Field cancerization: Treatment.

The goal of field cancerization treatment is to reduce the risk of developing keratinocyte carcinoma. Selecting the appropriate therapy depends on the degree of field cancerization and the number of invasive cutaneous squamous cell carcinomas. Other considerations include treatment efficacy, cost, side effects, and patient preference. Field therapies are preferred because they address clinically visible disease and subclinical atypia. However, lesion-directed therapies are useful for lesions that are more difficult to treat or those where a histologic diagnosis is required. Patients with extensive field cancerization benefit from a combination of field-directed and lesion-directed treatments. The second article in this continuing medical education series provides a framework to guide evidence-based decision making for field cancerization treatment.

Field cancerization: Definition, epidemiology, risk factors, and outcomes.

Field cancerization was first described in 1953 when pathologic atypia was identified in clinically normal tissue surrounding oropharyngeal carcinomas. The discovery of mutated fields surrounding primary tumors raised the question of whether the development of subsequent tumors within the field represented recurrences or additional primary tumors. Since this initial study, field cancerization has been applied to numerous other epithelial tissues, including the skin. Cutaneous field cancerization occurs in areas exposed to chronic ultraviolet radiation, which leads to clonal proliferations of p53-mutated fields and is characterized by multifocal actinic keratoses, squamous cell carcinomas in situ, and cutaneous squamous cell carcinomas. In the first article in this continuing medical education series, we define field cancerization, review the available grading systems, and discuss the epidemiology, risk factors, and outcomes associated with this disease.

Merkel Cell Carcinoma: Updates on Staging and Management.

Merkel cell carcinoma is an aggressive neuroendocrine carcinoma with increasing incidence over the past few decades. The TNM Staging System used for Merkel cell carcinoma was updated by the American Joint Committee on Cancer in 2017. Clinical practice guidelines were updated by the National Comprehensive Cancer Network on August 31, 2018. This article reviews the most recent evidence-based updates on staging and management.

Pediatric chondrodermatitis nodularis helicis (CNH) in a child with Beckwith-Wiedemann syndrome (BWS).

Chondrodermatitis nodularis helicis is an idiopathic degenerative process that presents as a painful nodule, papule, or ulcer on the helix or antihelix. It predominantly affects adults and is thought to be associated with trauma to the ear. We describe a case of pediatric chondrodermatitis nodularis helicis occurring in a child with a history of Beckwith-Wiedemann syndrome that was successfully treated with an excisional biopsy and relief from a recurrent source of pressure on the ear.

Immune checkpoint inhibitors and the development of granulomatous reactions.

Immune checkpoint inhibitors (ICPIs) have emerged as a frontline treatment for a growing list of malignancies. Disruption of the negative regulatory immune checkpoints by ICPIs has been associated with many immune-related adverse events. Granulomatous reactions, such as sarcoidosis-like reactions, granulomatous panniculitis, granuloma annulare, and granulomatous dermatitis, are uncommon but increasingly recognized immune-related adverse events seen in patients treated with ICPIs. The frequency and significance of these eruptions, including whether they portend responsiveness to treatment, remain unclear. Additionally, understanding the role of immune checkpoint blockade in these reactions may provide mechanistic insight into the relevant signaling pathways involved in sarcoidosis and other granulomatous disorders.

Physical characterization and in vivo organ distribution of coated iron oxide nanoparticles.

Citrate-stabilized iron oxide magnetic nanoparticles (MNPs) were coated with one of carboxymethyl dextran (CM-dextran), polyethylene glycol-polyethylene imine (PEG-PEI), methoxy-PEG-phosphate+rutin, or dextran. They were characterized for size, zeta potential, hysteresis heating in an alternating magnetic field, dynamic magnetic susceptibility, and examined for their distribution in mouse organs following intravenous delivery. Except for PEG-PEI-coated nanoparticles, all coated nanoparticles had a negative zeta potential at physiological pH. Nanoparticle sizing by dynamic light scattering revealed an increased nanoparticle hydrodynamic diameter upon coating. Magnetic hysteresis heating changed little with coating; however, the larger particles demonstrated significant shifts of the peak of complex magnetic susceptibility to lower frequency. 48 hours following intravenous injection of nanoparticles, mice were sacrificed and tissues were collected to measure iron concentration. Iron deposition from nanoparticles possessing a negative surface potential was observed to have highest accumulation in livers and spleens. In contrast, iron deposition from positively charged PEG-PEI-coated nanoparticles was observed to have highest concentration in lungs. These preliminary results suggest a complex interplay between nanoparticle size and charge determines organ distribution of systemically-delivered iron oxide magnetic nanoparticles.

