Parametric and nonparametric two-sample tests for feature screening in class comparison: a simulation study

Background. The identification of a location-, scale- and shape-sensitive test to detect differentially expressed features between two comparison groups represents a key point in high dimensional studies. The most commonly used tests refer to differences in location, but general distributional discrepancies might be important to reveal differential biological processes.                                                         Methods. A simulation study was conducted to compare the performance of a set of two-sample tests, i.e. Student's t, Welch's t, Wilcoxon-Mann-Whitney, Podgor-Gastwirth PG2, Cucconi, Kolmogorov-Smirnov (KS), Cramer-von Mises (CvM), Anderson-Darling (AD) and Zhang tests (ZK, ZC and ZA) which were investigated under different distributional patterns. We applied the same tests to a real data example.                   Results. AD, CvM, ZA and ZC tests proved to be the most sensitive tests in mixture distribution patterns, while still maintaining a high power in normal distribution patterns. At best, the AD test showed a loss in power of ~ 2% in the comparison of two normal distributions, but a gain of ~ 32% with mixture distributions respect to the parametric tests. Accordingly, the AD test detected the greatest number of differentially expressed features in the real data application.   Conclusion. The tests for the general two-sample problem introduce a more general concept of 'differential expression', thus overcoming the limitations of the other tests restricted to specific moments of the feature distributions. In particular, the AD test should be considered as a powerful alternative to the parametric tests for feature screening in order to keep as many discriminative features as possible for the class prediction analysis

Placing Multiple Tests on a Common Scale Using a Post-test Anchor Design: Effects of Item Position and Order on the Stability of Parameter Estimates

When there is an interest in tracking longitudinal trends of student educational achievement using standardized tests, the most common linking approach generally involves the inclusion of a common set of items across adjacent test administrations. However, this approach may not be feasible in the context of high-stakes testing due to undesirable exposure of administered items. In this paper, we propose an alternative design, which allows for the equating of multiple operational tests with no items in common based on the inclusion of common items in an anchor test administered in a post-test condition. We tested this approach using data from the assessment program implemented in Italy by the National Institute for the Educational Evaluation of Instruction and Training for the years 2010–2012, and from a convenience sample of 832 8th grade students. Additionally, we investigated the impact on functioning of common items of varying item position and orders across test forms. Linking of tests was performed using multiple-group Item Response Theory modeling. Results of linking indicated that operational tests showed little variation in difficulty over the years. Investigation of item position and order effects showed that changes in item position closer to the end of the test, as well as the positioning of difficult items at the beginning or in the middle section of a test lead to a significant increase in difficulty of common items. Overall, findings indicate that this approach represents a viable linking design, which can be useful when the inclusion of common items across operational tests is not possible. The impact of differential item functioning of common items on equating error and the ability to detect ability trends is discussed

Efectos de cadmio en compuestos fenolicos totales y flavonoides de Euglena gracilis

In the present study the production of phenolic acids and flavonoid compounds by E. gracilis exposed to two cadmium concentrations (0.02 and 0.14 mM) was evaluated using high-performance liquid chromatography (HPLC). The results showed that E. gracilis exposed to 0.02 mM Cd+2 increased significantly the total content of phenolic compounds (798.46 ± 12.61 ?g GA/g) and total flavonoids (241.34 ± 47.63 ?g QE/g) with respect to the control (137.34 ± 19.80 ?g QE/g DW and 549.00 ± 8.57 ?g GA/g DW, respectively). However, no significant increase in the total content of phenolic compounds (568.54 ± 17.42 ?g GA/g DW) and total flavonoids (141.11 ± 9.36 ?g QE/g DW) were observed in E. gracilis exposed to 0.14 mM Cd+2. Further research is necessary to determine the specific role of flavonoids in E. gracilis exposed to high concentrations of Cd+2.En el presente estudio la producción de compuestos fenolicos y flavonoides producidos por E. gracilis expuesto a dos concentraciones de cadmio fue evaluado usando cromatografía liquida de alta precisión (HPLC). Los resultados mostraron que 0.02 mM de Cd+2 incrementaba significativamente el contenido total de compuestos fenolicos (798.46 ± 12.61 ?g GA/g) y flavonoides (241.34 ± 47.63 ?g QE/g) con respecto al control (137.34 ± 19.80 ?g QE/g DW y 549.00 ± 8.57 ?g GA/g DW) respectivamente. Sin embargo, incrementos no significativos en el contenido de compuestos fenolicos (568.54 ± 17.42 ?g GA/g DW) y flavonoides totales (141.11 ± 9.36 ?g QE/g DW) fueron observados en E. gracilis expuestas a 0.14 mM de Cd+2. Futuros estudios son necesarios para determinar la función especifica de los flavonoides en E. gracilis expuesto a altas concentraciones de Cd+2

