International cancer seminars: a focus on kidney cancer.

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

Prospective glioma grading using single-dose dynamic contrast-enhanced perfusion MRI.

AIM: To evaluate the sensitivity and specificity of single-dose dynamic contrast-enhanced (DCE) perfusion magnetic resonance imaging (MRI) in prospective evaluation of glioma grading and to correlate the relative cerebral blood volume (rCBV) values with mitotic and ki-67 indexes obtained at histopathology. MATERIALS AND METHODS: A total of 53 histologically proven patients with glioma were included in this study. DCE-MRI perfusion with a single dose of contrast medium was included in brain tumour protocol and prospective grading of glioma into low and high grade was done based on a previously reported rCBV cut-off value of 3. Tumours with rCBV ≥ 3 were considered to be high grade and rCBV < 3 were considered to be low grade. The sensitivity and specificity of the cut-off value were estimated. Ki-67 and mitotic indexes were also obtained on histopathological analysis along with histological grading. RESULTS: Based on pre-defined rCBV cut-off values, prospective grading of low- and high-grade glioma was achieved with a sensitivity and specificity of 97.22% and 100%, respectively. Significant correlation was found between the mitotic/ki-67 indexes and rCBV values when data for high- and low-grade tumours was combined. CONCLUSION: DCE-MRI performed with a single dose of contrast medium is as effective as a protocol with a double-dose of contrast medium for glioma grading using 3 T MRI and could be added to the routine evaluation protocol of brain tumours.

Toward understanding the catalytic synergy in the design of bimetallic molecular sieves for selective aerobic oxidations.

Structure-property correlations and mechanistic implications are important in the design of single-site catalysts for the activation of molecular oxygen. In this study we rationalize trends in catalytic synergy to elucidate the nature of the active site through structural and spectroscopic correlations. In particular, the redox behavior and coordination geometry in isomorphously substituted, bimetallic VTiAlPO-5 catalysts are investigated with a view to specifically engineering and enhancing their reactivity and selectivity in aerobic oxidations. By using a combination of HYSCORE EPR and in situ FTIR studies, we show that the well-defined and isolated oxophilic tetrahedral titanium centers coupled with redox-active VO(2+) ions at proximal framework positions provide the loci for the activation of oxidant that leads to a concomitant increase in catalytic activity compared to analogous monometallic systems.

Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy.

BACKGROUND: We examine how changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. METHODS: In metastatic renal cancer patients treated with anti-angiogenic tyrosine kinase inhibitors, arterial phase contrast-enhanced computed tomography was used to simultaneously measure changes in: (a) tumour size, and (b) tumour enhancement (a surrogate marker of tumour vessel density) within individual lesions. RESULTS: No correlation between baseline tumour enhancement and lesion shrinkage was observed, but a reduction in tumour enhancement on treatment was strongly correlated with reduction in lesion size (r=0.654, P<0.0001). However, close examination of individual metastases revealed different types of response: (1) good vascular response with significant tumour shrinkage, (2) good vascular response with stabilisation of disease, (3) poor vascular response with stabilisation of disease and (4) poor vascular response with progression. Moreover, contrasting responses between different lesions within the same patient were observed. We also assessed rebound vascularisation in tumours that acquired resistance to treatment. The amplitude of rebound vascularisation was greater in lesions that had a better initial response to therapy (P=0.008). INTERPRETATION: Changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. The data provide insight into the mechanisms that underlie response and resistance to this class of agent.

Prognostic utility of pre-operative circulating osteopontin, carbonic anhydrase IX and CRP in renal cell carcinoma.

