Bevacizumab in recurrent ovarian cancer: could it be particularly effective in patients with clear cell carcinoma?

Purpose Treatment of recurrent ovarian carcinoma is a challenge, particularly for the clear cell (CCC) subtype. However, there is a preclinical rationale that these patients could achieve a benefit from antiangiogenic therapy. To assess this hypothesis, we used the growth modulation index (GMI), which represents an intrapatient comparison of two successive progression-free survival (PFS). Methods We conducted a retrospective real-world study performed on 34 patients with recurrent ovarian cancer, treated with bevacizumab-containing regimens from January 2009 to December 2017. The primary endpoint was GMI. An established cut-off > 1.33 was defined as a sign of drug activity. Results 73.5% of patients had high-grade serous ovarian carcinoma (HGSOC), and 17.7% had CCC; 70.6% of patients received carboplatin/gemcitabine/bevacizumab, and 29.4% received weekly paclitaxel/bevacizumab. According to histological subtype, the overall response rate and median PFS were 52% and 14 months for HGSOC and 83.3% and 20 months for CCC, respectively. The overall population median GMI was 0.99; it was 0.95 and 2.36 for HGSOC and CCC, respectively. CCC subtype was significantly correlated with GMI > 1.33 (odds ratio 41.67; 95% confidence interval 3.6–486.94; p = .03). Conclusion Adding bevacizumab to chemotherapy in recurrent CCC is associated with a remarkable benefit in this cohort. The efficacy of antiangiogenic drugs in CCC warrants further prospective evaluation (AU)

Bevacizumab in recurrent ovarian cancer: could it be particularly effective in patients with clear cell carcinoma?

PURPOSE: Treatment of recurrent ovarian carcinoma is a challenge, particularly for the clear cell (CCC) subtype. However, there is a preclinical rationale that these patients could achieve a benefit from antiangiogenic therapy. To assess this hypothesis, we used the growth modulation index (GMI), which represents an intrapatient comparison of two successive progression-free survival (PFS). METHODS: We conducted a retrospective real-world study performed on 34 patients with recurrent ovarian cancer, treated with bevacizumab-containing regimens from January 2009 to December 2017. The primary endpoint was GMI. An established cut-off > 1.33 was defined as a sign of drug activity. RESULTS: 73.5% of patients had high-grade serous ovarian carcinoma (HGSOC), and 17.7% had CCC; 70.6% of patients received carboplatin/gemcitabine/bevacizumab, and 29.4% received weekly paclitaxel/bevacizumab. According to histological subtype, the overall response rate and median PFS were 52% and 14 months for HGSOC and 83.3% and 20 months for CCC, respectively. The overall population median GMI was 0.99; it was 0.95 and 2.36 for HGSOC and CCC, respectively. CCC subtype was significantly correlated with GMI > 1.33 (odds ratio 41.67; 95% confidence interval 3.6-486.94; p = .03). CONCLUSION: Adding bevacizumab to chemotherapy in recurrent CCC is associated with a remarkable benefit in this cohort. The efficacy of antiangiogenic drugs in CCC warrants further prospective evaluation.

Prognostic value of neutrophil-to-lymphocyte ratio and other inflammatory markers in patients with high-risk soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) have a high risk of relapse in spite of the use of (neo)adjuvant chemotherapy. In this context, looking for new prognostic biomarkers is an interesting field of research. Our aim is to analyze the prognostic impact of neutrophil-to-lymphocyte ratio (NLR) and other serum markers in patients with STS who received chemotherapy with curative intent. MATERIALS AND METHODS: This is a retrospective observational study. We included all patients with STS (primary tumor, local recurrence or resected metastatic disease) treated with high-dose ifosfamide and epirubicin with curative intent from January 2007 to December 2018. The pretreatment NLR and other serum markers were calculated, selecting the median as the cut-off value for the survival and multivariate analysis. RESULTS: Seventy-nine patients were included. Median NLR, platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) were 2.83, 174.05 and 3.25, respectively. Median progression-free survival (PFS) was significantly longer in patients with low NLR [not reached (NR) vs 21, 92 months, P < 0.01]. No significant differences were found for PFS regarding PLR or LMR. For overall survival (OS), a significant survival advantage was also found for patients with low NLR (NR vs 65.45 months, P = 0.01), without differences for PLR or LMR. In multivariate analysis, NLR remains an independent prognostic factor for PFS. CONCLUSION: In our cohort, low NLR was significantly associated with a longer PFS and OS, and is consolidated as an independent prognostic factor.