Low-dose radiotherapy for primary cutaneous anaplastic large-cell lymphoma while on low-dose methotrexate.

Primary cutaneous anaplastic large-cell lymphoma (pcALCL) is part of a spectrum of CD30+ primary cutaneous lymphoproliferative disorders (pcLPDs) that also includes lymphomatoid papulosis (LyP). Localized radiotherapy at doses of 34 to 44 Gy is first-line treatment of pcALCL, but the use of low-dose radiotherapy for pcALCL has not been reported. We present the case of a patient with a history of pcALCL/LyP who was treated with low-dose radiotherapy while on oral low-dose methotrexate (MTX) once weekly. This report suggests that low-dose radiotherapy can be an effective palliative treatment of pcALCL. Low-dose radiotherapy may offer certain advantages over traditional radiotherapy, such as a more economical and efficient treatment for patients, potentially fewer short-term and long-term side effects, and the potential for concomitant use with low-dose MTX.

Magnetic nanoparticle hyperthermia enhances radiation therapy: A study in mouse models of human prostate cancer.

PURPOSE: We aimed to characterise magnetic nanoparticle hyperthermia (mNPH) with radiation therapy (RT) for prostate cancer. METHODS: Human prostate cancer subcutaneous tumours, PC3 and LAPC-4, were grown in nude male mice. When tumours measured 150 mm3 magnetic iron oxide nanoparticles (MIONPs) were injected into tumours to a target dose of 5.5 mg Fe/cm3 tumour, and treated 24 h later by exposure to alternating magnetic field (AMF). Mice were randomly assigned to one of four cohorts to characterise (1) intratumour MIONP distribution, (2) effects of variable thermal dose mNPH (fixed AMF peak amplitude 24 kA/m at 160 ± 5 kHz) with/without RT (5 Gy), (3) effects of RT (RT5: 5 Gy; RT8: 8 Gy), and (4) fixed thermal dose mNPH (43 °C for 20 min) with/without RT (5 Gy). MIONP concentration and distribution were assessed following sacrifice and tissue harvest using inductively coupled plasma mass spectrometry (ICP-MS) and Prussian blue staining, respectively. Tumour growth was monitored and compared among treated groups. RESULTS: LAPC-4 tumours retained higher MIONP concentration and more uniform distribution than did PC3 tumours. AMF power modulation provided similar thermal dose for mNPH and combination therapy groups (CEM43: LAPC-4: 33.6 ± 3.4 versus 25.9 ± 0.8, and PC3: 27.19 ± 0.7 versus 27.50 ± 0.6), thereby overcoming limitations of MIONP distribution and yielding statistically significant tumour growth delay. CONCLUSION: PC3 and LAPC-4 tumours represent two biological models that demonstrate different patterns of nanoparticle retention and distribution, offering a model to make comparisons of these effects for mNPH. Modulating power for mNPH offers potential to overcome limitations of MIONP distribution to enhance mNPH.

Atypical manifestations of graft-versus-host disease.

