Therapy of uveal melanoma aims to preserve the eye and its function and to avoid metastatic dissemination. The treatment choice is difficult and must keep into account several factors; the therapeutic strategy of uveal melanoma should therefore be personalized, sometimes requiring to combine different treatment techniques. Nowadays globe-sparing radiotherapy techniques are often preferred to enucleation. Plaque brachytherapy, the most commonly used eye-preserving therapy, is suitable for small- and medium-sized uveal melanomas. Proton beam radiotherapy is indicated for tumours with noticeable size, challenging shape and location, but is more expensive and less available than brachytherapy. Enucleation is currently restricted to advanced tumours, uveal melanomas with orbital or optic nerve involvement, blind and painful eyes because of treatment-related complications . The effect of proton beam therapy on neoplastic tissue is related to direct cytotoxic action of the radiations, impairment of neoplastic vascular supply and immunologic response. Complications after radiotherapy are frequent and numerous and mainly related to tumour thickness, radiation dose and distance between the tumour and optic nerve. The purpose of this pictorial review is to provide the radiologists with awareness about diagnostic methods and therapeutic options of uveal melanoma. In the present second section, we discuss the therapeutic management of uveal melanoma, describing the main ocular-conserving radiotherapic techniques. We subsequently present an overview of the effects of radiations on neoplastic tissue. Lastly, we review ocular complications following radiotherapy that should be evaluated by radiologists during follow-up MRI examinations. Plaque brachytherapy is suitable for small- and medium-sized uveal melanomas.Proton beam radiotherapy is feasible for large-sized tumors with challenging location.Enucleation is indicated for advanced melanomas and painful eyes because of complications.Radiation-induced necrosis is hypointense on T2-weighted sequences, because of melanin pigment dispersion.Panuveitis and endophthalmitis represent frequent inflammatory complications of proton beam radiotherapy.This pictorial essay aims to provide the radiologists with awareness about diagnostic methods and therapeutic options of uveal melanoma. In the previous first instalment, we described ophthalmological and radiological imaging techniques to diagnose uveal melanomas with emphasis on the role of MR imaging and reviewed MR imaging findings of uveal melanoma.In the present second instalment, we discuss the therapeutic management of uveal melanoma, describing the main ocular-conserving radiotherapic techniques and their indications. Finally, we present an overview of the effects of radiations on neoplastic tissue and of ocular complications following radiotherapy, using examples from our institution.The purposes of uveal melanoma treatment are to avoid the metastatic dissemination and to preserve the eye with useful vision . TreatmeSince different studies have demonstrated no significant difference in terms of survival rate between eye-preserving therapies and surgery, in recent years globe-sparing techniques are often preferred to surgical ones . In thisLaser methods induce necrosis into neoplastic tissues. However, because of their drawbacks represented by poor tissue penetration and requirement for multiple treatment sessions, laser techniques have very limited indications in the treatment of uveal melanomas .Previously used to treat small choroidal melanomas, currently laser photocoagulation has been largely replaced by transpupillary thermal therapy. Xenon arc photocoagulation showed a better tumor control than argon laser photocoagulation; however, the latter demonstrated a lower risk of complications  , 13, 14.In TTT, an infrared light (diode laser) is employed to target a lesion through the pupil. This laser technique is feasible for small- and medium-sized flat pigmented uveal melanomas of the extramacular, extrapapillary region and can be used alone or prior to plaque radiotherapy (sandwich therapy) , 13, 14.Radiation therapy is the most widely used globe-conserving therapy for uveal melanoma and encompasses brachytherapy  with various radioactive sources, charged-particle beam therapy and stereotactic radiosurgery. The different kinds of radiotherapy differ not only on the basis of the type of radiation employed, but also with respect to the ocular morbidity they cause .125I), palladium-103 (103Pd), iridium-192 (192Ir) and cobalt-60 (60C0);gamma-ray emitting isotopes: iodine-125 (106Ru).beta-particle-emitting isotopes: ruthenium-106 . After a temporal interval of 2–7 days (variable according to the applied radioisotope), the radioactive device is removed –70 Gy. A, 16–18. In this kind of teletherapy, an extremely collimated beam of protons or helium ions is used to concentrate a high and homogenous dose of radiation to the lesion; because of Bragg peak effect, the density of ionization of protons is concentrated in correspondence of the end of their path and the radiation dissipates beyond the tumor boundaries, thus reducing injuries to adjacent tissues. Adjacent tissue sparing is particularly efficient at the sides and posteriorly to the lesion, whereas at the beam entrance the dose of radiation is relatively high; therefore, tissues located along the beams route are exposed to a considerable radiation dose too , 22, 23.Proton-beam radiotherapy was employed for the first time in the treatment of uveal melanoma in 1975 . CurrentFor tumor involving the choroid and/or ciliary body, three-to-five tantalum clips (2.5 mm in diameter) are sutured to the sclera to delimit the tumor borders Fig. ; iris meOn the basis of ocular biometry, ultrasound findings, color photography, cranial X-rays and intra-operative marker measurements, a 3D computer model of the patient’s eye/tumor is generated  in order to plan an individualized irradiation field. This planning needs a close cooperation among the ophthalmologist, the radiation oncologist and the medical physicist Fig.  and is mA total radiation dose of 53–70 Gy is delivered in four consecutive daily fractions (30 s each). During the treatment, patient’s head immobilization is ensured by means of a custom-made face mask and dental bite block. Patient’s eye positioning is maintained constant through a visual target; irradiation is automatically temporarily suspended whenever the patient involuntarily moves the affected eye from the planned position. Safety margins may range from < 2 mm  to 4 mm (for ciliary body melanomas) , 25, 29.Proton beam therapy protocol includes the following phases:Charged particle radiotherapy allows to reach tumor control in about 95–98% of cases . In the A series of differences between proton beam radiotherapy and plaque brachytherapy must be kept into account when choosing the most suitable ocular-conserving radiotherapic treatment.highly collimated beams with very low scattering ,boosted radiation dose at the end of the pathway,optimal and uniform radiation dose delivery at the level of the tumor,healthy tissue relative sparing distally and, to a lesser extent, proximally to the targeted lesion , 31, 32.Owing to the physical properties of protons, proton beam radiotherapy has theoretical advantages as compared with other kinds of radiation therapy:All these features of accelerated proton beam are specifically relevant in the treatment of uveal melanoma, since this malignant neoplasm is relatively radioresistant and its radiotherapy requires high radiation dose .When treating tumors with noticeable size, challenging shape and location, proton beam radiotherapy may be more feasible than plaque brachytherapy since the former lessens the risk of recurrence and injury to the optic disc and fovea .Plaque brachytherapy is suitable for small- and medium-sized uveal melanomas because the radiation dose decreases with increasing distance from the radioactive plaque; for this reason, in large lesions the tumor apex does not receive a sufficient radiation dose, due to the excessive distance from the radiation source. Lesions close to the optic nerve head are challenging to treat with brachytherapy as well; for such lesions proton beam therapy represents the best treatment option , 33.Tantalum markers’ positioning for proton beam therapy needs lower surgical precision than insertion of plaque for episcleral brachytherapy . When faTumor regression is quicker after plaque brachytherapy than after proton beam radiotherapy, presumably as a consequence of a higher radiation dose provided to the tumor base through plaque radiotherapy .Usually complications affecting the anterior segment are more common following external beam radiotherapy then after plaque brachytherapy . AccordiSecondary enucleation rate at 5 years after radiotherapy is higher with proton beam therapy (5.4–14%) than with plaque brachytherapy (4%) , 25, 36.Local tumor recurrence rates at 5 years range from 2% to 8.4% following proton beam therapy  and fromProton beam therapy is more expensive as compared with plaque brachytherapy, with a treatment cost per patient of about €30,000 and €6,000, respectively. Furthermore, proton beam therapy is still less available than brachytherapy .Stereotactic radiotherapy involves the use of multiple photon beams focused towards the tumor from different directions . Tumor lStereotactic radiotherapy encompasses different modalities of irradiation such as Gamma Knife, Cyber Knife (both first used to treat brain tumors) and linear accelerator.Gamma Knife has demonstrated successful in treating uveal melanomas unsuitable for plaque brachytherapy, it is not routinely used because of its high rates of radiation-induced inflammation, radiation retinopathy and neovascular glaucoma , 314, 31Radiation-induced optic neuropathy is caused by a radiation dose > 50 Gy and clinically manifests with significant visual loss, generally 1.5–2 years after radiotherapy. Believed physiopathogical mechanisms include a direct neuropathic effects of radiation as well as radiation-induced vasculopathy. Histopathologically, the optic nerve demonstrates sectoral or diffuse atrophy with areas of demyelination, neuronal degeneration, necrosis and lymphocytic infiltrates , 23, 42.When treating uveal melanomas of the nasal area with proton-beam radiotherapy, medial canthus and puncta may lay in the radiation field. Radiation-related inflammation may determine canaliculitis, intraluminal adhesion, scarring and obstruction of the lacrimal drainage system, eventually resulting in intractable epiphora . On the During treatment with plaque brachytherapy, extraocular muscles may be exposed to a significant radiation dose. Muscles can show ultrastructural alterations consisting in decrease in muscular fibres and increase in fibroblasts and collagen. These disorders may impair extraocular muscle function with the onset of transient diplopia .At the level of periocular tissues, radiotherapy and radiation-related inflammatory response may determine dense fibrotic adhesions that can make it difficult the surgical intervention when secondary enucleation is required Fig.  32]. As. As32]. Cosmetic issues after irradiation encompass orbital hypoplasia, hyperpigmentation of the skin, radiation dermatitis and soft tissue fibrosis .Irradiation of the eyelid during proton beam radiotherapy can induce acute burn, then resulting in a depigmented scar and eyelash loss; squamous metaplasia of the tarsal conjunctiva and keratinization of the mucocutaneous junction in correspondence of the superior lid margin may develop as well. To avoid these complications, proton beam radiotherapy should be performed through the closed eye , 52.SO is characterized by an autoimmune inflammatory disease usually occurring as a consequence of penetrating ocular injury or intraocular surgery. The pathogenesis of SO lies on an autosensitization of blood and vitreous T lymphocytes against an antigenic protein from the uvea or retina. In patients with uveal melanoma treated with proton beam radiotherapy, SO involving the untreated eye has been reported as a rare complication with an incidence of 0.06% . In thisRegardless of the kind of radiotherapy employed, to regularly monitor patients undergoing globe-retaining therapies is mandatory in order to early detect and treat both recurrences and treatment-related complications. Basically, after radiotherapy, patients should be checked initially every 3–6 months for 2 years and subsequently every 6–12 months. At each follow-up, the ocular oncologist has to perform a full ocular examination completed with local tumor assessment.Systemic surveillance has the purpose of identifying metastatic disease as early as possible; nevertheless, there is no universally accepted consensus on the time interval and on the type of imaging examinations that should be performed. Liver US (performed every 6 months), computed tomography , magnetic resonance imaging (of the upper abdomen) and whole body positron emission tomography/computed tomography (PET/CT) are employed in the staging of uveal melanoma both at baseline and in the follow-up , 23, 56.Up to 50% of patients affected by uveal melanoma develop metastases. These latter have an elective tropism for the hepatic parenchyma, so that the liver represents the primary site of metastatization in more than 90% of cases and about 50% of these patients have purely liver metastases –61. WithIn recent years, there has been a gradual transition from open surgical techniques to minimally invasive approaches. The latter encompass hepatic intra-arterial chemotherapy, hepatic transarterial chemoembolization, hepatic perfusions and radioembolization. Such liver-targeted therapies have a twofold advantage: (1) to deliver a concentrated dose of chemotherapeutic agents to both radiologically appreciable and occult lesions, (2) to reduce the drug-related systemic toxicity.Hepatic intra-arterial (HIA) chemotherapy involves the administration of different chemotherapeutic agents  by the intra-arterial route through temporary or implantable catheters placed into the hepatic artery surgically or radiologically ; the catheters may be connected with a subcutaneous infusion pump. Median overall survival ranges between 9 and 21 months , 65. ProHepatic transarterial chemoembolization (TACE) manages to improve the dwell time of chemotherapy agents and to cause select ischemia in the neoplastic tissue, at the same time. The procedure involves the transarterial administration of chemotherapeutic agents followed by an embolic agent. Median overall survival is about 10 months , 65; nevIsolated hepatic perfusion (IHP) is an operative procedure implying the surgical isolation of the vascular supply to the hepatic parenchyma in order to deliver high dose of chemotherapeutic agents.In spite of encouraging results in terms of overall tumor response rates (33–62%) and median overall survival duration (10–24 months) , 60, 66,Percutaneous hepatic perfusion (PHP) is an easier and repeatable nonsurgical alternative to IHP, implying the administration of the chemotherapeutic agent through the hepatic artery and the isolation of hepatic venous flow through a double-balloon catheter placed in the inferior vena cava. The hepatic venous blood is filtered, via an extracorporeal filtration system, which eliminate the drug, before being re-injected into the systemic circulation. Under this system, it is possible to increase the dose of chemotherapeutic agent to the neoplastic tissue and concurrently to cut down drug-induced systemic toxicity , 63, 67.90Y) microspheres can be used as a first-line treatment or a second-line treatment in patients no longer responding to previous local or systemic therapies. This procedure allows to deliver high radiation dose within tumor tissue with relative protection of the surrounding parenchyma, since radioactive microspheres, due to their small size, mainly localize within neoplastic microcirculation [Localized radioembolization of branches of the hepatic artery employing yttrium-90 (culation , 65, 68.culation .Owing to the continuous advances of liver-targeted therapies, the interventional radiologists have gained importance in the clinical management of patients with uveal melanoma. However, we must not forget that the success of local therapies is linked to the extent of the metastatic involvement of the hepatic parenchyma which represents the main prognostic factor . TherefoThe diagnostic and therapeutic management of uveal melanoma requires a multidisciplinary approach involving the ocular oncologist, radiologist, radiation oncologist, pathologist and medical physicist. Owing to the advances of diagnostic imaging and the improvements of treatment methods, the indications of radiotherapy techniques undergo a continuous and significant updating and should be therefore intended as a constantly evolving entity. For this reason, the treatment strategy of uveal melanoma should be personalized, keeping into account tumor-related, patient-related and center-related factors. Especially in case of large tumors, to combine different treatment techniques is often necessary in order to increase the possibility of globe preservation and to improve patients’ quality of life. Patients should be closely followed up after any kind of treatment in order to promptly detect and treat possible recurrences as well as the different complications, for some of which MR imaging is particularly suitable. Lastly, when it comes to therapy of uveal melanoma it is important to remember treating not just the neoplasm, but first and foremost the patient; this latter, in addition to clinical and instrumental follow-up, should also be supported through proper psychological care.


Insect fossils dating 55 million-years-old from the Stolleklint Clay and Fur Formation of Denmark are known to preserve both fine morphological details and color patterns. To enhance our understanding on how such fragile animals are retained in the fossil record, we examined a pair of beetle elytra, a wasp and a damselfly using sensitive analytical techniques. In our paper, we demonstrate that all three insect fossils are composed of cuticular remains  that, in turn, are dominated by the natural pigment eumelanin. In addition, the beetle elytra show evidence of a delicate lamellar structure comparable to multilayered reflectors that produce metallic hues in modern insects. Our results contribute to improved knowledge on the process of fossilization of insect body fossils in marine environments.Marine sediments of the lowermost Eocene Stolleklint Clay and Fur Formation of north-western Denmark have yielded abundant well-preserved insects. However, despite a long history of research, in-depth information pertaining to preservational modes and taphonomic pathways of these exceptional animal fossils remains scarce. In this paper, we use a combination of scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDX), transmission electron microscopy (TEM) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to assess the ultrastructural and molecular composition of three insect fossils: a wasp (Hymenoptera), a damselfly (Odonata) and a pair of beetle elytra (Coleoptera). Our analyses show that all specimens are preserved as organic remnants that originate from the exoskeleton, with the elytra displaying a greater level of morphological fidelity than the other fossils. TEM analysis of the elytra revealed minute features, including a multilayered epicuticle comparable to those nanostructures that generate metallic colors in modern insects. Additionally, ToF-SIMS analyses provided spectral evidence for chemical residues of the pigment eumelanin as part of the cuticular remains. To the best of our knowledge, this is the first occasion where both structural colors and chemical traces of an endogenous pigment have been documented in a single fossil specimen. Overall, our results provide novel insights into the nature of insect body fossils and additionally shed light on exceptionally preserved terrestrial insect faunas found in marine paleoenvironments.  Konservat-Lagerstätte, and the underlying, less well known Stolleklint Clay of the Ølst Formation, which together constitute the so-called “mo-clay deposits” [Lowermost Eocene deposits of the Limfjord Region, Northwestern Jutland, Denmark, have yielded diverse biotas of exceptionally preserved plant and animal body fossils that frequently retain soft parts, such as feathers and skin ,2. The leposits” . Despiteeposits” , the fineposits” ,2. The ieposits” ,5.Insects are currently one of the most ubiquitous and numerically abundant groups of animals on Earth, and they have a fossil record that dates back to the Early Devonian ,7. ExcepIn the present contribution, we expand current knowledge on organic preservation by employing an integrated experimental approach to a selection of insect fossils from the Eocene of Denmark. We investigate and illustrate these specimens with the aim of achieving a better understanding of the biostratinomic, taphonomic and diagenetic processes that result in exceptional preservation. The fossils analysed in this study originate from the Ølst and Fur formations in the Limfjord Region, Northwestern Jutland, Denmark. In this area, the Ølst Formation is represented solely by the Stolleklint Clay—the lowermost unit of the formation ,36—whichThree insect fossils from the Stolleklint Clay and Fur Formation showing various states of preservation were selected for this study: (1) a pair of isolated but three-dimensional beetle elytra  collected from a calcium carbonate concretion near ash layer +15 in the Fur Formation; (2) a flattened yet fully articulated wasp  preserved in a calcium carbonate concretion, collected from the Fur Formation on the Island of Mors; and (3) a compressed but largely articulated damselfly  found in hardened clays of the Stolleklint Clay. All specimens are housed in collections at Museum Salling, Fur Museum, Fur, Denmark, and were photographed in 96% ethanol using an Olympus SZX16 stereo microscope equipped with an Olympus SC30 digital camera prior to ultrastructural and molecular analyses. 2 silicon drift detector from Oxford Instruments at an electron energy of 15 keV. Complementary imaging and elemental analyses were conducted in a Tescan Mira3 High Resolution Schottky FEG-SEM linked to an energy-dispersive spectrometer  from Oxford Instruments using an electron energy of 15 keV. Samples obtained from the beetle elytra (FUM-N-17627) were coated with a 15nanometer-thick gold-palladium film prior to analysis, whereas FUM-N-11263 and FUM-N-10904 were examined uncoated. All fossils were examined in a Zeiss Supra 40VP FEG-SEM using either an Everhart-Thornley type secondary electron detector (SE2) at an electron energy of 2 keV or a variable pressure secondary electron detector (VPSE) at 15 keV. Elemental analyses and mappings used a X-Max 50 mm2) of elytra were removed from FUM-N-17627 using a sterile scalpel and then dehydrated in a graded ethanol series. Following this procedure, the samples were embedded in epoxy resin (Agar 100) via treatment with acetone. Ultra-thin sections (70 nm) were cut using a Leica EM UC7 ultramicrotome equipped with a diamond knife. The sections were then mounted on copper grids without additional treatment or staining and examined in a JEOL JEM-1400 Plus transmission electron microscope at 100 kV. TEM analyses were performed only on samples from the beetle elytra (FUM-N-17627) because the relict cuticle in FUM-N-11263 and FUM-N-10904 was too thin and spatially incoherent to allow meaningful sampling. Small pieces  or high lateral resolution . Spectra and images were generated using the SurfaceLab software . ToF-SIMS analyses were carried out in a TOFSIMSIV instrument  using 25 keV Bim/z 48–146  and synthetic eumelanin . Principal components analysis (PCA) of mass spectral data was conducted using the Solo software , employing Poisson scaling and prior normalization of the peak intensities to the sum intensity of all included peaks. The analysis included all major “eumelanin” peaks  in the mass range 146 (see ). RefereFUM-N-17627 comprises a pair of three-dimensionally preserved beetle elytra with a faint metallic shine when visualized under conventional light A. At higAssociated with the inferred cuticular remains are two different sedimentary microfabrics that display impressions from the fossil. One fabric appears dense with a regular patterning, whereas the other one has less distinct hexagons, appears more granulate  and is significantly less coherent O. EDX analysis revealed enrichment of carbon and sulfur in the beetle remains relative to the surrounding sediment . Other im/z values and the relative intensity distribution of all major peaks associated with the eumelanin molecular structure [m(SiO2)n cluster ions, indicating a mixed silicon/iron mineral phase  showed considerably weaker signal intensities compared to the eumelanin standards, rendering confident molecular determination difficult. Spectral comparisons of the fossils and eumelanin standards by PCA showed peak intensity distributions in the damselfly that were consistent with eumelanin standards, whereas they clearly deviated in the wasp  could have been broken down into a heterogenous mixture of degradation products , each with a low concentration that could make it difficult to identify. Furthermore, cuticular components such as chitin would most likely overlap spatially with eumelanin in the sample, thereby preventing the possibility to extract spectra specifically from these other components and, consequently, aggravating their identification. Interestingly, in all three insects, body parts that likely were originally heavily melanized appear to better preserve cuticular remains. For instance, in the wasp, cuticle fragments were detected only in dark areas of the fossil . Conversely, the abdomen and legs (where such fragments are not observed) were likely dominated by yellow-colored pigments and, thus, may have lacked substantial eumelanin deposits ,79. SimiIn recent years, chemical evidence of eumelanin has been documented in a broad range of animal fossils from the laminated clay of the Stolleklint Clay and in calcareous concretions of the Fur Formation ,31,33,34The fossil beetle displays a higher degree of structural fidelity than the two other fossils. The rigid cuticle of extant beetles contains internal lamination and multiple pore canals . In our Associated with the beetle remains were calcium carbonate-dominated inorganics, representing the entombing concretion, as well as a silicon- and iron-rich mineral. We interpret the former as having formed early during diagenesis and been in close contact with the fossil based on the pristine appearance of the hexagonal cuticular impressions. This interpretation is further supported by our ToF-SIMS data, which show Ca-containing organic fragment ions localized to the dark-colored fossil matter, indicating a calcium-rich coating. Notably, calcium was not detected during our EDX analyses, suggesting that this element is present only at the surface of the dark matter (considering the high surface sensitivity of ToF-SIMS relative to EDX). Calcareous concretions are often considered to have sheltered newly formed fossils from both dissolution and compressional effects ,106. IndTo gain a better understanding of the retention of insect body fossils in the rock record, we investigated three exceptionally preserved specimens from the lowermost Eocene Stolleklint Clay and Fur Formation of Denmark. Our analyses show that these fossils are all preserved as organic but largely compressed remains of the exoskeleton. Specifically, ToF-SIMS data obtained directly from the cuticle revealed clear evidence of the natural pigment eumelanin, which seemingly dominates the dark-colored residues. Moreover, the beetle elytra exhibit high morphological fidelity with several unique nanostructures. Notably, TEM revealed remnants of an epicuticular multilayer reflector, a biophotonic structure that produces structural colors in modern insects. Our fossils further indicate a potential preservational bias: the preservation potential seems to be greatly diminished in regions of the cuticle that lacked substantial eumelanin deposits. Eumelanin has an inherent resistance to decay and, thus, may remain when most other components have degraded or been lost during diagenesis. The results of our study provide novel insights into the taphonomy of insect assemblages preserved in marine paleoenvironments.


Complex pathology of the distal arch and proximal descending thoracic aorta is usually approached by stent endografting or in situ graft replacement. Oftentimes, these options are not feasible due to unfavorable anatomy, multiple previous procedures, active infection, or presence of concomitant cardiac disease. Thoracic aortic extra-anatomic bypass, as part of an open surgical strategy, is a useful and often the only curative option left for the treatment in these patients. Herein, we describe two cases that illustrate the utility of extra-anatomic thoracic aortic bypass for complex aortic disease. Currently, both open in situ grafting and thoracic endovascular aortic repair (TEVAR) procedures are the first choice to treat complex aortic pathology such as aortopulmonary/esophageal fistulas, recurrent coarctation, aneurysms, and some infected vascular grafts. But in many cases, a more complex single or staged open procedure using thoracic aortic bypass is the only curative option left, representing a decision-making dilemma. We describe two clinical cases of thoracic ascending to descending aortic bypass (single and staged) used to treat unusual recurrent aortic problems that illustrate the usefulness of this strategy in complex aortic pathology.A 46-year-old male presented with severe intermittent claudication and dyspnea. His medical history included severe aortic valve stenosis, bicuspid aortopathy, and uncontrolled hypertension. He had aortic coarctation repair at the age of 11 years with a 16-mm Dacron graft. Computed tomography (CT) scan revealed a 5-cm ascending aortic aneurysm and a severely kinked Dacron graft in the descending aorta . A one-A 69-year-old hypertensive female presented with recurrent hemoptysis and pneumonias. She had a history of isthmus coarctation as a child repaired with a patch aortoplasty followed by aneurysm formation repaired with a Dacron tube graft at 46 years of age. She developed severe hemoptysis at 57 years of age, requiring a left subclavian-carotid bypass and stent endografting and fungal suppression therapy for a positive cryptococcus bronchial culture. She was admitted to our service 12 years later with hemoptysis and malaise. The chest CT angiography  revealeAscending-to-descending aortic bypass was described in 1980 by Vijayanagar et alLately, the extra-anatomic bypass (EAB) has been reserved for the more complex aortic problems where stenting is not suitable, or there is concomitant proximal aorta or cardiac pathology and/or infected grafts/endografts. The later patients often have graft and/or mediastinal infection and despite the initial palliation and chronic antimicrobial suppression, some patients will require further treatment unless too elderly or sick.A single stage operation (first case) is favored in patients with recurrent coarctations when TEVAR is anatomically unsuitable due to concomitant pathologies of the descending thoracic aorta/arch or associated proximal aortic and cardiac disease that requires repair through a median sternotomy. The EAB avoids an otherwise difficult and high-risk thoracotomy in a second stage and a potentially suboptimal result. A two-stage open surgical repair (second case) is less commonly used but often the only option for curative treatment in cases of graft infection with aortoesophageal, pulmonary-parenchymal or airway fistulization, or mediastinal involvement with false aneurysm.In conclusion, these two cases demonstrate the successful surgical management of a spectrum of complex thoracic aortic disease using thoracic aortic EAB. The use of a single versus a two-stage repair should be tailored to the patient's particular aortic process and surgeon's experience.


Despite life’s diversity, studies of variation often remind us of our shared evolutionary past. Abundant genome sequencing and analyses of gene regulatory networks illustrate that genes and entire pathways are conserved, reused, and elaborated in the evolution of diversity. Predating these discoveries, 19th-century embryologists observed that though morphology at birth varies tremendously, certain stages of vertebrate embryogenesis appear remarkably similar across vertebrates. In the mid to late 20th century, anatomical variability of early and late-stage embryos and conservation of mid-stages embryos (the “phylotypic” stage) was named the hourglass model of diversification. This model has found mixed support in recent analyses comparing gene expression across species possibly owing to differences in species, embryonic stages, and gene sets compared. We compare 186 microarray and RNA-seq data sets covering embryogenesis in six vertebrate species. We use an unbiased clustering approach to group stages of embryogenesis by transcriptomic similarity and ask whether gene expression similarity of clustered embryonic stages deviates from a null expectation. We characterize expression conservation patterns of each gene at each evolutionary node after correcting for phylogenetic nonindependence. We find significant enrichment of genes exhibiting early conservation, hourglass, late conservation patterns in both microarray and RNA-seq data sets. Enrichment of genes showing patterned conservation through embryogenesis indicates diversification of embryogenesis may be temporally constrained. However, the circumstances under which each pattern emerges remain unknown and require both broad evolutionary sampling and systematic examination of embryogenesis across species. SignificanceVertebrates, like arthropods or flowering plants, establish a conserved body plan during development from which species-specific elaborations develop. Yet, the generalizable rules that direct this conservation of embryogenesis across distantly related species have remained controversial for 200 years. We present a quantitative analysis of the primary literature to determine support for hypothesized patterns of conservation of embryogenesis. We then perform a comparative analysis of 186 publicly available microarray and RNA-seq expression data sets covering embryogenesis in six vertebrate species spanning ∼420 Myr of evolution. We find strong support for temporal patterning in diversification of gene expression and conclude that broad evolutionary sampling and systematic examination of embryogenesis will enable increasingly powerful inferences about the rules directing conservation of vertebrate embryogenesis.During embryogenesis, a single-cell zygote develops into a multicellular, functional embryo. Given the complexity of this process and the astonishing diversity of resultant phenotypes, the similarities in the developmental processes and anatomy of embryogenesis across species are striking and have captivated the imagination of biologists for nearly two centuries (bauplan”) from which species-specific variation and elaborations develop. Yet, whether there are generalizable rules that direct diversification of embryogenesis across distantly related species remains controversial SignificaCaenorhabditis elegans, Over the past decade, an increasing number of studies have leveraged the ever-growing genome-scale data and approaches to test omics-level predictions of the hourglass hypothesis and its underlying mechanistic basis  online. Any test of the developmental hourglass hypothesis faces several fundamental challenges. First, proper alignment of stages of embryogenesis across species is difficult. Despite several valiant attempts to overcome this difficulty , nomenclAlthough numerous studies have reported patterned expression divergence  through embryogenesis across species, what pattern is followed and whether that diversification pattern varies over evolutionary time remains unclear. Here, we perform a comparative analysis using 186 publicly available microarray and RNA-seq expression data sets covering embryogenesis in six vertebrate species spanning ∼420 Myr of evolution. We use an unbiased clustering approach to group stages of embryogenesis by transcriptomic similarity and ask whether gene expression similarity of clustered embryonic stages deviates from the null hypothesis that gene expression levels are invariant of developmental time. Second, we characterized the expression conservation pattern  exhibited by each