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma

BACKGROUND: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports

Long-term outcome of re-irradiation for recurrent or second primary head and neck cancer: A multi-institutional study of AIRO-Head and Neck working group

Background To report the long-term outcome of patients undergoing re-irradiation (re-RT) for a recurrent or second primary head and neck cancer (RSPHNCs) in seven Italian tertiary centers, while testing the Multi-Institution Reirradation (MIRI) recursive partitioning analysis (RPA) recently published. Methods We retrospectively analyzed 159 patients. Prognostic factors for overall survival (OS) selected by a random forest model were included in a multivariable Cox analysis. To externally validate MIRI RPA, we estimated the Kaplan-Meier group-stratified OS curves for the whole population. Results Five-year OS was 43.5% (median follow-up: 49.9 months). Nasopharyngeal site, no organ dysfunction, and re-RT volume <36 cm(3) were independent factors for better OS. By applying the MIRI RPA to our cohort, a Harrell C-Index of 0.526 was found indicating poor discriminative ability. Conclusion Our data reinforce the survival benefit of Re-RT for selected patients with RSPHNC. MIRI RPA was not validated in our population

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer

Background: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs. Methods: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models. Results: Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS. Conclusions: Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response

Diagnostic role of circulating extracellular matrix-related proteins in non-small cell lung cancer.

BACKGROUND: Interactions between cancer cells and the surrounding microenvironment are crucial determinants of cancer progression. During this process, bi-directional communication among tumor cells and cancer associated fibroblasts (CAF) regulate extracellular matrix (ECM) deposition and remodeling. As a result of this dynamic process, soluble ECM proteins can be released into the bloodstream and may represent novel circulating biomarkers useful for cancer diagnosis. The aim of the present study was to measure the levels of three circulating ECM related proteins (COL11A1, COL10A1 and SPARC) in plasma samples of lung cancer patients and in healthy heavy-smokers controls and test whether such measurements have diagnostic or prognostic value. METHODS: Gene expression profiling of lung fibroblasts isolated from paired normal and cancer tissue of NSCLC patients was performed by gene expression microarrays. The prioritization of the candidates for the study of circulating proteins in plasma was based on the most differentially expressed genes in cancer associated fibroblasts. Soluble ECM proteins were assessed by western blot in the conditioned medium of lung fibroblasts and by ELISA assays in plasma samples. RESULTS: Plasma samples from lung cancer patients and healthy heavy-smokers controls were tested for levels of COL11A1 and COL10A1 (n = 57 each) and SPARC (n = 90 each). Higher plasma levels of COL10A1 were detected in patients (p ≤ 0.001), a difference that was driven specifically by females (p < 0.001). No difference in COL11A1 levels between patients and controls was found. SPARC levels were also higher in plasma patients than controls (p < 0.001) with good performance in discriminating the two groups (AUC = 0.744). No significant association was observed between plasma proteins levels and clinicopathological features or survival. CONCLUSION: Soluble factors related to proficient tumor-stroma cross-talk are detectable in plasma of primary lung cancer patients and may represent a valuable complementary diagnostic tool to discriminate lung cancer patients from healthy heavy-smokers individuals as shown for the SPARC protein

Involvement of GTA protein NC2β in Neuroblastoma pathogenesis suggests that it physiologically participates in the regulation of cell proliferation

<p>Abstract</p> <p>Background</p> <p>The General Transcription Apparatus (GTA) comprises more than one hundred proteins, including RNA Polymerases, GTFs, TAFs, Mediator, and cofactors such as heterodimeric NC2. This complexity contrasts with the simple mechanical role that these proteins are believed to perform and suggests a still uncharacterized participation to important biological functions, such as the control of cell proliferation.</p> <p>Results</p> <p>To verify our hypothesis, we analyzed the involvement in Neuroblastoma (NB) pathogenesis of GTA genes localized at 1p, one of NB critical regions: through RT-PCR of fifty eight NB biopsies, we demonstrated the statistically significant reduction of the mRNA for NC2β (localized at 1p22.1) in 74% of samples (p = 0.0039). Transcripts from TAF13 and TAF12 (mapping at 1p13.3 and 1p35.3, respectively) were also reduced, whereas we didn't detect any quantitative alteration of the mRNAs from GTF2B and NC2α (localized at 1p22-p21 and 11q13.3, respectively). We confirmed these data by comparing tumour and constitutional DNA: most NB samples with diminished levels of NC2β mRNA had also genomic deletions at the corresponding locus.</p> <p>Conclusion</p> <p>Our data show that NC2β is specifically involved in NB pathogenesis and may be considered a new NB biomarker: accordingly, we suggest that NC2β, and possibly other GTA members, are physiologically involved in the control of cell proliferation. Finally, our studies unearth complex selective mechanisms within NB cells.</p

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen.

The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500\u2009mg/m2). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS