Progress in Personalizing Chemotherapy for Bladder Cancer

Platinum-based chemotherapy is commonly used for the treatment of locally advanced and metastatic bladder cancer. However, there are currently no methods to predict chemotherapy response in this disease setting. A better understanding of the biology of bladder cancer has led to developments of molecular biomarkers that may help guide clinical decision making. These biomarkers, while promising, have not yet been validated in prospective trials and are not ready for clinical applications. As alkylating agents, platinum drugs kill cancer cells mainly through induction of DNA damage. A microdosing approach is currently being tested to determine if chemoresistance can be identified by measuring platinum-induced DNA damage using highly sensitive accelerator mass spectrometry technology. The hope is that these emerging strategies will help pave the road towards personalized therapy in advanced bladder cancer

Aplicación de las matemáticas en el primer enlace geodésico entre Europa y África

La figura que más se acerca a la verdadera forma de la tierra es el Geoide, pero su expresión matemática es muy compleja. Por tanto, para poder hacer mediciones sobre ella debe ser sustituida por diversas superficies de referencia más sencillas (planos, esferas, elipsoides...). Ha sido la Geofísica, a través de la modelización matemática y a partir de diversas reducciones, la que ha permitido a la Geodesia pasar de una superficie a otra. La figura más aproximada a la forma real de la Tierra y matemáticamente sencilla de representar es el elipsoide de revolución. A lo largo de la historia han sido muchos los elipsoides adoptados, según se adaptasen a las necesidades locales de cada nación. Está siendo la universalización del uso del GPS la razón por la que se tiende a usar un único elipsoide de referencia: el WGS-84 (World Geodetic System), admitido como el que mejor se adapta con carácter general al globo terráqueo. Como aplicación práctica de todo esto se ha analizado el enlace hispano-argelino realizado en 1879, con métodos modernos de cálculo. El resultado de este trabajo pone de manifiesto la alta calidad del enlace original

Multifunctional targeting micelle nanocarriers with both imaging and therapeutic potential for bladder cancer.

BackgroundWe previously developed a bladder cancer-specific ligand (PLZ4) that can specifically bind to both human and dog bladder cancer cells in vitro and in vivo. We have also developed a micelle nanocarrier drug-delivery system. Here, we assessed whether the targeting micelles decorated with PLZ4 on the surface could specifically target dog bladder cancer cells.Materials and methodsMicelle-building monomers (ie, telodendrimers) were synthesized through conjugation of polyethylene glycol with a cholic acid cluster at one end and PLZ4 at the other, which then self-assembled in an aqueous solution to form micelles. Dog bladder cancer cell lines were used for in vitro and in vivo drug delivery studies.ResultsCompared to nontargeting micelles, targeting PLZ4 micelles (23.2 ± 8.1 nm in diameter) loaded with the imaging agent DiD and the chemotherapeutic drug paclitaxel or daunorubicin were more efficient in targeted drug delivery and more effective in cell killing in vitro. PLZ4 facilitated the uptake of micelles together with the cargo load into the target cells. We also developed an orthotopic invasive dog bladder cancer xenograft model in mice. In vivo studies with this model showed the targeting micelles were more efficient in targeted drug delivery than the free dye (14.3×; P < 0.01) and nontargeting micelles (1.5×; P < 0.05).ConclusionTargeting micelles decorated with PLZ4 can selectively target dog bladder cancer cells and potentially be developed as imaging and therapeutic agents in a clinical setting. Preclinical studies of targeting micelles can be performed in dogs with spontaneous bladder cancer before proceeding with studies using human patients

Geodetic works carried out in the Strait of Gibraltar

The proximity between Europe and Africa and the fact that the Strait of Gibraltar has historically acted as a link between races, cultures and religions have made absolutely necessary to establish a relationship between the Northern African coast and the Southern European equivalent. From the Nineteenth Century the possibility of building a permanent link between both continents through the Strait of Gibraltar has been taken into account. In order to establish that relationship it is necessary to have coastal zones completely geo-referenced, under the same geodetic system and with a unique projection system. The paper describes the work carried out in the Strait of Gibraltar for this purpose

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

PurposeCabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.MethodsThis was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).ResultsSixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.ConclusionsDespite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients

BACKGROUND: Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (TTP-HUS) are related and uncommon disorders with a high fatality and complication rate if untreated. Plasma exchange therapy has been shown to produce high response rates and improve survival in patients with many forms of TTP-HUS. We performed a retrospective cohort study of 178 consecutively treated patients with TTP-HUS and analyzed whether clinical or laboratory characteristics could predict for important short- and long-term outcome measures. RESULTS: Overall 30-day mortality was 16% (n = 27). 171 patients (96%) received plasma exchange as the principal treatment, with a mean of 8 exchanges and a mean cumulative infused volume of 42 ± 71 L of fresh frozen plasma. The rate of complete response was 65% or 55% depending on whether this was defined by a platelet count of 100,000/μl or 150,000/μl, respectively. The rate of relapse was 18%. The Clinical Severity Score did not predict for 30-day mortality or relapse. The time to complete response did not predict for relapse. Renal insufficiency at presentation was associated with a decreased risk of relapse, with each unit increase in serum creatinine associated with a 40% decreased odds of relapse. 72% of our cohort had an idiopathic TTP-sporadic HUS, while 17% had an underlying cancer, received a solid organ transplant or were treated with a mitomycin-based therapy. The estimated overall 5-year survival was 55% and was significantly better in those without serious underlying conditions. CONCLUSION: Plasma exchange therapy produced both high response and survival rates in this large cohort of patients with TTP-HUS. The Clinical Severity Score did not predict for 30-day mortality or relapse, contrary to our previous findings. Interestingly, the presence of renal insufficiency was associated with a decreased risk of relapse. The most important predictor of mortality was the presence or absence of a serious underlying disorder

Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models.