BACKGROUND: Objectively measured circulating biomarkers of prognosis complementing existing clinicopathological models are needed in renal cell carcinoma (RCC). METHODS: Blood samples collected from 216 RCC patients in Leeds before nephrectomy (median follow-up 7 years) were analysed for C-reactive protein (CRP), osteopontin (OPN) and carbonic anhydrase IX (CA9) and prognostic significance determined. RESULTS: CA9, OPN and CRP were univariately prognostic for overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) with CRP and CA9 being independently prognostic for OS/CSS and OS, respectively. Including CA9, OPN and CRP with other conventional prognostic factors gave a superior predictive capacity when compared with a previously published pre-operative clinical nomogram (Karakiewicz et al, 2009). Osteopontin outperformed this nomogram and the post-operative SSIGN score for OS but not for CSS, being significantly predictive for non-cancer deaths. Osteopontin, CRP and CA9 outperformed stage (c-index 76% compared with 70% for stage) and OPN or CA9 identified several subsets of poor prognosis patients including in T1 patients, who may benefit from adjuvant therapy and increased surveillance. CONCLUSION: Circulating CA9, OPN and CRP add value to existing clinicopathological prognostic factors/models and support further studies to investigate their potential use in improving the clinical management of RCC.

Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy.

AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.

Association of serum amyloid A protein and peptide fragments with prognosis in renal cancer.

BACKGROUND: In renal cell carcinoma (RCC), the discovery of biomarkers for clinical use is a priority. This study aimed to identify and validate diagnostic and prognostic serum markers using proteomic profiling. METHODS: Pre-operative sera from 119 patients with clear cell RCC and 69 healthy controls was analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry with stringent in-house quality control and analysis routines. Following identification of one prognostic peak as a fragment of serum amyloid A (SAA), total serum SAA and CRP were also determined by immunoassay for further validation. RESULTS: Several peptides were identified as having independent prognostic but not diagnostic significance on multivariable analysis. One was subsequently identified as a 1525 Da fragment of SAA (hazard ratio (HR)=0.26, 95% CI 0.08-0.85, P=0.026). This was weakly negatively correlated with total SAA, which was also of independent prognostic significance (HR=2.46, 95% CI 1.17-5.15, P=0.017). Both potentially strengthened prognostic models based solely on pre-operative variables. CONCLUSIONS: This is the first description of the prognostic value of this peptide in RCC and demonstrates proof of principle of the approach. The subsequent examination of SAA protein considerably extends previous studies, being the first study to focus solely on pre-operative samples and describing potential clinical utility in pre-operative prognostic models.

Improving the accuracy of pre-operative survival prediction in renal cell carcinoma with C-reactive protein.

BACKGROUND: Validated objective biomarkers are needed for patients with renal cell carcinoma (RCC) to guide patient management and define high-risk populations for follow-up or for therapeutic purposes. METHODS: Patients undergoing nephrectomy for RCC (n=286 all stages, 84% with conventional clear cell type) were included with a median duration follow-up of 5 years. The prognostic significance of pre-operative haematological and biochemical variables, including C-reactive protein (CRP) values were examined and whether they added additional information to a recently published pre-operative scoring system was determined. RESULTS: C-reactive protein was the most significant predictor of overall survival (OS; χ(2)=50.9, P<0.001). Five-year OS for patients with CRP ≤ 15 mg l(-1) vs >15 mg l(-1) was 72% (95% CI 65-78%) and 33% (95% CI 23-44%), respectively. Similar results were seen for cancer-specific survival (CSS) and disease-free survival. On multivariate analysis, CRP remained highly significant for CSS (χ(2)=17.3, P<0.0001) and OS (χ(2)=9.8, P<0.002), in addition to other pre-operative variables including log of neutrophil/lymphocyte ratio, red blood cell count and white cell count. C-reactive protein was significant in addition to the pre-operative nomogram score (χ(2)=12.5, P=0.0004 for OS, χ(2)=16.2, P=0.0001 for CSS and χ(2)=8.6, P=0.003 for DFS) and was still significant when other pre-operative variables were included. CONCLUSION: C-reactive protein and other haematological and biochemical variables have independent prognostic significance in RCC and may enhance pre-operative scoring systems.

Synergistic behavior of bimetallic rhenium cluster catalysts: spectroscopic investigation into the nature of the active site.

