46%), followed by diagnosis/staging (21%), tumor characterization (18%) and technical evaluations (15%). The average number of patients included was 114 (median = 71; range 20-1419), and the average number of high-order features calculated per study was 31 (median = 26, range 1-286). CONCLUSIONS: PET radiomics is a promising field, but the number of patients in most publications is insufficient, and very few papers perform in-depth validations. The role of standardization initiatives will be crucial in the upcoming years.

Is FDG-PET texture analysis related to intratumor biological heterogeneity in lung cancer?

OBJECTIVES: We aimed at investigating the origin of the correlations between tumor volume and 18F-FDG-PET texture indices in lung cancer. METHODS: Eighty-five consecutive patients with newly diagnosed non-small cell lung cancer (NSCLC) underwent a 18F-FDG-PET/CT scan before treatment. Seven phantom spheres uniformly filled with 18F-FDG, and covering a range of activities and volumes similar to that found in lung tumors, were also scanned. Established texture indices were computed for lung tumors and homogeneous spheres. The dependence between textural indices and volume in homogeneous spheres was modeled and then used to predict texture indices in lung tumors. Correlation analyses were carried out between predicted and texture features measured in lung tumors. Cox proportional hazards regression was used to investigate the associations between overall survival and volume-adjusted textural features. RESULTS: All textural features showed strong, non-linear correlations with volume, both in tumors and homogeneous spheres. Correlations between predicted versus measured texture features were very high for contrast (r2 = 0.91), dissimilarity (r2 = 0.90), ZP (r2 = 0.90), GLNN (r2 = 0.86), and homogeneity (r2 = 0.82); high for entropy (r2 = 0.50) and HILAE (r2 = 0.53); and low for energy (r2 = 0.30). Cox regressions showed that among volume-adjusted features, only HILAE was associated with overall survival (b = - 0.35, p = 0.008). CONCLUSION: We have shown that texture indices previously found to be correlated with a number of clinically relevant outcomes might not provide independent information apart from that driven by their correlation with tumor volume, suggesting that these metrics might not be suitable as intratumor heterogeneity markers. KEY POINTS: • Associations between texture FDG-PET indices and overall survival have been widely reported in lung cancer, with tumor volume also being associated with overall survival, and therefore, it is still unclear whether the predictive power of textural indices is simply driven by this correlation. • Our results demonstrated strong non-linear correlations between textural indices and volume, showing an analogous behavior for lung tumors from patients and homogeneous spheres inserted in phantoms. • Our findings showed that texture FDG-PET indices might not provide independent information apart from that driven by their correlation with tumor volume.

PET study of ocular and blood pharmacokinetics of intravitreal bevacizumab and aflibercept in rats.

Intravitreal injections are the standard procedure in the treatment of retinal pathologies, such as the administration of the anti-VEGF antibodies in age-related macular degeneration. The aim of this study is to evaluate the intraocular and blood pharmacokinetics after an intravitreal injection of 89Zr-labelled bevacizumab and 89Zr-labelled aflibercept in Sprague-Dawley rats using Positron Emission Tomography. First, both antibodies were radiolabelled to zirconium-89 with a maximum specific activity of 15 Mbq/mg for bevacizumab and 10 Mbq/mg for aflibercept. Four µL containing 1-1.2 Mq of 89Zr-labelled compound were injected into the vitreous through a 35 G needle. A microPET acquisition was carried out immediately after the injection and at different time points through a 12-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration above 95% for both agents. Both antibodies ocular curves followed a two-compartment model in which an intraocular elimination half-life of 16.44 h was found for 89Zr-bevacizumab and 4.51 h for 89Zr-aflibercept, considering the alpha phase as the elimination phase. Regarding the beta phase, a half-life of 3.23 days for 89Zr-bevacizumab and 4.69 days for 89Zr-aflibercept were observed. With regards to blood concentration, 89Zr-bevacizumab showed a blood half-life of 7.08 days, whereas 89Zr-aflibercept's was 3.18 days, by a one-compartment model with first-order absorption kinetics. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis after intravitreal injection of aflibercept and bevacizumab in rats.

