Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy.

STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

Mobility and transformation of CdSe/ZnS quantum dots in soil: Role of the capping ligands and ageing effect.

The increasing application of Quantum Dots (QDs) is cause of concern for the potential negative effects for the ecosystem, especially in soils that may act as a sink. In this study, soil leaching experiments were performed in quartz sand packed columns to investigate the behavior of core-shell CdSe/ZnS QDs coated with either small ligands (TGA-QDs) or more complex polymers (POAMA-QDs). Fluorescence emission was compared to mass spectrometric measurements to assess the nanoparticles (NPs) state in both the leachate (transported species) and porous media (deposited amounts). Although both QDs were strongly retained in the column, large differences were observed depending on their capping ligand stability. Specifically, for TGA-QDs elution was negligible and the retained fraction accumulated in the top-columns. Furthermore, 74% of the NPs were degraded and 38% of the Se was found in the leachate in non-NPs state. Conversely, POAMA-QDs were recovered to a larger extent (78.1%), and displayed a higher transport along the soil profile. Further experiments with altered NPs showed that homo-aggregation of the QDs prior injection determined a reduced mobility but no significant changes in their stability. Eventually, ageing of the NPs in the column (15 days) caused the disruption of up to 92% of the original QDs and the immobilization of NPs and metals. These results indicate that QDs will accumulate in top-soils, where transformations phenomena will determine the overall transport, persistency and degradation of these chemicals. Once accumulated, they may act as a source for potentially toxic Cd and Se metal species displaying enhanced mobility.

An Isotopic Exchange Kinetic Model to Assess the Speciation of Metal Available Pool in Soil: The Case of Nickel.

In this study an innovative approach is proposed to predict the relative contribution of each mineral phase to the total metal availability in soils, which, in other words, could be called the available metal fractionation. Through the use of isotopic exchange kinetics (IEK) performed on typical Ni bearing phases (i.e., two types of serpentines, chlorite, smectite, goethite, and hematite) the isotopic exchange and metal-solid interaction processes are connected, considering both the thermodynamic and kinetic aspects. Results of Ni IEK experiments on mineral phases are fitted with a pseudo-first order kinetic model. For each Ni bearing phase, this allows to (i) determine the number and size of exchangeable pools (ENi(i)), (ii) assess their corresponding kinetic constants (k(i)), and (iii) discuss the mechanism of Ni isotopic exchange at mineral surfaces. It is shown that all the phases investigated, with the only exception of hematite, present at least two distinct reactive pools with significantly different k(i) values. Results suggest also that metal involved in outer-sphere complexes would display isotopic exchange between 100 and 1000 times faster than metal involved in inner-sphere complexes, and that the presence of high and low affinity sites may influence the rate of isotopic exchange up to 1 order of magnitude. Moreover, the method developed represents a tool to predict and estimate Ni mobility and availability in natural soil samples on the basis of soil mineral composition, providing information barely obtained with other techniques.

Behavior and fate of industrial zinc oxide nanoparticles in a carbonate-rich river water.

The present study precisely describes the solubility patterns of commercial uncoated and organic coated ZnO NPs (nc-NPs and c-NPs, respectively) in a natural carbonate-rich water and the physicochemical processes involved. NPs transformation rates were determined with the Donnan Membrane approach (DMT, to obtain Zn(2+) concentration) and ultrafiltration (i.e. Zn(2+) and Zn bound to small organic ligands) and modeled with VMinteQ. XPS measurements evidenced the presence on native nc-NPs of a Zn(OH)2 layer which accounts for almost 22% of total Zn. This Zn(OH)2 phase is more soluble than ZnO, and could control the early dissolution steps of the nc-NPs in our system. Indeed, nc-NPs display a fast (<1 h) dissolution step reaching 19 µM Zn in solution (<1% of the total initial zinc concentration). Comparatively, c-NPs progressively release zinc during the first 48 h, to finally reach a maximum of 197 µM (10% of total Zn), which is 10 times the maximum value measured for nc-NPs. Over the long term, dissolved Zn concentrations decrease in both systems, corresponding to the neoformation of carbonate phases observed by TEM imaging. The kinetic modeling allows highlighting two different ranges of time, corresponding to (i) first 10h with a fast precipitation (kp(')=-182.10(-4)) related to a highly oversaturated solution with respect to carbonate zinc mineral and (ii) a second slower precipitation step (kp(')=-8.10(-4)), related to the embedding of NPs in the precipitated carbonate matrix. The steady state is reached after 3 months of interaction.

