Precision medicine is a new approach to the diagnosis and treatment of cancer that considers individual patient differences and avoids a one-size-fits-all approach to treatment. Lung neuroendocrine tumors are increasingly common cancers with a wide spectrum of clinical behaviors. Lung neuroendocrine tumors have lagged behind other cancers in the incorporation of precision medicine approaches to treatment. However, this is beginning to change as our understanding of the molecular underpinnings of neuroendocrine tumor carcinogenesis expands and our clinical trial repertoire increases. In particular, advances in radiotheragnostics hold promise for yielding new personalized approaches to treatment. In this review, we summarize established and emerging precision medicine approaches to the treatment of lung neuroendocrine tumors.Well-differentiated lung neuroendocrine tumors (LNETs) are heterogeneous cancers that are increasing in incidence. Treatment options for LNETs have expanded in recent years, and our knowledge of the molecular subtypes has also advanced. Multidisciplinary teams have an established role in personalizing the best treatment for individual patients. Other precision medicine approaches for the treatment of LNETs have lagged behind those for non-small-cell lung cancer, with only rare actionable molecular alterations identified and few established predictive factors to guide therapy selection. However, as summarized in this review, there is increasing potential for personalized treatment of patients with LNETs. In particular, advances in radiotheragnostics may allow us to tailor the treatment of individual patients with NETs in the coming years. These advances may soon deliver the promise of more effective, less toxic treatments and better outcomes for patients with these increasingly common cancers. Lung neuroendocrine neoplasms (LNENs) are an increasingly common, heterogeneous group of cancers that arise from enterochromaffin cells. NENs are characterized by their site of origin, histologic grade, and ability to secrete peptide hormones. The histologic classification of LNENs incorporates morphology (well-differentiated neuroendocrine tumors (NETs) versus poorly differentiated neuroendocrine carcinomas (NECs)), mitotic count, and the presence or absence of necrosis . Well-diLNETs account for approximately 2% of all lung cancers in adults . LNETs tWhile the more common non-small-cell lung cancers (NSCLCs) have seen an explosion of precision medicine approaches to treatment over the last decade, LNETs have lagged behind. Recently, however, progress has been made in identifying molecular characteristics and biological subsets of LNETs that may pave the way for more personalized treatment approaches in the future. In addition, randomized controlled trials have become more common in LNETs, expanding our knowledge about how to treat patients and increasing the number of therapeutic options. Advances in molecular imaging and radiotheragnostics, in particular, have revealed the power and potential of personalized treatments for NETs. In this review, we discuss established and emerging precision medicine approaches for the treatment of well-differentiated LNETs, distinct from the high-grade NECs of the lung.Well-differentiated LNETs have a wide spectrum of clinical behaviors. Some patients with advanced LNETs  have very indolent disease, while other patients  can have a more aggressive course. There is both the possibility of interpatient and intrapatient tumor heterogeneity, with variable somatostatin receptor expression, molecular changes, and Ki-67 proliferation indices. There is also increasing appreciation for the challenges of grade progression, where some NETs, particularly those of pancreatic origin, can evolve over time to a more aggressive form, necessitating treatment changes .RB1 and/or TP53) or radiographic features . Multidisciplinary discussions are essential given the wide range of clinical behaviors. The multidisciplinary approach to assessing patients with LNETs is itself a form of clinical precision medicine, whereby the team synthesizes multiple aspects of a given patient’s presentation to determine the best-individualized treatment strategy. International guidelines for NETs emphasize the importance of collaboration among medical subspecialties as a cornerstone to deliver optimal, personalized care [Standard systemic therapy options for LNETs include somatostatin analogs (SSAs); targeted therapies like everolimus; and chemotherapies, including capecitabine/temozolomide or platinum/etoposide. There are limited randomized data on how to sequence these available therapies. Due to their rarity, patients with LNETs have been excluded from most clinical trials of NET therapies, and treatment principles are largely extrapolated from gastroenteropancreatic (GEP) NETs. Treatment decisions for patients with LNETs are complex and must take into account several different aspects of a patient’s presentation, including histologic features, tumor growth rate, degree of symptoms, and hormone hypersecretion, along with any concerning molecular features  and telomere maintenance [RASSF1 and p15INK4b, has been described in LNETs [Next-generation sequencing (NGS) is frequently used in NSCLCs to identify actionable genomic alterations and select patients to treat with targeted therapies, but such approaches have not been widely used for NETs. However, interest has grown in identifying reliable biomarkers to help differentiate subgroups of NETs and enable more personalized treatment approaches. Over the last decade, the molecular and clinical classification of NETs has evolved. Mutational analysis of LNETs via high-throughput sequencing approaches has provided insight into their molecular characteristics. Whole-genome sequencing revealed that well-differentiated NETs have a very low mutation rate compared with many other malignancies, and they are characterized by mutations in genes involved in histone modification/chromatin remodeling  more characteristic of typical carcinoids rather than RB1 or TP53 alterations that are typical of NECs [RB1 and TP53 would suggest an underlying diagnosis of a neuroendocrine carcinoma [While the WHO pathologic classification system has been useful for standardizing the nomenclature of NETs and helping predict clinical behavior, it does not fully reflect the biological heterogeneity of NETs. There is increasing recognition of the existence of lung tumors with well-differentiated carcinoid morphologies but elevated mitotic counts of >10 per 2 mm of >20% . These h of NECs . Conversarcinoma .Rather than constituting one single pathologic entity, more advanced multi-omics testing suggests that there may actually be several distinct biologic subtypes of lung carcinoids based on variations in gene expression, methylation, and mutational profiles ,24. For Neuroendocrine tumors are unique among cancers in that the most widely implemented predictive test for treatment response is not genomic analysis of tumor tissue, but rather functional imaging. The advent of radiotheragnostics like peptide receptor radionuclide therapy (PRRT), which combines diagnostic imaging with targeted therapies, has transformed the treatment of NETs.177Lu)-DOTATATE. 177Lu-DOTATATE is a radiopharmaceutical that binds to SSTRs and allows for the targeted delivery of radiation to neuroendocrine cancer cells systemically with high precision, resulting in DNA single-strand breaks and activating programmed cell death. 177Lu-DOTATATE was approved for the treatment of GEP-NETs based on the results of the NETTER-1 trial in patients with progressive SSTR-positive mid-gut NETs [Neuroendocrine tumors have the unique property of somatostatin receptor (SSTR) expression, a feature that was exploited for the development of synthetic SSAs. The possibility of labeling SSAs with radionuclides emerged in the early 1990s. Although other agents were initially used, the therapeutic breakthrough came with the development of beta-emitters coupled to DOTA-chelated compounds, most notably lutetium-177 , which is used to identify patients with high SSTR expression who are most likely to benefit from treatment. variable . In one variable . Howeverse rates ,30. Ongoor LNETs . Discordor LNETs . However177Lu-DOTATATE is typically administered with fixed doses of injected radioactivity over a set number of treatment cycles regardless of the extent and distribution of a given patient’s metastases. Individual patients absorb differing doses into both tumors and healthy organs, reflecting the difficulty in predicting how the radiopharmaceutical is distributed, metabolized, and excreted across individuals. Patient-specific dosimetry is the process of quantifying the absorbed dose in different regions of the body from the post-treatment SPECT/CT images obtained after each dose. Dosimetry holds promise for potentially improving PRRT outcomes by ensuring both that the absorbed tumor dose is sufficient and also ensuring that the absorbed dose by healthy organs  does not exceed safe limits over time [Looking to the future, several efforts are underway to better select patients and improve the administration of PRRT. Personalized radiation dosimetry is one area of active research. At present, ver time . Down th177Lu-DOTATATE treatment [177Lu-DOTATATE, prior systemic treatments, symptoms, tumor burden in critical organs, and the presence of peritoneal carcinomatosis. In an analysis of 248 patients with well-differentiated NETs of a variety of primary sites, an increasing CS was associated with a worse progression-free survival [Separately, clinical tools are being validated to help inform PRRT treatment decisions. The clinical score (CS) is one prognostic score that has potential utility in patients with well-differentiated NETs being considered for reatment . This scsurvival . There wAnother area of research is using molecular tests, particularly those that incorporate growth factor signaling and tumor metabolism, to better predict responders versus non-responders to PRRT . Efforts177Lu-DOTATATE directly into the hepatic artery to achieve a particularly high concentration within liver metastases for patients with liver-dominant disease to improve treatment outcomes.The time interval between consecutive PRRT treatment cycles is also under study. It may be that the treatment interval should differ depending on a given patient’s proliferation index/Ki-67 to better target the tumor cells in the active phase of the cell cycle that may be most susceptible to PRRT. Lastly, another investigational approach is intra-arterial administration of PRRT via injection of Next, we highlight recent and potential therapeutic advances for the treatment of LNETs, focusing on emerging precision medicine approaches and active clinical trials enrolling patients with LNETs (summarized in α), stem cell factor receptor (KIT), and RET) [Several protein and tyrosine kinase pathways appear to be dysregulated in NET carcinogenesis, which has provided a basis for targeted treatment approaches. The mammalian target of rapamycin (mTOR) signaling pathway plays a key role in cell growth, metabolism, and apoptosis in cancer cells, and dysregulated mTOR signaling contributes to NET development ,40. The and RET)  and suruand RET) , either In the future, correlative studies to identify predictive biomarkers for the outcomes of treatment with TKIs will be key to identifying the patients most likely to benefit. In addition, much like for NSCLCs, there is interest in using circulating tumor DNA changes over time to monitor responses to various treatments (including TKIs) to identify patients likely to respond. This approach is under study in clinical trials.LNETs generally have low proliferation indices, so cytotoxic chemotherapy often has limited effectiveness. LNETs may be less sensitive to chemotherapy than pancreatic NETs, but potentially more sensitive than small bowel NETs. Chemotherapy can be considered for LNET patients with rapidly progressive and/or high-volume disease. SCLC regimens like platinum/etoposide are often utilized, particularly for atypical carcinoids with more aggressive pathologic features such as elevated Ki-67 and/or mitotic counts. Several small retrospective studies on metastatic LNETs suggest response rates to platinum/etoposide between 20 and 25% ,49,50. TThere is also interest in identifying biomarkers of susceptibility to temozolomide and other alkylator therapy. Temozolomide's mechanism of action is via the alkylation/methylation of DNA, causing base pair mismatch and subsequent tumor cell death. The enzyme O6-methylguanine-DNA methyltransferase (MGMT), which repairs DNA damage mediated by temozolomide, has emerged as a potential biomarker of alkylator therapy responses. MGMT can remove the alkyl group, allowing tumor cells to resist the effects of treatment . The expThe most important treatment breakthrough in extensive-stage SCLC in the last several decades was the addition of immunotherapy to platinum/etoposide chemotherapy as a new standard first-line treatment based on the results of the Impower133 and Caspian trials ,59. In c177Lu-DOTATATE for NETs, several novel PRRT treatment approaches are under study  are SSTR agonists, which bind to receptors and are subsequently internalized and accumulate within cancer cells. Initially, it was thought that SSTR agonists would be more suitable therapeutic agents compared with antagonists because of this internalization, which brings the radioactivity close to the cell’s DNA. SSTR antagonists stay bound on the cell surface and are not internalized. However, recent data suggest that despite the fact that SSTR antagonists internalize poorly into tumor cells, they may actually have higher tumor uptake, possibly because a larger number of receptor binding sites may be recognized by antagonists compared with agonists [177Lu-satoreotide tetraxetan are now being investigated as a promising new approach both for imaging and therapeutic purposes in NETs. This may open up the possibility of treating tumors with relatively lower SSTR expression, including patients with LNETs with insufficient uptake for standard PRRT.There has also been renewed interest in SSTR antagonists for PRRT. All SSTR-targeting radiopharmaceuticals in current clinical use (including agonists ,68. By bAnother approach under consideration to try to improve PRRT efficacy is through conjugating DOTATATE to Evans blue analogs, which reversibly bind to circulating serum albumin . This maAlthough treatment of patients with LNETs remains a challenge, the number of available therapies has increased. Over the last several years, progress has been made toward developing personalized treatment approaches for patients with LNETs. Still, there remains an unmet need for biomarkers to help predict the effectiveness of available therapies. Novel personalized therapeutic approaches hold promise to improve outcomes and will hopefully allow us to better treat patients with these increasingly common malignancies in the near future.


