Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.     

Reactivity of white blood cell flux to hyperoxia in patients infected with human immunodeficiency virus

Purpose: The aetiology of the apparently vasoocclusive phenomena in human immunodeficiency virus (HIV)‐related retinopathy is not well understood. Several hypotheses, including infectious damage of the retinal vasculature and altered retinal haemodynamics, have been postulated. Direct measurement of oxygen tension in the retina is not possible in vivo and indirect methods have to be employed. The objective of this study was to investigate the retinal vascular response to 100% oxygen breathing in patients with HIV. Methods: Twelve patients infected with HIV and 12 healthy individuals, matched for age, sex and smoking habits, were studied in an open study using the blue‐field entoptic technique for the measurement of retinal white blood cell (WBC) flux. Reactivity in retinal blood flow during 100% O₂ breathing over 15 min was measured and expressed as percentage change over baseline. Results: WBC velocity during oxygen inhalation decreased over baseline by 9.0 ± 5.8% in HIV‐infected patients and by 18.6 ± 5.4% in healthy participants (p < 0.04 between groups, anova ). The decrease in WBC velocity was paralleled by a decrease in WBC density. This decrease tended to be more pronounced in healthy participants (13.6 ± 7.9%) than in HIV‐infected patients (8.0 ± 10.8%), but the difference was not statistically significant (p = 0.1 between groups, anova ). WBC flux decrease was 16.2 ± 11.4% in HIV‐infected patients and 29.5 ± 9.5% in the control group and was significant between groups (p = 0.007 between groups, anova ). Conclusion: Our results indicate a reduced reactivity of WBC flux to systemic hyperoxia in patients with HIV. Whether abnormal retinal haemodynamics in HIV‐infected persons contributes to the pathogenesis of HIV‐related microvascular diseases or is a consequence of the structural changes associated with the disease is unknown.     

Evaluation of retinal functional loss in branch retinal vein occlusion

Purpose: Branch retinal vein occlusion (BRVO) induces variable functional deficits depending on the grade of vascular occlusion and its localisation. Theses deficiences are not easily defined by visual acuity measurements. However, microperimetry offers topical mapping of retinal function, allowing precise documentation of the intensity and dimension of retinal functional loss in BRVO.     

The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP-mediated cell death.

Here we analyze limb development after the conditional inactivation of Fgf8 from the epiblast, using the previously described MORE (Mox2Cre) line. This line drives variable mosaic recombination of a floxed Fgf8 allele, resulting in a small proportion of AER cells that maintain Fgf8 expression. The phenotype of Mox2Cre;Fgf8 limbs is most similar to that of Msx2Cre;Fgf8 forelimbs, indicating that a small but durable expression of FGF8 is equivalent to an early normal, but transitory, expression. This functional equivalence likely relies on the subsequent Fgf4 upregulation that buffers the differences in the pattern of Fgf8 expression between the two conditional mutants. The molecular analysis of Mox2Cre;Fgf8 limbs shows that, despite Fgf4 upregulation, they develop under reduced FGF signaling. These limbs also exhibit an abnormal area of cell death at the anterior forelimb autopod, overlapping with an ectopic domain of Bmp7 expression, which can explain the abnormal morphogenesis of the anterior autopod.     

Primary prophylaxis with granulocyte colony-stimulating factor (GCSF) reduces the incidence of febrile neutropenia in patients with non-Hodgkin lymphoma (NHL) receiving CHOP chemotherapy treatment without adversely affecting their quality of life: cost–benefit and quality of life analysis

Purpose

Treatment of non-Hodgkin lymphoma (NHL) with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) is known to be associated with a significant risk of febrile neutropenia (FN) of up to 50 % [Osby et al. 2003 Blood 101(10): 3840–3848; Lyman and Delgado 2003 Cancer 98(11): 2402–2409]. This study sought to examine the impact of primary granulocyte colony-stimulating factor (GCSF) prophylaxis on the incidence of FN, quality of life and overall cost.

Methods

In this retrospective cohort study, a group of 65 consecutive patients who received CHOP chemotherapy for NHL between December 2006 and October 2009 was studied. Patients either received filgrastim (300 mcg, average of seven doses), pegylated filgrastim (6 mg, single dose), or no GCSF prophylaxis. In addition, 19 patients were asked to complete Functional Assessment of Cancer Therapy: General quality-of-life questionnaires.

Results

Overall, patients who received primary GCSF prophylaxis had significantly fewer FN compared to those who did not (5 vs. 60 %, p?<?0.0001; numbers needed to treat of 1.8; 95 % confidence interval, 1.6–2.9). Cost–benefit analysis showed that the GCSF prophylaxis was associated with only a small increase in direct financial cost ($238 NZD [US$189] more to give primary GCSF prophylaxis per patient vs. no prophylaxis). The quality of life assessment showed that the patients’ quality of life scores were similar to the published data from the validation study population (466 patients with mixed cancers) for Functional Assessment of Cancer Therapy.

Conclusions

Our study shows that primary GCSF prophylaxis is effective in preventing FN in patients receiving CHOP chemotherapy for NHL without adversely affecting their quality of life, and is cost effective.     

[68Ga]NODAGA-RGD for imaging ��v��3 integrin expression

Purpose

A molecular target involved in the angiogenic process is the ??_v??₃ integrin. It has been demonstrated in preclinical as well as in clinical studies that radiolabelled RGD peptides and positron emission tomography (PET) allow noninvasive monitoring of ??_v??₃ expression. Here we introduce a ⁶⁸Ga-labelled NOTA-conjugated RGD peptide ([⁶⁸Ga]NODAGA-RGD) and compare its imaging properties with [⁶⁸Ga]DOTA-RGD using small animal PET.

Methods

Synthesis of c(RGDfK(NODAGA)) was based on solid phase peptide synthesis protocols using the Fmoc strategy. The ⁶⁸Ga labelling protocol was optimized concerning temperature, peptide concentration and reaction time. For in vitro characterization, partition coefficient, protein binding properties, serum stability, ??_v??₃ binding affinity and cell uptake were determined. To characterize the in vivo properties, biodistribution studies and microPET imaging were carried out. For both in vitro and in vivo evaluation, ??_v??₃-positive human melanoma M21 and ??_v??₃-negative M21-L cells were used.

Results

[⁶⁸Ga]NODAGA-RGD can be produced within 5?min at room temperature with high radiochemical yield and purity (> 96%). In vitro evaluation showed high ??_v??₃ binding affinity (IC₅₀?=?4.7?±?1.6?nM) and receptor-specific uptake. The radiotracer was stable in phosphate-buffered saline, pH 7.4, FeCl₃ solution, and human serum. Protein-bound activity after 180?min incubation was found to be 12-fold lower than for [⁶⁸Ga]DOTA-RGD. Biodistribution data 60?min post-injection confirmed receptor-specific tumour accumulation. The activity concentration of [⁶⁸Ga]NODAGA-RGD was lower than [⁶⁸Ga]DOTA-RGD in all organs and tissues investigated, leading to an improved tumour to blood ratio ([⁶⁸Ga]NODAGA-RGD: 11, [⁶⁸Ga]DOTA-RGD: 4). MicroPET imaging confirmed the improved imaging properties of [⁶⁸Ga]NODAGA-RGD compared to [⁶⁸Ga]DOTA-RGD.

Conclusion

The introduced [⁶⁸Ga]NODAGA-RGD combines easy accessibility with high stability and good imaging properties making it an interesting alternative to the ¹⁸F-labelled RGD peptides currently used for imaging ??_v??₃ expression.