Journal articles on the topic 'Non-hairy skin'

Purpose: Azelaic acid is a natural keratolytic, comedolytic, and antibacterial drug that is used to treat acne. The topical application of azelaic acid is associated with problems such as irritation and low permeability. For dissolving, the problem is that microemulsion (ME) is used as a drug carrier. The aim of this study was to increase the azelaic acid affinity in the follicular pathway through ME. Methods: Azelaic acid-loaded MEs were prepared by the water titration method. The properties of the MEs included formulation stability, particle size, drug release profile, thermal behavior of MEs, the diffusion coefficient of the MEs and skin permeability in the non-hairy ear skin and hairy abdominal skin of guinea pig were studied in situ. Results: The MEs demonstrated a mean droplet size between 5 to 150 nm. In the higher ratios of surfactant/co-surfactant, a more extensive ME zone was found. All MEs increased the azelaic acid flux through both hairy and non-hairy skin compared with an aqueous solution of azelaic acid as a control. This effect of the ME was mainly dependent on the droplet diffusion coefficient and hydrodynamic radius. MEs with a higher diffusion coefficient demonstrated higher azelaic acid flux through hairy and non-hairy skin. Drug flux through both skins was affected by the surfactant/co-surfactant ratio in that the higher ratio increased the azelaic acid affinity into the follicular pathway. Conclusion: Finally, the ME with the highest droplet diffusion coefficient and the lowest surfactant/co-surfactant ratio was the best ME for azelaic acid delivery into the follicular pathway.

AbstractObjectiveThe objective of this study was to test if offset analgesia could be evoked using a noncontact thermal stimulator. Offset analgesia [J. Neurophysiol. 87:2205–2208, 2002] is defined as an unproportionally large decrease in pain intensity following a slight decrease in stimulation intensity. The importance of differences in thermal properties between human hairy and glabrous skin was investigated.MethodsA 20W diode laser (970 nm) was used for the thermal stimulation. A fast (50 images/s) infrared camera measured the skin temperature and a temperature controlled feedback control loop adjusted the laser power. 8 subjects participated in this study. Stimulations were applied on the dorsum side and in the palm of the hand. Subjects were instructed to continuously rate the pain intensity. First the subject was stimulated using both a rising 35–45 °C staircase and a decreasing 45–35 °C staircase in both skin types; each staircase step was 1 °C and lasted for 15 s. Offset analgesia was tested by stimulating the hairy skin on the dorsum of the hand using two sequential temperature plateaus (48–48 °C, 48–49 °C, 49–48 °C and 49–49 °C). Each plateau was held for 5 s.ResultsFor the staircase stimulations identical surface temperatures were perceived significantly higher in glabrous than in hairy skin (p < 0.001). The offset analgesia test showed that a decrease in temperature from 49 to 48 °C evoked a drop in the pain rating which was significantly lower than observed during a 48–48 °C stimulation (p < 0.001) indicating offset analgesia.ConclusionA non-contact thermal stimulator is able to evoke offset analgesia. Furthermore, it was noted that a high penetration laser causes higher pain ratings in glabrous skin than in hairy skin—a relationship which is opposite to low penetration lasers (CO2 laser) and contact heat stimulation.

We contrasted the physiology and peripheral targets of subclassified nociceptive and nonnociceptive afferents that express acid-sensing ion channel (ASIC)–like currents. The threshold for current activation was similar in eight distinct cell subclasses regardless of functional modality (pH 6.8). When potency was determined from concentration–response curves, nonnociceptors exhibited currents with significantly greater potency than that of all but one class of nociceptors (pH50 = 6.54 and 6.75 vs. 6.20–6.34). In nonnociceptive cells, acid transduction was also confined to a very narrow range (0.1–0.3 vs. 0.8–1.4 pH units for nociceptors). Simultaneous whole cell recording and ratiometric imaging of three peptidergic nociceptive classes were consistent with the expression of Ca2+-permeable ASICs. Sensitivity to psalmotoxin and flurbiprofen indicated the presence of Ca2+-permeable ASIC1a. Immunocytochemistry on these subclassified populations revealed a differential distribution of five ASIC proteins consistent with Ca2+ permeability and differential kinetics of proton-gated currents (type 5: ASIC1a, 1b, 2a, 2b, 3; type 8a: ASIC1a, 1b, 3; type 8b: ASIC1a, 1b, 2a, 2b, 3). Using DiI tracing, we found that nociceptive classes had discrete peripheral targets. ASIC-expressing types 8a and 9 projected to hairy skin, but only types 8a and 13 projected to glabrous skin. Non-ASIC–expressing types 2 and 4 were present only in hairy skin. We conclude that ASIC-expressing nociceptors differ from ASIC-expressing nonnociceptors mainly by range of proton reactivity. ASIC- as well as non-ASIC–expressing nociceptors have highly distinct cutaneous targets, and only one class was consistent with the existence of a generic C polymodal nociceptor (type 8a).

Vibrotactile interfaces are an inexpensive and non-invasive way to provide performance feedback to body-machine interface users. Interfaces for the upper extremity have utilized a multi-channel approach using an array of vibration motors placed on the upper extremity. However, for successful perception of multi-channel vibrotactile feedback on the arm, we need to account for vibration propagation across the skin. If two stimuli are delivered within a small distance, mechanical propagation of vibration can lead to inaccurate perception of the distinct vibrotactile stimuli. This study sought to characterize vibration propagation across the hairy skin of the forearm. We characterized vibration propagation by measuring accelerations at various distances from a source vibration of variable intensities (100–240 Hz). Our results showed that acceleration from the source vibration was present at a distance of 4 cm at intensities >150 Hz. At distances greater than 8 cm from the source, accelerations were reduced to values substantially below vibrotactile discrimination thresholds for all vibration intensities. We conclude that in future applications of vibrotactile interfaces, stimulation sites should be separated by a distance of at least 8 cm to avoid potential interference in vibration perception caused by propagating vibrations.

Abstract Chronic lymphocytic leukemia and other B-cell malignancies have been associated with melanoma and non-melanoma skin cancers (NMSC). However, an analysis of Surveillance, Epidemiology and End Results (SEER) data from 1973-2007 found that hairy cell leukemia (HCL), while associated with an increased second cancer risk overall, was not associated with melanoma. In addition, the incidence of NMSC in HCL patients has not been described to our knowledge. Per recent SEER data, the median age at melanoma diagnosis in the general population was 61 years with an age-adjusted incidence rate of 0.02%/year. Methods We identified 372 patients seen at Memorial Sloan-Kettering Cancer Center (MSKCC) over the past 30 years (1983-2013) with a morphologic diagnosis of HCL. Of these, we found 267 patients with ≥2 months of follow-up. We examined the medical records of these 267 patients for demographic data, treatment with purine analogs (PA), and co-occurring skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Skin cancers were considered to be “co-occurring” if they were diagnosed up to 1 year before or any time after the diagnosis of HCL. Results In this 267 patient cohort, the median age at HCL diagnosis was 52.1 years (range 19.6-86.1), and the vast majority of patients were white, non-Hispanic males [Table 1]. 225 patients (84%) were treated with a PA, either cladribine or pentostatin. Of 267 patients, 34 (12.7%) developed skin cancer: 11 (4.1%) melanoma and 25 (9.4%) NMSC [Table 2]. Twelve patients had SCC and 22 BCC. Eleven of 34 patients (32%) had >1 type of skin cancer: 9 BCC and SCC, 1 BCC and melanoma, and 1 SCC and melanoma.For the 34 patients with skin cancer, median follow-up from HCL diagnosis was 10 years (0.7-33.6), median age at HCL diagnosis was 57.5 years, and almost all patients were white, non-Hispanic males. Twenty-nine of the 34 patients (85%) received a PA. Nine patients (27%) either did not receive or were diagnosed with skin cancer before PA therapy. Eighteen patients (53%) were diagnosed with skin cancer between 1 year before and 5 years after HCL; 16 patients (47%) were diagnosed >5 years after HCL. Conclusions In 267 HCL patients with very long follow-up, we found a high incidence of all skin cancers (12.7%), melanoma (4.1%), and NMSC (9.4%). Furthermore, the risk of melanoma appears to be considerably higher in the HCL cohort than the general population (0.02%/year). Although these groups were not age, sex, or race-matched, both HCL and melanoma typically occur in white individuals, and one might expect the risk of melanoma to be lower in HCL patients if there was no association given that HCL usually presents at a younger age. Although a previous analysis of SEER data did not show an association between HCL and melanoma, many of these data were collected before PA therapy was introduced. Moreover, almost all melanoma patients in our cohort were previously treated with a PA, possibly explaining the increased risk. The pathogenesis of this apparent association is elusive, but immunosuppression induced by PA therapy in addition to inherent immunosuppression from HCL itself may be responsible. There also appears to be an increased risk of NMSC in our cohort; however, the precise incidence of NMSC in the general population is not available for comparison to our knowledge. Our findings reinforce that HCL patients should be screened aggressively for skin cancer, particularly given the risk of synchronous melanoma. Disclosures: No relevant conflicts of interest to declare.

Background: It is not unusual for oral manifestations to occur in dermatological diseases. The aim of this study was to observe and evaluate oral manifestations in patients diagnosed with dermatological diseases. Methods: A cross-sectional study based on a convenient sampling technique was conducted among patients with dermatological conditions who visited the polyclinic of King Faisal University Polyclinic of Al-Ahsa, Saudi Arabia from Sep-Nov 2021. Results: Sixty-one percent were females, 50% were aged >30 years, 77% had higher education, 61% were unemployed, 82% were non-smokers, and 20% had some medical conditions. 14.5% suffered from immune-mediated skin disease, 25.3% had eczema, 21.7% showed dermatitis infections, 3.6% had Genodermatosis, 9.6% were with psoriasis and other keratinizing disorders, and 25.3% had miscellaneous skin conditions. 85.5% of skin patients did not have any oral manifestations; oral lesions were of perioral dermatitis (1.2%), melanotic macule (1.2%), fissured tongue (2.4%), oral lichen planus (2.4%), mucocele (2.4%), and one case of each with geographic tongue, herpes labialis, and hairy tongue. Practical ImplicationsThis study highlights the importance of integration of oral health into general health for management of oral diseases associated with other body diseases. Conclusion: The majority of the patients in this study sample with skin diseases did not show any oral manifestations. More females and aged patients had more skin conditions. Keywords: Prevalence, Oral manifestations, Dermatological conditions, Cross-sectional study

Background. Trichotillomania is one of the topical problems in dermatovenerology. Annually the number of people who visit dermatologists with hair loss problem is increasing and makes up to 8–10% in structure of dermatologic illnesses.Clinical Case Description. There are patients with primary psychiatric disorders in practice of dermatologist. This disorders are accompanied by self-injurious behavior and secondary skin changes and/or its appendages. We are performing clinical survey of trichotillomania of hairy part of the head, onychophagy, trichophagy with following developing of trichobezoar in teenage girl. To treat this girl we have carried out surgical operation. Later we have performed complex drug and non-drug treatment under control of pediatric psychiatrist, psychotherapist and dermatologist. The prognosis and perspectives of pathologic process development have been estimated. Possible etiology, clinical signs and dermatological aspects of diagnosis and treatment of disease were discussed.Conclusion. This clinical case has to draw attention of dermatovenerologists, paediatricians, psychiatrists to the problem of factitial dermatitis.

1. Localized cortical cooling was employed in anesthetized cats for the rapid reversible inactivation of the distal forelimb region within the primary somatosensory cortex (SI). The aim was to examine the responsiveness of individual neurons in the second somatosensory area (SII) in association with SI inactivation to evaluate the relative importance for tactile processing of the direct thalamocortical projection to SII and the indirect projection from the thalamus to SII via an intracortical path through SI. 2. Response features were examined quantitatively before, during, and after SI inactivation for 29 SII neurons, the tactile receptive fields of which were on the glabrous or hairy skin of the distal forelimb. Controlled mechanical stimuli that consisted of l-s trains of either sinusoidal vibration or rectangular pulses were delivered to the skin by means of small circular probes (4- to 8-mm diam). 3. Twenty-three of the 29 SII neurons (80%) showed no change in response level (in impulses per second) as a result of SI inactivation. These included seven neurons activated exclusively or predominantly by Pacinian corpuscle (PC) receptors, six that received hair follicle input, four activated by convergent input from hairy and glabrous skin, and six driven by dynamically sensitive but non-PC inputs from the glabrous skin. 4. Six SII neurons (20%), also made up of different functional classes, displayed a reduction in response to cutaneous stimuli when SI was inactivated. 5. Stimulus-response relations, constructed by plotting response level in impulses per second against the amplitude of the mechanical stimulus, showed that the effect of SI inactivation on individual neurons was consistent over the whole response range. 6. The reduced response level seen in 20% of SII neurons in association with SI inactivation cannot be attributed to direct spread of cooling from SI to the forelimb area of SII, as there was no evidence for a cooling-induced prolongation in SII spike waveforms, an effect that is known to precede any cooling-induced reduction in responsiveness. 7. As SI inactivation produced a fall in spontaneous activity in the affected SII neurons, we suggest that the inactivation removes a source of background facilitatory influence that arises in SI and affects a small proportion of SII neurons. 8. Phase-locking and therefore the precision of impulse patterning were unchanged in the responses of SII neurons to vibration during SI inactivation. This was the case whether response levels of neurons were reduced or unchanged by SI inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract Context.—Low-grade non-Hodgkin lymphomas frequently involve extranodal sites including the gastrointestinal tract, skin, and lung, either selectively or as part of widespread dissemination. Differentiation from inflammatory or infectious conditions requires knowledge of specific histologic characteristics of the various entities as well as ancillary techniques. Objective.—To describe the key features and provide diagnostic clues to the identification of specific extranodal low-grade lymphomas of T-cell and B-cell types including small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, extranodal marginal zone B-cell lymphomas of mucosal-associated lymphoid tissue, and hairy cell leukemia. Histologic and cytologic features are highlighted, as well as appropriate integration of results of ancillary diagnostic studies including flow cytometry, immunohistochemistry, molecular features, and cytogenetics. Data Sources.—The published literature as well as personal experience from a specialized hematopathology practice at a large university medical center. Conclusions.—Correct identification of extranodal low-grade lymphomas and differentiation from hyperplastic and inflammatory or infectious processes require the ability to distinguish each of the specific entities discussed. Ancillary studies are often indispensable in reaching a correct diagnosis.

In order to describe the clinical features of HIV (non-AIDS), particularly injection drug use (IDU) related HIV, in patients attending the Regional Infectious Diseases Unit in Edinburgh, a prospective review utilizing the WHO staging system of the 680 HIV positive patients, 30% of whom were women and 68% were infected via IDU, was undertaken. Despite the fact that the majority of drug users and heterosexuals enrolled asymptomatic, by 1993, 71% of the patients had developed some HIV related clinical problem . The im portant clinical problems observed for the cohort were; minor skin problems, m inor bacterial infections, major bacterial sepsis, oral thrush, oral hairy leucoplakia, significant weight loss of >10%, HIV related thrombocytopenia and of course AIDS. Unlike previous reports from other areas, in Edinburgh drug users were not more likely than other risk groups to develop severe bacterial disease. Differences in morbidity and mortality rates by risk group but not by gender were noted but these may well be affected by the very different enrolment pattern observed in the various risk groups. The pre-AIDS mortality rates for drug users were remarkably similar to published rates from other centres.

Abstract Abstract 4600 Targeted intervention against driver mutations is beginning to transform cancer treatment. A particular activating mutation of the BRAF serine/threonine protein kinase, BRAF V600E, is found in virtually all cases of hairy-cell leukemia (HCL), suggesting disease-specific oncogene dependence. Here, we present the extended follow up of a patient with chemotherapy refractory HCL who was treated with a short course of vemurafenib, a specific BRAF inhibitor. Before vemurafenib treatment, the patient had an almost complete bone marrow (BM) infiltration by hairy cells and massive splenomegaly (24.8×8.3 cm) leading to severe cytopenias (leukocytes, 680/μl; hemoglobin, 10 g/dl; platelets, 36,000/μl). No objective response could be achieved by three lines of purine analogue based treatment regimens (Cladribine, Pentostatin and R-Cladribine). We demonstrated the presence of the BRAFV600E mutation with a mutation specific antibody and 454 sequencing. In order to investigate if recurrent mutations may have contributed to refractoriness to purine analogues, a panel of genes commonly mutated across lymphoid malignancies were analysed (EZH2, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, SF3B1, or TP53). No mutations were demonstrated Because of limited treatment options and recent success with vemurafenib in BRAF mutated melanoma we decided to use experimental treatment with vemurafenib after intensive counseling and started treatment with 240 mg twice daily after a single loading dose of 960 mg. The dose was slowly escalated to 1,920 mg/d which is the standard dose used in melanoma. After 6 and 16 days of 240mg bid the spleen size had shrunk to 18.8 × 5.8 and 14×5 cm, respectively. Blood counts rapidly recovered and sCD25 which is considered a reliable marker of HCL cell load dropped quickly to normal levels already at the lowest dose of 240 mg vemurafenib bid (Figure 1). There was no evidence of tumor lysis. Response was further evaluated by repeated trephine biopsies on days -1, 6, 17 and 36. After only 6 days of vemurafenib treatment p-ERK signaling was almost completely abolished in HCL cells in vivo, followed by apoptosis of HCL cells as shown by Tunnel staining and finally complete clearance of hairy cells on day 36. CR criteria were achieved on day 43. Because of the excellent disease control and the risk of short-latency non-melanoma skin cancers during therapy with vemurafenib, we discontinued vemurafenib after 56 days. CR continues to persist in the absence of drug exposure for more than 6 months at the time of abstract preparation (Figure 1). Massively parallel DNA sequencing was used to detect remaining mutant BRAF alleles in peripheral blood leukocytes on day 36. Among over 105 sequencing reads, the BRAF V600E mutation was not detectable above background (<0.3% of variant reads). Minimal residual disease (MRD by FACS) assessment of the peripheral blood revealed an approximately 100-fold reduction of hairy cells by day 22 of treatment and a complete eradication from day 36, which continues to persist for more than 6 months. Our observations show that targeting of a single mutated oncogene can provide durable disease control in this leukemia. Trials exploring chemotherapy-free treatment approaches with BRAF inhibitors in HCL are highly warranted. Disclosures: No relevant conflicts of interest to declare.

We present a 6-month-old male patient, who was consulted with dermatologist by his parents, because of a pigmented lesion, present since birth, covering almost the all skin of the back and buttocks. A sharply bordered, unequally coloured congenital pigmented nevus, measuring approximately 21 cm in diameter was observed in the whole body skin examination. The lesion was affecting the lower 2/3 of the skin of the back and the top half of the gluteus area, extending to the lateral part of the tors, forward the abdomen and the upper lateral part of the hips, composed by multiple darker-pigmented nests and several lighter areas, with single depigmented zones, hairy surface, irregularly infiltrated on palpation. Congenital melanocytic nevi are presented in approximately 1% of newborns, while giant congenital melanocytic nevi (GCMN) are the most uncommon subtype of them; with occurrence rate 1 in 50,000 births. They affect 2% of a total body surface or presenting in a diameter larger than 20 cm in older children. Although not common, the possible malignant transformation remains one of the most important considerations related to them, as the related lifetime risk of melanoma is 4% to 10%. Treatment recommendations include non-surgical methods as dermabrasion only within the first two weeks of life, for prevention the possible melanocytic deeper migration, while serial surgical excisions or tissue expanders could be useful treatment tool even in later stages. Nevertheless, cosmetic result is not always satisfactory, and the risk of malignant changes remains, in cases of previous melanocytic migration in deeper layer. Recent article suggests the potential role in the treatment of GCMN with NRAS inhibitor trametinib, approved for treatment of advanced melanoma, associated with underlying NRAS mutations. Although promising, the drug could be useful in paediatric patients, only with associated NRAS gene mutation. It is still unclear whether it could be helpful, independent of the NRAS status.