Celia's encephalopathy and c.974dupG in BSCL2 gene: a hidden change in a known variant.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy (PELD)) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. Clinical characterization, biochemistry, and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification, and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. One with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy, and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene and is responsible for a variant of Celia's encephalopathy, with variable phenotypic expression.

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Texture analysis of high-resolution dedicated breast 18 F-FDG PET images correlates with immunohistochemical factors and subtype of breast cancer.

PURPOSE: This study aims to determine whether PET textural features measured with a new dedicated breast PET scanner reflect biological characteristics of breast tumors. METHODS: One hundred and thirty-nine breast tumors from 127 consecutive patients were included in this analysis. All of them underwent a 18F-FDG PET scan before treatment. Well-known PET quantitative parameters such as SUV m a x , SUV m e a n , metabolically active tumor volume (MATV) and total lesion glycolysis (TLG) were extracted. Together with these parameters, local, regional, and global heterogeneity descriptors, which included five textural features (TF), were computed. Immunohistochemical classification of breast cancer considered five subtypes: luminal A like (LA), luminal B like/HER2 - (LB -), luminal B like/HER2+ (LB+), HER2-positive-non-luminal (HER2pnl), and triple negative (TN). Associations between PET features and tumor characteristics were assessed using non-parametric hypothesis tests. RESULTS: Along with well-established associations, new correlations were found. HER2-positive tumors had significantly higher uptake (p < 0.001, AUCs > 0.70) and presented different global and regional heterogeneity (p = 0.002, p = 0.016, respectively, AUCs < 0.70). Nine out of ten analyzed features were significantly associated with immunohistochemical subtype. Uptake was lower for LA tumors (p < 0.001) with AUCs ranging from 0.71 to 0.88 for each subgroup comparison. Heterogeneity metrics were significantly associated when comparing LA and LB - (p < 0.01), being regional heterogeneity metrics more discriminative than any other parameter (AUC = 0.80 compared to AUC = 0.71 for SUV). LB+ and HER2pnl tumors also showed more regional heterogeneity than LA tumors (AUCs = 0.79 and 0.84, respectively). After comparison with whole-body PET studies, we observed an overall improvement in the classification ability of both non-heterogeneity metrics and textural features. CONCLUSIONS: PET parameters extracted from high-resolution dedicated breast PET images showed new and stronger correlations with immunohistochemical factors and immunohistochemical subtype of breast cancer compared to whole-body PET.

Evaluation and optimization of occupational eye lens dosimetry during positron emission tomography (PET) procedures.

The last recommendations of the International Commission on Radiological Protection for eye lens dose suggest an important reduction on the radiation limits associated with early and late tissue reactions. The aim of this work is to quantify and optimize the eye lens dose associated to nurse staff during positron emission tomography (PET) procedures. PET is one of the most important diagnostic methods of oncological and neurological cancer disease involving an important number of workers exposed to the high energy isotope F-18. We characterize the relevant stages as preparation and administration of monodose syringes in terms of occupational dose. A direct reading silicon dosimeter was used to measure the lens dose to staff. The highest dose of radiation was observed during preparation of the fluorodesoxyglucose (FDG) syringes. By optimizing a suitable vials' distribution of FDG we find an important reduction in occupational doses. Extrapolation of our data to other clinical scenarios indicates that, depending on the work load and/or syringes activity, safety limits of the dose might be exceeded.

Breastfeeding and Immunohistochemical Expression of ki-67, p53 and BCL2 in Infiltrating Lobular Breast Carcinoma.

BACKGROUND/AIM: Invasive lobular breast carcinoma is the second most common type of breast cancer after invasive ductal carcinoma. According to the American Cancer Society, more than 180,000 women in the United States find out they have invasive breast cancer each year. Personal history of breast cancer and certain changes in the breast are correlated with an increased breast cancer risk. The aim of this work was to analyze breastfeeding in patients with infiltrating lobular breast carcinoma, in relation with: 1) clinicopathological parameters, 2) hormonal receptors and 3) tissue-based tumor markers. MATERIALS AND METHODS: The study included 80 women with ILC, 46 of which had breastfeed their children. Analyzed parameters were: age, tumor size, axillary lymph node (N), distant metastasis (M), histological grade (HG), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2. RESULTS: ILC of non-lactating women showed a larger (p = 0.009), lymph node involvement (p = 0.051) and distant metastasis (p = 0.060). They were also more proliferative tumors measured by Ki-67 (p = 0.053). Breastfeeding history did not influence the subsequent behavior of the tumor regardless of histological subtype. CONCLUSION: Lactation seems to influence the biological characteristics of ILC defining a subgroup with more tumor size, axillary lymph node involvement, distant metastasis and higher proliferation measured by ki-67 expression.

Impact and correction of the bladder uptake on 18 F-FCH PET quantification: a simulation study using the XCAT2 phantom.

The spill-in counts from neighbouring regions can significantly bias the quantification over small regions close to high activity extended sources. This effect can be a drawback for (18)F-based radiotracers positron emission tomography (PET) when quantitatively evaluating the bladder area for diseases such as prostate cancer. In this work, we use Monte Carlo simulations to investigate the impact of the spill-in counts from the bladder on the quantitative evaluation of prostate cancer when using (18)F-Fluorcholine (FCH) PET and we propose a novel reconstruction-based correction method. Monte Carlo simulations of a modified version of the XCAT2 anthropomorphic phantom with (18)F-FCH biological distribution, variable bladder uptake and inserted prostatic tumours were used in order to obtain simulated realistic (18)F-FCH data. We evaluated possible variations of the measured tumour Standardized Uptake Value (SUV) for different values of bladder uptake and propose a novel correction by appropriately adapting image reconstruction methodology. The correction is based on the introduction of physiological background terms on the reconstruction, removing the contribution of the bladder to the final image. The bladder is segmented from the reconstructed image and then forward-projected to the sinogram space. The resulting sinograms are used as background terms for the reconstruction. SUV max and SUV mean could be overestimated by 41% and 22% respectively due to the accumulation of radiotracer in the bladder, with strong dependence on bladder-to-lesion ratio. While the SUVs measured under these conditions are not reliable, images corrected using the proposed methodology provide better repeatability of SUVs, with biases below 6%. Results also showed remarkable improvements on visual detectability. The spill-in counts from the bladder can affect prostatic SUV measurements of (18)F-FCH images, which can be corrected to less than 6% using the proposed methodology, providing reliable SUV values even in the presence of high radioactivity accumulation in the bladder.

Cell membrane CD44v6 levels in squamous cell carcinoma of the lung: association with high cellular proliferation and high concentrations of EGFR and CD44v5.

Membranous CD44v6 levels in tumors and surrounding samples obtained from 94 patients with squamous cell lung carcinomas were studied and compared to clinical stage, cellular proliferation, membranous CD44v5 levels, epidermal growth factor receptor EGFR and cytoplasmatic concentrations of CYFRA 21.1. CD44v6 positive values were observed in 33/38 non-tumor samples and in 76/94 tumor samples, but there were not statistically significant differences between both subgroups. In CD44v6 positive tumor samples, CD44v6 was not associated with clinical stage, histological grade, ploidy and lymph node involvement, but significant association was found with high cellular proliferation. Likewise, CD44v6 positive tumors had significantly higher levels of EGFR and CD44v5. In patients with squamous cell lung carcinomas and clinical stage I, positive CD44v6 cases were associated with the same parameters. Furthermore, positive CD44v5 squamous tumors were associated significantly with histological grade III and lower levels of CYFRA21.1. Our findings support the value of CD44v6 as a possible indicator of poor outcome in patients with squamous lung carcinomas.

