Electrochemotherapy for the palliative management of non-skin-origin head and neck cancer: case series and UK national survey.

OBJECTIVES: Electrochemotherapy uses electric fields to facilitate the influx of chemotherapy into cancer cells, producing a targeted effect. For head and neck cancer, it is mainly used for palliation of non-skin-origin metastases. It is used infrequently in the UK. This paper presents our experience and a UK survey to identify its frequency of use. METHODS: Between 2016 and 2019, a prospective database was created and reviewed. Only patients with non-skin-origin metastatic head and neck cancer, with no other palliative options, were included. Survival length, complications and symptomatic benefit were assessed. The survey was conducted via e-mail. RESULTS: Five patients were included: three with squamous cell carcinoma, one with esthesioneuroblastoma and one with hepatocellular carcinoma. Survival ranged from 1 month to over 20 months. Minor complications were seen. Only 15 out of 69 UK head and neck multidisciplinary teams offer electrochemotherapy. CONCLUSION: Electrochemotherapy is a well-tolerated adjunct to standard palliation of metastatic head and neck cancer, and is offered by a limited number of UK multidisciplinary teams.

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.

Depressed Supercooling Point and Increased Glycerol Concentration in Overwintering Adult Tiger Beetles (Cicindelida).

BACKGROUND: Tiger beetles are a widely distributed group including species that may be exposed to sub-freezing temperature overwinter. Despite being well studied, little is known about tiger beetle cold tolerance. OBJECTIVE: We investigated seasonal changes in cold hardiness of two northerly distributed tiger beetle species (Cicindela repanda and Cicindela limbalis). MATERIALS AND METHODS: We monitored the supercooling point (SCP), glycerol concentration, and hemolymph osmolality of adult tiger beetles during a 3.5-month acclimation to winter. RESULTS: SCP decreased during winter acclimation for C. repanda, but not for C. limbalis. Both species modestly increased glycerol concentration, and C. repanda increased hemolymph osmolality by 38%. CONCLUSION: This initial investigation into the cold-hardiness of adult tiger beetles suggests that they are capable of lowering their SCP as winter approaches, which may help them survive sub-freezing winter temperatures. Further assessment of their chill and freeze tolerance and of their overwintering conditions in the field is needed to better understand their winter physiology.

Development of an international core outcome set for peripheral vascular malformations: the OVAMA project.

BACKGROUND: An important limitation in vascular malformation research is the heterogeneity in outcome measures used for the evaluation of treatment outcome. OBJECTIVES: To reach international consensus on a core outcome set (COS) for clinical research on peripheral vascular malformations: lymphatic (LM), venous (VM) and arteriovenous malformations (AVM). In this consensus study, we determined what domains should constitute the COS. METHODS: Thirty-six possibly relevant outcome domains were proposed to an international group of physicians, patients and the parents of patients. In a three-round e-Delphi process using online surveys, participants repeatedly rated the importance of these domains on a five-point Likert scale. Participants could also propose other relevant domains. This process was performed for LM, VM and AVM separately. Consensus was predefined as 80% agreement on the importance of a domain among both the physician group and the patient/parent group. Outcomes were then re-evaluated in an online consensus meeting. RESULTS: 167 physicians and 134 patients and parents of patients with LM (n = 50), VM (n = 71) and AVM (n = 29) participated in the study. After three rounds and a consensus meeting, consensus was reached for all three types of vascular malformations on the core domains of radiological assessment, physician-reported location-specific signs, patient-reported severity of symptoms, pain, quality of life, satisfaction and adverse events. Vascular malformation type-specific signs and symptoms were included for LM, VM and AVM, separately. CONCLUSIONS: Our recommendation is that therapeutic-efficacy studies on peripheral vascular malformations should measure at least these core outcome domains.

Bleomycin electrosclerotherapy: new treatment to manage vascular malformations.

Venous malformations are congenital anomalies of the vascular system. The injection of bleomycin (a cytotoxic, antitumour drug) into the lesion is a safe and effective treatment for low-flow (venous and lymphatic) malformations, but its use systemically has been associated with pulmonary fibrosis. Intralesional injection of bleomycin is considered to have a lower risk, but caution should be used when planning treatment, with particular regard to respiratory function. Electroporation is the temporary application of an electrical field across a tissue to increase (briefly) the permeability of the cell membrane in that tissue. We successfully treated a venous malformation in a patient with severe respiratory compromise with a low dose of bleomycin into the lesion, which we augmented using electroporation. To the best of our knowledge, this is the first reported use of bleomycin electrosclerotherapy in the management of a venous malformation.