Características clínicas e histopatológicas de ojos enucleados por melanoma uveal en un hospital terciario en España / Clinical and histopathological features of choroidal melanoma-related enucleated eyes in a Spanish tertiary hospital

Objetivo: Estudiar las variables clínicas y anatomopatológicas de mal pronóstico en una muestra de pacientes con melanoma maligno de úvea que requirieron enucleación como tratamiento definitivo en un hospital terciario en Madrid (España) durante un período de tiempo de 6 años. Material y métodos: Estudio retrospectivo, observacional, longitudinal. Se analiza la presencia de factores clínicos y anatomopatológicos conocidos de mal pronóstico y otros en 30 melanomas malignos: 20 enucleados de novo (grupo A) y 10 tras recibir tratamiento con radioterapia (grupo B). Se estudia el grado de fiabilidad diagnóstica de la resonancia magnética nuclear, comparándola con la histología (gold standard) para predecir la presencia de invasión escleral y extraescleral. Resultados: El tamaño tumoral, la rotura de la membrana de Bruch, la invasión escleral y la proximidad al nervio óptico fueron los factores de mal pronóstico más determinantes. Se logró controlar la enfermedad en el 93% de los casos, con una incidencia de diseminación metastásica del 6% y una supervivencia del 100% a una media de seguimiento de 3 ± 1,5 (rango 1,2-6) años. La sensibilidad de la resonancia magnética nuclear, en nuestra población, para detectar infiltración escleral fue del 27%, y extraescleral, del 100%. Conclusiones: El análisis de los datos clínicos e histopatológicos recogidos justifican la enucleación como tratamiento final en los pacientes estudiados. La resonancia magnética nuclear no resultó un buen método de cribado para detectar la extensión escleral

Objective: To study clinical and pathological variables leading to a poor prognosis in a sample of uveal malignant melanoma patients who required eyeball enucleation as final treatment approach. All patients were seen and treated in the same public tertiary hospital in Madrid (Spain) within a 6-year time-period. Materials and methods: Longitudinal observational retrospective study. The presence of clinical and pathologic factors known to be linked to poor prognosis, as well as other features, was assessed in 30 malignant melanoma: 20 de novo-enucleated malignant melanoma eyes (group A), and 10 in eyes that received radiotherapy prior to enucleation (group B). The diagnostic reliability of magnetic resonance imaging was assessed by comparing it with the histology results (gold standard) as a means to detect scleral and extra-scleral extension. Results: Tumour size, Bruch's membrane rupture, scleral infiltration, and distance to the optic nerve were the most decisive factors for a poor prognosis in the study sample. In 93% of cases the condition was under control, with a 6% incidence rate of metastatic spread and a 100% rate of overall survival for a mean follow-up period of 3 ± 1.5 (range 1.2-6) years. In the study population, the sensitivity of the magnetic resonance imaging to detect scleral infiltration was 27%, which increased to 100% for identifying extra-scleral involvement. Conclusions: The analyses of the clinical and pathological data collected within the framework of this study justify enucleation as the treatment of choice for the patients of this study. Magnetic resonance imaging was not found to be an optimum screening method to detect scleral infiltration in this study sample

Clinical and histopathological features of choroidal melanoma-related enucleated eyes in a Spanish tertiary hospital. / Características clínicas e histopatológicas de ojos enucleados por melanoma uveal en un hospital terciario en España.

OBJECTIVE: To study clinical and pathological variables leading to a poor prognosis in a sample of uveal malignant melanoma patients who required eyeball enucleation as final treatment approach. All patients were seen and treated in the same public tertiary hospital in Madrid (Spain) within a 6-year time-period. MATERIALS AND METHODS: Longitudinal observational retrospective study. The presence of clinical and pathologic factors known to be linked to poor prognosis, as well as other features, was assessed in 30 malignant melanoma: 20 de novo-enucleated malignant melanoma eyes (group A), and 10 in eyes that received radiotherapy prior to enucleation (group B). The diagnostic reliability of magnetic resonance imaging was assessed by comparing it with the histology results (gold standard) as a means to detect scleral and extra-scleral extension. RESULTS: Tumour size, Bruch's membrane rupture, scleral infiltration, and distance to the optic nerve were the most decisive factors for a poor prognosis in the study sample. In 93% of cases the condition was under control, with a 6% incidence rate of metastatic spread and a 100% rate of overall survival for a mean follow-up period of 3±1.5 (range 1.2-6) years. In the study population, the sensitivity of the magnetic resonance imaging to detect scleral infiltration was 27%, which increased to 100% for identifying extra-scleral involvement. CONCLUSIONS: The analyses of the clinical and pathological data collected within the framework of this study justify enucleation as the treatment of choice for the patients of this study. Magnetic resonance imaging was not found to be an optimum screening method to detect scleral infiltration in this study sample.