Pneumococcal infections in oncohematological patients after the introduction of conjugate vaccine.

OBJECTIVES: To know the symptoms and predominant serotypes of pneumococcal infection in patients with oncohematological illness after introduction of 7-valent pneumococcal conjugate vaccine. PATIENTS AND METHODS: A prospective study (january 2006-may 2011) was made of all the incident cases of infection in oncohematological patients over 17 years of age in whom Streptococcus pneumoniae was isolated. RESULTS: A total of 131 episodes of incident cases of pneumococcal infection in 122 patients (median age of 67 years) were detected. Of these, 50% were related to health/nosocomial care (P<.001), 39.7% pneumonias and 45.1% lower respiratory tract infections, without radiological condensation. In comparison to the 803 incident cases of pneumococcal infection during the same period as in patients without oncohematological disease, the oncohematological patients were more frequently males (P<.001), had pneumonia episodes with higher FINE scores (P<.001), lower risk of death non-directly associated with pneumococcal infection (P=.006) and showed reduced susceptibility to levofloxacin (P=.043). Non-vaccine serotypes predominated. CONCLUSIONS: Pneumococcal infections in oncohematological patients are more frequent in males, mainly with lung neoplasms. They are heath care related, but not related to chemotherapy or neutropenia. After the introduction of heptavalent conjugate vaccines in pediatrics, the non-vaccine serotypes predominate.

Status epilepticus with visual seizures in ketotic hyperglycemia.

Metabolic disturbances are often associated with epileptic seizures, but the pathogenesis of this relationship is poorly understood. We describe the case of a 48-year-old man who presented with complex partial status epilepticus with visual seizures in the context of ketotic hyperglycemia. The EEG revealed a temporal epileptogenic focus and alterations were apparent on MRI in the acute phase and 4 months later. Very few cases of seizures in ketotic patients have been reported because ketone bodies have a protective effect against epilepsy. Seizures in hyperglycemia tend to be partial, and the only reports of visual seizures were due to occipital foci. Neuroradiological alterations have been reported in epileptic seizures, although usually in generalized seizures. The clinical, electrical, and imaging characteristics of this case are interesting and suggest that partial seizures can also cause long-term neuronal damage.

[Immunohistochemical expression of p53, p21, p16, and cyclin D1 in superficial bladder cancer. A tissue microarray study]. / Expresión inmunohistoquímica de p53, p21, p16 y ciclina D1 en el cáncer de vejiga superficial. Estudio en un soporte de tissue microarray.

INTRODUCTION AND OBJECTIVES: To retrospectively assess the relationship between immunohistochemical expression of p53, p21, p16, and cyclin D1, with recurrence, progression and survival in superficial bladder cancer. METHODS: 163 patients undergoing transurethral resection for superficial bladder cancer between February 1995 and March 2004. Tumor samples were included in a tissue microarray support that was serially sectioned for immunohistochemical staining. Grade and stage associations for each marker were evaluated by the Chi-square test. Assessment of the relationship with recurrence, progression, and survival Kaplan-Meier curves and log-rank test were used. RESULTS: There were no statistically significant differences in marker expression depending on tumor grade and stage, with the exception of Cyclin D1, that was significantly different depending on tumor stage (p=0.030). p21 expression was related to tumor recurrence (p=0.035), progression (p=0.008) and survival (p=0.034). p16 expression was also related to recurrence (p=0.048) and survival (p=0.047), but not to tumor progression (p=0.116). p53 and Cyclin D1 were not statistically associated with tumor recurrence, progression or survival. CONCLUSIONS: In our experience, only p16 and p21 may be useful in the management of superficial bladder tumors, as they are predictors of recurrence and survival in Ta and T1 patients.

[Nonalcoholic steatohepatitis associated with ovarian stromal hyperplasia]. / Esteatohepatitis no alcohólica asociada a hiperplasia estromal ovárica.

Alterations in liver function tests have previously been reported in patients with ovarian disease. We report the case of a woman with prolonged hypertransaminasemia, significant hirsutism and android phenotype who was diagnosed with nonalcoholic steatohepatitis and ovarian stromal hyperplasia.

Bladder blood flow and de-obstructive open prostatectomy: correlation with clinical and urodynamic parameters.

PURPOSE: To assess the relation between tissue blood flow changes during surgery with clinical and urodynamic parameters in obstructed patients. MATERIAL AND METHODS: A prospective study was conducted in 18 symptomatic patients with bladder outlet obstruction undergoing retropubic prostatectomy. A symptom assessment and a preoperative urodynamic study were performed. To measure bladder blood flow a BLF-10 laser Doppler flowmeter and a blunt-tipped probe were used intraoperatively. Tissue flow was measured in TPU units (1 TPU unit=1 ml per minute per 100 mg of tissue). Six measurements were taken: two control in the rectus abdominis muscle and four in the detrusor, two before the incision of the prostatic capsule and two after closure. For the statistical analysis, Wilcoxon test and a regression analysis were performed. RESULTS: Mean age was 70 years (range: 56-84). Six patients had an episode of acute urinary retention (AUR). No differences were found in the initial and final values of bladder blood flow of the rectus muscle and the bladder dome. A decrease of bladder blood flow in the anterior bladder wall was observed after prostate enucleation. AUR patients showed no differences in bladder blood flow values. Bladder blood flow (BBF) changes showed no correlation with any urodynamic or clinical parameter. CONCLUSIONS: Laser Doppler flowmetry is useful to study BBF with low morbidity, ease of use and reproducibility. Following de-obstructive surgery, a decrease in BBF occurs, probably associated with surgery. These changes are similar in patients with and without AUR and show no correlation with other parameters studied.

Chromosomal high-polysomies predict tumour progression in T1 transitional cell carcinoma of the bladder.

UNLABELLED: The main prognostic factor generally accepted for tumour progression in T1 transitional cell carcinoma (TCC) of the bladder is histological grade. Despite this fact it is considered inaccurate to make clinical decisions on individuals. It appears that progression from minimally invasive to deeply invasive cancer is concurrent with the acquisition of genomic alterations that increase the malignant potential of cancer cells. The aim of this study is to determine if changes in chromosomes 7, 8, 9 and 17 copy number can be used to predict recurrence and progression in patients with T1 TCC of the urinary bladder. METHODS: Thirty-one T1 TCC samples were analyzed for chromosomal alterations by fluorescence in situ hybridization using centromeric probes for chromosomes 7, 8, 9 and 17. Clinical data were collected from the patients' clinical records and correlated with chromosomal studies. RESULTS: Histological grade was confirmed as a prognostic factor of tumour progression (p=0.01). None of the cytogenetic alterations demonstrated in the studied group could be related to tumour recurrence. The high-polysomies (five or more copies) of chromosomes 8, 9 and 17 showed predictive value (p=0.05, 0.05, 0.03 respectively) for tumour progression since it was observed that patients with high-polysomy of these chromosomes showed more risk of tumour progression towards muscle-invasive disease than those without high-polysomy alteration. CONCLUSION: Our findings suggest a possible prognostic significance of highly aneuploid cells (high-polysomies of chromosomes 8, 9 and 17) in tumour progression of T1 TCC bladder tumours. FISH analysis is a reproducible technique for evaluating cytogenetic alterations and could contribute to the assessment of the individual prognosis of T1 transitional cell carcinoma of the bladder.

Renal cell carcinoma with syncytial giant cell component.

We report a case of clear cell renal cell carcinoma in which a prominent multinucleated giant cell component was intermingled with clear, granular, and spindle cells. Histological, ultrastructural, cytometric, and cytogenetic features of giant cells were similar to those of mononucleated cells in the tumor, and therefore they were not from stromal or osteoclast derivation. These giant cells had homogeneous, finely granular, abundant cytoplasm, often with scalloped cell borders, and contained from 5 to more than 50 nuclei, all of them very similar in size and shape, with prominent central nucleoli. Occasionally, surrounding inflammatory cells were also engulfed in the cytoplasm. This syncytial appearance was more similar to that of some giant cell carcinomas from the lung than to the pleomorphic giant cells often encountered in high grade renal cell tumors. Although the patient is alive and free of disease 6 years after diagnosis, a longer follow-up will be required to assess the potential prognostic influence of this peculiar histological appearance.

Ultrastructural morphometry of nucleoli: potential usefulness for objective grading of clear cell renal cell carcinoma.

The authors attempted to determine the potential prognostic value of several ultrastructural morphometric parameters, including nuclear, nucleolar, and cytoplasmic features, that could be used in the objective and reproducible histological grading of clear cell renal cell carcinoma. Several nuclear and cytoplasmic parameters were assessed by ultrastructural morphometry in 26 consecutive cases of clear cell renal cell carcinoma. The nuclear and nucleolar sizes, the number of nucleoli per nuclear section and the number of marginated nucleoli, Fuhrman's nuclear grade, and Robson's stage were recorded. In addition, the proportion of cytoplasmic components was semiquantitatively estimated and compared to light microscopic appearance. Follow-up ranged from 5 to 15 years (mean = 10 years). Statistical evaluations were performed by means of the Pearson or Spearman correlation coefficient tests, and differences in survival were estimated, using the Mantel-Cox proportional risk method. Differences in survival among patients with a mean nuclear area over and under 160 microm2, and among those with a mean nucleolar area over and under 10 microm2, were statistically significant. (Cutoff points were selected at the median value for both parameters; Mantel-Cox test: chi2 = 7.102, p < .01; and chi2 = 11.096, p < .001, respectively). Fuhrman's nuclear grade (p < .01) and tumor stage at diagnosis (p < .001) were also related to survival. These data suggest that, out of all the ultrastructural morphometric features, nucleolar area is the most useful in the reproducible and accurate grading of clear cell renal cell carcinoma.

Comparative genomic hybridization analysis of transitional cell carcinomas of the renal pelvis.

We used comparative genomic hybridization to analyze 10 primary tumor samples from patients with transitional cell carcinoma of the renal pelvis. The most frequent loss was located at 9q, that is, in 50% of the tumors. Gains of DNA sequences were most frequently observed in chromosome regions 1q21 approximately q23, 2p23 approximately p25, 8q21.1 approximately q22 and in the whole chromosome 20. High level amplifications at 1q21 approximately q25, 6p22 approximately p23, 8q21 approximately q22, 8q22 approximately q24.1, 11q13, and 12q14 approximately q21 were detected. Most of these regions have previously been reported to be involved in transitional cell carcinoma of the bladder, thus confirming the importance of an increasing number of chromosome imbalances in the development and progression of this type of tumors.

Detection of chromosomal imbalances in papillary bladder tumors by comparative genomic hybridization.

OBJECTIVES: To identify those genetic alterations that are associated with bladder cancer invasion and progression. METHODS: A total of 30 specimens of transitional cell carcinoma of the bladder were analyzed by comparative genomic hybridization. The results were compared and summarized with previously reported studies. RESULTS: The most frequent chromosome changes detected in our series of tumors were losses in 9q, 9p, 8p, and 11p and gains in 8q, 1q, 20q, and 11q. Three regions of deletion on chromosome 9 were delineated, at 9p21-p22, 9q13-q22, and 9q31-q34. Gains in 1q and losses on 11p were significantly more frequent in pT1G2 tumors than in superficial (pTa) ones. In our study, the most striking differences were seen between pT1G3 and pT1G2 tumors. Gains on 10p and 6p and losses at 5q, 6q, and 18q were significantly more frequent in the former. CONCLUSIONS: A summary of our results and those available from published reports suggest that several groups of chromosomal imbalances may be associated with specific steps along bladder cancer progression. These genetic changes assume two different patterns: those that are shared, but are more intensive in one stage than in the other, and those such as a gain on 3p that are unique to invasive tumors.

Study of allelic losses on 3p, 6q, and 17p in human urothelial cancer.

Forty-eight transitional cell carcinomas of the bladder and three transitional cell carcinomas of the renal pelvis were examined for loss of heterozygosity (LOH) on chromosomes 3p, 6q, and 17p. The most frequent allelic loss was seen on 17p (18/36, 50%) followed by 6q (6/22, 27%), and 3p (5/22, 23%). In cases with LOH at more than one locus, the same DNA sample often varied in degree of signal reduction for missing alleles. This observation indicates that LOH studies can serve to detect intratumor heterogeneity. No correlation was found between allelic losses at these chromosome arms and tumor grade and stage. Allelic losses on 6q were associated with tumors having a solid growth pattern; in this kind of tumors, allelic losses on 3p were associated with invasion.

