Rationale for different approaches to combined melphalan and hyperthermia in regional isolated perfusion

The addition of hyperthermia (HT) to regional isolated perfusion (RIP) with Melphalan theoretically has two advantages. Firstly, heat can selectively kill cells in poorly vascularised areas that are usually not reached by the drug. Secondly, in vitro data have revealed that the effect of Melphalan is enhanced at temperatures 39-45 degrees C. However, for the simultaneous application of Melphalan and HT, as it is given in most institutes, both normal and tumour tissues within the volume are treated with both modalities. It is unclear whether-for the same heat dose-the cytoxicity of Melphalan is enhanced more in tumour tissue than in normal tissues. As the applied dose of Melphalan in RIP is selected on maximum acceptable toxicity, any enhancement of toxicity is undesired. Indeed, Melphalan application at temperatures >41 degrees C has resulted in unacceptable toxicity. In most institutes, the hyperthermia dose is reduced in comparison to application as a single-modality treatment, to allow simultaneous combination without unacceptable toxicity. In this review, the rationale for two different approaches is summarised which may make it possible to improve the benefit from the theoretical advantage of the use of HT in RIP. It is meant to stimulate discussion as a possible first step in the design of new treatment protocols. (C) 1997 Elsevier Science Ltd

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation

Technologic (r)evolution leads to detection of more sentinel nodes in patients with melanoma in the head and neck region

Sentinel lymph node (SN) biopsy (SNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technologic refinements, including the introduction of SPECT/CT, as well as radioguidance and fluorescence guidance. The purpose of the current study was to evaluate the effect of this technologic evolution on SNB in the head and neck region. The primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN, and postoperative complications. Methods: A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided into 4 groups: 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a y-ray detection probe and patent blue (n = 30); 2006-2007, with addition of preoperative road maps based on SPECT/CT (n = 15); 2008-2009, with intraoperative use of a portable y-camera (n = 40); and 2010-2016, with addition of near-infrared fluorescence guidance (n = 192). Results: In total, 277 patients were included. At least 1 SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%): 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%), and 40 in group 4 (20.8%). Regional recurrences in patients with tumor negative SNs resulted in an overall FN rate of 11.9% (group 1, 16.7%; group 2, 0%; group 3, 14.3%; group 4, 11.1%). The number of harvested nodes increased with advancing technologies (P = 0.003), whereas Breslow thickness and operation time per harvested SN decreased (P = 0.003 and P = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time, and complication rate between the different groups. Conclusion: The use of advanced detection technologies led to a higher number of identified SNs without an increase in overall operation time, possibly indicating an improved surgical efficiency. Operation time per harvested SN decreased; the average FN rate remained 11.9% and was unchanged over 23 y. There was no significant change in postoperative complication rate.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .)

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma

Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P = 70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.Analysis and support of clinical decision makin

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN () and phase 2 OpACIN-neo () studies(1,2). While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-gamma score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-gamma score/high TMB; patients with high IFN-gamma score/low TMB or low IFN-gamma score/high TMB had pRRs of 91% and 88%; while patients with low IFN-gamma score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-gamma score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma