Renal cell carcinoma with venous extension: prediction of inferior vena cava wall invasion by MRI

Abstract

Background

Renal cell carcinoma (RCC) are accompanied by inferior vena cava (IVC) thrombus in up to 10% of the cases, with surgical resection remaining the only curative option. In case of IVC wall invasion, the operative procedure is more challenging and may even require IVC resection. This study aims to determine the diagnostic performance of contrast-enhanced magnetic resonance imaging (MRI) for the assessment of wall invasion by IVC thrombus in patients with RCC, validated with intraoperative findings.

Methods

Data were collected on 81 patients with RCC and IVC thrombus, who received a radical nephrectomy and vena cava thrombectomy between February 2008 and November 2017. Forty eight patients met the inclusion criteria. Sensitivity and specificity as well as the positive and negative predictive values were calculated for preoperative MRI, based on the assessments of the two readers for visual wall invasion. Furthermore, a logistic regression model was used to determine if there was an association between intraoperative wall adherence and IVC diameter.

Results

Complete occlusion of the IVC lumen or vessel breach could reliably assess IVC wall invasion with a sensitivity of 92.3% (95%-CI: 0.75–0.99) and a specificity of 86.4% (95%-CI: 0.65–0.97) (Fisher-test: p-value< 0.001). The positive predictive value (PPV) was 88.9% (95%-CI: 0.71–0.98) and the negative predictive value reached 90.5% (95%-CI: 0.70–0.99). There was an excellent interobserver agreement for determining IVC wall invasion with a kappa coefficient of 0.90 (95%CI: 0.79–1.00).

Conclusions

The present study indicates that standard preoperative MR imaging can be used to reliably assess IVC wall invasion, evaluating morphologic features such as the complete occlusion of the IVC lumen or vessel breach. Increases in IVC diameter are associated with a higher probability of IVC wall invasion.

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The role of vimentin in the tumor marker Nup88-dependent multinucleated phenotype

Abstract

Background

Nucleoporin Nup88, a component of nuclear pore complexes, is known to be overexpressed in several types of tumor tissue. The overexpression of Nup88 has been reported to promote the early step of tumorigenesis by inducing multinuclei in both HeLa cells and a mouse model. However, the molecular basis of how Nup88 leads to a multinucleated phenotype remains unclear because of a lack of information concerning its binding partners. In this study, we characterize a novel interaction between Nup88 and vimentin. We also examine the involvement of vimentin in the Nup88-dependent multinucleated phenotype.

Methods

Cells overexpressing tagged versions of Nup88, vimentin and their truncations were used in this study. Coprecipitation and GST-pulldown assays were carried out to analyze protein-protein interactions. Vimentin knockdown by siRNA was performed to examine the functional role of the Nup88-vimentin interaction in cells. The phosphorylation status of vimentin was analyzed by immunoblotting using an antibody specific for its phosphorylation site.

Results

Vimentin was identified as a Nup88 interacting partner, although it did not bind to other nucleoporins, such as Nup50, Nup214, and Nup358, in HeLa cell lysates. The N-terminal 541 amino acid residues of Nup88 was found to be responsible for its interaction with vimentin. Recombinant GST-tagged Nup88 bound to recombinant vimentin in a GST-pulldown assay. Although overexpression of Nup88 in HeLa cells was observed mainly at the nuclear rim and in the cytoplasm, colocalization with vimentin was only partially detected at or around the nuclear rim. Disruption of the Nup88-vimentin interaction by vimentin specific siRNA transfection suppressed the Nup88-dependent multinucleated phenotype. An excess amount of Nup88 in cell lysates inhibited the dephosphorylation of a serine residue (Ser83) within the vimentin N-terminal region even in the absence and presence of an exogenous phosphatase. The N-terminal 96 amino acid residues of vimentin interacted with both full-length and the N-terminal 541 residues of Nup88.

Conclusions

Nup88 can affect the phosphorylation status of vimentin, which may contribute to the Nup88-dependent multinucleated phenotype through changing the organization of vimentin.

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Pretherapeutic FDG-PET total metabolic tumor volume predicts response to induction therapy in pediatric Hodgkin’s lymphoma

Abstract

Background

Standardized treatment in pediatric patients with Hodgkin's lymphoma (HL) follows risk stratification by tumor stage, erythrocyte sedimentation rate and tumor bulk. We aimed to identify quantitative parameters from pretherapeutic FDG-PET to assist prediction of response to induction chemotherapy.