Single-site Re nanoparticles were produced by anchoring dirhenium organometallic clusters on to the inner walls of mesoporous silica. The presence of oxophilic atoms (Sb or Bi) is essential to obtain well dispersed Re(0) centers. The interaction between the organometallic cluster and the silica support is critical for the generation of well-defined and isolated Re(0) single sites. FTIR spectroscopy was used to track the decomposition of the organometallic precursors and the adsorption of probe molecules such as CO on the metal sites sheds valuable information on the catalytic potential of this new class of bimetallic nanocatalysts.

Pre-operative urinary cathepsin D is associated with survival in patients with renal cell carcinoma.

BACKGROUND: No circulating markers are routinely used for renal cancer. The objective of this pilot study was to investigate whether conditioned media (CM) from renal cancer cell lines contains potential biomarkers that, when measured in clinical fluids, have diagnostic or prognostic utility. METHODS: Comparative 2D PAGE profiling of CM from renal cell carcinoma (RCC) and normal renal cultures identified cathepsin D that was subsequently validated in urine samples from 239 patients and healthy and benign disease subjects. RESULTS: Urinary cathepsin D was found to be significantly associated with overall (OS) (hazard ratio, HR, 1.33, 95%CI [1.09-1.63], P=0.005) and cancer-specific survival (HR 1.36, 95%CI [1.07-1.74], P=0.013) in RCC patients on univariate analysis. An optimal cut point (211 ng ml(-1) micromolCr(-1)) around which to stratify patients by OS was determined. Five-year OS equal to/above and below this value was 47.0% (95%CI 35.4%, 62.4%) and 60.9% (48.8%, 76.0%), respectively. On multivariable analysis using pre-operative variables, cathepsin D showed some evidence of independent prognostic value for OS (likelihood ratio test P-value=0.056) although requiring further validation in larger patient numbers with sufficient statistical power to determine independent significance. CONCLUSION: These data establish an important proof of principle and show the potential of proteomics-based studies. Cathepsin D may be of value as a pre-operative urinary biomarker for RCC, alone or in combination.

Chemoselective alkane oxidation by superoxo-vanadium(V) in vanadosilicate molecular sieves.

Electron paramagnetic resonance (EPR) spectroscopy of reactive superoxo-vanadium(V) species in vanadosilicate molecular sieves (microporous VS-1 and mesoporous V-MCM-41) generated on contact with H2O2, tert-butyl hydroperoxide (TBHP), or (H2+O2) is reported for the first time. By suitable choice of the silicate structure, solvent, and oxidant, we could control the vanadium-(O2-*) bond (i.e., the V-O bond) covalency, the mode of O-O cleavage (in the superoxo species), and, therefore, chemoselectivity in the oxidation of n-hexane: Oxidation by TBHP over V-MCM-41, for example, yielded 27.2% of (n-hexanol+n-hexanal+n-hexanoic acid), among the highest chemoselectivities for oxidation of the terminal -CH3 in a linear paraffin reported to date. Over these vanadosilicates, oxidation of the primary C-H bond occurs only via a homolytic O-O bond cleavage; the secondary C-H bond oxidations may proceed via both the homo- and heterolytic O-O cleavage mechanisms.

Intravenous irinotecan plus oral ciclosporin.

We previously reported a phase I study of intravenous irinotecan plus oral ciclosporin, in which dose-limiting diarrhoea was not observed, supporting the hypothesis that pharmacokinetic modulation of irinotecan by ciclosporin may improve its therapeutic index. We now report results of a further 34 patients treated at the recommended dose. A low rate of diarrhoea of grade 3 or above (3%) was again seen, with useful anti-tumour activity. The regimen is to be formally evaluated as part of a future phase III trial.

Diabetes and lower-limb amputations in the community. A retrospective cohort study. DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland/Medicines Monitoring Unit.