Histological grade (HG) in invasive ductal carcinomas of the breast of less than 1 cm: clinical and biological associations during progression from HG1 to HG3.

AIM: To study the clinical and biological (cellular proliferation and hormone-dependence) associations during the progression of histological grade (HG), from HG1 to HG3, in invasive ductal carcinomas of the breast (IDC) <1 cm. PATIENTS AND METHODS: The study group included 119 women with IDCs ≤1 cm, aged between 27 and 88 years (median=61 years). The parameters analyzed were: histological grade (HG1: 52; HG2: 45; HG3: 22); axillary lymph node involvement (N); distant metastasis (M); and immunohistochemical expression of estrogen (ER), progesterone (PR) and androgen (AR) receptors, and Ki67, p53 and B-cell lymphoma 2 (BCL2). RESULTS: Compared to HG3 tumors, HG1s exhibited an increased expression of ER, AR and BCL2, as well as lower expression of p53 and Ki67. In HG1 tumors, significant (p<0.05) associations were found between ER and PR (positive), ER and p53 (negative), ER and Ki67 (negative), PR and AR (positive), PR and p53 (negative), AR and p53 (negative), p53 and BCL2 (negative), and between BCL2 and Ki67 (negative). HG3s only showed significant (p<0.05) associations between ER and Ki-67 (negative) and between BCL2 or Ki-67 (negative). Only two significant relationships (ER-Ki67 and BCL2-Ki67) persisted in all three grades. CONCLUSION: Our results lead us to the following conclusions: i) compared HG1, HG3 ductal carcinomas exhibited decreased expression of ER, AR and BCL2 and increased expression of p53 and Ki67; and ii) only two significant and negative relations (ER-Ki67 and BCL2-Ki67) persisted in all three grades.

Clinicopathological characteristics of infiltrating lobular breast carcinoma in elderly women: Preliminary results.

This study was conducted to investigate the clinicopathological parameters in elderly women (aged >70 years) with infiltrating lobular carcinoma (ILC) of the breast and compare the results with those obtained from younger patients (aged 55-70 years). The study sample included a total of 46 women with ILCs, 10 aged >70 and 36 aged 55-70 years. The parameters analysed were tumor size, histological grade (HG), axillary lymph node involvement, distant metastasis and immunohistochemical expression of estrogen, progesterone and androgen receptors, Ki67, p53 and B cell lymphoma 2. Compared to women aged 55-70 years, ILCs in women aged >70 years were commonly of larger size (P=0.068) and were more frequently HG3 (P=0.024). There were no statistically significant differences in the other parameters analysed. Furthermore, we were unable to determine differences in cancer recurrence and mortality in the two patient subgroups during our follow-up. In conclusion, our preliminary results, based on the limited number of cases included in this study, indicate that i) ILCs in women aged >70 years tended to be larger compared to those in women aged 55-70 years and were more frequently of grade 3; and ii) there were no significant differences in terms of recurrence and mortality between the two patient subgroups during our follow-up.

The contrasting epigenetic role of RUNX3 when compared with that of MGMT and TIMP3 in glioblastoma multiforme clinical outcomes.

Glioblastoma multiforme (GBM) is the most frequent and malignant astrocytic glioma in the adult, with a survival rate at 5 years less than 5%. In the GBM pathogenesis, the importance of genes methylation involved in cell cycle, tumor suppression, DNA repair and genome integrity, as well as tumor invasion and apoptosis has been described. We analyzed epigenetic regulation involvement of two genes related with apoptosis: TIMP3 and RUNX3 in order to define a clinical profile and compare with the most studied gene in GBM: MGMT. Eighty samples from GBM patients were evaluated by methylation specific PCR (MSP). Data from each patient were collected from medical histories to relate survival rates with gene methylation patterns. Methylation percentages obtained were: MGMT 45%, RUNX3 30% and TIMP3 28%. The study of MGMT methylation had prognostic value in patients with glioblastoma multiforme because at 8 months, 28% of patients survived with the gene methylated, while none of them lived with the gene unmethylated (P=0.016). RUNX3 behavior was opposite to TIMP3 and MGMT. TIMP3action, in terms of patient's survival, was similar to that observed with MGMT, percentage of patients surviving at 8 months with the gene methylated was 27%, compared with 7% of those with the unmethylated gene; there being a tendency to statistical significance (p=0.09).