Transport of d-galactose by the gastrointestinal tract of the locust, Locusta migratoria.

Due to exoskeleton, the absorption of nutrients in adult insects takes place across the gastrointestinal tract epithelium. In most physiological studies, sugar intestinal absorption has been described as a diffusional process and to date no sugar transporter has been cloned from the digestive tract of insects. In the present work, the existence of a saturable transport system for galactose in the gastric caeca of Locusta migratoria is clearly demonstrated. This transport shows a relatively high affinity for galactose (apparent K0.5=2-3 mM) and is inhibited by glucose, 2-deoxyglucose and with less potency by fructose and alpha-methyl-d-glucoside. The absence of sodium or the presence of phloridzin hardly affects galactose absorption, indicating that it is not mediated by a SGLT1-like transporter. The absence of K+, Cl-, Mg2+ and Ca2+ or changes in the pH do not modify galactose absorption either. Nevertheless, phloretin, cytochalasin B and theophylline (inhibitors of facilitative transporters) decrease sugar uptake around 50%. Xenopus laevis oocytes microinjected with poly A+ RNA isolated from gastric caeca show sodium-independent galactose uptake that is three times higher than in non-injected oocytes, further supporting the existence of a mRNA coding for at least one equilibrative sugar transporter in L. migratoria gastric caeca.

Effect of adrenomedullin and proadrenomedullin N-terminal 20 peptide on sugar transport in the rat intestine.

Previous studies have shown immunostaining of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) throughout the gastrointestinal tract. Based on these data, we decided to investigate the effect of these peptides on intestinal sugar absorption using everted rings from Wistar rat intestine. PAMP increases alpha-methylglucoside (MG) uptake at concentrations ranging from 10(-12) to 10(-7) M. AM shows a dual effect inhibiting sugar absorption at low concentrations (10(-12) to 10(-11) M) and increasing MG uptake at higher concentrations (10(-8) to 10(-6) M). In all cases, the effect is phloridzin-sensitive, indicating that the peptides alter SGLT1 function without modifying the non-mediated component of absorption. The enhancing effect of 10(-8) M AM and PAMP seems to be mediated by elevation of cAMP and is accompanied by an increase on SGLT1 expression in the brush-border membrane of the enterocytes. The inhibitory effect of 10(-12) M AM could be mediated by either cAMP reduction or, more probably, by other second messenger able to inhibit sugar absorption. PKC is not involved in the action of either AM or PAMP. These results demonstrate that both peptides play a role in the regulation of the active transport of sugars in the intestine.

Pharmacological properties of quinoxaline derivatives as a new class of 5-HT3 receptor antagonists.

The pharmacological profile of five quinoxaline derivatives, a new class of 5HT3 receptor antagonists, is reported in the present study. All of the new compounds antagonized the effect of the selective 5-HT3 receptor agonist 2-methyl-5-HT in the isolated longitudinal muscle-myenteric plexus preparation (LMMP) of guinea-pig ileum. One of them, VC-605) was approximately three orders of magnitude more potent than ondansetron. In binding studies to 5-HT3 receptors from rat cerebral cortex membranes only VC-605 showed an affinity comparable to ondansetron. In the isolated rat oesophageal tunica muscularis mucosae preparation the new compounds, like 2-methyl-5-HT, only produced relaxation of the contraction induced by carbachol at high concentrations. In vivo, the quinoxaline derivatives were weak antagonists of the bradycardia response to 5-HT in the anesthetized rat. The quinoxaline derivatives, in particular VC-501 and VC-603, prevented retches and vomiting induced by 2-methyl-5-HT and cis-platinum in the ferret. The new compounds also enhanced the gastric emptying of solids in rats. The results obtained are probably indicative of the suggested species- and tissue-dependent differences in 5-HT3 receptor subtypes. The high potency and selectivity of one of the new quinoxaline derivatives, VC-605, at 5-HT3 receptors of guinea-pig ileum is remarkable. VC-605 may be a useful tool for further characterizing this possible 5-HT3 receptor subtype.

On the multiplicity of sugar transport systems in guinea pig jejunum.

A study has been made in everted sacs of guinea pig jejunum to see if the two transport systems of glucose analogues characterized at the brush border membrane vesicles are operative. The transport kinetics of D-galactose and alpha-methylglucoside up to 80 mM concentrations has been studied, as well as the mutual inhibitions between them at low and high concentrations of the substrate and at different concentrations of the inhibitor. Low temperature (20 degrees C) inhibits galactose transport at 0.1 mM (70%) and 40 mM (78%) concentrations. A mass transfer coefficient, KD, somewhat higher for galactose than for alpha-methylglucoside, was obtained when the transport component was abolished by phlorizin. The transport of D-galactose and alpha-methylglucoside seemed to be compatible with the function of one system shared by both substrates, which presents greater affinity for alpha-methylglucoside. The functional existence of two systems of active transport at the brush border of guinea pig was not evidenced in intestinal preparations of whole tissue, due perhaps to the effect of the unstirred water layers. However, differences in KD values and some results of the mutual inhibitions may suggest a second system.

On the multiplicity of glucose analogues transport systems in rat intestine.

A study has been made to test if in intact epithelium of rat jejunum with in vivo and in vitro techniques, two transport systems for glucose and analogues, as those characterized in brush border membrane vesicles from guinea pig jejunum, are operative. The passive and mediated transport components of the D-galactose and methyl alpha-D-glucopyranoside intestinal absorption and the mutual inhibitions between both substrates at different relative concentrations have been measured. The effects of cytochalasin B and low temperature (20 degrees C) on the transport in vitro have also been observed. Cytochalasin B inhibits galactose and alpha-methylglucoside transport at 0.1 and 40 mM concentrations in similar percentage. Transport of 0.1 and 40 mM galactose is inhibited 61 and 77% respectively by low temperature (20 degrees C). The transport of galactose and alpha-methylglucoside could be explained by the assumption of just one transport system shared by both substrates, with a higher affinity for alpha-methylglucoside. Operation of two systems was not demanded by the results, due perhaps to species specificity or to the distorting action of the unstirred water layers.

[Bioelectric behaviour of intestinal wall in the earthworm Scherotheca sp (author's transl)]. / Comportamiento bioeléctrico de la pared intestinal de la lombriz de tierra Scherotheca sp.

Transmural potential difference (TPD) and short circuit current in the Scherotheca sp. intestinal wall in in vitro preparations have been studied, as well as their variations as related to ionic substitutions. Sodium ion seems to participate the most in the genesis of registered potential, so that its total substitution in the medium brings about the disappearance of the potential. Transmural potential relies on metabolic energy and is inhibited by N2, 2,4-DNP and CNK. Ouabain inhibits TPD only when present on the serosal side. This might indicate the existence on that side of a Na+ pump responsible for the active transport of the cation from mucosal.

Intestinal absorption of sugars and amino acids in the earthworm.

Absorption of glucose, galactose, fructose and leucine from luminal to coelomic compartments across the intestinal wall of Scherotheca sp. seems to be a simple diffusion process and not a product of active transport or facilitated diffusion. A concentration gradient never developed from identical initial concentrations of the 14C-labelled substrates on either side of in vitro everted intestinal sacs. The rates of net passage of glucose and galactose were in linear function with the respective sugar concentration gradient. A competition between these two sugars was not observed. The diffusion rate of glucose was higher from mucosal to serosal than in reverse direction. Intestinal tissues synthesized glycogen from glucose in the medium, this process being strongly inhibited by dinitrophenol.

Response of chicken intestine to calcium omission on electrical potential and short-circuit.

A comparison of the endogenous PD and ISC, galactose transfer PD and ISC, and leucine transfer PD and ISC by rat and chicken intestine in a buffer with and without calcium, was made. The electrical activity in presence or absence of actively transported substrates was altered in the chicken intestine when a calcium-free buffer was used. No significant differences were observed with rat intestine.