Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing ...the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.
We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of ...tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (
= 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (
= 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (
= 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.
•The prognostic role of histomorphological subtyping in papillary renal cell carcinoma (papRCC) is an issue of debate due to previously reported controversial outcomes.•Type 2 is found to be ...associated with advanced nuclear grade, pT and pN stages in this study.•Type 2 is found to predict worse recurrence free- and cancer specific survival.•Histomorphological subtyping is relevant from the point of prognostic view.•It may guide follow-up after curative surgery and selection of adjuvant treatment candidates.
The role of histomorphological subtyping is an issue of debate in papillary renal cell carcinoma (papRCC). This multi-institutional study investigated the prognostic role of histomorphological subtyping in patients undergoing curative surgery for nonmetastatic papRCC.
A total of 1,086 patients undergoing curative surgery were included from a retrospectively collected multi-institutional nonmetastatic papRCC database. The patients were divided into 2 groups based on histomorphological subtyping (type 1, n = 669 and type 2, n = 417). Furthermore, a propensity score-matching (PSM) cohort in 1:1 ratio (n = 317 for each subtype) was created to reduce the effect of potential confounding variables. The primary outcome of the study, the predictive role of histomorphological subtyping on the prognosis (recurrence free survival RFS, cancer specific survival CSS and overall survival OS) in nonmetastatic papRCC after curative surgery, was investigated in both overall and PSM cohorts.
In overall cohort, type 2 group were older (66 vs. 63 years, P = 0.015) and more frequently underwent radical nephrectomy (37.4% vs. 25.6%, P < 0.001) and lymphadenectomy (22.3% vs. 15.1%, P = 0.003). Tumor size (4.5 vs. 3.8 cm, P < 0.001) was greater, and nuclear grade (P < 0.001), pT stage (P < 0.001), pN stage (P < 0.001), VENUSS score (P < 0.001) and VENUSS high risk (P < 0.001) were significantly higher in type 2 group. 5-year RFS (89.6% vs. 74.2%, P < 0.001), CSS (93.9% vs. 84.2%, P < 0.001) and OS (88.5% vs. 78.5%, P < 0.001) were significantly lower in type 2 group. On multivariable analyses, type 2 was a significant predictor for RFS (HR:1.86 95%CI:1.33–2.61, P < 0.001) and CSS (HR:1.91 95%CI:1.20–3.04, P = 0.006), but not for OS (HR:1.27 95%CI:0.92–1.76, P = 0.150). In PSM cohort balanced with age, gender, symptoms at diagnosis, pT and pN stages, tumor grade, surgical margin status, sarcomatoid features, rhabdoid features, and presence of necrosis, type 2 increased recurrence risk (HR:1.75 95%CI: 1.16–2.65; P = 0.008), but not cancer specific mortality (HR: 1.57 95%CI: 0.91–2.68; P = 0.102) and overall mortality (HR: 1.01 95%CI: 0.68–1.48; P = 0.981)
This multiinstitutional study suggested that type 2 was associated with adverse histopathologic outcomes, and predictor of RFS and CSS after surgical treatment of nonmetastatic papRCC, in overall cohort. In propensity score-matching cohort, type 2 remained the predictor of RFS. Eventhough 5th WHO classification for renal tumors eliminated histomorphological subtyping, these findings suggest that subtyping is relevant from the point of prognostic view.
BACKGROUND: The role of active surveillance (AS) has been recognized as a management strategy for localized small renal masses (SRMs). The EAU guidelines suggest AS can be offered to frail and/or ...comorbid patients diagnosed with SRM due to the low cancer-specific-mortality (CSM) and higher competing-cause mortality. As specific cut-offs defining the characteristics of frail and comorbid patients who may benefit from AS remain less clear, our objective is to conduct a systematic review aiming to identify potential characteristics that could assist physicians in shared decision-making. METHODS: The systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two authors independently screened the literature according to the PICOs criteria previously outlined in our registered review protocol (via Pubmed, Embase, and the Cochrane Central Register of Controlled Trials), extracted data, and assessed the risk of bias, using Newcastle-Ottawa Scale. Studies that analyzed differences in patient’s tumor-related and molecular characteristics associated with any differences in growth rate (GR), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS), were considered eligible. RESULTS: Nineteen studies comprising a total of 5105 patients were analyzed. Patient-specific factors such as age and cardiovascular index, which demonstrated a predominant impact on OS, exhibited a high degree of consistency across the analyzed studies. Less concordance was found when exploring GR, with the main predictors being ethnicity, age, sex, comorbidity, symptoms, and eGFR. The analysis of tumor-related characteristics, such as tumor size, nephrometry score, and mass histology, among others, yielded contradictory outcomes concerning their impact on GR and CSS. CONCLUSION: Age, cardiovascular index, and chronic kidney disease have shown to be reliable predictors of OS. Nonetheless, significant debates persist regarding tumor characteristics or molecular markers that may influence survival and GR. Further research is awaited to shed light on the potential to identify prognostic factors. This would aid in pinpointing the subgroup of patients who could experience additional benefits from AS, potentially leading to a reduced risk of progression. It is imperative to standardize approaches to AS and reporting of results, as this will be pivotal for future quantitative analyses.