Low-frequency air–bone gap (ABG) associated with pulsatile tinnitus (PT) and normal impedance audiometry represents a common finding in patients with third window syndromes. Other inner disorders, including Meniere’s disease (MD), perilymphatic fistula and intralabyrinthine schwannoma, might sometimes result in a similar scenario. On the other hand, PT is frequently associated with dural arteriovenous fistula (DAVF), while conductive hearing loss (CHL) is extremely rare in this clinical setting. A 47-year-old patient was referred to our center with progressive left-sided PT alongside ipsilateral fullness and hearing loss. She also experienced headache and dizziness. Otoscopy and video-oculographic examination were unremarkable. Conversely, a detailed instrumental audio-vestibular assessment revealed low-frequency CHL with normal impedance audiometry, slight left-sided caloric weakness, slightly impaired vestibular-evoked myogenic potentials on the left and normal results on the video-head impulse test, consistent with an MD-like instrumental profile. Gadolinium-enhanced brain MRI revealed an early enhancement of the left transverse sinus, consistent with a left DAVF between the left occipital artery and the transverse sinus, which was then confirmed by angiography. A trans-arterial embolization with Onyx glue was performed, resulting in a complete recession of the symptoms. Post-operatively, the low-frequency ABG disappeared, supporting the possible role of venous intracranial hypertension and abnormal pressure of inner ear fluids in the onset of symptoms and offering new insights into the pathomechanism of inner ear CHL. Tinnitus and conductive hearing loss (CHL) are common symptoms usually managed in everyday clinical practice for otolaryngologists. However, this association can offer a diagnostic challenge if not combined with middle ear abnormalities. Tinnitus may be defined as a conscious awareness of a sound in the absence of an external auditory stimulus. If the sound can also be heard by the examiner, it is defined “objective”; when it is synchronous with the heartbeat, it is called pulsatile tinnitus (PT) and could represent a sign of a vascular abnormality . AdvanceDAVFs represent pathological shunts between dural arteries and dural venous sinuses, meningeal veins or cortical veins, accounting for 10–15% of intracranial AVMs . Most DAOn the other hand, CHL associated with PT and normal impedance audiometry represents a key finding for the diagnosis of inner ear disorders, leading to a third mobile window mechanism (TMWM). In fact, according to the most widely accepted theories, labyrinthine capsule abnormalities, including canal dehiscence, enlarged vestibular aqueduct (EVA) and an array of other bony defects exposing the inner ear sensors to the action of the surrounding structures, account for a low-impedance pathway for sounds and pressure stimuli resulting in a TMWM ,14,15,16In this study, we describe the clinical and instrumental findings of a patient with a DAVF between the left occipital artery and the transverse sinus, presenting with low-frequency CHL and PT that receded after endovascular treatment. Interestingly, pre-operative instrumental findings were consistent with left MD. A similar case was previously described by Cassandro et al., and our case represents the second description of this unusual combination in the literature . We alsoA 47-year-old female was referred to us with a two-month history of progressive left-sided PT, aural fullness and slight ipsilateral HL. She noted that tinnitus became incapacitating during physical efforts. She also experienced headache and dizziness, and denied vertigo attacks or a history of head trauma. Her body mass index was 21. She was then submitted to a complete audio-vestibular assessment. Otoscopic examination revealed normal tympanic membranes. A pulsatile bruit could be palpably appreciated over her left mastoid tip and could be almost totally abolished with a soft compression of the same area. Pure tone audiometry revealed a normal hearing threshold on the right side and a low-frequency ABG in her left ear. Type-A tympanograms with normal acoustic reflexes could be registered . NeitherWhile PT is widely considered a typical manifestation of DAVFs , the assBefore providing a possible explanation for the symptoms and signs depicted in our patient, a brief recall on the relationships between intracranial vascular structures, CSF and inner ear fluids (perilymph and endolymph) should be presented. The premise is the Monro–Kellie principle, which states that the intracranial compartment is an incompressible structure and that the overall volume of its contents remains constant. A DAVF represents an alteration in venous intracranial circulation: the lack of high resistances in the arteriolar bed and the presence of a low-resistance nidus result in a high blood-flow rate and hypotension in the feeding artery combined with intranidal and draining vein hypertension. An impairment of cerebral venous outflow can produce intracranial hypertension, mimicking benign intracranial hypertension . SeveralIt should be also mentioned that intracranial and intralabyrinthine fluids are deeply connected: while the perilymph communicates with the intracranial fluids through the cochlear aqueduct, the endolymph is connected with the intracranial fluids via the endolymphatic sac. The balance between perilymph and endolymph is maintained by the Reissner’s membrane and other labyrinthine membranes. The cochlear aqueduct seems to act as a low-pass filter, preventing the spreading of the variation in intracranial hypertension to the inner ear. This function could lose effectiveness due to interindividual age-related decline . According to the aforementioned mechanisms, we can reasonably assume that, in our case, a type-I DAVF resulted in general intracranial venous hypertension due to abnormal venous drainage. This mechanism might lead to a non-structural and reversible clinical manifestation, even far from the AVM nidus, generating subclinical intracranial hypertension, as reported by Hurst et al. . NeverthEven though the data obtained from pre-operative instrumental assessment and the restoration of symptoms and signs after the treatment of the DAVF strongly support our theories offering new insights into the relationships between intracranial and intralabyrinthine fluids, the present report presents some limitations. First, CSF pressure was not measured, nor was the presence of papilledema checked. Also, delayed MRI acquisitions following contrast injection to objectively detect signs of EH were not obtained, as 3T MRI was not available in our institution. Moreover, despite the patient herein reported exhibiting an MD-like instrumental profile, she neither reported acute vertigo spells nor had fluctuating auditory symptoms, resulting in an incomplete clinical picture for MD diagnostic criteria . AdditioWhen low-frequency CHL and PT occur together with normal middle ear status, additional pathomechanisms other than TMWM should be searched for, including increased pressure of intralabyrinthine fluids. DAVFs can likely result in increased intracranial venous pressure, generating subclinical CSF hypertension, which, in turn, might lead to perilymphatic hydrops and EH. Further studies are needed to support these interesting insights on the relationships between the intracranial venous system and the homeostasis of intralabyrinthine fluids.


Acute optic neuritis (AON) is a common cause of sudden visual loss in young patients. Because of the risk of demyelinating disease, patients affected by unilateral or bilateral optic neuritis should be evaluated and treated accordingly. Despite advancements in imaging of the brain and retina, misdiagnosis of AON is not uncommon. Indeed, some acute disorders of the retina have the potential to mimic AON and their prompt diagnosis may avoid unnecessary neurologic investigation, psychological stress to the patient, and delays in treatment. This review describes uncommon retinal disorders presenting with sudden-onset visual loss and absent or subtle funduscopic manifestation that can mimic AON. Multimodal retinal imaging is essential in detecting these conditions and in their differential diagnosis. It behooves neurologists and general ophthalmologists to be aware of these entities and be familiar with multimodal imaging of the retina. Sudden-onset visual loss may result from a number of lesions along the anterior visual pathway and traditionally a comprehensive ophthalmic evaluation including fundus examination was usually sufficient to detect the site of the lesion. When the ophthalmic examination is unrevealing a patient may be referred to a neurologist or a neuro-ophthalmologist with the suspicion of acute optic neuritis (AON) or other neurological disorders, not uncommonly after a number of costly procedures are performed, such as brain magnetic resonance imaging (MRI). However, some acute retinal diseases may present with symptoms  and signs  that can mimic AON. These retinal conditions may present with subtle or no apparent changes on fundus examination .Recent advances in non-invasive multimodal retinal imaging, especially high-resolution optical coherence tomography (OCT) and fundus autofluorescence (FAF) make it possible to identify the typical features of these retinal conditions .Neurologists and general ophthalmologists should be aware of those unilateral or bilateral retinal conditions able to mimic AON and always consider multimodal retinal imaging in the differential diagnosis process .This narrative review will focus on those retinal conditions with an acute onset that may be misdiagnosed as AON and will discuss their presentation on retinal imaging and their differential diagnosis. These disorders are presumed to be either inflammatory or ischemic in nature and have a so far poorly understood pathophysiology.We have identified a group of different acquired retinal disorders with a sudden onset of symptoms that are mostly affecting young adults. History, clinical characteristics, and fundus findings are paramount but not always sufficient to detect these retinal disorders. We first detail the symptoms and signs that may suggest a retinal disorder and we then detail each of these retinal conditions focusing on their presentation and multimodal retinal imaging features.Retinal phosphenes: more visible in the dark, are commonly caused by vitreous traction on the retina. However retinal inflammation may also produce flickering and shimmering. Phosphenes may rarely occur in optic neuritis  but painMetamorphopsia: distortion of images is a clear indicator of a maculopathy as the cause of visual loss. Straight lines appear wavy and may be accompanied by central or paracentral scotoma and micropsia .Blind spot enlargement: if a blind spot enlargement is seen on the visual field test, a retinal disorder affecting the peripapillary retina should be suspected, especially in the absence of optic disc swelling. Optic disc edema usually does not cause such enlargement unless it is very severe.Photo stress test: after exposure to bright light, there is a slow recovery in cases of retinal disorder affecting the cone function.Absence of relative afferent pupillary defect (RAPD): optic neuropathy (such as optic neuritis) is associated with RAPD unless bilateral and symmetric. Thus, visual loss in the absence of RAPD usually points to the macula as the site of the lesion. However, one must remember that disorders of the peripapillary retina may be accompanied by mild disc swelling and a RAPD .Lack of pain with eye movement: the typical presentation for AON is a young female with acute loss of vision, evidence for an optic neuropathy , pain with eye movement, and a normal fundus. The absence of pain with eye movement should raise suspicion for an alternative diagnosis .Acute idiopathic maculopathy (AIM) is a rare and rapidly evolving macular condition first described by Yannuzzi et al. in 1991 . OriginaDespite how the etiology remains unclear, several reports suggest that coxsackievirus infection or vaccination may play a certain role ,7,8,9. AA disease staging based on OCT and different FAF patterns has been recently proposed by Pajtler Rosar et al. . PatternThe disease is self-limiting and on average it takes 4 months (range 1–7 months) for the vision to recover and recurrences are rare ,11. OCT Jung et al.  postulatSrour et al.  describeAIM must be differentiated from other macular conditions. Central serous chorioretinopathy mostly affects healthy middle-aged adults, usually with anxiety, and shows neurosensory detachment of the macula in the acute phase. Unlike AIM, prodromal illness is absent and recurrences are common. FAF may show multifocal areas of decreased and increased signal and FA shows one or more RPE leaks with choroid hyper-permeability on ICGA. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is characterized by multifocal placoid lesions at the posterior pole and mid periphery, typically affecting both eyes, most commonly with foveal sparing. While in the early phases FA and ICGA show both hypofluorescence, in the late phases FA shows hyperfluorescence while ICGA keeps showing hypofluorescence (FA-ICGA dissociation) . APMPPE Acute retinal pigment epitheliitis (ARPE), also named Krill’s disease, was first described by Krill and Deutman in 1972 ,21.Etiology and pathophysiology remain unknown, but flu-like symptoms may precede the onset of ARPE, suggesting a correlation between viral infections and the disease . PatientPreviously thought to be an inflammatory disease of the RPE, recent studies using high-resolution OCT have revealed that the primary inflammation area in ARPE is located at the outer retinal layers, with abnormal hyperreflectivity, especially involving the interdigitation zone (IZ), ellipsoid zone (EZ), and ELM  20,21].,21.20,21Differential diagnosis includes the most frequent causes of acute, unilateral visual loss in young adults, including AON, multiple evanescent white dot syndrome (MEWDS), acute macular neuroretinopathy (AMN), and AIM. AON is the most common cause of acute unilateral visual loss in young people, with female predilection. Unlike ARPE, in AON the acute visual loss is accompanied by pain and the examination of patients typically reveals visual field loss, color vision defect, and a RAPD in the involved eye. The funduscopic examination in AON is generally normal, with less than 25% of patients presenting with optic disc swelling . The macMEWDS is a rare primary inflammatory choriocapillaropathy, part of the so-called “white dot syndromes”, affecting young women most frequently. Like ARPE, MEWDS is a self-limiting condition characterized by prodromal influence-like episodes and unilateral decreased vision or scotoma. In contrast to ARPE, MEWDS is not confined to the macula and its typical fundus findings include foveal granularity and white dot lesions extending from the posterior pole and the peripapillary area to the equator. FA and ICGA are useful in the differential diagnosis with ARPE. In MEWDS, FA shows diffuse punctate hyperfluorescence, whereas ICGA reveals multiple hypocyanescent dots that can outnumber the lesions seen clinically or with FA .AMN is characterized by reddish-brown paracentral lesions in a petaloid or tear-drop configuration pointing toward the fovea. Similar to ARPE, patients experience sudden central or paracentral scotoma. However, OCT in AMN shows the disruption of EZ and hyperreflective plaques at the border of the outer plexiform layer and outer nuclear layer, possibly due to ischemia of the deep retinal capillary plexus .ARPE requires no treatment because of its self-limiting nature. The prognosis is excellent and a complete functional recovery with disappearance of the fundus and OCT abnormalities is expected within a few weeks. However, incomplete visual recovery and persistent disruption of the EZ have been reported ,31.First described by Bos and Deutman in 1975, acute macular neuroretinopathy (AMN) is a rare disease characterized by darkish brown-red, wedge-shaped dots in the macula pointing to the fovea . Since tThe pathogenesis of AMN is unclear, but recent studies using OCT point to deep capillary plexus (DCP) ischemia as a possible pathogenic mechanism . One sinThe typical wedge-shaped lesions are arranged in a petaloid, oval, or tear-drop configuration. In some cases, they are not clinically identifiable and multimodal imaging is necessary to reveal paracentral macular changes . Rarely,OCT and NIR reflectance imaging represent the most sensitive imaging techniques to diagnose and follow AMN patients, even when clinical examination is normal. The most common finding seen on OCT is EZ disruption; hyperreflective plaques at the border of the outer nuclear layer (ONL) and the outer plexiform layer (OPL), IZ disruption, and RPE abnormalities may also be detectable. With time, EZ generally reconstitutes but IZ disruption may persist. The hyporeflective changes shown by NIR correlate with EZ and IZ disruption on OCT and the latter could represent a subclinical derangement of RPE melanin . NormaliOnly a small percentage of patients with AMN that undergo full-field electroretinography (ffERG) show abnormalities, including reduced a-wave and/or b-wave and diminished rod and cone response. mfERG is a more sensitive electrophysiology testing for patients with AMN. It usually reveals most frequently reduced amplitudes and occasionally diminished implicit time. Visual field testing shows paracentral scotomas consistent with AMN lesions.AMN should be differentiated from other entities, such as ARPE, AON, and white dot syndromes, including MEWDS and APMPPE. Interestingly, a new association between AMN and AON has been recently reported . The occAlthough AMN has a self-limiting course and outer retinal recovery is observed, usually patients complain of persistent scotomas with good visual acuity. To date, there is no causative treatment for AMN and only an observational approach is recommended.Paracentral acute middle maculopathy (PAMM) is an OCT manifestation presenting with hyper-reflective band-like lesions involving the outer plexiform layer/inner nuclear layer (OPL/INL) junction resulting in permanent INL thinning and variable vision loss  44]..44].PAMM has been considered a possible variant of AMN first reported by Sarraf et al. in 2013 . Using OPatients with PAMM present with sudden onset of one or more paracentral scotomas in one or both eyes. Visual acuity can be normal, mildly, or severely decreased. Fundus examination may show either no significant abnormalities or subtle parafoveal lesions that usually appear deeper, smoother, and greyer than common cotton wool spots. The main age of presentation is 49–53 years with no gender predilection .PAMM can be either associated with several conditions, such as retinal vascular diseases and other ophthalmic conditions, systemic diseases, vasculopathic and environmental risk factors, or idiopathic. In the latter case, PAMM usually affects younger, female, and otherwise healthy individuals. A recent history of flu-like episodes, post-H1N1 vaccination status, and pregnancy have been suggested as possible contributing factors to the development of the disease ,47,48.Many retinal vascular diseases have been related to PAMM, including arterial or venous occlusion, Purtscher’s retinopathy, sickle cell retinopathy (SCR), inflammatory occlusive vasculitis, hypertensive retinopathy, and diabetic retinopathy ,47. ThesPAMM has also been associated with other ophthalmic conditions, such as inflammatory chorioretinopathies, congenital glaucoma, foveal hypoplasia (FH), juvenile dermatomyositis, ophthalmic surgeries, and eye compression injury . SystemiIovino et al. analyzed coincident or sequential PAMM and AMN lesions in the same eye in patients with retinal vein occlusion, Purtscher’s retinopathy, and retinal phlebitis suggesting a common pathogenic pathway that may result from impairment of the venous outflow and hypoperfusion at the level of the DCP, possibly leading to Müller cell injury in the Henle’s fiber layer .A few cases of PAMM and/or AMN have been reported among patients with COVID-19 and after COVID-19 vaccination .Recently, a novel variant of PAMM, called central acute middle maculopathy (CAMM), has been recognized in foveal hypoplasia . In CAMMIn patients with PAMM, swept-source (SS)-OCT may reveal undulations of the margins of the characteristic band-like hyperreflectivity in the INL, as a sign of reperfusion and resolution of microvascular infarction . With OCWith en face OCTA, three patterns of distribution of PAMM associated with retinal microvascular ischemia have been identified: 1. sectoral distribution, coherent with transient occlusion of a large arteriolar vessel with rapid restoration of blood flow; 2. globular pattern, as one or multiple ovoid hyperreflective patches probably due to precapillary occlusion related to SCR or embolic events; 3. fern-like pattern of hyperreflectivity that may be seen in central retinal vein occlusion, as a result of stasis and hypo-oxygenation of total retinal circulation due to perivenular ischemia . En faceAn appropriate diagnostic work-up should be individualized to rule out cardiovascular risk factors, taking into account the patient’s past medical history and their systemic and ocular findings. As first level examination, it is advisable to prescribe a complete blood cell count, metabolic and lipid panel, screening for hypercoagulability, infectious agents, autoimmune and inflammatory markers, blood pressure, echocardiography, and carotid Doppler ultrasonography.The main differential diagnosis of PAMM remains AMN; as discussed above, the characteristic fundus appearance and the deeper lesions at the junction of the OPL and ONL detectable by OCT may help to easily differentiate AMN from PAMM.The prognosis of PAMM is variable, and its natural course is not clearly understood. Several patients may have INL thinning, ONL thickening, abnormal vasculature , and, rarely, focal serous retinal detachment with persistent scotomas and affected visual acuity, but spontaneous improvement has been reported . No treaAcute annular outer retinopathy (AAOR) is a rare entity characterized by a peripapillary gray-white ring, disruption of the outer retina within the affected area, and sudden onset of a scotoma . It was Many authors have speculated that AAOR is part of an acute zonal occult outer retinopathy (AZOOR) complex and is secondary to an immune reaction following a viral illness. Recently, two cases of AZOOR have been described following COVID-19 vaccination . AZOOR iA stricter definition of AZOOR based on multimodal retinal imaging findings, including a demarcating line of progression between the involved and uninvolved retina and a trizonal pattern of chorioretinal degeneration, has been recently proposed .Several AAOR and AZOOR reports describe an afferent pupillary defect and absence of inflammation in the anterior chamber or vitreous. These features have led many physicians to refer the patient to a neurologist suspecting optic nerve disease.Shindo et al. described the case of a 30-year-old woman with recurrent episodes of sudden visual field defects and photopsia diagnosed with optic neuritis and treated with corticosteroid therapy with no improvement. MRI of the head with contrast was normal and after 15 years of mislabeling her condition, she was finally diagnosed with AZOOR . Chen etIn conclusion, AZOOR/AAOR diagnosis is not always straightforward, and they can be mistaken for a neurologic condition thus leading to expensive and time-consuming procedures like a brain MRI. Multimodal imaging is of great help and visual field testing along with electrophysiology are essential to reach a definite diagnosis.Acute idiopathic blind spot enlargement syndrome (AIBSE) is a condition affecting the peripapillary retina. It is due to dysfunction of the outer segment of the retinal photoreceptor layer usually presenting with photopsia, blurring, and dyschromatopsia in young myopic patients. The blind spot enlargement is visible on a visual field test and FAF usually shows increased autofluorescence around the optic disc .AIBSE was originally described in 1988 by Hoyt et al. in seven patients with photopsia and acute enlargement of the blind spot . In all In 1984, Jampol et al. described the coincidence of enlarged blind spots with MEWDS, raising the hypothesis of blind spot enlargement being a manifestation of MEWDS . Takeda In 1993, Gass hypothesized that AIBSE, MEWDS, AMN, AZOOR, and multifocal choroiditis (MFC)/punctate inner choroidopathy (PIC) were different entities of the same disease spectrum, involving the outer retina in young myopic women. Since then, many authors have used the term “AZOOR complex” or “white dot syndromes” to define this group of diseases, although distinct subcategories have been recognized . Some yeVolpe et al. in 2001 reviewed 27 patients, all women, with acute onset of blind spot enlargement demonstrated on visual field testing. Intraocular inflammation, mild optic disc edema (inadequate to explain the blind spot enlargement), peripapillary pigmentary changes, afferent pupil defects, and white dot lesions were not uncommon. They observed that despite the resolution of these abnormalities, there was persistence of the visual field defect in all the patients. They concluded that AIBSE was a distinct entity and was characterized by symptomatic enlargement of the blind spot caused by occult peripapillary retinal dysfunction and persistence of scotoma. Despite persistent scotoma and despite six patients having recurrences, none of them showed a progressive condition . As oppoSeveral other small series and clinical cases have been reported in the last few years with different features, making it difficult to distinguish AIBSE from other entities, especially AZOOR ,76,77. AGiven the variability of clinical findings, AIBSE can be misdiagnosed for other entities. When disc hyperemia or white dots are present, it can be mistaken for inflammatory diseases like MEWDS or other white dot syndromes. The development of chorioretinal lesions typical of MFC has been reported in patients with AIBSE . When thIn conclusion, AIBSE is a condition characterized by enlargement of the blind spot demonstrated on the visual field. It can present with different features and particular awareness should be raised when patients describe photopsia and enlargement of the blind spot to avoid misdiagnosis and the potential for unnecessary investigations. The discussion about considering AIBSE as a spectrum or a separate entity is still open.Multiple evanescent white dot syndrome (MEWDS) is an idiopathic retinal disease, first described in 1984 by Jampol et al. . It typiMEWDS is a typically unilateral condition, although bilateral and recurrent cases have been described . Fundus On the basis of multimodal imaging, many hypotheses on the origin of these lesions have been proposed. It has not been fully elucidated if MEWDS is a primary photoreceptoritis or a RPE disease that secondarily involves the photoreceptors. Some authors supported the hypothesis of MEWDS being a disease of the choriocapillaris . HoweverVisual field testing can show different patterns of defects, with the two most common being an enlarged blind spot and a centrocecal scotoma. A few studies have been conducted on MEWDS and electroretinography. Oh et al. found that in the acute phase, all of their patients had focal areas of reduced retinal function on the mfERG first order responses corresponding to enlargement of the blind spot. Four patients also demonstrated diffuse loss of b-waves with greater loss around the blind spot. In the recovery phase, all eyes with MEWDS demonstrated complete recovery of retinal function on mfERG first order responses . In anotAmong the neuro-ophthalmological conditions mimicking MEWDS, optic neuritis had the same presenting symptoms of unexplained unilateral visual loss in a young woman. RAPD and dyschromatopsia can be present in both MEWDS and optic neuritis, respectively, due to retinal or optic nerve dysfunction. However, a history of viral prodrome, lack of pain at ocular movement, and multimodal imaging are of great help in the diagnosis. Dodwell et al. described five patients with MEWDS where the subtlety of the white spots made the diagnosis difficult. They had variable presentations of primary nerve disease with RAPD, optic disc edema, and dyschromatopsia. Two patients were first diagnosed with “optic neuritis”, two with “retrobulbar optic neuritis”, and one with “optic nerve edema and vitreitis” . KhaleelAcute-onset retinal conditions may present with subtle or normal-appearing fundus examination and thus are referred to neurologists as possible neurological conditions such as AON. Timely recognition of these cases is therefore important for optimal management . These rMultimodal retinal imaging including OCT, NIR, FAF, color fundus photography, and possibly retinal angiography play a crucial role in the diagnosis of these retinal diseases. These specific investigations are rarely available in a neurology clinic or in a general ophthalmologist’s office, but clinicians should be familiar with their interpretation and know when and what to request.While a detailed differential diagnosis between these retinal conditions and other acquired sudden-onset retinal conditions is not the aim of the present manuscript, infectious conditions such as syphilis and either latent or active tuberculosis presenting with placoid lesions on the retina should be kept in mind .In cases of unilateral or bilateral unexplained visual loss, retinal disease should be included in the differential diagnosis of neurological vision loss, as either an optic neuropathy or as a “central” disorder. When the visual loss is monocular, the differential diagnosis between retinal disorder and optic neuropathy is usually straightforward when obvious retinal abnormalities are found. In the case of binocular vision loss and normal-appearing fundus examination, neurological causes can often be identified by visual field defect patterns. By contrast, a lack of optic nerve enhancement in presumed AON on orbital and brain post-contrast MRI may be suggestive of a retinal condition.Clinicians should suspect acute retinal disease mimicking AON in patients with acute painless visual loss. The presence of ophthalmoscopically visible lesions in the fundus should of course prompt multimodal retinal imaging. The absence of visible pathology in the fundus, however, should not refrain the clinician from considering multimodal retinal imaging, especially when symptoms , signs (lack of RAPD), or neuroimaging (lack of optic nerve enhancement or demyelinating white matter lesions for multiple sclerosis) suggest a diagnosis other than AON.Misdiagnosis of acute retinal disorder as AON can lead to inappropriate and potentially expensive and unnecessary neurologic evaluations. A detailed review of signs and symptoms along with multimodal retinal imaging are essential in detecting these retinal conditions and in their differential diagnosis.