Metastasis is a major cause of mortality for cancer patients and remains as the greatest challenge in cancer therapy. Driven by multiple factors, metastasis may not be controlled by the inhibition of single target. This study was aimed at assessing the hypothesis that drugs could be rationally combined to co-target critical DNA, RNA and protein molecules to achieve "saturation attack" against metastasis. Independent actions of the model drugs DNA-intercalating doxorubicin, RNA-interfering miR-34a and protein-inhibiting sorafenib on DNA replication, RNA translation and protein kinase signaling in highly metastatic, human osteosarcoma 143B cells were demonstrated by the increase of γH2A.X foci formation, reduction of c-MET expression and inhibition of Erk1/2 phosphorylation, respectively, and optimal effects were found for triple-drug combination. Consequently, triple-drug treatment showed a strong synergism in suppressing 143B cell proliferation and the greatest effects in reducing cell invasion. Compared to single- and dual-drug treatment, triple-drug therapy suppressed pulmonary metastases and orthotopic osteosarcoma progression to significantly greater degrees in orthotopic osteosarcoma xenograft/spontaneous metastases mouse models, while none showed significant toxicity. In addition, triple-drug therapy improved the overall survival to the greatest extent in experimental metastases mouse models. These findings demonstrate co-targeting of DNA, RNA and protein molecules as a novel therapeutic strategy for the treatment of metastasis

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0-12.9, 12.9-22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity

Resection of multifocal non–small cell lung cancer when the bronchioloalveolar subtype is involved

AbstractObjectiveBronchioloalveolar lung cancer is commonly multifocal and can also present with other non–small cell types. The staging and treatment of multifocal non–small cell cancer are controversial. We evaluated the current staging of multifocal bronchioloalveolar carcinoma and the therapeutic effectiveness of resection when this tumor type is involved.MethodsWe reviewed our experience between 1992 and 2000 with complete pulmonary resections for bronchioloalveolar carcinoma. Kaplan-Meier survival curves were calculated from the dates of pulmonary resection.ResultsAmong 73 patients with bronchioloalveolar carcinoma, 14 patients, 7 male and 7 female with a mean age of 65 years (51-87 years), had multifocal lesions without lymph node metastases. Follow-up was 100% for a median of 5 years (range 2.6-8.5 years). Tumor distribution was unilateral in 9 patients and bilateral in 5 patients. The multifocal nature of the disease was discovered intraoperatively in 4 patients. Nine patients had 2 lesions, 4 patients had 3 lesions, and 1 patient had innumerable discrete foci in a single lobe. Operative mortality was 0. Postoperatively, 10 patients were staged pIIIB or pIV on the basis of multiple foci of similar morphology; 4 patients had some differences in histology (implying multiple stage 1 primaries). The median survival time to death from cancer was 14 months (141 days–5.6 years). The overall 5-year survival after resection of multifocal bronchioloalveolar carcinoma was 64%. Unilateral or bilateral distribution had no impact on survival.ConclusionsThe current staging system is not prognostic for multifocal bronchioloalveolar carcinoma without lymph node metastases. Complete resection of multifocal non–small cell lung cancer when bronchioloalveolar carcinoma is a component may achieve survivals similar to that of stage I and II unifocal non–small cell lung cancer. When bronchioloalveolar carcinoma is believed to be one of the cell types in multifocal disease without lymph node metastases, consideration should be given to surgical resection

The Influence of Light on Olive (Olea europaea L.) Fruit Development Is Cultivar Dependent

In olive, the response to environmental conditions, such as light availability, is under genetic control and requires a combination of biochemical and physiological events. We investigated the effect of irradiance in fruit development in two Italian cultivars, Leccino and Frantoio. Morphological and cyto-histological analyses, as well as water and oil content determination, were carried out in fruits exposed to a different light regime (named as light and shade fruits). Results demonstrated that the influence of light availability on fruit development depends on the cultivar. In Leccino, the fresh and the dry weight, the percentage of dry matter, the kernel and fruit diameter, the mesocarp thickness and the mesocarp cell size were higher in the light exposed fruits than in the ones grown in the shade. In Frantoio, differences between light and shade fruits were observed only at 140 DAF (Days After Flowering) and only in the kernel and fruit diameter and in the dry and fresh weight, which were higher in the light exposed fruits. Leccino, therefore, showed a greater sensitivity to the light availability. This may be related to the observed delay in the endocarp lignification as compared to the Frantoio cultivar. In each cultivar, moreover, shade and light fruits did not show differences in the timing of cell differentiation. Finally, the investigation of oil storage carried out in cyto-histological studies demonstrated that differences in oil content between fruit subjected to different light regimes correlated with the number of oil containing cells, rather than the oil content per cell. A different behaviour was observed in the two cultivars: in Leccino, the mesocarp cell size was almost twice of Frantoio, while oil drops were only 30% larger; therefore, the percentage of cell volume occupied by the oil drops was lower in Leccino than in Frantoio. The chemical analysis confirmed this observation