Hemangiomas, benign vascular masses, occasionally occur in the kidneys, presenting as rare, small, unilateral, and solitary growths. Venous hemangiomas, a renal subtype, are atypical. While ...clinically nonspecific, they are typically asymptomatic and may be incidentally discovered during unrelated clinical workups. Diagnosing renal hemangioma preoperatively is challenging due to rarity, lacking standard radiographic criteria, and poor differentiation from aggressive renal neoplasms on contrast-enhanced imaging. These tumors commonly follow a benign course, with no documented recurrence. This video article showcases the robot-assisted excision of a renal vein hemangioma, addressing the expertise needed in managing this uncommon condition robotically.
BackgroundEnteric-type adenocarcinoma of the lung (lung-ETAC) is a rare form of lung cancer with histologic similarities to colorectal cancer, with aggressive behavior and unfavorable prognosis.Case ...PresentationAn 81-year-old man presented with discolored skin lesions on the chest and abdomen. After comprehensive evaluation, including skin biopsy and molecular profiling, the patient was diagnosed with having lung-ETAC with a BRAF p.V600E mutation. Treatment with dabrafenib and trametinib initially resulted in positive results, with improvement in skin lesions and overall clinical condition. Nevertheless, approximately 6 months after, the disease had progression with new skin lesions reappearing.ConclusionsWe reported a unique case of a patient with BRAF p.V600E-mutant lung-ETAC with metastatic skin lesions achieving complete cutaneous response after targeted treatment with dabrafenib and trametinib, highlighting the potential for targeted therapy in patients with lung-ETAC harboring a BRAF p.V600E mutation.
This paper provides a comphrensive review of the critical aspects of nonlinear modeling for evaluating the seismic response of masonry structures, emphasizing the issues relevant to engineering ...practice. Currently, the specialized technical community shares the opinion that, for a performance-based approach, numerical models are the only tools sufficiently effective to support the seismic assessment of existing buildings. However, their potential often falls short when attempting to accurately describe the behavior of masonry structures. In fact, these structures feature highly complex architectural configurations, different masonry types, and various structural solutions, meaning that extra care is required in numerical modeling. This is especially true when the modelers do not have a solid background in the software chosen and may not be practiced using the vast variety of options offered by the software houses. They are often unaware of the consequences that questionable modeling choices may have on the results obtained by the models. These extremely complex topics are treated in the paper from an engineering practice perspective, providing an in-depth overview of the challenging issues related to the use of different modeling strategies. The paper covers strategies ranging from the Equivalent Frame approach (widely used in common engineering practice) to more refined techniques like 2D and 3D Finite Element procedures based on continuous, discrete, and micro-mechanical approaches. Critical aspects in the modeling of both in- and out-of-plane responses of masonry, as well as the critical issues in wall-to-wall connections and diaphragm roles are investigated. All the examined issues are clarified through numerical examples highlighting also how a consistent and integrated use of different procedures may be beneficial. Finally, some of most relevant challenging issues concerning the use of numerical models in seismic assessment with the nonlinear static approach are presented and discussed.
The success of metal halide perovskite solar cells stems from high absorption combined with a low recombination rate. Despite the fact these properties are inherent to the perovskite material, the ...choice of selective contacts is critical to achieve high voltages according to experimental evidence. In this work, the impedance and the open-circuit photopotential are measured for two excitation wavelengths (blue and red light), in two illumination directions (back and front), and at different temperatures. The open-circuit recombination characteristics of two different perovskite compositions, i.e., pure MAPbI3 and mixed ion-based (FAPbI3)0.85(MABr3)0.15, and with two different hole selective layers (Spiro-OMeTAD and P3HT) have been studied. Our results indicate that, for the studied devices, the recombination process that determines the open-circuit potential is governed by the bulk of the perovskite layer via a trap-limited mechanism, but surface-mediated recombination cannot be ruled out for P3HT contact or degraded devices. Further, we propose a model that provides a general interpretation of the nature of recombination in perovskite solar cells.
The protein kinase C (PKC) family has been clearly implicated in T-cell activation as have several nonreceptor protein-tyrosine kinases associated with the T- cell receptor, including p59fyn. This ...report demonstrates that theta PKC and p59fyn specifically interact in vitro, in the yeast two-hybrid system, and in T-cells. Further indications of direct interaction are that p59fyn potentiates theta PKC catalytic activity and that theta PKC is a substrate for tyrosine phosphorylation by p59fyn. This interaction may account for the localization of theta PKC following T-cell activation pharmacological disruption of which results in specific cell-signaling defects. The demonstration of a physical interaction between a PKC and a protein-tyrosine kinase expands the class of PKC-anchoring proteins (receptors for activated C kinases (RACKs)) and demonstrates a direct connection between these two major T-cell- signaling pathways.
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