BACKGROUND: Cutaneous graft-versus-host disease (GVHD) is classically described as morbilliform when acute and lichen planus-like or sclerotic when chronic. In addition to these well-known clinical forms, there are many other presentations of GVHD that are important to recognize. As the number of patients undergoing stem cell transplantation increases and the survival after transplantation improves, the prevalence of GVHD is expected to rise, and its various presentations will be increasingly encountered in clinical practice. OBJECTIVE: We sought to report unusual manifestations of skin GVHD and provide a summary of typical and atypical presentations of GVHD reported in the literature. METHODS: Patients with stem cell transplantation who developed unusual eruptions after transplantation had biopsy specimens taken to evaluate for histopathologic evidence of GVHD. RESULTS: Six patients presented with unusual cases of biopsy-proven GVHD, including follicular hyperkeratosis, thick-appearing white tongue, inverse pityriasis rosea-like, and eczema craquelé-like GVHD. LIMITATIONS: This study is limited by case number. CONCLUSIONS: Because of the high rate of cutaneous involvement with GVHD, the accessibility of the skin for diagnosis, and the morbidity associated with severe or long-standing skin involvement, it is important for dermatologists to recognize and accurately diagnose cutaneous GVHD in all its protean manifestations.

A case of phrynoderma in a patient with Crohn's disease.

Phrynoderma is a type of follicular hyperkeratosis associated with nutritional deficiencies. It is rarely seen in developed countries, although cases have been reported in patients with severe malnutrition or malabsorption secondary to various causes. This report describes a 19-year-old patient with poorly controlled Crohn's disease and malnutrition who developed the characteristic hyperkeratotic papules and plaques on his trunk and extremities in the setting of low serum vitamin A levels. To our knowledge, there are no reports of phrynoderma associated with Crohn's disease. It is likely that our patient's low vitamin A level and subsequent phrynoderma was the result of increased Crohn's disease activity and malnutrition.

Method to reduce non-specific tissue heating of small animals in solenoid coils.

PURPOSE: Solenoid coils that generate time-varying or alternating magnetic fields (AMFs) are used in biomedical devices for research, imaging and therapy. Interactions of AMF and tissue produce eddy currents that deposit power within tissue, thus limiting effectiveness and safety. We aim to develop methods that minimise excess heating of mice exposed to AMFs for cancer therapy experiments. MATERIALS AND METHODS: Numerical and experimental data were obtained to characterise thermal management properties of water using a continuous, custom water jacket in a four-turn simple solenoid. Theoretical data were obtained with method-of-moments (MoM) numerical field calculations and finite element method (FEM) thermal simulations. Experimental data were obtained from gel phantoms and mice exposed to AMFs having amplitude >50 kA/m and frequency of 160 kHz. RESULTS: Water has a high specific heat and thermal conductivity, is diamagnetic, polar, and nearly transparent to magnetic fields. We report at least a two-fold reduction of temperature increase from gel phantom and animal models when a continuous layer of circulating water was placed between the sample and solenoid, compared with no water. Thermal simulations indicate the superior efficiency in thermal management by the developed continuous single chamber cooling system over a double chamber non-continuous system. Further reductions of heating were obtained by regulating water temperature and flow for active cooling. CONCLUSIONS: These results demonstrate the potential value of a contiguous layer of circulating water to permit sustained exposure to high intensity alternating magnetic fields at this frequency for research using small animal models exposed to AMFs.

The effect of cell cluster size on intracellular nanoparticle-mediated hyperthermia: is it possible to treat microscopic tumors?

AIM: To compare the measured surface temperature of variable size ensembles of cells heated by intracellular magnetic fluid hyperthermia with heat diffusion model predictions. MATERIALS & METHODS: Starch-coated Bionized NanoFerrite (Micromod Partikeltechnologie GmbH, Rostock, Germany) iron oxide magnetic nanoparticles were loaded into cultured DU145 prostate cancer cells. Cell pellets of variable size were treated with alternating magnetic fields. The surface temperature of the pellets was measured in situ and the associated cytotoxicity was determined by clonogenic survival assay. RESULTS & CONCLUSION: For a given intracellular nanoparticle concentration, a critical minimum number of cells was required for cytotoxic hyperthermia. Above this threshold, cytotoxicity increased with increasing cell number. The measured surface temperatures were consistent with those predicted by a heat diffusion model that ignores intercellular thermal barriers. These results suggest a minimum tumor volume threshold of approximately 1 mm(3), below which nanoparticle-mediated heating is unlikely to be effective as the sole cytotoxic agent.

Preliminary study of injury from heating systemically delivered, nontargeted dextran-superparamagnetic iron oxide nanoparticles in mice.

AIM: To assess the potential for injury to normal tissues in mice due to heating systemically delivered magnetic nanoparticles in an alternating magnetic field (AMF). MATERIALS & METHODS: Twenty three male nude mice received intravenous injections of dextran-superparamagnetic iron oxide nanoparticles on days 1-3. On day 6, they were exposed to AMF. On day 7, blood, liver and spleen were harvested and analyzed. RESULTS: Iron deposits were detected in the liver and spleen. Mice that had received a high-particle dose and a high AMF experienced increased mortality, elevated liver enzymes and significant liver and spleen necrosis. Mice treated with low-dose superparamagnetic iron oxide nanoparticles and a low AMF survived, but had elevated enzyme levels and local necrosis in the spleen. CONCLUSION: Magnetic nanoparticles producing only modest heat output can cause damage, and even death, when sequestered in sufficient concentrations. Dextran-superparamagnetic iron oxide nanoparticles are deposited in the liver and spleen, making these the sites of potential toxicity. Original submitted 16 August 2011; Revised submitted 21 March 2012; Published online 26 July 2012.

Membrane fluidity and lipid order in ternary giant unilamellar vesicles using a new bodipy-cholesterol derivative.

Cholesterol-rich, liquid-ordered (L(o)) domains are believed to be biologically relevant, and yet detailed knowledge about them, especially in live cells under physiological conditions, is elusive. Although these domains have been observed in model membranes, understanding cholesterol-lipid interactions at the molecular level, under controlled lipid mixing, remains a challenge. Further, although there are a number of fluorescent lipid analogs that partition into liquid-disordered (L(d)) domains, the number of such analogs with a high affinity for biologically relevant L(o) domains is limited. Here, we use a new Bodipy-labeled cholesterol (Bdp-Chol) derivative to investigate membrane fluidity, lipid order, and partitioning in various lipid phases in giant unilamellar vesicles (GUVs) as a model system. GUVs were prepared from mixtures of various molar fractions of dioleoylphosphatidylcholine, cholesterol, and egg sphingomyelin. The L(d) phase domains were also labeled with 1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine (DiI-C(12)) for comparison. Two-photon fluorescence lifetime and anisotropy imaging of Bdp-Chol are sensitive to lipid phase domains in GUVs. The fluorescence lifetime of Bdp-Chol in liquid-disordered, single-phase GUVs is 5.50 +/- 0.08 ns, compared with 4.1 +/- 0.4 ns in the presence of DiI-C(12). The observed reduction of fluorescence lifetime is attributed to Förster resonance energy transfer between Bdp-Chol (a donor) and DiI-C(12) (an acceptor) with an estimated efficiency of 0.25 and donor-acceptor distance of 2.6 +/- 0.2 nm. These results also indicate preferential partitioning (K(p) = 1.88) of Bdp-Chol into the L(o) phase. One-photon, time-resolved fluorescence anisotropy of Bdp-Chol decays as a triexponential in the lipid bilayer with an average rotational diffusion coefficient, lipid order parameter, and membrane fluidity that are sensitive to phase domains. The translational diffusion coefficient of Bdp-Chol, as measured using fluorescence correlation spectroscopy, is (7.4 +/- 0.3) x 10(-8) cm(2)/s and (5.0 +/- 0.2) x 10(-8) cm(2)/s in the L(d) and L(o) phases, respectively. Experimental translational/rotational diffusion coefficient ratios are compared with theoretical predictions using the hydrodynamic model (Saffman-Delbrück). The results suggest that Bdp-Chol is likely to form a complex with other lipid molecules during its macroscopic diffusion in GUV lipid bilayers at room temperature. Our integrated, multiscale results demonstrate the potential of this cholesterol analog for studying lipid-lipid interactions, lipid order, and membrane fluidity of biologically relevant L(o) domains.