CA15.3 serum concentrations in older women with infiltrating ductal carcinomas of the breast.

Breast cancer is currently becoming a disease of the elderly. We have studied the relation between CA 15.3 serum concentrations and clinical-pathological parameters in 69 women with IDC aged over 70 years (76.3±4.2; range: 71-88; median 76). A group of 205 women with the same tumor but aged <70 years (62.8±4.0; range: 55-70; median 63) was also considered for comparison. Tumor size, axillary lymph node involvement, distant metastasis and histological grade were taken account. Serum CA 15.3 was determined by luminescence assay. CA 15.3 serum concentrations ranged between 6 and 85 U/mL (median 22.9 U/mL), and were higher only in patients with greater (qualitative and quantitative; p: 0.041) tumor size. Our results show that in women with IDCs, and aged over 70 years, serum CA 15.3 serum concentrations are associated exclusively with a greater tumor size, being these findings different to those described in women with the same subtype of tumor considered as a whole or with lower age.

Positive immunohistochemical expression of bcl-2 in hormone-independent breast carcinomas is associated with a greater lymph node involvement and poor outcome.

To study the immunohistochemical expression of bcl-2 in patients with hormone-independent breast infiltrating ductal carcinomas (IDC) and its possible association with other clinico-biological parameters and outcome. Our study group included 72 females with hormone-independent (ER and PgR negative) infiltrating ductal breast carcinomas. Age, tumor size, axillary lymph node involvement (N), distant metastasis and histological grade, as well as the immunohistochemical expression of Ki67, p53 and androgen receptor (AR), were analyzed. We follow up 57 patients during a period of time ranged between 20 and 193 months (80.2 ± 58.3; median 78 months). Of all IDCs included in our study, 18 were ER-/PgR-/bcl-2+ and 54 ER-/PgR-/bcl-2-. The percentages of slightly bcl-2-positive (+) and bcl-2-strong positive (++) cases were 25 and 19 %, respectively, values lower than those observed in ER+/PgR+ tumors (79.3 and 86.8 %, respectively). Breast IDC with positivity (+) for bcl-2 showed, exclusively, greater lymph node involvement higher than 3 nodes (N+ >3) (p 0.021) and a great number of deaths due to the tumor (p 0.011). Same results were obtained when we compared bcl-2-negative and bcl-2-strong positive (++) subgroups. Our results led us to consider that the positive (+ or ++) immunohistochemical expression of bcl-2 in hormone-independent (ER and PgR negative) breast carcinomas is associated with greater axillary lymph node involvement and a greater number of deaths in the follow-up, being these data opposite to that observed in hormone-dependent tumors.

Does percutaneous nephrolithotomy and its outcomes have an impact on renal function? Quantitative analysis using SPECT-CT DMSA.

To assess the functional effects of percutaneous nephrolithotomy (PCNL) and its outcomes in the operated kidney, we prospectively studied 30 consecutive cases undergoing PCNL. Kidney function was evaluated preoperatively and 3 months after surgery with serum creatinine, glomerular filtration rate (GFR), and with (99m)Tc-DMSA SPECT-CT scans to determine the differential renal function (DRF). PCNL effects in the operated kidney DRF were considered globally (DRFPLANAR, DRFSPECT) and in the region of percutaneous access (DRFACCESS). PCNL functional impact was also assessed depending on its outcomes, namely success (stone-free status) and the development of perioperative complications. PCNL has rendered 73 % of the cases completely stone free with a 33 % complication rate. After PCNL, serum creatinine and GFR did not change significantly, whereas DRFPLANAR and DRFSPECT dropped 1.2 % (p = 0.014) and 1.0 % (p = 0.041), respectively. The highest decrease was observed in DRFACCESS (1.8 %, p = 0.012). Stone-free status after PCNL did not show any impact on kidney function. Conversely, cases that suffered from a complication showed impairment in serum creatinine (0.1 mg/dL, p = 0.028), in GFR (11.1 mL/min, p = 0.036) as well as in DRFPLANAR (2.7 %, p = 0.018), DRFSPECT (2.2 %, p = 0.023) and DRFACCESS (2.7 %, p = 0.049). We conclude that PCNL has a minimal impact on global kidney function, which is mainly located in the region of percutaneous access. The advent of perioperative complications increased PCNL functional damage, whereas the stone-free status did not show any meaningful effect.

Association between tumor size and immunohistochemical expression of Ki-67, p53 and BCL2 in a node-negative breast cancer population selected from a breast cancer screening program.

BACKGROUND/AIM: Breast cancer is the most common type of cancer among women. Breast infiltrating ductal carcinoma (IDC) is the most common type of breast cancer, approximately 80% of all breast carcinomas. The aim of this study was to analyze the association of tumor size, evaluated after histopathological analysis, with different clinical and biological parameters in IDC. MATERIALS AND METHODS: The study group included 251 women with IDC without axillary lymph node involvement, aged between 27 and 81 years. Analyzed parameters were: age, histological grade, menopausal status, menarche, pregnancy, abortion, breastfeeding, contraceptive use, hormone replacement therapy, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2. RESULTS: Pathological tumor size was between 0.2 and 5.1 cm (1.43±0.86 cm). Tumors in 45 cases exceeded 2 cm, in eight 3 cm and only in one 5 cm. Pathological size was significantly associated with age >70 vs. <50 years (p=0.054), histological grade III vs. I (p=0.0003), positivity for Ki-67 (p=0.0003) and for p53 (p=0.0032). CONCLUSION: Tumor size was significantly associated with age >70 years, histological grade 3 and immunohistochemically-augmented expression of Ki-67 and p53.

A new seipin-associated neurodegenerative syndrome.

BACKGROUND: Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied. METHODS: Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting. RESULTS: Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus. CONCLUSIONS: Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.

A novel in silico reverse-transcriptomics-based identification and blood-based validation of a panel of sub-type specific biomarkers in lung cancer.

Lung cancer accounts for the highest number of cancer-related deaths worldwide. Early diagnosis significantly increases the disease-free survival rate and a large amount of effort has been expended in screening trials and the development of early molecular diagnostics. However, a gold standard diagnostic strategy is not yet available. Here, based on miRNA expression profile in lung cancer and using a novel in silico reverse-transcriptomics approach, followed by analysis of the interactome; we have identified potential transcription factor (TF) markers that would facilitate diagnosis of subtype specific lung cancer. A subset of seven TF markers has been used in a microarray screen and was then validated by blood-based qPCR using stage-II and IV non-small cell lung carcinomas (NSCLC). Our results suggest that overexpression of HMGA1, E2F6, IRF1, and TFDP1 and downregulation or no expression of SUV39H1, RBL1, and HNRPD in blood is suitable for diagnosis of lung adenocarcinoma and squamous cell carcinoma sub-types of NSCLC. Here, E2F6 was, for the first time, found to be upregulated in NSCLC blood samples. The miRNA-TF-miRNA interaction based molecular mechanisms of these seven markers in NSCLC revealed that HMGA1 and TFDP1 play vital roles in lung cancer tumorigenesis. The strategy developed in this work is applicable to any other cancer or disease and can assist in the identification of potential biomarkers.