Massimo Fanelli

Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth facto...

Angiogenesis spectrum in the stroma of B‐cell non‐Hodgkin's lymphomas. An immunohistochemical and ultrastructural study

Abstract: Samples of lymph nodes from 88 patients with B‐cell non‐Hodgkins lymphoma (B‐NHL) grouped by the Working Formulation (WF) and from 15 patients with benign lymphadenopathies were investigated immunohistochemically and ultrastructurally for changes in angiogenesis and stromal distribution of two subendothelial basement membrane (BM) components, namely laminin and type IV collagen. The microvessel number was usually low in lymphadenopathies, and increased significantly in low‐grade B‐NHL. Intermediate‐grade tumors displayed a further significant increase that was mainly due to their diffuse subtypes rather than to the follicular subtype. High‐grade B‐NHL showed the highest counts. By contrast with the lymphadenopathies studied, the stroma of B‐NHL reacted intensely with both BM components, whose linear co‐expression was significantly associated with low‐grade and follicular intermediate‐grade B‐NHL, while expression of laminin alone in a granular pattern was detected in diffuse intermediate‐grade and high‐grade tumors. Ultrastructural analysis revealed immature vessels more frequently in diffuse intermediate‐grade, and in high‐grade B‐NHL. These in situ data suggest that angiogenesis occurring in B‐NHL increases along their progression path, and emphasize the importance of angiogenesis as an epigenetic phenomenon of B‐NHL progression.

Thalidomide: a new anticancer drug?

Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.

Expression of tenascin is related to histologic malignancy and angiogenesis in B-cell non-Hodgkin’s lymphomas

The topography of and the area covered by tenascin, laminin and type IV collagen (all components of the subendothelial basement membrane), and the microvessel area (an index of angiogenesis), as evaluated with factor VIII, were investigated immunohistochemically in 61 B-cell non-Hodgkins lymphomas (B-NHL) and 30 benign lymphadenopathies as controls. The three components were located in the microvessels and in a microvessel-bound stromal reticular network, the expression of tenascin being always more extended and finer than the other components. Of the lymphadenopathies, reactive and atypical lymphoid hyperplasias showed vessels and stromal network in the interfollicular zone only, whereas in Castlemans and angioimmunoblastic forms these structures were widely scattered in the tissue, and the area of the three components and that of the microvessels were significantly larger. Of the low-grade B-NHL, follicular subtypes had vessels and stromal network confined to the interfollicular inflammatory zone, but not in tumor follicles, whereas these structures were irregularly distributed throughout the small lymphocytic subtype. The levels of areas in low-grade B-NHL overlapped those of Castlemans and angioimmunoblastic lymphadenopathies. Among the intermediate-grade tumors, the follicular subtype resembled the follicular tumors, and the diffuse subtypes displayed vessels and stromal network throughout the tissue in close association with the neoplastic cells, and with significant increments of both the tenascin and the microvessel areas, but with a significant reduction of both the laminin and the type IV collagen areas. Distribution was similar in high-grade B-NHL, but tenascin and microvessel area variations, on the one hand, and those of laminin and type IV collagen areas were still more apparent than in the intermediate-grade. A high correlation was demonstrated in all groups of tissues between tenascin and microvessel area. In addition, in the diffuse intermediate-grade and high-grade B-NHL highly immature vessels were frequently detected by ultramicroscopy. The results show that tenascin expression and angiogenesis are closely related, and that both increase in function of tumor malignancy. Unlike laminin and type IV collagen, tenascin is associated with highly immature vessels in B-NHL. We suggest that tenascin expression and angiogenesis are governed by the B-NHL-associated inflammatory infiltrate, as well as by the B-NHL cells, particularly in more malignant tumors.

Safety and activity of the combination of pegylated liposomal doxorubicin and weekly docetaxel in advanced breast cancer.

Background. The present study was designed with the aim of evaluating the tolerability and activity of pegylated liposomial doxorubicin (PLD) in combination with weekly docetaxel as first line treatment of advanced breast cancer. Patients and methods. Fifty-seven patients entered the study. PLD was administered at escalating doses starting from 30 mg/m, on day 1; docetaxel was administered at the fixed dose of 35 mg/m on days 2 and 9. A cycle of therapy consisted of 21 days. Results. The MTD was achieved at the dose of 40 mg/m of PLD, being febrile neutropenia and palmar-plantar-erythrodisesthesia (PPE) the dose-limiting toxicities (DLTs), so that the fixed dose of PLD for the Phase II study was 35 mg/m. Forty-two consecutive patients received treatment at the established dose for a total of 194 cycles: among these, three patients were withdrawn for severe allergic reaction at the first administration of PLD. Hematological toxicity was moderate, the most common grade 1–3 non-hematological toxicities were stomatitis and PPE, occurring in 20 (47.5%) and 16 (38%) patients, respectively. No cardiac toxicity was recorded. According to the intent to treat analysis a major objective response was observed in 59.5% of patients (95% CI, 43.3–74.4%), with a median time to progression of 9months and an estimated overall survival at 18 months of 62%. Conclusion. The combination of PLD and weekly docetaxel is an effective first-line therapy for patients with advanced breast cancer. PPE and mucositis are the most relevant side effects of such a combination.