OBJECTIVE: There are few U.K. data on the incidence rates of amputation in diabetic subjects compared with the nondiabetic population. RESEARCH DESIGN AND METHODS: We performed a historical cohort study of first lower-extremity amputations based in Tayside, Scotland (population 364,880) from 1 January 1993 to 31 December 1994. The Diabetes Audit and Research in Tayside Scotland (DARTS) database was used to identify a prevalence cohort of 7,079 diabetic patients on 1 January 1993. We estimated age-specific and standardized incidence rates of lower-limb amputations in the diabetic and nondiabetic cohorts. Results were compared with a previous study that evaluated lower-extremity amputations in diabetic patients in Tayside in 1980-1982. RESULTS: There were 221 subjects who underwent a total of 258 nontraumatic amputations. Of the 221 subjects, 60 (27%) patients were diabetic (93% NIDDM), and 63% were first amputations. The median duration of diabetes was 6 years (range: newly diagnosed to 41 years). Nonhealing ulceration (31%) and gangrene (29%) were the two main indications for amputation in the diabetic subjects. Of the 161 nondiabetic subjects, 140 (80%) underwent first amputations. The adjusted incidences in the diabetic and nondiabetic groups were 248 and 20 per 100,000 person-years, respectively. Tayside patients with diabetes thus had a 12.3-fold risk of an amputation compared with nondiabetic residents (95% CI 8.6-17.5). The estimated proportion of diabetic patients in the population rose from 0.81% in 1980-1982 to 1.94% in 1993-1994, whereas the absolute rate of amputation in diabetic subjects was unchanged from that in 1980-1982. CONCLUSIONS: These population-based U.K. amputation data are similar to amputation rates in the U.S. Amputation rates appear to have decreased significantly since 1980-1982. The impact of diabetes education and prevention programs that target the processes leading to amputation can now be evaluated.

Ru(x)Pt(y)Sn(z) cluster-derived nanoparticle catalysts: spectroscopic investigation into the nature of active multinuclear single sites.

Cluster-derived Ru(x)Pt(y)Sn(z) nanoparticles are active catalysts in the hydrogenation of nitrobenzene. The nature of the active sites has been elucidated by FTIR spectroscopy using CO and NO as probe molecules. A new metal carbonyl cluster precursor, Pt(2)Ru(2)(SnBu(t)(3))(2)(CO)(9)(µ-H)(2), has been synthesized to obtain a Ru(2)Pt(2)Sn(2)/SiO(2) catalyst, that displayed remarkably high levels of conversion and selectivities compared to other bi-and monometallic analogues. Spectroscopic comparisons with Ru(5)PtSn/SiO(2) indicate that both the nature and the stoichiometry of the metals play a key role in modulating the catalytic activities and selectivities. A multinuclear single-site containing Pt centers, which facilitate the hydrogen activation, coupled with a highly reactive Ru site, possibly involved in the nitrobenzene activation, can be hypothesized. The oxophilicity of tin helps with the anchoring of the nanoparticles, aids the dispersion of the other metals, and can play an important role in influencing the selectivity to aniline.

India: using stakeholder analysis to forecast success.

PIP: This article presents the use of stakeholder analysis to examine the efficacy of health reform programs in India. Stakeholder analysis assists planners in identifying groups affected by proposed activities, their reactions to prospective changes, and the roles they might play in supporting or opposing them. Such information is then used to develop strategies involving national and local officials and communities in reform. Stakeholder analysis was used by the US Agency for International Development (USAID) for the proposed Women's and Children's Health (WACH) project. It involved interviews among major stakeholders regarding their views on the effectiveness of the current health system, the new roles that health care organizations and individuals would have after changes in service delivery under WACH, and their institutional capacity to handle new roles. In addition to stakeholder analysis, three other tools are available to policy managers and health sector reform teams to help them manage and influence the process of health sector reform: 1) institutional mapping, which involves identification and analysis of an organization's structure; 2) political mapping through graphic display of sources and degrees of political support and opposition; and 3) interest mapping, a combination of stakeholder analysis and political mapping. With the use of stakeholder analysis, USAID was provided with crucial information for the evaluation of community support and success capability of the WACH project.^ieng