Conventional immediate-release delivery systems are simple, industrially reproducible, acceptable, and easy-to-use by most patients. Nevertheless, these dosage forms have received critique for not being able to consistently provide optimum therapy for chronic disease conditions, as well as for their potential to induce adverse effects. This is primarily due to the typical rapid, pulse-release and absorption patterns of their drug cargo leading to rapidly fluctuating systemic drug concentration .Long-acting drug delivery systems (LADDS) encompass a range of formulations and technologies that can be used to precisely deliver drug molecules into target tissues. These operate either through systemic circulation or via localized organs/tissues  to treat chronic diseases like diabetes, cancer, and brain disorders, as well as for age-related eye diseases. LADDS have been shown to prolong drug release from several hours up to 3 years depending on characteristics of the drug, disease and delivery system ,3. LADDSThe Special Issue, entitled “Recent Advances in Long-Acting Drug Delivery and Formulations”, encompasses versatile and innovative research domains of oral, ocular, brain and topical delivery systems and chemical approaches , highlighting the progress made in identifying excipients ), polymers, and molecular targets to achieve a more effective sustained release systems and safer medicine. A total of 78 authors have contributed to this publication, with 11 original research articles, spanning five contents  providing important insights into the pharmaceutical sciences. I would like to encourage the readers to go through each paper and imbibe deeply the published state-of-the-art work in the field; before that, I will to summarize key research findings of interest.One fascinating paper in this Special Issue concerned the exploration of three basic amino acids . These were used to form three salts with ketoprofen (one of commonly prescribed NSAIDs for chronic pain and inflammation). Analgesic activity was significantly enhanced and proceed for these acids in the following order Tris >> lysine > arginine > ketoprofen base. The least severe gastric side effects were experienced by patients treated with lysine and arginine salts.Abd-Ellah et al.  investigThe corneal permeability in three animal models—rabbit, pigs, and cows— was studied for 25 drugs in an attempt to relate corneal permeability to drug physicochemical properties and tissue thickness via the analysis of quantitative structure permeability relationships (QSPRs) . These tOne study tested a microwave-treated, physically cross-linked polymer blend film , prepared via the solvent casting method, for its potential to optimize microwave treatment time. This procedure also allowed researchers to testing for physicochemical attributes and wound healing potential in diabetic animals . The stuHybrid gels of hydroxyl propyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were studied in order to enable sustained release topical skin delivery with unique features of superior adhesiveness, spreading ability, and greater cosmetic acceptability than homopolymers alone. These binary hydrogels showed low viscosity, but high bioadhesiveness. Indeed, they still can be applied on the skin comfortably, while providing for the controlled release of the drug over extended periods of time.Drug repurposing is useful a method for accelerating the drug development process by finding a new clinical use for a substance already on the market and registered for a different indication. On this front, two articles were published that sought to repurpose salbutamol and fenofibrate for treatment of muscle atrophy and retinal diseases, respectively ,11.Kumar et al. studied the repurposing potential of the bronchodilator drug salbutamol (β2-receptor agonist) for a beneficial role in diabetics with muscle atrophy. The oral administration of salbutamol increased voluntary muscle strength in diabetic rat models.In diabetic rats, salbutamol greatly boosted lean muscle mass and grip strength. Additionally, salbutamol therapy increased antioxidant levels in muscles, decreased muscular atrophy and inflammatory markers, and restored muscle damage biomarkers, all of which suggested salbutamol’s potential to lower muscle inflammation and oxidative stress.Novel 3D polymeric scaffold implantable systems were investigated for intraocular injection in order to retinal diseases. The 3D scaffolds, comprising alginate (ALG) and bovine serum albumin (BSA) containing fenofibrate, were prepared via the freeze-drying technique.Alzheimer’s disease is a brain ailment that gradually impairs thinking and memory abilities as well as the capacity to perform even the most basic tasks. The majority of Alzheimer’s patients exhibit their initial symptoms later in life. Various estimates show that more than 6 million Americans, the majority of whom are 65 or older, may be affected by Alzheimer’s disease. In this Special Issue, two studies covering novel treatment strategies of Alzheimer’s disease are published. Memantine HCl and Tramiprosate-loaded solid lipid nanoparticles (SLNs) were prepared and characterized for the clearance of Aβ on SHSY5Y cells in a rat hippocampus. Additionally, the neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, were discussed in the context of an animal model of aluminum-induced Alzheimer’s disease.In terms of sustained release, forming polymer chitosan has shown superior mechanical properties when cross-linked with trimesic acid. 5-fluorouracil (5-FU)-loaded hydrogels crosslinked with trimesic acid demonstrated the most sustained release profile among the formulations studied in a 3 h period, with 35 to 50% release.In conclusion, LADDS hold promise for the treatment of a variety of chronic diseases, offering safer and more efficient alternatives to the traditional (immediate-release) medication administration method. By creating APIs  using long-acting drug delivery systems (LADDS), both efficacy and safety can be improved. LADDS provide advantages that are acknowledged and supported by regulatory bodies, medical professionals, and patients. For individuals who would often need lifelong treatment for debilitating chronic ailments such eye diseases, diabetes, cancer, and brain disorders, LADDS can offer both lasting systemic and local effects.The cost and accessibility of the biomaterials used to create LADDS, the complexity of some LADDS’ complex systems, and the dependence of some LADDS’ drug carriers on external stimuli  to achieve consistent drug release are just several of the hurdles that require resolution. These problems make some LADDS ineligible for regulatory approval. The skyrocketing cost of biomaterials, inadequate scientific knowledge, and a dearth of excipients suitable for recently developing technologies like 3D printing and microneedle systems also hinder the advancement of this technology. The majority of novel long-acting anticancer drug delivery system concepts have been tested in animal models; nevertheless, regulatory organizations have voiced strong ethical and technological objections to translating such success in animal models to clinical phases.Finally, the guest editors of this Special Issue extend their sincere appreciation for all the authors and reviewers who responded to our invitation. Your willingness to share the outcomes of your outstanding research has greatly enriched this collection, and your contributions have been invaluable in the meticulous evaluation of the manuscripts.


Microsatellite instability (MSI) is a genome-wide genetic alteration initially discovered in colorectal cancers (CRC) in 1993, where about 15% of tumors presented this phenotype that bears relevant information for diagnostics, prognostics and prediction of therapeutic response . MSI is Aska et al., presented a fundamental study of genome-wide single-cell mononucleotide microsatellites of MMR-proficient and MMR-deficient thymic T cells in mouse model, aiming to decipher the mutationnal dynamics of MSI in vivo. By comparing WES data from Mlh1−/− and Mlh1+/+ T cells, their analyses revealed several specific genomic features of MSI in MMRD cells, distinguishing deletion and insertion dynamics . They notably showed that deletions far outnumbered insertions as in MSI tumors and also preferentially affected long A/T mononucelotide microsatellites of 10–14 nt and later-replicating genes . Moreover, their results indicated that longer-than-average and transcriptionnally active genes were areas of fragility more prone to MSI, which could potentially explain why some microsatellites are more unstable than others depending on the cancer type.Due to the considerable clinical implication of MSI for cancer patient’s management, the study of MSI in cancer was marked by a renewed interest in the biomedical community, either for basic researches, development of new approaches for MSI detection, or assessment of its clinical significance in various cancer types and sub-types. In this Research Topic dedicated to ‘Microsallite and Microsatellite Instability’, Han et al., proposed an overall and updated review that summerized the clinical, genomic and tumor immunobiology of sporadic and familial MSI cancers with a particular attention to metastatic or recurrent disease. They notably focused in three cancer types with high frequencies of MSI, i.e., colorectal, gastric and endometrial cancer and emphatised in the differences of MSI cancers compared to their microsatellite stable (MSS) counterparts . Treatment options and results of clinical trials were discussed, including notably patients response to ICI and resistance mechansims, and they suggested several perspectives about the possible evolution of MSI cancer treaments including multi-combined therapies.In the second article of this Research Topic, Liu et al., indentifyed a fatty-acid metabolism-related (FAM) gene signature from colon adenocarcinoma TCGA RNA-seq data and developed a FAM risk-score associated with a better prognostic value (AUC = 0.734) than other clinicopathological parameters. In addition, they showed that the high-risk group of CRC patients was enriched in MSI (high and low) phenotypes compared to the low-risk group and sugested that their risk score might also be a predicator of chemotherapy or immunotherapy . Although further validations are needed for this FAM risk score, identifying new predicators of ICI is still highly valuable as neither MSI, TMB nor PD-L1 expression alone can fully predict response to ICI and they should be combined with other biomarkers to improve prediction performances in the different cancer types and sub-types.In a third study, HSP110 gene that showed improved sensitivity for similar specificity in CRC compared to the pentaplex panel  on 5-FU associated with oxaliplatin. Interestingly, their results confirmed HT17 as a good marker for MSI detection achieving 95.5% sensitivity, even allowing the detection of false-positive MSI samples by the pentaplex panel. However, neither HSP110 expression nor deletion size correlated with time to recurrence in patients with stage II and III CRC having received or not an adjuvant chemotherapy , highlighting the importance of validation studies on independent cohorts.The gold-standard approach for MSI detection in cancer still remains to date PCR and capillary electrophoresis fragment analysis of a panel of five microsatellites, which can be either the pentaplex or the first recommended NCI/Bethesda panel. The NCI/Bethesda panel was proposed for MSI CRC and Lynch syndrome diagnosis but presented several limitations and Research Topic, notably due to use of three highly polymorphic di-nucleotide microsatellites . Severalex panel , while tex panel . Tachon In conclusion, this Research Topic on ‘Microsatellite and Microsatellite Instability’ covers different aspects of basic, translational and clinical research on MSI, including its importance in oncology for cancer patients’ management. We thank the contributing authors and hope that their papers will be appreciated by their readers and that the interest for microsatellites and MSI will continue to grow within the biomedical community.


This review paper is intended to show that changes in body composition are key in the pathogenesis of bone fragility amongst patients with breast and prostate cancer receiving hormone deprivation therapies (HDTs) and that the mechanism is based on the development of alterations in bone quality rather than in bone quantity.Preclinical and clinical data suggest a tight connection amongst bone, adipose and muscular tissues by means of several soluble mediators, potentially leading to (1) bone resorption and bone quality deterioration in sarcopenic obese subjects, (2) bone mineral deposition in healthy trained subjects. Cancer patients treated with HDTs frequently fall into the first condition, named osteosarcopenic obesity.Current clinical guidelines for the prevention of treatment-induced osteoporosis focus on bone mineral density (BMD) as a main predictive factor for fracture risk; however, the pathophysiology underlying HDT-induced bone fragility differs from that of primary and postmenopausal osteoporosis, suggesting a prevalent role for bone quality alterations. Focusing on available data from clinical trials, in our review we suggest osteosarcopenic obesity as a common target for the prevention and treatment of HDTs-related metabolic and skeletal complications, beyond a BMD-centred approach. Androgen deprivation therapy (ADT) by luteinizing hormone releasing hormone agonists or antagonists is the mainstay of treatment of men with progressive prostate cancer, in addition to next generation hormonal agents (NGHAs), chemotherapy or targeted agents . OestrogBoth hormone deprivation therapies (HDTs) lead to profound alterations in the hormonal milieu. In men with prostate cancer, ADT is associated with a deep fall of testosterone serum levels and a reduction of oestrogen levels by lacking the substrate for aromatase . In postABCSG-18 study, a large randomized clinical trial which enrolled patients with early breast cancer treated with adjuvant AIs, showed that denosumab, a RANK-L inhibitor, reduces the incidence of new clinical and vertebral fractures (VFs) . NoteworIn a single-centre cross-sectional study that recruited postmenopausal women with early breast cancer, whether or not treated with AIs, BMD was significantly associated with the prevalence of VFs in untreated but not in treated patients .As to prostate cancer patients, another cross-sectional study, recruiting men with non-metastatic disease, receiving ADT for at least 6 months, showed that the use of BMD (spine and hip) alone resulted in the misdiagnosis of approximately 75% of patients with clinically defined osteoporosis  .Finally, in a real-life clinical practice study, which investigated the accuracy of FRAX algorithm for the prediction of VFs in breast and prostate cancer patients receiving HDTs, BMD was shown to be associated with morphometric vertebral fractures at a more restrictive cutoff (i.e. −1.0 SD) compared to the recommended reference value (i.e. −2.5 SD) •.Taken together, these data qualify BMD as a weak predictor for fracture risk in the context of secondary osteoporosis, despite bone loss is a common side effect during HDTs. This apparent contradiction can be explained inferring a potential prevalent role for bone quality alterations rather than bone loss in the development of HDTs induced bone fragility. Bone quality is a complex issue and refers to the multifaceted properties of bone tissue  contributing, together with BMD, to determine fracture risk ,15.Over the recent years, many dual-energy X-ray absorptiometry (DXA)-based tools have been developed to explore skeletal features of bone quality and to refine fracture risk prediction. As a matter of fact, trabecular bone score (TBS), a texture parameter coming from lumbar spine DXA images and reflecting bone microarchitecture , was shown to decrease early during HDTs independently of BMD .Even though both postmenopausal and HDTs related bone fragility are associated with a drop of sexual hormones, a differential pathophysiology is required to explain why BMD is no longer the most relevant predictor for fracture in the latter condition, where bone quality alterations seem to prevail.Noteworthy, besides measurement of BMD and bone quality parameters, DXA is a non-invasive tool to measure reliably body composition alterations, which frequently result as an effect of HDTs. The relationship between body composition and bone metabolism is an emerging area of research and clinical interest . As a maIn this narrative review we dissected the available evidence supporting the role of body composition as a clinical variable implied in bone fragility and bone quality impairments amongst prostate and breast cancer patients on HDTs.Adipose tissue is progressively emerging as a modulator of whole-body homeostasis, including bone metabolism. Fat-bone interplay is mediated by several mechanisms: 1) secretion of peptides named adipokines with paracrine and endocrine activity, (2) proinflammatory cytokines, (3) differentiation of common cell precursors   secretioAmongst the adipokines, a key role is played by leptin and adiponectin. Leptin, mainly known as one of the principal endocrine regulators of appetite and energy expenditure, has also been shown to have effects on bone turnover by inhibiting the deposition of new mineralized mass. Counterwise, adiponectin supports bone mass formation by enhancing osteoblasts proliferation, migration and survival, whilst concomitantly limiting osteoclasts maturation. A clinical validation of the differential roles of these adipokines can be found amongst obese patients, where high levels of leptin and low levels of adiponectin result in a significant depletion of bone mass .Another hormonal regulation of fat-bone metabolism is mediated by insulin. Insulin acts as a primary regulator of adipose tissue, both from a metabolic point of view (e.g. glucose cellular uptake) as well as altering fat-bone interplay. As a matter of fact, insulin resistance affects both adipose and bone metabolism: compensatory hyperinsulinemia acts on adipokine levels, induces an inflammatory milieu via the attraction of macrophages and stimulates bone resorption. In detail, it has been shown that insulin reduces osteoblast-mediated expression of osteoprotegerin, allowing receptor activation of nuclear factor-kB (NF-kB) ligand to enhance osteoclastic activity with consequent bone resorption .Induction and maintenance of low-grade chronic inflammation by pro-inflammatory cytokines, locally produced in the adipose tissue, is another proposed pathway for bone metabolism derangement in obese subjects . High leFinally, studies on the interplay between bone marrow adipose tissue (BMAT) and bone remodelling offer a unique opportunity to understand the interaction between adipocytes, osteoblasts and osteoclasts inside the same microenvironment. It is well recognized that adipogenesis is tightly linked to osteogenesis in the bone marrow milieu, since osteoblasts and adipocytes share a common precursor (i.e. the MSC) . DetermiIn conclusion, the complex interplay between adipose and bone tissues can be elucidated assuming that an increase in fat mass causes an uncoupling process between bone resorption and deposition, finally leading to bone quality alterations. However, obesity is traditionally viewed as a protective factor for bone health because of well-established positive effects of mechanical loading and increased oestrogen production by action of aromatase enzyme expressed in adipocytes. Along this line a low BMI is known to be a strong independent predictor of fracture risk in postmenopausal osteoporosis .The coexistence of these two opposing mechanisms—detrimental through deterioration of bone quality, protective through increase in BMD—is known as “obesity paradox” . A practPatients treated with HDTs for breast and prostate cancer frequently encounter alterations in body composition similarly to women during menopause period and men after development of endogenous hypogonadism ,33,34.However, whilst in HDT-naive subjects fat mass counterbalances and usually overcomes the deleterious effect of adiposity by means of preserved/increased BMD Fig. a, when HTherefore, obese patients could dramatically shift from a potentially protected condition to a high fracture risk when treated with HDTs Fig. .Some published evidence supports the aforementioned pathophysiological model.A single-centre, cross-sectional study investigating the prevalence of VFs in a large series of postmenopausal women with early-stage breast cancer enrolled two different subgroups of patients which were either AI-naive or AI-treated for at least 2 years. The study results showed that amongst AI-naive subgroup VFs prevalence was higher in subjects presenting with fat body mass (FBM) below the median. Conversely, in AI-treated group the proportion of VFs showed an opposite pattern being higher in patients with FBM above the median. The apparently contradictory association of VFs prevalence with FBM values according to AI group was confirmed by multivariable analysis with a significant interaction test .A retrospective longitudinal study enrolling non-metastatic prostate cancer patients showed that increased FBM upon ADT was associated with a higher risk of skeletal related events .>25 kg/m2) was a strong predictor of VFs in prostate cancer patients who were under ADT [In another retrospective cross-sectional study, high BMI  in response to exercise .In this perspective, the “bone-muscle” unit would be the site of privileged exchanges in which the two tissues communicate via paracrine and endocrine signals to modulate the local microenvironment and distant tissues. The regulation of bone metabolism by muscle occurs through the secretion of specific factors, called myokines .Myostatin is a member of the tumour growth factor-β (TGF-β) family and acts as a negative regulator of muscle mass. Increased levels of myostatin correlate with a state of muscle disuse and sarcopenia. In a similar theme, myostatin negatively impacts bone remodelling, inducing a catabolic, resorptive state, by increasing osteoclastogenesis, and limiting bone formation, via osteoblasts inhibition ••.Irisin is one of the newly discovered hormones, resulting from the proteolytic cleavage of fibronectin type III domain 5 (FNDC5), which is secreted mainly by muscular tissue.Exercise promotes irisin expression and induces anti-inflammatory effects, via downregulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein 88 (MyD88) downstream pathway and decrease of NF-kB phosphorylation, leading to a reduced secretion of pro-inflammatory cytokines .As to bone metabolism, irisin promotes osteoblast differentiation through the Wnt-β-catenin pathway and, on the other hand, inhibits osteoclast differentiation and proliferation by suppressing the Receptor Activator of Nuclear Factor κ B ligand (RANKL)/NFATc1 pathway .Reinforcing the strong correlation between myokines and inflammatory response, several ILs are secreted by skeletal muscle, with a wide range of systemic effects.One of the most significant, interleukin (IL)-6, mostly synthesized by the liver with pro-inflammatory action, could also be released by muscles in response to exercise, inducing anti-inflammatory effects and increasing glucose uptake and insuline-sensitivity . DespiteIL-7 and IL-15 are also strongly related to inflammatory responses and have been shown to be expressed in muscle. IL-7 is a mediator of the acquired immune system, whilst IL-15 is a potent proliferator of innate immune cells. Both demonstrated a strong action on bone resorption, increasing osteoclastogenesis, largely via RANK-L stimulation .Besides myokines, a small number of factors secreted by bone have recently been identified as having effects systemically on a range of tissues, including muscle.Osteocalcin is a hormone secreted mainly by osteoblasts. Multiple clinical studies have shown that osteocalcin levels increase after exercise, and this has been associated with various metabolic implications with the overall effect of elevated insulin secretion and sensitivity . Indeed,Sclerostin, mainly secreted by mature osteocytes, acts as a suppressor of bone formation via thecanonical Wnt/β-catenin pathway. Osteocytes are mechanosensitive cells that coordinate the adaptive response of bone to mechanical stimuli. Hence, sclerostin secretion increases in response to bedrest or unloading, whilst its levels reduce with muscle or bone loading .In conclusion, acute exercise induces the release of pro-anabolic molecules by skeletal muscle and bone, providing effects on both tissues (i.e. determining bone turnover and muscular hypertrophy).Chronic degenerative conditions such as muscle disuse, atrophy, sarcopenia and ageing are instead associated with the expression of a second set of mediators, which in turn enhance osteoclastogenesis and bone resorption.Clinical data supporting the influence of decreased muscle mass on HDT-induced bone fragility mainly derive from studies enrolling subjects with prostate cancer under ADT.BLADE study was designed to assess changes in body composition (i.e. FBM and LBM by DXA scan) and bone metabolism (i.e. fragments of collagen and BMD) amongst patients affected by non-metastatic prostate cancer receiving an LHRH-antagonist (degarelix) during a period of 12 months •.Twenty-nine patients were enrolled and submitted to DXA scan evaluation and blood test before (baseline) and after (12 months) degarelix administration. At final analysis LBM failed to correlate with markers of bone turnover, both at baseline and after treatment. Changes in bone turnover markers were not influenced by baseline LBM either. Appendicular Lean Mass Index (ALMI), representing the sum of lean tissue in the arms and legs, is considered a more reliable parameter of skeletal muscle mass with respect to LBM, being less influenced by skin, internal organs, tendons, and other non-fatty components . In factRegional changes in body composition were explored in a further analysis of the BLADE study: LBM was shown to consistently decrease at upper limbs (−4.5%) whilst it did not differ at lower limbs after 12 months of degarelix administration •. This hTaken together, these data are consistent with published report describing skeletal muscle mass as a causative factor for 15 to 20% of BMD variability at femoral neck in elderly men . The infThere are few published data regarding the relationship between LBM and bone health in post-menopausal women undergoing AIs. A South African cross-sectional study found that lean mass index (LMI), and not fat mass, was independently associated with baseline osteoporosis . This stFurther prospective data correlating the incidence of clinical and morphometric fractures with specific training programmes are needed.As above described, adipose and muscular tissues are both involved in the regulation of bone turnover, with different mechanisms. Moreover, skeletal muscle is also the final target of many metabolic alterations caused by adipocyte hyperplasia and hypertrophy. One of the most extensively described pathways of fat-muscle cross-talk is represented by the induction of an inflammatory microenvironment through local recruitment of immune cells  and contextual production of pro-inflammatory adipokines, such as leptin and several interleukins, by activated adipocytes ,54,55.In addition, adipose tissue is characterized by excessive production and disturbed capacity to store lipids, which accumulate ectopically inside skeletal muscles .Intramuscular lipids and their derivates induce mitochondrial dysfunction characterized by impaired β-oxidation capacity and increased ROS formation, providing lipotoxic environment and insulin resistance. In response to oxidative stress, muscles produce pro-inflammatory myokines contributing to chronic low-grade systemic inflammation .Obesity induced inflammation is also associated with age-related muscle wasting and sarcopenia, skeletal muscle disuse and catabolism: for instance, chronically elevated IL-6 activates the JAK/STAT3 pathway leading to skeletal muscle atrophy . In factOverall obesity sets a vicious cycle in which disrupted skeletal muscle is at the same time target and driver of self-maintained chronic inflammation, in a condition called sarcopenic obesity .Both the above-mentioned molecular underpinnings and clinical observations contribute to define a complex anatomic/functional unit which integrates adipose tissue, muscles and bone.Whilst in healthy individuals the interplay amongst the single components is part of physiological ageing, considering cancer patients treated with HDTs the resulting effect is a similar, but more pronounced and accelerated process, leading to sarcopenia, osteoporosis and increased fat mass   Fig. 3)3).Fig. 3Clinical experiences investigating osteosarcopenic obesity in cancer patients are scarce. A cross-sectional clinical study enrolling post-menopausal breast cancer patients who were either AI-naïve or AI-treated sought to evaluate the role of LBM and the interaction between LBM and FBM in predicting the occurrence of VFs •. No intThis evidence suggests that the net effect of HDTs on bone health could be exerted by a shared mechanism in which both adipose and muscular tissues take part.Clinical management of subjects at higher risk for fracture is well established and described in international guidelines ,37. HoweThis review paper focused on the preclinical rationale and initial clinical data supporting a significant role for fat and lean (muscular) body mass variations in determining bone fragility during HDTs in patients with breast and prostate cancer.As to fat mass, adipose tissue can interfere with bone metabolism through endocrine and paracrine signals, as well as by means of self-maintained chronic inflammation, leading to both bone resorption and impaired bone quality. Counterwise, muscular mass has a trophic role on bone tissue, so that profound alterations in bone quantity and quality are often seen in sarcopenic subjects.Whilst in non-treated men and women physiologic oestrogen levels do mitigate body composition variations and their relative consequence on bone health, cancer patients under HDTs undergo an extreme condition of hormonal annihilation leading to increased adiposity, loss of muscular mass and enhanced bone fragility.Though a mechanistic basis supporting this phenomenon in a condition of hormonal deprivation is well established, clinical data on patients under HDTs are currently limited.Higher fat mass is associated with an excess in morphometric fractures in women  and men Finally, a causative role of higher fat mass and lower lean mass (i.e. sarcopenic obesity) in the deterioration of bone health during HDTs can be supported. However, these data are limited by the absence of a global analysis focused on the simultaneous effect of fat and lean mass variations, as well as a strong common clinical endpoint (e.g. incidence of new morphometric fractures).Along this line, convincing clinical evidence in favour of an adipose-muscular interplay on bone fragility is coming from a single-centre, cross-sectional study and suggests that in a hormone-deprived context the higher incidence of VFs would be observed in subjects with higher fat and lower lean mass •.The described increase in bone fragility linked to body composition alterations may be explained through bone quality rather than bone quantity impairment, as suggested by the observed marginal role of BMD in predicting fracture risk for patients undergoing HDTs ••.If this interaction is confirmed, it would be reasonable to add sarcopenic obesity to other known risk factors for bone fragility, possibly with the greatest impact for cancer patients under HDTs, leading to a new clinical condition called osteo-sarcopenic obesity.Furthermore, besides bone fragility, sarcopenic obesity is associated with the risk of cardiovascular events in the general population, being possibly implicated in HDTs induced cardiotoxicity as well . This asAn important issue in these patients is how to identify and follow-up fat and lean mass alterations, in order to prompt adequate therapeutic approaches, such as the use of bone resorptive agents and lifestyle modifications. Since BMI, though extensively applied, does not take into account the individual proportion of LBM and FBM , other mTherapeutic approaches to sarcopenic obesity could counteract bone fragility and cardiovascular complications in cancer patients receiving HDTs, representing a relevant matter of research.To now, physical activity is considered the most effective intervention, given its many biological effects, such as the reduction of oxidative stress, the increase in number and size of muscle fibres, the promotion of insulin sensitivity and the downregulation of systemic inflammatory biomarkers . AvailabHDTs induce profound physical and metabolic derangements, involving adipose and muscular tissues: accumulating evidence support these alterations to be regarded as the most prominent mechanism of toxicity, leading to bone fragility as well as cardiovascular disease.Targeting osteosarcopenic obesity for the prevention and treatment of HDTs-related metabolic and skeletal complications is promising and worth further research.