Complete resolution of post-traumatic high-flow priapism with conservative treatment.

The most frequent cause of high-flow priapism is penile or perineal closed trauma with laceration of the cavernous artery and the formation of an arterial-lacunar fistula. We present the case of a high-flow priapism due to closed perineal trauma and damage to the left cavernous artery which completely resolved following conservative treatment. The case was documented by duplex Doppler ultrasound and selective pudendal arteriogram before and after resolution.

Serum bone alkaline phosphatase levels enhance the clinical utility of prostate specific antigen in the staging of newly diagnosed prostate cancer patients.

The aim of this study was to analyse the clinical utility of serum bone alkaline phosphatase (BAP) in addition to prostate-specific antigen (PSA) in the staging of newly diagnosed untreated prostate cancer patients. A prospective study was conducted, analysing serum BAP and PSA concentrations in 295 consecutive newly diagnosed untreated prostate cancer patients (T1-4, N0-1, M0-1b), 93 of whom had bone metastases on bone scan. The relationship of each marker with extent of bone disease, the influence of several clinical variables on both serum marker levels, the efficiency in predicting bone metastasis through receiver operating characteristic curves and, finally, the clinical utility in avoiding unnecessary bone scans were determined. Significant differences were found in the serum levels of both BAP and PSA between patients with and patients without bone metastases. Multiple regression analysis showed the extent of bone disease to be the only variable that influenced both serum levels. However, while serum BAP levels showed a statistical relationship with extent of bone disease, serum PSA levels did not. The best prediction of bone scan findings was obtained with the combination of both markers using a cut-off of 20 ng/ml, with positive and negative predictive values of 46.5% and 100%, respectively. This greater efficiency could permit 32.2% of initial bone scans to be avoided. False-positive and false-negative rates of BAP were 7.5% and 14%, respectively. This study suggests that serum BAP levels could play a complementary role in the diagnosis of bone metastasis in prostate cancer patients. This marker could provide useful clinical information on the degree of skeletal metastasis and constitute an easy way of enhancing the clinical utility of PSA. The addition of this marker to PSA in the initial evaluation could permit staging bone scan to be avoided at a PSA range of 10-20 ng/ml, with significant implications for cost saving.

Chromosome instability in lymphocytes from two patients affected by three sequential primary cancers: the role of fragile sites.

The chromosomal aberration rate and the expression of fragile sites induced by aphidicolin were evaluated in metaphase chromosomes obtained from peripheral blood lymphocytes of two untreated patients with multiple primary cancers. Spontaneous aberrations of chromosome number and structure and chromosome fragility were compared with controls with the use of the same methods. Chromosomal aberration rates and expression frequencies of fragile sites were significantly higher in the patients than in normal control subjects. In the patients, all but one structural chromosome aberration involved at least one fragile site. Our results suggest that fragile sites may be unstable regions of the human genome, which might play an important role in the genetic instability associated with cancer predisposition.

Analysis of 3p allelic losses in renal cell carcinomas: comparison with cytogenetic results.

We performed a study of loss of heterozygosity (LOH) at 3p by restriction fragment length polymorphism analysis in a series of 22 renal tumors. In 11 cases, molecular results could be compared with those of cytogenetic studies. The highest frequency of allelic losses at 3p was seen in clear cell non-papillary renal tumors, whereas none of the papillary renal cell carcinomas showed LOH at 3p. Allelic losses on 3p were found to be independent of tumor grade or stage or both. One case analyzed showed a discrepancy between cytogenetic and LOH studies. This tumor displayed rearrangements of chromosome 3 and no LOH at the c-RAF-1 (close to the Von Hippel Lindau gene) locus.

Low-grade spindle cell carcinoma of the kidney.

The authors report a renal cell carcinoma composed largely of spindle cells of Fuhrman's nuclear grade II in which the bland appearance of the cells and low mitotic index were reminiscent of a benign or low-grade smooth muscle tumor. Keratin immunostaining was positive, but evidence of epithelial differentiation was obtained by electron microscopy. The tumor was an incidental finding and it did not invade the perirenal fat or the renal vein. Follow-up is only 24 months but the histological features suggest that the prognosis may be better than that of a classic sarcomatoid renal cell carcinoma.