Health-related quality of life trajectories in melanoma patients after electrochemotherapy: real-world insights from the InspECT register.

BACKGROUND: Electrochemotherapy (ECT) effectively controls skin metastases from cutaneous melanoma. OBJECTIVES: This study aimed to evaluate health-related quality of life (HRQoL) in melanoma patients pre-/post-ECT and its effect on treatment outcome. METHODS: The analysis included prospective data from the International Network for Sharing Practices of ECT register. Following the Standard Operating Procedures, patients received intravenous or intratumoural bleomycin (15,000 IU/m2 ; 1000 IU mL/cm3 ) followed by 100-microsecond, 1000-V/cm electric pulses. Endpoints included response (RECIST v3.0), local progression-free survival (LPFS), toxicity (CTCAE v5.0), and patient-reported HRQoL at baseline, one, two, four and ten months (EuroQol [EQ-5D-3L], including 5-item utility score [EQ-5D] and visual analogue scale for self-reported health state [EQ-VAS]). Comparisons within/between subgroups were made for statistical and minimal important differences (MID). HRQoL scores and clinical covariates were analysed to identify predictors of response in multivariate analysis. RESULTS: Median tumour size was 2 cm. Complete response rate, G3 toxicity and one-year LPFS in 378 patients (76% of the melanoma cohort) were 47%, 5%, and 78%. At baseline, age-paired HRQoL did not differ from the general European population. Following ECT, both EQ-5D and EQ-VAS scores remained within MID boundaries, particularly among complete responders. A subanalysis of the EQ-5D items revealed a statistically significant deterioration in pain/discomfort and mobility (restored within four months), and self-care and usual activities (throughout the follow-up) domains. Concomitant checkpoint inhibition correlated with better EQ-5D and EQ-VAS trajectories. Baseline EQ-5D was the exclusive independent predictor for complete response (RR 14.76, p=0.001). CONCLUSIONS: HRQoL of ECT melanoma patients parallels the general population and is preserved in complete responders. Transient deterioration in pain/discomfort and mobility and persistent decline in self-care and usual activities may warrant targeted support interventions. Combination with checkpoint inhibitors is associated with better QoL outcomes. Baseline HRQoL provides predictive information which can help identify patients most likely to respond.

Electrochemotherapy of unresectable cutaneous tumours with reduced dosages of intravenous bleomycin: analysis of 57 patients from the International Network for Sharing Practices of Electrochemotherapy registry.

BACKGROUND: Electrochemotherapy (ECT) is currently used to treat unresectable superficial tumours of different histotypes through the combination of cytotoxic chemotherapy and local application of electric pulses. In 2006, a collaborative project defined the ESOPE (European Standard Operating Procedures of Electrochemotherapy) guidelines to standardize the procedure. The International Network for Sharing Practices of Electrochemotherapy (InspECT) aims to refine the ESOPE and improve clinical practice. Limiting patient exposure to systemic chemotherapy would be advisable to ameliorate ECT safety profile. OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicity of ECT with reduced chemotherapy dosages. METHODS: In a retrospective analysis of a prospectively maintained database (InspECT registry), we evaluated the outcome of patients who received ECT with reduced dosages of bleomycin (7500, 10 000 or 13 500 IU/m2 , instead of the standard dose of 15 000 IU/m2 ). Tumour response in melanoma patients was compared with melanoma patients of the InspECT registry who received the standard dose of bleomycin. RESULTS: We identified 57 patients with 147 tumours (melanoma, 38.6%; squamous cell carcinoma, 22.8%; basal cell carcinoma, 17.5%; breast cancer 7%; Kaposi sarcoma 7%; other histotypes, 7.1%). Per-tumour complete response (CR) rate at 60 days was 70.1% (partial, 16.3%); per-patient CR was 57.9% (partial, 21.1%). Local pain was the most frequently reported side-effect (n = 22 patients [39%]), mostly mild; two patients experienced flu-like symptoms, one patient nausea. We observed the same CR rate (55%) in patients with melanoma treated by reduced or conventional bleomycin dosages (P = 1.00). CONCLUSIONS: Electrochemotherapy performed with reduced bleomycin dosages could be as effective as with currently recommended dose. Patients with impaired renal function or candidate to multiple ECT cycles could benefit from a reduced dose protocol. Our findings need prospective confirmation before being adopted in clinical practice.

Electrochemotherapy in the treatment of metastatic malignant melanoma: a prospective cohort study by InspECT.