Game-based approaches, or gamification, are popular learning strategies in medical education for health care providers and patients alike. Gamification has taken the form of serious educational games and simulations to enable learners to rehearse skills and knowledge in a safe environment. Dermatology learners in particular may benefit from gamification methods, given the visual and procedural nature of the field.This narrative review surveys current applications of gamification within general medical training, in the education of dermatology students, and in dermatology patient outreach.A literature search was performed using PubMed, Google Scholar, and ResearchGate to access and review relevant medical education- and dermatology-related gamification studies published in peer-reviewed journals. Two independent researchers with education and experience in dermatology screened publications to select studies featuring a diversity of gamification approaches and study subjects for in-depth examination.A total of 6 general medical education–related and 7 dermatology-specific gamification studies were selected. Gamification generally increased motivation and engagement, improved reinforcement of learning objectives, and contributed to more enjoyable and positive educational experiences compared to traditional modes of instruction. Enhancing examination scores, building confidence, and developing stronger team dynamics were additional benefits for medical trainees. Despite the abundance of gamification studies in general medical education, comparatively few instances were specific to dermatology learning, although large organizations such as the American Academy of Dermatology have begun to implement these strategies nationally. Gamification may also a provide promising alternative means of diversifying patient education and outreach methods, especially for self-identification of malignant melanoma.Serious games and simulations in general medical education have successfully increased learner motivation, enjoyment, and performance. In limited preliminary studies, gamified approaches to dermatology-specific medical education enhanced diagnostic accuracy and interest in the field. Game-based interventions in patient-focused educational pilot studies surrounding melanoma detection demonstrated similar efficacy and knowledge benefits. However, small study participant numbers and large variability in outcome measures may indicate decreased generalizability of findings regarding the current impact of gamification approaches, and further investigation in this area is warranted. Additionally, some relevant studies may have been omitted by the simplified literature search strategy of this narrative review. This could be expanded upon in a secondary systematic review of gamified educational platforms. These novel and innovative strategies use game design elements such as the concept of a player or players, rules, conflicts, and predetermined goals in an artificial setting ,2. Previpurposes ,4. Relatnowledge . Becausenowledge , for theGenerally, gamification provides a structured, safe, and low-risk environment for learners to build skills and confidence without real-world consequences ,6. It caMany gamification formats in medical education have been presented including simulations, virtual/alternative reality environments, and social and cooperative gaming . MoreoveDermatology, as a highly visual and procedural field, is well positioned to take advantage of the learning methods employed in many game-based approaches. This narrative review therefore aims to survey gamification in medical training as well as to explore how the current knowledge base of gamification applications can be expanded in dermatology education for both providers and patients alike through further evidence-based examination of game-based learning.gamification, games, game-playing, serious games, and simulation games, in combination with terms such as healthcare, healthcare education, medical education, dermatology, and dermatology education. PubMed electronic database searches were supplemented by Google Scholar and ResearchGate to retrieve the full English-language text of each article and remove duplicate search results. The articles included studies from multiple academic institutions worldwide, and they included randomized controlled trials, cohort studies, and case studies. The participants in the studies encompassed medical students, medical residents, and members of the general public. To provide a broad overview of gamification and game-based interventions, both serious games and simulations were surveyed. Two independent researchers with education and experience in dermatology performed separate screenings of the article titles and abstracts, ultimately selecting 6 general medical education–related studies and 7 dermatology-related studies featuring a diversity of gamification approaches and study subjects for in-depth discussion in this narrative review. Additional consultation with board-certified dermatologists involved in medical education led to the inclusion of two recent Jeopardy game show–like events tailored toward dermatology residents at national conferences. A survey of peer-reviewed scientific literature was performed throughout January and February of 2021, with the purpose of identifying studies for a narrative review of gamification in health care education and dermatology. Key search terms included Gamification has been employed by medical schools and training programs to engage learners outside the traditional text-based or didactic setting. The effectiveness of gamification in general medical education has been the subject of several studies, many of which examine the impact of game-based learning on objectives such as knowledge, skills, professional attitudes, or satisfaction. Although we retrieved several hundred articles in our initial literature search, the vast majority discussed gamification approaches in general medical education and were not specific to dermatology learning. We discuss a selection of applications of gamification in general medical education below.One example of a serious game in general medical education is Kaizen, which tested clinical knowledge of medical residents in several university departments using a web-based multiple-choice quiz . AchieveVirtual reality and simulation games have proved to be very popular among medical learners of all levels. Stanford University recently used the existing 360 Virtual Reality platform, which is already used in entertainment, military training, and pilot training, to create a training module for mass casualty incident training . Actors Jeopardy-style game shows were found to increase resident satisfaction, training scores, and board examination pass rates. The competitive nature of the trainees may be a contributing factor to the success of the gamification interventions [Blended gamified approaches and applications of gamification to traditional education have likewise been favorably received. For instance, an “escape room” game in which groups solved puzzles and completed tasks within a time limit boosted team-building and multitasking skills for emergency medicine residents. These games may be effective approaches to fulfill difficult-to-teach core Accreditation Council for Graduate Medical Education competencies, such as teamwork . Incorpoventions ,21. Corrventions . Integraventions . Video gventions . ClearlyWhile gamification has been shown to have a positive impact on general medical education, we also sought to examine whether this held true in dermatology-specific game-based learning. The visual and procedural nature of dermatology would be expected to align well with the gamified educational methods discussed previously. As with gamification in general medical education, every dermatology-focused study reported beneficial effects of gamification on learning outcomes or student satisfaction, although it appears that only 7 dermatology-specific games are reported in the literature overall. Thus, further research and game development is needed in this area to fully elucidate the impact and future dermatology-specific utility of gamification.One instance of adapting games previously used in general medical education for dermatology students was seen in Kahoot!, a widely used and free real-time platform for formative educational assessment. Participants can compete for top scores in game-based quizzes, surveys, puzzles, and discussion forums. Kahoot! was previously found to motivate medical students to study, prioritize topics, and self-reflect on their learning . The plaSkinquizition is another serious game using educational quizzes for formative assessment . The gamJeopardy have been leveraged to exciting effect at the American Academy of Dermatology annual meetings, where resident teams can compete in competitions related to dermatology and dermatopathology knowledge, trivia, and correct diagnoses of cases and images. Multiple fast-paced competition rounds and single elimination of contestants in front of a national conference audience have made the game show events perennial favorites among trainees. Prizes have included educational grants [Similar elements from l grants , gift cal grants , and “brP<.005) after playing. Student confidence in describing, drawing, and recognizing skin diseases also grew. As with other studies of serious games, students responded positively and appreciated the learning techniques of visual representation and group work promoted by the game. In addition to building confidence and recognition during the limited time available for dermatology learning, i-DERMIFY also had the advantage of building the transferable clinical skills of accurately documenting skin conditions in medical records, and it allowed students to practice the concise verbal descriptions of skin lesions that are essential to communicating as future physicians. Thereafter, the game was incorporated into the regular medical school curriculum and made freely available for educational use.i-DERMIFY is an additional serious game learning tool developed to specifically harness dermatology’s visual and descriptive nature . Teams oBecause serious educational games have been found to build confidence and reduce student stress and anxiety, the card-based board game Stud2yBuddy was specially designed to help medical students study dermatology for final examinations . LearninBlending a serious game with a simulation in an “escape room” format also worked well for dermatology trainees, similar to the results of aforementioned studies in general medical education. Surveys of British medical students previously established that trainees have misconceptions about the field of dermatology, along with feelings of being inadequately prepared to manage skin conditions. It was speculated that these were possible barriers to engagement with dermatology as a specialty. After participating in a “zombie apocalypse”–themed escape room featuring a deadly skin disease outbreak, which consolidated previous lecture-based and clinical teaching, the majority of students reported a desire to experience more dermatology, and all enjoyed the session . HoweverSuccessfully implemented gamification strategies in medical and dermatology education have also been applied to patient education, especially in regard to recognizing melanoma. Because most malignant melanomas are initially identified by the patients themselves or their partners, impactful melanoma education for the general public is essential . Past efOne example of a game-based intervention for nonmedical learners successfully taught features of malignant melanoma and alarming lesions. In a study of 271 adolescents, participants who were randomly selected to learn from a gamified six-round image matching program with built-in feedback such as “this lesion image shows irregular borders and uneven coloration, notice the irregular black spots on the left edge of this melanoma” performed significantly better than those receiving traditional “ABCDE” melanoma identification instruction . AnotherIt is apparent that relatively few gamification studies specifically focused on dermatology currently exist in the literature, and of those studies, many are limited by small sample sizes or poor study design; for example, a control group where the gamification intervention was not administered was often lacking. Small numbers of participants and effect sizes as well as flaws in study design were detrimental to the quality of reported evidence. Our results corroborate recent systematic reviews of gamification interventions in general health care education, which have recognized that the extent of any positive impact is highly variable and nonuniformly measured  and largOur narrative review is limited by its highly simplified search strategy, in which only a small subset of English-language peer-reviewed publications indexed in PubMed, Google Scholar, and ResearchGate were examined in detail. A secondary systematic review could be beneficial in extending the preliminary survey we have presented. Gamification is a relatively new approach to education, made possible by the increasing ubiquity of the internet and digital applications in daily life. Given the extreme pace of technology development, it follows that in-depth scientific studies of many gamified platforms may not yet be published; for example, a new iPhone and Android mobile game called “Top Derm: A Game for Dermatologists” is being increasingly advertised on Facebook and Doximity as of July 2021 . CreatedOverall, previous studies indicate that gamification approaches—both serious games and simulations—provide a promising means of future dermatology-related education for students, professionals, and patients. The numerous advantages and reviews of gamification in medical education, however, are in stark contrast to the dearth of available gamification resources for dermatology-specific learning. Moreover, the moderate observed benefits for learner engagement and knowledge require further examination beyond pilot studies. Although there may be widespread support for gamification, our review of current literature provides a case for further investment in large-scale studies of gamified educational platforms, especially in dermatology, and more robust assessment of the true long-term impact of this learning enhancement on standardized outcomes.