Purpose: The clinical significance of intratumoral or peritumoral lymph vessel density is not known. LYVE-1, a lymphatic endothelium-specific hyaluronan receptor, is a novel lymphatic vessel marker that is expressed on lymph vessel endothelial cells of both normal and neoplastic tissues. Experimental Design: We investigated expression of LYVE-1 by immunhistochemistry in 180 unilateral, invasive ductal breast carcinomas and assessed the presence and density of lymph vessels within the tumor and at the tumor periphery. Results: A minority (12%) of breast carcinomas had intratumoral lymph vessels, whereas peritumoral lymph vessels were identified in almost all cases (94%). No substantial association was found between the number of LYVE-1–positive vessels and the number of CD31 or vascular endothelial growth factor receptor-3–positive vessels, or vascular endothelial growth factor-C expression. The number of metastatic axillary lymph nodes increased in parallel with increasing lymph vessel counts (P = 0.033). A higher than the median lymph vessel count at the tumor periphery was significantly associated with unfavorable distant disease-free survival and overall survival. Women with high peritumoral lymph vessel density had only 58% (95% confidence interval, 46–70%) 5-year distant disease-free survival as compared with 74% (66–83%) among those with a low peritumoral lymph vessel density (P = 0.0088). In contrast, the presence of intratumoral lymph vessels was associated with neither axillary nodal status nor survival. Lymph vessel density was not an independent prognostic factor in a multivariate survival analysis. Conclusions: A high peritumoral lymph vessel density is associated with a poor outcome in ductal breast cancer.

Few predictive factors for efficacy of vascular endothelial growth factor pathway-targeted therapies have been identified. We studied whether bevacizumab treatment-related hypertension is associated with outcome. Forty-three consecutive patients with metastatic progressive renal cell cancer (RCC), of whom 41 had cytokine-refractory disease, were treated with bevacizumab [administered either 5 mg/kg every 2 weeks (n = 37) or 7.5 mg/kg every 3 weeks (n = 6)] from June 2004 to March 2007 in our hospital. We used this dose since it was widely used in the treatment of colorectal cancer at the time when RCC patients were accrued [1]. Blood pressure was measured before each bevacizumab infusion and antihypertensive medication was initiated or intensified whenever blood pressure was >150/100 mmHg.

Hypertension and hypothyreoidism are frequent side effects of VEGFR-inhibitors. We investigated whether hypertension or hypothyreoidism diagnosed during sunitinib treatment is associated with treatment efficacy. Sixty-four consecutive patients with metastatic renal cell cancer (RCC) were treated with sunitinib in a single center. Hypertension was defined as persistent blood pressure >150/100 mmHg or blood pressure requiring intensification of pre-existing anti-hypertensive medication. Hypothyreoidism was defined as elevation of TSH levels and clinical symptoms requiring hormone replacement therapy (≥Gr. II hypothyreoidim). Twenty-four (38%) patients developed hypertension and 12 (19%) hypothyreoidism. The dose of sunitinib administered was not significantly associated with hypertension or hypothyreoidism. There was no correlation between hypertension and hypothyreoidism. Hypertension was associated with frequent tumor response to sunitinib, a long time to disease progression and long overall survival (p= 0.001, 0.0003 and 0.001, respectively). In a multivariate analysis, hypertension was an independent predictor of progression-free survival (hazard ratio, 0.21; 95% CI 0.076 to 0.59, p=0.0030). There were no statistically significant differences in the frequency of ≥ grade 3 adverse events between patients with or without hypertension. Sunitinib-associated hypertension may be a strong predictive marker for treatment efficacy in metastatic RCC.

Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell–targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8+ T-cell–mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1–targeting antibodies for cancer treatment. Patients and Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti–Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305–induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase–mediated endosomal acidification and improved the ability of macrophages to activate CD8+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.

BACKGROUND: Endostatin is a cleaved fragment of collagen Type XVIII and has antiangiogenic activity. The clinical significance of circulating, soluble endostatin (S‐endostatin) is not known.METHODS: Pretreatment S‐endostatin and serum vascular endothelial growth factor (S‐VEGF) levels were measured in 143 patients with non‐Hodgkin lymphoma (NHL) using competitive enzyme immunoassays and were compared with the levels from a control group (n = 24 participants).RESULTS: S‐endostatin levels varied widely from 4.5 ng/mL to 116 ng/mL (median, 29.6 ng/mL), and the median level was higher in patients with NHL compared with patients in the control group (16.4 ng/mL; P = 0.05). High S‐endostatin levels were associated with advanced disease stage (P < 0.0001) and high serum VEGF levels at diagnosis (P = 0.017). The median 5‐year survival rate for patients who had S‐endostatin concentrations within the highest tertile (> 36.0 ng/mL) was only 34% compared with 57% in patients who had lower S‐endostatin levels (P = 0.019). A high S‐endostatin level also was associated with a poor outcome in patients with large cell diffuse and immunoblastic lymphoma, which was the largest subgroup within the series (n = 60 patients). Patients who had high pretreatment levels of both S‐VEGF and S‐endostatin had particularly poor outcomes. High S‐endostatin levels had an independent, adverse influence on survival it was entered as a factor into a multivariate analysis together with the factors included in the International Prognostic Index (relative risk, 1.80; 95% confidence interval, 1.08–2.98; P = 0.0024).CONCLUSIONS: High pretreatment levels of S‐endostatin are associated with high serum VEGF levels and poor survival in patients with NHL. Prospective studies are warranted to establish the clinical value of longitudinal S‐endostatin measurements. Cancer 2003;97:2767–75. © 2003 American Cancer Society.DOI 10.1002/cncr.11399

Objectives: To evaluate the clinical significance of hypertension ( HTN ), neutropaenia and thrombocytopaenia as possible new biomarkers of sunitinib efficacy in non‐trial patients with metastatic renal cell carcinoma ( mRCC ). Patients and Methods: In all, 181 consecutive patients with mRCC were treated with sunitinib; 39 (22%) received sunitinib 50 mg/day 4 weeks on/2 weeks off, 80 (44%) received 37.5 mg/day continuously and 62 (34%) received 25 mg/day continuously as their starting dose. Treatment‐induced adverse events ( AEs ) and their impact on outcome were analysed on multiple sunitinib doses. Results: During sunitinib treatment 60 patients (33%) developed ≥grade 2 HTN , 88 (49%) ≥grade 2 neutropaenia and 135 (75%) ≥grade 1 thrombocytopaenia. These AEs were associated significantly with longer progression‐free survival ( PFS ; 15.7 vs 6.7; 14.6 vs 6.9; 10.4 vs 4.2 months, respectively; P < 0.001) and overall survival ( OS ; 37.5 vs 16.2; 33.7 vs 13.2; 22.3 vs 13.2 months, respectively, P ≤ 0.008). Although only neutropaenia was associated with a significantly improved PFS and OS in all sunitinib doses, a similar trend was also seen with HTN and thrombocytopaenia in all sunitinib doses. In multivariate analysis, HTN and neutropaenia were significantly associated with PFS and OS and thrombocytopaenia was significantly associated with PFS . In a 12‐week landmark analysis, HTN and thrombocytopaenia were significantly associated with PFS and OS . Patients who developed all three AEs (a favourable biomarker profile) had significantly better outcome than patients without these AEs (a poor biomarker profile); response rate 47% vs 4%, median PFS 27.1 vs 3.5 months and OS not reached vs 5.3 months (all P < 0.001). Conclusion: HTN , neutropaenia and thrombocytopaenia were all biomarkers of sunitinib efficacy in patients with mRCC . Our results may help to individualise sunitinib dosing during therapy based on these common sunitinib‐related AEs .