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.

Access to site-specific Fc-cRGD peptide conjugates through streamlined expressed protein ligation.

An ideal drug should be highly effective, non-toxic and be delivered by a convenient and painless single dose. We are still far from such optimal treatment but peptides, with their high target selectivity and low toxicity profiles, provide a very attractive platform from which to strive towards it. One of the major limitations of peptide drugs is their high clearance rates, which limit dosage regimen options. Conjugation to antibody Fc domains is a viable strategy to improve peptide stability by increasing their hydrodynamic radius and hijacking the Fc recycling pathway. We report the use of a split-intein based semi-synthetic approach to site-specifically conjugate a synthetic integrin binding peptide to an Fc domain. The strategy described here allows conjugating synthetic peptides to Fc domains, which is not possible via genetic methods, fully maintaining the ability of both the Fc domain and the bioactive peptide to interact with their binding partners.

Electrochemotherapy treatment of a recalcitrant earlobe keloid scar with chronic lymphocytic leukaemia infiltration.

Electrochemotherapy, a tumour ablation modality, which facilitates intracellular delivery of poorly-permeable cytotoxic drugs, such as bleomycin, has shown promising results in the treatment of cutaneous and subcutaneous melanomatous and non-melanomatous metastases. We report the case of a 52-year-old Caucasian gentleman with a keloid scar to his left earlobe that developed following a piercing. Despite multiple intralesional steroidal injections, five intralesional excisions and a course of superficial radiotherapy the keloid scar remained over nine years later. For 15 years the patient had also suffered chronic lymphocytic leukaemia with no nodal disease or systemic involvement. However, histological analysis of the final surgical excision specimen showed chronic lymphocytic leukaemia infiltration of the keloid scar. Further surgical excision seemed unwise considering the recalcitrance of the keloid scar. Additionally, no systemic chemotherapy treatment options were feasible. Electrochemotherapy was performed under local anaesthesia with the aim of eradicating the chronic lymphocytic leukaemia deposit within the keloid lesion. Four sessions of electrochemotherapy using bleomycin were deployed over 11 months. A deep core biopsy of the treated keloid performed three months following the last electrochemotherapy session showed no evidence of chronic lymphocytic leukaemia. Serendipitously, following the initial electrochemotherapy treatment no further growth of the keloid scar was observed. Furthermore, subsequent electrochemotherapy led to a substantial reduction in size of the keloid sustained for 14 months at last follow-up. This report highlights the exciting potential of electrochemotherapy and bleomycin in the treatment of recalcitrant scars. Larger, well-designed clinical and in-vitro studies are required to further elucidate the exact role, mechanism and cost-effectiveness of electrochemotherapy in this area.

Screening for breast cancer post reduction mammoplasty.

AIM: To investigate whether remodelling of the breast after breast reduction surgery has an effect on mammographic cancer detection. METHODS AND MATERIALS: For women who attended population-based screening between January 1998 to December 2007, data were extracted on their age, history of previous breast reduction, and the result of screening (recall for further assessment, cancer, or no cancer). The number of cancers detected, recalls per 1000 screens and the characteristics of the cancers detected in the two groups was compared. RESULTS: In total 244,147 women with 736,219 screening episodes were reviewed. In the 4743 women who had a breast reduction, 51 breast cancers were detected [age standardized rate (ASR) of 4.28 per 1000 screening episodes; 95% CI 3.11-5.46], compared with 4342 breast cancers in 239 404 women screened in the non-reduction group (ASR of 5.99 per 1000 screening episodes; 95% CI 5.81-6.16). There were fewer cancers in the breast reduction group with a relative risk of 0.71. There was no significant difference in the rate of recall between the two groups, with a crude recall rate of 46.1 per 1000 screening episodes post-breast reduction compared with 50.7 per 1000 screening episodes for women without breast reduction. There was no significant difference in the pathological type or location of the cancer between the two groups of women. CONCLUSION: Postoperative breast changes following reduction mammoplasty do not significantly hinder analysis of the screening mammogram.

Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations.

Successful treatment of vascular anomalies has eluded the physician until now, despite various treatments utilised. Bleomycin has been successfully used in intralesional injection treatment of cystic hygromas and haemangiomas, based specifically on a high sclerosing effect on vascular endothelium. In a prospective study of 95 patients, the effectiveness of intralesional bleomycin injection (IBI) treatment in haemangiomas and vascular malformations was evaluated and documented. Complete resolution or significant improvement occurred in 80% of all patients treated. Complete resolution occurred in 49% of haemangiomas, 32% of venous malformations, and 80% of cystic hygromas. Significant improvement occurred in 38% of haemangiomas, 52% of venous malformations, 13% of cystic hygromas and 50% of lymphatic malformations. Of the six patients who presented with a painful lesion, four experienced complete resolution and two had significant improvement to treatment. Local complications encountered were superficial ulceration occurring in 2 patients, and cellulitis in 1 of the 95 patients. Systemic complications were flu-like symptoms in three patients and partial, transient hair loss in two patients. None of the patients presented with haematological toxic effects or signs of pulmonary involvement (fibrosis, hypertension). IBI is an effective treatment in haemangiomas and vascular malformation lesions, obviating the need for invasive primary surgery or systemic treatment regimens in 80% of cases, and allowing for limited need of secondary surgical or adjunctive procedures in cases with a moderate result.

Sarcolemma agonist-induced interactions between InsP3 and ryanodine receptors in Ca2+ oscillations and waves in smooth muscle.

Smooth muscle cells respond to InsP(3)-generating (sarcolemma-acting) neurotransmitters and hormones by releasing Ca(2+) from the internal store. However, the release of Ca(2+) does not occur uniformly throughout the cytoplasm but often into a localized area before being transmitted to other regions of the cell in the form of Ca(2+) waves and oscillations to actively spread information within and between cells. Yet, despite their significance, our understanding of the generation of oscillations to waves is incomplete. A major aspect of controversy centres on whether or not Ca(2+) released from the InsP(3) receptor activates RyRs (ryanodine receptors) to generate further release by Ca(2+)-induced Ca(2+) release and propagate waves or whether the entire process arises from InsP(3) receptor activity alone. Under normal physiological conditions the [Ca(2+)] required to activate RyR (approx. 15 microM) exceeds the bulk average [Ca(2+)](c) (cytoplasmic Ca(2+) concentration) generated by InsP(3) receptor activity (<1 microM). Progression of waves and oscillations by RyR activity would require a loss of control of RyR activity and an unrestrained positive feedback on Ca(2+) release. Under store-overload conditions, RyR Ca(2+) sensitivity is increased and this enables waves to be induced by RyR activity. However, the relevance of these Ca(2+)-release events to normal physiological functioning is unclear. The InsP(3) receptor, on the other hand, is activated by Ca(2+) over the physiological range (up to 300 nM) and deactivated by higher [Ca(2+)](c) (>300 nM), features that favour intermittent activity of the receptor as occurs in waves and oscillations. Experimental evidence for the involvement of RyR relies mainly on pharmacological approaches in the intact cell where poor drug specificity could have led to ambiguous results. In this brief review the possible interactions between InsP(3) receptors and RyR in the generation of oscillations and waves will be discussed. Evidence is presented that RyRs are not required for InsP(3)-mediated Ca(2+) transients. Notwithstanding, ryanodine can inhibit InsP(3)-mediated Ca(2+) responses after RyR activity has been induced by caffeine or by steady depolarization which evokes spontaneous transient outward currents (a sarcolemmal manifestation of RyR activity). Ryanodine inhibits InsP(3)-mediated Ca(2+) transients by depleting the store of Ca(2+) rather than by RyR involvement in the InsP(3)-mediated Ca(2+) increase.

Societal costs of exposure to toxic substances: economic and health costs of four case studies that are candidates for environmental causation.