gene at each evolutionary node after correcting for phylogenetic nonindependence and ask whether the number of genes that fall into a given pattern deviates from a biologically meaningful null expectation. Finally, we discuss challenges of comparative analyses that rely on publicly available transcriptome data and suggest several novel approaches for future tests of the hourglass hypothesis.We identified 1,626 and 1,782 one-to-one orthologs for the microarray and RNA-seq data in our analysis, respectively, consistent with other comparative gene expression studies spanning vertebrates . In the RNA-seq comparison, median pairwise rank correlations increased to its highest median score at cluster 2 and dropped through later stages of embryogenesis 3, with cluster 5 having the lowest median . Although this pattern appears consistent with the developmental hourglass, conserved cluster 2 contains gastrula stages  and neurula stages  which occur earlier in embryogenesis than what is typically considered the phylotypic stage .We then quantified interspecific gene expression correlation for each of the t median B. When cP < 10e-4, hourglass P < 10e-4, inverse hourglass P < 10e-4, late conservation P < 10e-4, time invariance P < 10e-4; RNA-seq: early conservation P < 10e-4, hourglass P = 0.02, inverse hourglass P = 0.4, late conservation P < 10e-4, time invariance P < 10e-4). Enrichment/depletion of genes for each conservation pattern across anurans (microarray only), amniotes, and tetrapods are provided in P < 10e-4 indicates that none of the 1,000 permutation iterations resulted in enrichment/depletion at or above/below the observed level.Next, we used ctsGE time series analysis  to charaFinally, we compared conservation pattern assignment for the 255 one-to-one orthologous gene groups shared between microarray and RNA-seq gene sets and found that across platforms gene expression patterns are not concordant at the major phylogenetic nodes. Specifically, only 25% of genes (63/255) in amniotes, 19% (49/255) in tetrapods, and 20% (52/255) in vertebrates exhibited concordant expression conservation patterns.In the present study, we examined patterns of expression diversification throughout embryogenesis in six vertebrate species using a comparative analysis of 112 microarray and 74 RNA-seq data sets B. First,Over the past decade, the debate of whether diversification of embryogenesis follows generalizable rules has been reinvigorated by the ability to test predictions of the hourglass, developmental burden, and other hypotheses A on a geAligning stages of early animal development is complicated by taxon-specific sampling practices as well as pervasive heterochrony in developmental events across distantly related species, leading some researchers to question the validity of anatomical hourglass hypotheses . We founConsistent with the mixed support for the hourglass and other models of developmental divergence  found across studies, our comparisons of expression variation in all one-to-one orthologs present across species in the microarray and RNA-seq data yielded significant but different patterns. Specifically, the observed gene expression correlations (as a measure of conservation) differed through embryogenesis for both microarray and RNA-seq, yet only the RNA-seq data showed a pattern that differed significantly from the null expectation that gene expression levels should be invariant of developmental time . For theInconsistency across studies and gene expression profiling technology also suggests that comparing the whole transcriptome may not be appropriate. Specifically, patterns of expression conservation at the whole transcriptome level may be biased by abundant and constitutively expressed genes  was excluded because of likely abundance of maternal transcripts, and time points after 4 dpf were excluded due to substantial completion of the developmental program  (“Log2-transformed”). For RNA-seq data, SOLiD data were converted to fastq using the Sequence Read Archive toolkit, and raw reads were checked for quality using FastQC (biomaRt was used to assign corresponding ENSEMBL gene ID(s) to each Affymetrix probe set and RNA-seq transcript  for all k. To determine an appropriate number of clusters, we used 1) the “elbow” effect  and 2) determined the k where clustering of groups maintained temporal order of embryogenesis . Other unsupervised soft clustering approaches  from the pairwise comparisons to prevent biasing the outcome as a consequence of high correlations in gene expression between the two congeneric anuran species at each cluster of embryonic stages. Due to the high correlations between these two species, similar results were recovered when X. tropicalis was removed from the analysis instead of X. laevis. We used permutation analysis to assess whether correlations are higher or lower than expected by chance. Specifically, for each species we randomly assigned stages to a cluster maintaining the original number of stages included in the observed cluster and computed the rank correlation for all pairwise species comparison. We conducted 1000 permutations and assessed significance by comparing the observed rank correlation to distribution of rank correlations generated by permutation analysis. Permutation P values were defined as the percentile of the observed median Spearman’s rho in the distribution of permuted Spearman’s rho values. Because correlation coefficients that are either greater or smaller than expected by chance (as determined by a two-tailed test) were of equal interest, we used the empirical cumulative distribution function in R to calculate both the percentile and one-percentile rank and report the lower of the two values.For both microarray and RNA-seq data, we assessed transcriptomic similarity at early, middle, and late phases of embryogenesis across species by calculating the Spearman’s rank correlation for all pairwise comparisons of species for each of the five clusters of embryonic stages. For microarray data, we excluded one frog , below (−1), or within (0) the cutoff range (±0.7) of the median value at each time step (here cluster of embryonic stages). Optimal cutoff range was determined using the default setting that tests cutoffs between 0.5 and 0.7, in increments of 0.05, toward assigning an equal number of genes to each index. Each index of expression conservation across embryogenesis was assigned to a conservation pattern based on median transitions across the assigned significance cutoff. For early conservation: similarity decreases through embryogenesis; hourglass: similarity increases and then decreases; inverse hourglass: similarity decreases and then increases; late conservation: similarity increases; invariant: similarity does not vary or does not follow other conservation patterns through embryogenesis (To assess conservation of gene expression for each gene at each cluster of embryonic stages and each node, we calculated a difference in expression rank scaled by the divergence time between the groups  online. ogenesis A. IndiceP values were defined as the probability of obtaining enrichment/depletion of genes at or above/below the observed number in the permutation set as described above.To examine enrichment of genes in each conservation pattern, we first calculated the proportion of indices in each conservation pattern and defined the expected number of genes as the equivalent proportion of total genes. We determined significance of enrichment/depletion of genes exhibiting each pattern using a permutation analysis. For each gene, we first randomized the order of conservation scores across the clusters of embryonic stages. Second, we characterized conservation trajectory using ctsGE and the index assignment rules described above. Finally, for each iteration we calculated enrichment/depletion of genes compared with the random expectation for each conservation pattern. We repeated this permutation 1000 times for each node and gene expression profiling technology and assessed by comparing the observed enrichment/depletion to the null distribution generated by the permutation analysis. Permutation Genome Biology and Evolution online.evab160_Supplementary_DataClick here for additional data file.


Atherosclerosis, myocardial infarction (MI) and heart failure (HF) are the main causes of mortality and morbidity around the globe. New therapies are needed to better manage ischemic heart disease and HF as existing strategies are not curative. Resveratrol is a stilbene polyphenolic compound with favorable biological effects that counter chronic diseases. Current evidence suggests that resveratrol is cardioprotective in animal models of atherosclerosis, ischemic heart disease, and HF. Though clinical studies for resveratrol have been promising, evidence remains inadequate to introduce it to the clinical setting. In this narrative review, we have comprehensively discussed the relevant compelling evidence regarding the efficacy of resveratrol as a new therapeutic agent for the management of atherosclerosis, MI and HF. In a key report, the World Health Organization identified cardiovascular disease as one of the foremost challenges to be dealt with in order to improve global health as an estimated 17.9 million people globally are adversely affected annually . In viewA focused PubMed/Scopus search was done to find peer-reviewed articles published in journals in English language till September 2021. Ex vivo, in vivo and randomized, placebo-controlled, double-blinded clinical trials along with meta-analyses and systematic reviews were given more precedence for this review to concentrate on the pertinent available articles only. The searches were done with pre-specified keywords based on the topic of this review such as resveratrol, cardiovascular disease, coronary artery disease, atherosclerosis, ischemia/reperfusion, myocardial infraction, heart failure clinical trial, and randomized, and placebo-controlled, double-blind trial either alone or in combination to maximise the search results. References from the bibliography of previously published peer-reviewed articles were also directly accessed when available in English language. The study designs of the pre-clinical and clinical publications being considered were diligently reviewed before inclusion in the manuscript.Resveratrol falls under a class of molecules known as stilbene polyphenol. Resveratrol is present in many different dietary constituents such as varieties of grapes, berries, plums, and nuts including peanuts in varying amounts . It natuPhytoalexins form an integral part of the intrinsic immune reaction by plants against infectious diseases ,15,16. PPolygonum cuspidatum, a plant which is widely used in oriental traditional medicine. The cardioprotective capacity of resveratrol has been extensively studied after it received a great amount of attention due to its suggested role in “French paradox”  resveratrol. It is also suggested that this bio-transformation phase is a rate limiting factor in terms of resveratrol’s bioavailability as it affects the fate of the absorbed resveratrol in the body. Certainly, the plasma concentration of resveratrol depends on a dose and time dependent regimen and maximum total concentration was estimated as 2.4 µM (~500 ng/mL) after oral administration of a high dose of 5 g whereas a low dose of 25 mg resulted in a very negligible plasma concentration (5 ng/mL) [14C]-resveratrol resulted in average peak concentrations of 0.6 and 137 μmol/L, respectively.Interestingly, the oral bioavailability of resveratrol is quite low albeit the total absorption in the intestine is as high as 70%, which is very high compared to other polyphenols . The max5 ng/mL) ,19. Inte5 ng/mL) . Of note5 ng/mL) . Althoug5 ng/mL) . Oral inResveratrol and its metabolites may also accumulate in different tissues and the latter may bring about their effect in target sites due to the enzymatic breakdown via tissue beta-glucuronidases and sulfatases. In colon cancer patients who have undergone surgery and resveratrol treatment (prior to the procedure), tissue specific distribution of resveratrol metabolites was identified . AdditioLastly, novel formulations and a targeted drug delivery system could also improve the bioavailability of resveratrol many folds through improving the solubility and tissue specific delivery. Current formulations used for resveratrol administration suffer from poor aqueous solubility and stabilisation, which affect their pharmacodynamics. Cyclodextrin carrier systems have been found to improve the solubility of resveratrol but it did not significantly augment its bioavailability. Targeted delivery of resveratrol to the desired tissues or increasing the stabilisation of resveratrol in the body by developing sustained release systems can overcome its early degradation in the intestine and liver and its elimination, and thereby augment the bioavailability. Multiparticulate forms and colloidal carriers have been proven as efficient agents for sustained release of resveratrol in specific areas as described elsewhere . PromisiCoronary artery disease (CAD) impedes the adequate blood flow in the coronaries due to atherosclerosis ,29. AtheThe human myocardium is not capable of any meaningful large-scale regeneration of cardiomyocytes, to overcome the ischemic cell death and regain its normal functional capacity following ischemia . In contThe extracellular matrix (ECM) of the myocardium consists of a variety of constituent proteins which can serve as structural and adhesion agents in dynamic contractile machinery that hold together all other components. The scar development progresses by the process of cross-links formation of collagen fibers to attain sufficient tensile strength to withhold the force generation and to partially maintain the normal geometry of the left ventricle (LV) to ensure that loss of functional tissue does not severely limit cardiac function . AdequatHeart failure (HF) is a clinical condition regarded as the inability of the myocardium to sustain sufficient organ perfusion in the body due to inefficient myocardial filling and pumping capacity secondary to the damage and/or weakening of the myocardium ,51,52. H−/−) mice under a standard diet suggesting its anti-atherogenicity potential [Resveratrol is considered as a molecule of interest in managing the risk factors of atherosclerosis and its development and progression due to its multi-faceted action. In this regard, resveratrol has been shown to lower atherosclerosis risk factors such as total cholesterol (TC), low density lipoprotein cholesterol (LDLC), very low-density lipoprotein cholesterol (VLDLC), apolipoprotein-B (Apo B), lipoprotein-A (Apo A), free-fatty acids (FFA) and triglycerides (TG) ,56,57. Iotential . Resveraotential . In anototential . On the otential . In contotential . Resvera−/− mice by decreasing TMAO levels via reducing trimethylamine (TMA) by altering gut microbiota in mice [−/− mice [−/−Fas−/− double knockout mice, which display a lupus profile with accelerated atherosclerosis, resveratrol was able to prevent atherosclerosis progression [However, resveratrol does not show a be-all and end-all lipid lowering effect to produce anti-atherosclerosis action. It is interesting to note that it may also produce anti-atherosclerosis outcome in the absence of a lipid lowering effect. This signifies the role of resveratrol in modulating the pathogenesis of atherosclerosis via other signaling pathways . Notably in mice . Resvera−/− mice . In ApoEgression . In highgression . In rabbgression . Hence igression . Howevergression . That bePlatelet aggregation plays an important role in acute coronary syndrome and resveratrol appears to block this process ,70. EndoAngioplasty with drug eluting stents is a preferred treatment for stenosis and occlusions in coronary arteries associated with MI. However, there are unavoidable drawbacks with this therapy as well. Interestingly, a rodent study mimicking arterial angioplasty and stenting with resveratrol-eluting stents tested the effects resveratrol on neointimal hyperplasia and re-endothelialization . The delResveratrol has been extensively explored for its cardioprotective action against myocardial ischemia/reperfusion injury. Initial ex vivo studies specifically focused on the potential of resveratrol as an ischemic preconditioning agent as it has been