BACKGROUND: (ECT) is an effective local treatment for cutaneous metastasis. Treatment involves the administration of chemotherapeutic drugs followed by delivery of electrical pulses to the tumour. OBJECTIVES: To investigate the effectiveness of ECT in cutaneous metastases of melanoma and to identify factors that affect (beneficially or adversely) the outcome. METHODS: Thirteen cancer centres in the International Network for Sharing Practices on Electrochemotherapy consecutively and prospectively uploaded data to a common database. ECT consisted of intratumoral or intravenous injection of bleomycin, followed by application of electric pulses under local or general anaesthesia. RESULTS: In total, 151 patients with metastatic melanoma were identified from the database, 114 of whom had follow-up data of 60 days or more. Eighty-four of these patients (74%) experienced an overall response (OR = complete response + partial response). Overall, 394 lesions were treated, of which 306 (78%) showed OR, with 229 showing complete response (58%). In multivariate analysis, factors positively associated with overall response were coverage of deep margins, absence of visceral metastases, presence of lymphoedema and treatment of nonirradiated areas. Factors significantly associated with complete response to ECT treatment were coverage of deep margins, previous irradiation of the treated area and tumour size (< 3 cm). One-year overall survival in this cohort of patients was 67% (95% confidence interval 57-77%), while melanoma-specific survival was 74% (95% confidence interval 64-84%). No serious adverse events were reported, and the treatment was in general very well tolerated. CONCLUSIONS: ECT is a highly effective local treatment for melanoma metastases in the skin, with no severe adverse effects noted in this study. In the presence of certain clinical factors, ECT may be considered for local tumour control as an alternative to established local treatments, or as an adjunct to systemic treatments.

Electrochemotherapy in the treatment of cutaneous malignancy: Outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy database for 2482 lesions in 987 patients (2008-2019).

BACKGROUND: Electrochemotherapy (ECT) is a treatment for both primary and secondary cutaneous tumours. The international Network for sharing practices on ECT group investigates treatment outcomes after ECT using a common database with defined parameters. METHODS: Twenty-eight centres across Europe prospectively uploaded data over an 11-year period. Response rates were investigated in relation to primary diagnosis, tumour size, choice of electrode type, route of bleomycin administration, electrical parameters recorded and previous irradiation in the treated field. RESULTS: Nine hundred eighty-seven patients, with 2482 tumour lesions were included in analysis. The overall response (OR) rate was 85% (complete response [CR]: 70%, partial response rate: 15%, stable disease: 11%, and progressive disease: 2%). For different histologies, OR and CR rates for metastases of malignant melanoma were 82% and 64%, basal cell carcinoma were 96% and 85%, breast cancer metastases were 77% and 62%, squamous cell carcinoma were 80% and 63% as well as Kaposi's sarcoma were 98% and 91%, respectively. Variance was demonstrated across histotypes (p < 0.0001) and in accordance with size of lesion treated (dichotomised at diameter of 3 cm (p < 0.0001). Hexagonal electrodes were generally used for larger tumours, but for tumours up to 3 cm, linear array electrodes provided better tumour control than hexagonal electrodes (80%:74%, p < 0.003). For tumours more than 2 cm, intravenous administration was superior to intratumoural (IT) administration (p < 0.05). Current recorded varied across tumour histologies and size but did not influence response rate. In previously irradiated areas, responses were selectively lower for IT administration. CONCLUSIONS: These cumulative data endorse efficiency of ECT across a broad range of histotypes. Analysis of 2482 lesions details subgroup analysis on treatment response informing future treatment choices.

In vivo targeting of malignant melanoma by 125Iodine- and 99mTechnetium-labeled single-chain Fv fragments against high molecular weight melanoma-associated antigen.

Monoclonal antibodies (MAbs) against high-molecular-weight melanoma-associated antigen (HMW-MAA) have been used in vivo to target melanoma. More recently, single chain Fv (scFv) antibody fragments against HMW-MAA have been described that may improve melanoma targeting. However, there have been few in vivo studies with antimelanoma scFvs because these have proved difficult to label with isotopes (e.g., 99mTc) suitable for imaging. We have generated a series of scFvs against HMW-MAA by chain shuffling and antibody phage selection on melanoma cells. In preliminary experiments we identified one scFv (RAFT3) as suitable for in vivo melanoma targeting. Direct radiolabeling of RAFT3 scFv with 99mTc was simple, yielding a radiochemical purity of >90%. The label remained stable for 24 h in vitro. 125I- and 99mTc-labeled RAFT3 scFv were tested in a nude mouse xenograft model for human melanoma and were compared with the parent MAb LHM2 and its F(ab')2 fragment versus nonmelanoma-specific MAb and scFv. RAFT3 scFv accumulated specifically in the tumor and showed greater tumor specificity compared with LHM2 with faster pharmacokinetics (t(1/2)alpha, 8 min; t(1/2)beta, 189 min; and t(1/2)alpha, 37 min; t(1/2)beta, 384 min, respectively) and reduced background in liver, lung, and spleen. Nonspecific accumulation of 99mTc-labeled RAFT3 scFv in the kidney was high but tumor:normal tissue ratios were better compared with 125I-labeled RAFT3 scFv and LHM2 F(ab')2. Overall, tumor-targeting efficiency at equivalent time points was scFv > IgG > F(ab')2 in good agreement with previously described scFvs engineered for 99mTc labeling. We discuss the potential use of RAFT3 scFv for imaging and therapy of metastatic melanoma.

Reducing renal accumulation of single-chain Fv against melanoma-associated proteoglycan by coadministration of L-lysine.

In view of the rising melanoma incidence and the absence of effective treatments for metastatic disease, there is an urgent need for new methods that allow the early detection of melanoma. To this end, in vivo detection by patient imaging with single-chain Fv (scFv) antibody fragments is an attractive diagnostic approach. However, high non-specific accumulation of scFvs in the kidney reduces image quality in this body area and prevents the use of scFvs for melanoma radioimmunotherapy. We have tested the effect of coadministration of L-lysine with (125)I-labelled scFvs against melanoma-associated proteoglycan on kidney accumulation in a nude mouse xenograft model. Coadministration of L-lysine had no significant effect on tumour accumulation of scFvs or blood clearance, but decreased kidney accumulation by factors of 2.25, 2.3, 6.3 and 5.8, respectively, at 1, 3, 6 and 18 h post-injection, and improved tumour to muscle contrast. The reduction in kidney accumulation was maximal at time points that can be extrapolated to patient studies. The time dependence of the effect suggests that further improvements could be achieved with an optimized dosing regimen. When combined with other strategies to reduce kidney accumulation of scFvs, coadministration of L-lysine has the potential to significantly improve tumour to kidney contrast.

Muscle herniation: a complication at the anterolateral thigh perforator flap donor site.

The anterolateral perforator flap is becoming the flap of choice for a wide variety of complex defects. It has been known to provide excellent donor site morbidity even in cases where vastus lateralis is included within the flap. We report a case of herniation of the vastus lateralis and rectus femoris muscles through the overlying fascia, following ALT perforator flap harvest. In this case muscle herniation at the donor site required surgical repair.

Histological evidence of tumour rejection after active immunotherapy in human malignant disease.

Active immunotherapy with multiple doses of tumour homogenate incorporated in complete Freund adjuvant was used to treat 12 patients with advanced malignant disease. Evidence of some tumour destruction was observed in 10. Improvement in general clinical condition and the disappearance of symptoms referable to tumour occurred in seven of the patients. The duration of improvement varied considerably. Histological evidence of lymphocytic infiltration, necrosis, and fibrous replacement of tumour tissue is presented.

Transience of immune responses to tumour antigens in man.

By examining serial serum samples from patients undergoing surgical removal of malignant tumours an increased incidence of tumour-specific antibodies has been detected. Antibody responses to tumour neoantigens seem to be transient, and this is held to account for the rarity of detections where a single sample of serum is examined.

Tumour specific T-like antigen of human breast carcinoma.

An autoantibody response against a breast carcinoma tumour specific neoantigen is described. The antigen, which was present in 6 of 11 breast carcinomata examined, was shown to have similarities to the T antigen of DNA virus induced animal tumours. In addition a different antigen (or antigenic determinant) was shown to be present in one breast carcinoma. This was not strictly tumour specific, being present in lower concentration in normal breast from the same individual.

Are triglyceride breast implants really biocompatible?

A case of augmentation mammaplasty with triglyceride implants is presented. Histological examination of the capsules 3 years postimplantation showed retained, irregular, refractile yellow-brown fragments embedded in granulomatous tissue.

Improved production by domain inversion of single-chain Fv antibody fragment against high molecular weight proteoglycan for the radioimmunotargeting of melanoma.

Melanoma is among the few cancers with rising incidence. Currently there is no effective treatment for metastatic disease, but improved detection of melanoma has the potential to benefit the management of patients with early disease. Radioimmunodection by imaging with single-chain Fv (scFv) antibody fragments is one such emerging diagnostic method. However, the amount of scFv that can be produced at a scale suitable for use in patients is limiting. We have previously shown that the bacterial expression of a scFv derived from a monoclonal antibody (MAb) specific for melanoma-associated proteoglycan can be increased by light chain shuffling. In this report we show that a further increase in expression yield can be obtained by reversing the usual V(H)-V(L) orientation of scFvs to V(L)-V(H). Such seemingly minor changes have previously been reported to have unexpected effects on the in vitro and in vivo binding properties of recombinant antibodies. Our results show that reversal of the V domain orientation of the scFv improves expression by 150% without an adverse effect on melanoma binding in vitro and tumor targeting in vivo. Therefore, our results show that alteration of V domain orientation can improve the production yield of clinically useful antibody fragments. When used in combination with other antibody engineering approaches for increased antibody production changing the domain orientation is a simple strategy to achieve significant improvements in the production of scFvs for tumor radioimmunodetection for patient studies.