Four outcomes that evidence suggests are candidates for "environmental causation" were chosen for analysis: diabetes, Parkinson's disease (PD), neurodevelopmental effects and hypothyroidism, and deficits in intelligence quotient (IQ). These are an enormous burden in the United States, Canada, and other industrial countries. We review findings on actual social and economic costs, construct estimates of some of the costs from pertinent sources, and provide several hypothetical examples consistent with published evidence. Many detailed costs are estimated, but these are fragmented and missing in coverage and jurisdiction. Nonetheless, the cumulative costs identified are very large, totaling $568 billion to $793 billion per year for Canada and the United States combined. Partial Canadian costs alone are $46 billion to $52 billion per year. Specifics include diabetes (United States and Canada), $128 billion per year; PD in the United States, $13 billion to $28.5 billion per year; neurodevelopmental deficits and hypothryoidism are endemic and, including estimates of costs of childhood disorders that evidence suggests are linked, amount to $81.5 billion to $167 billion per year for the United States and $2 billion per year in Ontario; loss of 5 IQ points cost $30 billion per year in Canada and $275 billion to $326 billion per year in the United States; and hypothetical dynamic economic impacts cost another $19 billion to $92 billion per year for the United States and Canada combined. Reasoned arguments based on the weight of evidence can support the hypothesis that at least 10%, up to 50% of these costs are environmentally induced--between $57 billion and $397 billion per year.

Vascular injury during tension-free vaginal tape procedure for stress urinary incontinence.

BACKGROUND: Tension-free vaginal tape procedure is a popular surgical treatment of genuine stress urinary incontinence. CASES: Two cases of retropubic hematoma after tension-free vaginal tape procedure are reported. One woman with an 8 x 10 cm hematoma localized to the retropubic space required transfusion of two units of packed red blood cells for symptomatic relief. Neither case required reoperation, and both patients' hematomas resolved over 6 months without treatment. Both patients were continent 9-12 months after surgery. CONCLUSION: Although the tension-free vaginal tape procedure is a minimally invasive operation for stress urinary incontinence and appears to be effective, significant vascular complications can result.

Metanephric adenoma, nephrogenic rests, and Wilms' tumor: a histologic and immunophenotypic comparison.

Metanephric adenoma (MA) is a renal tumor that is generally detected in adults and occasionally in children. These tumors usually behave in a benign fashion. Although the histogenesis of MA is unclear, a morphologic similarity to Wilms' tumor (WT) complex exists. Six cases of MA, five cases of childhood WT (CWT), two cases of adult WT (AWT), and four cases of treated MWT and/or nephrogenic rests (MWT/NR), with paraffin blocks available for use, were retrieved from the surgical pathology files of the Mayo Clinic. Clinical information was extracted from the medical record. Immunoperoxidase stains for WT1, AE1, CK7, CD57, CD56, and desmin were performed on paraffin sections from all cases. All six cases of MA were strongly and diffusely positive with antibodies to WT1 and CD57 and focally positive with antibodies to CK7. Three cases showed focal faint staining in <5% of the cells with keratin AE1. Stains for CD56 and desmin were negative. All seven cases of WT, including five CWT and two AWT, were strongly and diffusely positive with WT1 in the blastema and epithelium but showed only weak focal positivity in stromal cells. Six cases were diffusely positive for CD56 and one case showed focal positivity. Keratin AE1 was positive in one case of AWT and focally positive in the other AWT. The blastema of all cases of WT were negative for desmin, CK7, and CD57, although staining for keratin AE1, CD56, and CD57 was seen in maturing tubules of CWT cases. Of the five CWT cases, two had associated NR and two showed maturing WT after treatment. The areas of NR and maturing WT were histologically similar to MA and were composed of small tubules with uniform nuclei with no mitotic activity, scant cytoplasm, and focal calcifications. All four cases of maturing WT/NR were positive for WT1 and focally positive for CD57, CK7, and AE1. Stains for CD56 and desmin were negative except in foci of residual blastema, which stained for CD56 but lacked CD57 and CK7 staining. Five cases each of renal cell carcinoma, papillary renal cell carcinoma, and oncocytoma were negative for WT1. Two of five cases of chromophobe carcinoma showed very weak staining present in <10% of tumor nuclei. Metanephric adenoma is histogenetically related to WT and is morphologically and immunophenotypically identical to maturing WT and nephrogenic rests.

Fluorescent monitoring of kinase activity in real time: development of a robust fluorescence-based assay for Abl tyrosine kinase activity.

Fluorescent biosensors hold great promise for drug discovery. Using a solid-phase version of protein semi-synthesis, we incorporated two fluorophores at specific sites within a truncated version of the c-Crk-II protein. The resulting fluorescent protein biosensor permits the real-time monitoring of Abl kinase activity and provides a robust and rapid method for assaying Abl kinase inhibitors.