an area of avid interest . ResveraLonger duration of treatment with resveratrol before ischemia/reperfusion has been proven beneficial in relieving myocardial ischemia/reperfusion injury ex vivo. Resveratrol has also been able to preserve cardiac function when the heart was subjected ischemia/reperfusion ex vivo . One-weeA meta-analysis also showed that pre-treatment with resveratrol was also associated with a significant limitation in infarct size after ischemia–reperfusion insult ex vivo in mice and rats without any co-morbidities . Based oShort-term administration of resveratrol also provides cardioprotection against ischemia and reperfusion in vivo. Pre-treatment with resveratrol before induction of ischemia by LAD ligation followed by reperfusion improves LV pressure and reduces infarct size in rats . ResveraIt is worthwhile to explore the long-term benefits of resveratrol treatment in vivo, especially MI related remodeling that can lead to cardiac dysfunction and HF. Resveratrol pre-treatment for two weeks reduced infarct size and improved cardiac function, perfused capillary network and myocardial blood flow, in 24 h LAD occluded rats under normal state and dobutamine stress condition . ResveraTreatment with resveratrol for four weeks after induction of an MI also improved infarct size and LV structure and function in rats . It was Resveratrol pre-treatment for four weeks in Yorkshire swine on a hypercholesterolemia diet followed by another three more weeks after left circumflex artery occlusion conserved local wall motion, improved flow during LV pacing, and increased vasodilation in the ischemic heart . ResveraContrary to the studies discussed above, some studies have also reported that resveratrol treatment was not effective in MI-induced animals. For example, in male New Zealand white rabbits, resveratrol did not affect infarct size or improve regional myocardial blood flow after MI . In anotIn order to be successful in a clinical setting, resveratrol treatment should provide beneficial patient outcomes in ischemic heart disease patients being treated with existing medications. Only a few studies have been carried out to unravel the potential of resveratrol as a combination therapy together with proven cardiac medication . A combiMicroRNAs (miRs) have been described as smaller sized non-coding RNAs regulators of various molecular events . Resverab-oligomerization ) nanoparticle carrier containing resveratrol protective against ischemia/reperfusion [Orally administrated treatments have to escape the degradation of active forms in the gut, which is a main obstacle for bioavailability . Nanoparerfusion .+Lin−CD45−CXCR+ very small embryonic-like stem cell (VSEL) mobilisation may provide cardioprotection [+ CSC in the peri-infarct zone. This revealed that resveratrol improves the viability of stem cells [+) cardiac stem cells also increased capillary network and reduced apoptosis in the peri-ischemic area, and enhanced the effects of CSCs transplantation [Inducing myocardial cell therapy may help in managing MI related cardiac complications ,129. Regotection . Resveraotection . Cardiacem cells . Resveraem cells . Cardiacem cells . Resveraantation . Transplantation . OxidatiTissue-engineered grafts and scaffolds may be useful to provide support to the myocardium after an MI. Direct transfer of resveratrol to the injured heart muscle is also an area of interest due its high efficacy but low plasma bioavailability of the native form after oral administration. Resveratrol (5 mg/mL) and ferulic acid loaded in core–shell electrospun fibers made of chitosan and polycaprolactone (PCL) graft on full-thickness excision skin wounds has been shown to result in 100% wound closure by two weeks . ResveraDue to the evidence from a large number of pre-clinical studies, a great level of enthusiasm exists for exploring the cardioprotective role of resveratrol in patients with ischemic heart disease and HF. In this section, evidence from clinical trials will be analyzed . To dateA double-blinded, placebo-controlled, randomized, three-month clinical study showed that resveratrol treatment in 40 post-MI patients including 26 men and 14 women was able to improve diastolic function and systolic function. The study consisted of placebo and 10 mg/day resveratrol group, and both groups also received routine post-MI medication. Endothelial function, red blood cell deformability, LDLC and platelet aggregation were also improved in resveratrol treated group . TC, HDLIn a HF clinical trial , 60 out In view of the emerging clinical trial data, large randomized clinical trials should be conducted in relevant patient population such as persons with risk of CVD, and post-MI and HF patients. This will lead to development of resveratrol as novel therapy for managing cardiovascular disease.This comprehensive review concludes that current evidence from pre-clinical studies strongly support the role of resveratrol as a very promising bioactive molecule with a wide range of cardioprotective action in the context of ischemic heart disease and HF. In essence, the emerging clinical evidence also largely corroborate this observation. Further clinical studies are needed to fulfil the promise of the translational potential of resveratrol in ischemic heart disease and HF.


Idiopathic multicentric Castleman disease (iMCD) is characterized by the benign proliferation of lymphoid cells in multiple regions. However, the co-occurrence of epithelial malignancy and idiopathic multicentric Castleman disease (iMCD) is rarely reported. Herein, we present a case of iMCD mimicking lymph nodal metastasis of Marjolin’s ulcer in the lower extremity. A 53-year-old male presented with an unhealed chronic ulcer on the left lower leg and foot accompanied by an enlarged mass in the left inguinal region. Intralesional biopsy was performed, and pathological examination showed squamous cell carcinoma (SCC). Imaged studies revealed left calcaneus bone invasion, and lymph nodal metastasis was suspected by the cancer TNM staging of T4N2M0 pre-operatively. The patient received below-knee amputation and lymph node dissection; intraoperative histological examination showed no lymphatic nodal malignancy and diagnosed the patient as having iMCD with lymphadenopathy. The patient recovered uneventfully and was referred to a hematologist for further treatment. Castleman disease (CD), also known as angio-follicular lymph node hyperplasia, is a rare disorder characterized by the benign proliferation of lymphoid cells. Histologically, the CD is subdivided into plasma cell, hyalinized vascular, and intermediate variant types . ClinicaCastleman disease, especially idiopathic multicentric Castleman disease (iMCD), reportedly may lead to the development of malignancies , the morA 53-year-old male came to our clinic complaining of a unhealed left leg wound that lasted over many years accompanied by constitutional symptoms of fatigue and loss of appetite. A physical examination revealed excessive granulation tissue with an irregular base and everted wound edges below his left knee covered with necrotic tissue A. An obvCastleman disease (CD) was first reported by Castleman et al. as a rare disorder featuring benign lymphoproliferation and the constellation of enlarged lymph nodes in one region, most commonly the mediastinum ,11. GabaAnother subset of CD, termed iMCD, has clinicopathological features that overlap with those of HHV8-MCD but have no known etiology . iMCD waMalignant diseases are not commonly associated with CD and the risk of malignancy in patients with iMCD is still unclear. However, iMCD has a threefold increase in the frequency of malignancy compared with age-matched controls . The exaIn summary, we reported an extremely rare case of iMCD with SCC presenting as Marjolin’s ulcer in the lower extremity. Lymph nodal metastasis was initially suspected but down-staged by the histological iMCD diagnosis, which guided different subsequent managements. Thus, we suggest that benign lymphoid diseases, such as iMCD, should be taken into consideration in patients with suspected lymph nodal metastasis from epithelial malignancy.