Methods

Retrospective analysis in 50 children with HL (f:18; m:32; median age, 14.8 [4–18] a) consecutively treated according to EuroNet-PHL-C1 (n = 42) or -C2 treatment protocol (n = 8). Total metabolic tumor volume (MTV) in pretherapeutic FDG-PET was defined using a semi-automated, background-adapted threshold. Metabolic (SUVmax, SUVmean, SUVpeak, total lesion glycolysis [MTV*SUVmean]) and heterogeneity parameters (asphericity [ASP], entropy, contrast, local homogeneity, energy, and cumulative SUV-volume histograms) were derived. Early response assessment (ERA) was performed after 2 cycles of induction chemotherapy according to treatment protocol and verified by reference rating. Prediction of inadequate response (IR) in ERA was based on ROC analysis separated by stage I/II (1 and 26 patients) and stage III/IV disease (7 and 16 patients) or treatment group/level (TG/TL) 1 to 3.

Results

IR was seen in 28/50 patients (TG/TL 1, 6/12 patients; TG/TL 2, 10/17; TG/TL 3, 12/21). Among all PET parameters, MTV best predicted IR; ASP was the best heterogeneity parameter. AUC of MTV was 0.84 (95%-confidence interval, 0.69–0.99) in stage I/II and 0.86 (0.7–1.0) in stage III/IV. In patients of TG/TL 1, AUC of MTV was 0.92 (0.74–1.0); in TG/TL 2 0.71 (0.44–0.99), and in TG/TL 3 0.85 (0.69–1.0). Patients with high vs. low MTV had IR in 86 vs. 0% in TG/TL 1, 80 vs. 29% in TG/TL 2, and 90 vs. 27% in TG/TL 3 (cut-off, > 80 ml, > 160 ml, > 410 ml).

Conclusions

In this explorative study, high total MTV best predicted inadequate response to induction therapy in pediatric HL of all pretherapeutic FDG-PET parameters – in both low and high stages as well as the 3 different TG/TL.

Trial registration

Ethics committee number: EA2/151/16 (retrospectively registered).

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Development and evaluation of oral Cancer quality-of-life questionnaire (QOL-OC)

Abstract

Background

In this study scales and items for the Oral Cancer Quality-of-life Questionnaire (QOL-OC) were designed and the instrument was evaluated.

Methods

The QOL-OC was developed and modified using the international definition of quality of life (QOL) promulgated by the European Organization for Research and Treatment of Cancer (EORTC) and analysis of the precedent measuring instruments. The contents of each item were determined in the context of the specific characteristics of oral cancer. Two hundred thirteen oral cancer patients were asked to complete both the EORTC core quality of life questionnaire (EORTC QLC-C30) and the QOL-OC. Data collected was used to conduct factor analysis, test-retest reliability, internal consistency, and construct validity.

Results

Questionnaire compliance was relatively high. Fourteen of the 213 subjects accepted the same tests after 24 to 48 h demonstrating a high test-retest reliability for all five scales. Overall internal consistency surpasses 0.8. The outcome of the factor analysis coincides substantially with our theoretical conception. Each item shows a higher correlation coefficient within its own scale than the others which indicates high construct validity.

Conclusions

QOL-OC demonstrates fairly good statistical reliability, validity, and feasibility. However, further tests and modification are needed to ensure its applicability to the quality-of-life assessment of Chinese oral cancer patients.

https://ift.tt/2HIQuzY

Vemurafenib in Chinese patients with BRAF V600 mutation–positive unresectable or metastatic melanoma: an open-label, multicenter phase I study

Abstract

Background

Melanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAF^V600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients.

Methods

This phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAF^V600 mutation–positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26).

Results

After 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0–67.1%). Median progression-free survival was 8.3 months (95% CI 5.7–10.9%); median overall survival was 13.5 months (95% CI 12.2%–not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%).

Conclusion

Overall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients.

Trial registration

ClinicalTrials.gov identification: NCT01910181. Registered 29 July 2013, prospectively registered.

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Cancers, Vol. 10, Pages 132: Aptamers: Promising Tools for Cancer Diagnosis and Therapy

Cancers, Vol. 10, Pages 132: Aptamers: Promising Tools for Cancer Diagnosis and Therapy

Cancers doi: 10.3390/cancers10050132

Authors: Laura Cerchia

The most common approaches to cancer treatment have been, for decades, based on surgical excision, radio- and/or chemotherapy, which, in spite of their modest survival benefits, still encounter several limitations, in part due to their lack of specificity [...]

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Cancers, Vol. 10, Pages 131: Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer

Cancers, Vol. 10, Pages 131: Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer

Cancers doi: 10.3390/cancers10050131

Authors: Lorenzo Stramucci Angelina Pranteda Gianluca Bossi

TP53 is universally recognized as a pivotal protein in cell-cycle fate and apoptotic induction and, unsurprisingly, it is one of the most commonly hijacked control mechanisms in cancer. Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid tumor being linked to mutant p53 gain-of-function. In this review, we summarize the delicate relationship among p53 mutational status, MKK3/MKK6 and the downstream activated master kinase p38MAPK, dissecting a finely-tuned crosstalk, in a potentially cell-context dependent scenario that urges towards a deeper characterization of the different molecular players involved in this signaling cascade and their interactions.

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