P. Pilati

Peptide-Based Anticancer Vaccines: Recent Advances and Future Perspectives

Anticancer active immunotherapy embodies the ideal antitumor therapy, as it theoretically combines target specificity with long-term disease control. Peptide-based cancer vaccines represent the most specific approach to polarize the immune system against malignant cells, since they are preparations made of single epitopes, the minimal immunogenic region of an antigen. Despite the strong rational, the promising preclinical results and the frequent induction of antigen-specific immune responses, peptide-based cancer vaccines have yielded relatively poor results in the clinical setting, a phenomenon likely due to the immunosuppressive properties of the tumor microenvironment that allow malignant cells to evade both naturally occurring and therapeutically induced immune surveillance. Nevertheless, advances in the engineering of peptides and in our understanding of the molecular mechanisms underlying an effective immune response against tumors have renewed the enthusiasm for peptide-based vaccination regimens in the setting of cancer, and a variety of clinical trials are being conducted based on the use of peptides. This review will describe the most recent insights in the rational design of peptide-based cancer vaccines, as well as the challenges to successful anticancer immunotherapy based on these short amino acid chains.

Sentinel node biopsy and ultrasound scanning in cutaneous melanoma: clinical and technical considerations

1.5 mm and in all cases with two metastatic SNs, further positive additional nodes were found. The mean counts per 10 s (CP10S) ratio for SN and non-SN values was 5.62 (1.29-23.51) and 3.09 (1.03-10.99) in the intra-operative and extra-operative phases, respectively. US scanning and preoperative lymphoscintigraphy associated with PBD allows preoperative patient selection and accurate SN(s) identification. Breslow thickness and the number of metastatic SN(s), but not their type, are correlated with disease spread; CP10S contributed to the differentiation amongst the nodes and the determining of procedures completion.

Strategies to enhance the anticancer potential of TNF.

Although tumor necrosis factor (TNF) antitumor activity is evident in several preclinical models and in non-comparative clinical trials, no evidence exists that TNF-based treatments increase patient survival. Furthermore, due to systemic toxicity, TNF can only be administered via sophisticated drug-delivery systems in patients with solid tumors confined to one extremity or organ. The impossibility to administer TNF systemically does not allow to test the effectiveness of this cytokine in other clinical settings for the treatment of a broader spectrum of tumor types. Dissecting the cascade of molecular events underlying tumor sensitivity to TNF researchers will allow to further exploit the anticancer potential of this molecule. The rational for the development of strategies aimed at sensitizing malignant cells to TNF is to modulate tumor-specific molecular derangements in order to maximize the selectivity of TNF cytotoxicity towards cancer. This would enhance the anticancer activity of current TNF-based locoregional regimens and would pave the way to the systemic administration of this cytokine and thus to a much wider clinical experimentation of TNF in the oncology field.

Cancer Resistance to Type II Topoisomerase Inhibitors

Type II topoisomerases (TOPO2) are ubiquitously expressed enzymes that overcome topological problems in genomic DNA, which can result from DNA replication, transcription and repair. The class of compounds targeting TOPO2 includes some of the most active chemotherapy agents currently available for the treatment of patients with different cancer types. Therefore, understanding of the molecular mechanisms underlying resistance to these drugs is of pivotal importance to improve their efficacy and ultimately increase the life expectancy of cancer patients. The first aim of this review is to summarize the molecular biology of TOPO2 inhibitors, which is the key to understand cancer resistance to them; the second part of this work is dedicated to overview and discuss the available evidence on the mechanisms of resistance to these drugs, with special attention to the strategies that might be useful to circumvent this phenomenon on the clinical ground.

Hyperthermic Isolated Perfusion with Low-Dose TNFα and Doxorubicin in Patients with Locally Advanced Soft Tissue Limb Sarcomas

Summary We report here the results of 27 patients who underwent hyperthermic isolated limb perfusion with low-dose TNFα (1 mg) and doxorubicin (8.5 mg/l of limb volume) for locally advanced soft tissue sarcomas. A tumor response was observed in 85% of cases. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 82 and 85% of patients, respectively. Locoregional toxicity was low or mild in 14 patients, while 2 patients had severe limb toxicity. Systemic side effects were negligible. The perfusate/plasma area under the curve (AUC) ratio for TNFα was 56. HILP with low-dose TNFα and DXR proved to be an active neoadjuvant drug regimen against limb-threatening STS.

Hypoxic Antiblastic Stop-Flow Perfusion: Clinical Outcome and Pharmacokinetic Findings.

Summary Stop-flow perfusion (SFP) is a recently implemented locoregional treatment based on the vascular isolation of the tumor bearing body district through a radiointerventistic technique. SFP is currently under investigation as a palliative therapeutic option for patients with locally advanced tumors. This paper reports on the results of our prospective study of limb and pelvic SFP. Thirty-seven patients were treated with SFP. No postoperative deaths occurred. Locoregional and systemic toxicity were observed after 22 and 31 treatments, respectively; complete and partial response after 3 (6%) and 24 (51%) SFPs, respectively. The pharmacokinetic study showed that pelvic SFP was associated with a leakage rate higher than femoral SFP (38% vs 28%). In conclusion, SFP is a feasible procedure. Toxicity and tumor response rates strictly depend upon drug leakage control.

Sentinel node biopsy in cutaneous melanoma patients: Technical and clinical aspects

The role of the patent blue dye (PBD) technique and intraoperative probe-guided lymphoscintigraphy (LS) in detecting the sentinel node (SN) was investigated in a group of 130 consecutive stage I cutaneous melanoma patients. The preoperative workup included high-resolution US scanning and LS performed 15–18 hours before surgery. On the basis of preoperative LS, in the group of examined patients a total of 143 lymphatic drainage basins were identified and surgically explored: 41.6% in the axilla, 52.8% in the groin, and 5.6% in the head/neck. A total of 228 SNs were intraoperatively detected and removed; 110 lymphatic basins contained histologically negative SNs, while 33 basins had metastatic SNs. The sensitivity for SN detection using PBD alone was 93%, while it was 100% when PBD was combined with intraoperative LS. Preoperative and intraoperative LS appears to be a highly sensitive technique for SN detection in cutaneous melanoma patients. Furthermore, in view of the limited skin incision when radioguided surgery is performed, SN biopsy could be feasible under local anesthesia.

Hypoxic antiblastic stop-flow limb perfusion: a novel treatment for in transit melanoma metastases. Clinical outcome and pharmacokinetic findings

BackgroundHypoxic antiblastic stop-flow perfusion (SFP) has recently been proposed as a therapeutic option for patients with locally advanced tumors. The present paper reports on the clinical and pharmacological results of our prospective study of limb SFP for the treatment of in transit melanoma metastases. Patients and methodsTwenty-three patients with limb-sited melanoma metastases were treated with melphalan (10 mg/l) based pelvic (n=11, group A) or femoral (n=12, group B) SFP under hypoxic conditions. Systemic and locoregional toxicity, tumor response rate, and local progression–free survival were analyzed. Melphalan concentrations were measured in the perfusate and systemic circulation during SFP, and after 30-minute hemofiltration. Perfusate-to-plasma leakage was assessed using a scintigraphic method. ResultsNo postoperative deaths occurred. Mild locoregional toxicity was observed in 5 patients (18%), and systemic toxicity was mild to severe in 8 patients (30%), the incidence being higher in group A. Tumor response rate (complete + partial response) and time to local disease progression were significantly different in group A and B (9% vs 58% and 7 vs 13 months, respectively). The pharmacokinetic study showed that pelvic SFP was associated with a higher leakage rate and a lower area under the curve ratio than femoral SFP (44% vs 31% and 5.6 vs 9.8, respectively). ConclusionsLimb SFP is a feasible and relatively simple procedure, and is associated with an acceptable toxicity rate. Tumor response rates are encouraging and strictly depend upon drug leakage. Further efforts should be made to exploit the potential anti-tumor activity of this novel locoregional drug delivery system.