PURPOSE: The purpose of the present study was to assess the risk of second cancers in patients with hairy cell leukemia (HCL). PATIENTS AND METHODS: We investigated the incidence of additional cancers in those patients registered in the nationwide registry of the Italian Cooperative Group for the Study of HCL, asking the cooperating centers for additional information on initial and subsequent therapies and on time and type of second malignancies, if they developed. Here we report the final results of this survey, consisting of 54 cases of second malignancies (excluding nine cases of epithelial skin cancer) which developed in 54 patients of 1,022 with adequate follow-up. RESULTS: The cumulative risk of development of a second cancer was 5%, 10%, and 14% at 5, 10, and 15 years, respectively. The incidence of second malignancies was not significantly higher than the expected rate (standardized incidence ratio [SIR], 1.01; 95% confidence interval [CI], 0.74 to 1.33; P = 1.0). However, the SIR of non-Hodgkin’s lymphoma in the entire cohort was 5.3 (95% CI, 1.9 to 11.5). Second malignancies occurred in eight (4.7%) of 386 patients who never received interferon (IFN), nine (5.9%) of 495 patients treated with IFN at the time of diagnosis, and seven (6.9%) of 102 patients who received IFN as second-line therapy. These differences were not statistically significant. Analysis of the separate calendar periods did not reveal any particular trends with respect to variations in SIR. CONCLUSION: The present study does not support the suspicion that patients with HCL are at increased risk of additional second malignancies, although the incidence of lymphoid neoplasms was significantly higher than expected. In addition, our data indicate that IFN therapy did not exert an oncogenic effect in such patients.

1. Responses of dorsal horn neurons to cutaneous mechanical stimulation were studied in an in vitro preparation of hamster spinal cord with partially intact innervation from an isolated patch of hairy skin. Stable extracellular and intracellular recordings were obtained from cells with different mechanoreceptive properties similar to those reported for other species in vivo. Analyses were made of the intracellular responses of 25 dorsal horn neurons activated selectively by mechanical stimulation to the skin patch. 2. Bath application of the broad spectrum, excitatory amino acid (EAA) receptor antagonist, kynurenic acid (1 mM) blocked excitation of 7 of 8 high-threshold mechanoreceptive units by either cutaneous nerve volleys or mechanical stimulation of the skin. This concentration of kynurenic acid suppressed peripherally evoked responses in 8 of 14 neurons responsive to innocuous mechanical stimuli. 3. High-threshold mechanoreceptive neurons of the superficial dorsal horn exhibited one of three distinctive patterns of postsynaptic potentials in response to electrical stimulation of cutaneous afferent fibers: 1) a simple fast excitatory postsynaptic potential (EPSP), 2) a fast EPSP with a prolonged decay phase lasting between 100 and 1,000 ms, and 3) a multiphasic response dissociable on the basis of stimulus strength consisting of a fast EPSP followed by a hyperpolarizing inhibitory postsynaptic potential (IPSP) (duration 80–100 ms). Gentle mechanical stimuli initiated inhibition from areas adjacent to the high-threshold mechanically excitatory field; this suggests that membrane hyperpolarization in these neurons was evoked by input from low-threshold mechanoreceptors. 4. Bath application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), a competitive EAA antagonist selective for non-N-methyl-D-aspartate (non-NMDA) receptor subtypes, substantially or completely (56–100%) suppressed EPSPs evoked from cutaneous afferent fibers in high-threshold mechanoreceptive neurons. CNQX also decreased the membrane depolarization, the frequency of EPSPs, and the frequency of action potentials evoked by mechanical stimulation of the receptive field. 5. CNQX (10 microM) or kynurenic acid (1 mM) had considerably weaker effects on IPSPs than on EPSPs evoked from the periphery in superficial dorsal horn neurons. IPSP amplitudes were unchanged by these agents in some neurons and decreased by only 20–25% in others. 6. We conclude that L-glutamate acting on non-NMDA receptors mediates fast synaptic excitation of superficial dorsal horn neurons from peripheral mechanical nociceptors with myelinated fibers. Furthermore, the observations imply either an agent other than L-glutamate or one acting at different membrane receptors is a synaptic mediator for other peripheral afferent units including some activated by innocuous mechanical stimuli.

Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

Abstract Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.

BACKGROUND: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder. The BRAF V600E mutation was shown to be the underlying genetic driver for the vast majority of classical HCL (HCLc) cases and treatment with the BRAF inhibitor (BRAFi), vemurafenib, has proven extremely successful. Dabrafenib is an oral BRAFi used in melanoma, often in conjunction with trametinib, a MEK inhibitor. Data exists on the use of dabrafenib combined with trametinib in HCLc but there is no efficacy or safety data on either single agent dabrafenib or dabrafenib combined with rituximab. We present a small series of 7 patients treated with either single agent dabrafenib or combination dabrafenib and rituximab. METHODS: Since 2018 dabrafenib was accessible via a Novartis managed access programme for BRAF V600E mutated HCLc patients who had no alternative treatment options. Six patients received dabrafenib, 2 as single agent due to recent prior ineffective rituximab therapy or severe rituximab infusion reaction and the remaining 4 patients with dabrafenib and rituximab. Dabrafenib was given at 150mg twice daily on a continuous 28 day cycle. Rituximab 375mg/m2 IV was given once every 2 weeks for a total of 8 doses. As there was no availability for re-treatment on cessation of therapy and no other suitable/accessible treatment options, patients with ongoing response and good tolerance were continued on indefinite therapy. One additional patient was treated with frontline dabrafenib and rituximab due to various comorbidities including end stage renal failure limiting other treatment options. RESULTS: Mean age on commencing dabrafenib was 73 (52-87) and in the relapsed patients the median number of prior lines of therapy was 5 (3-13). Four patients had undergone prior splenectomy. Two patients had received prior BRAFi therapy with vemurafenib and 3 had received prior Moxetumomab. Patients received a median of 8 cycles of dabrafenib. 4 patients received all 8 cycles of rituximab with 1 discontinuing rituximab due to adverse drug reaction. Adverse drug reactions to dabrafenib were mostly grade 1-2. The most common reaction was benign keratotic skin lesions occurring in 5/7 patients. Their onset was typically after 4 weeks of treatment, persisting whilst therapy continued. Other notable adverse drug reactions were hair thinning and palmar-plantar erythrodysesthesia both occurring in 3/7 patients. Hair thinning did seem to improve with decreasing the dosage and resolve on cessation of the drug. Palmar-plantar erythrodysesthesia was managed with dose reduction and non-steroidal anti-inflammatory drugs. Response assessment criteria used were from the 2017 hairy cell leukemia foundation consensus guidelines for the diagnosis and management of patients with HCLc. All patients responded to therapy. Hematological response was rapid, most patients achieving hematological CR after 2-3 cycles. Five patients achieved a CR, 2 were MRD+ve, 2 were MRD-ve and 1 was a radiological CR. The remaining 2 patients achieved a hematological response, 1 partial and 1 complete. Six patients had sufficient follow up for assessment with 2/6 having relapsed and 4/6 remaining in remission. Median follow up was 17 months, median DOR and median OS were not reached. The 2 patients in our cohort (patients 1 and 3) receiving prior vemurafenib each received 6 cycles, 1 achieving CR lasting 3 months, the other achieving PR lasting 11 months. Both responded rapidly to dabrafenib, one treated with dabrafenib and rituximab achieved an MRD+ve CR with DOR 21 months. The other received single agent dabrafenib and achieved a hematological response with DOR 15.2 months. Treatment response and survival are shown in table 1 and figure 1. Figures 2-7 show the hematological response at time points within the first year of therapy. DISCUSSION: In this small cohort we have shown that dabrafenib as a single agent or combined with rituximab is a safe and effective therapy in BRAF V600E mutated HCLc, even in those patients with prior time limited duration BRAFi therapy. There was no hematological toxicity noted. The main adverse drug effect was development of skin lesions however none were malignant. The only malignant lesion noted pre dated the commencement of dabrafenib. Dermatological surveillance is therefore recommended. Hematological response was rapid with significant improvement seen as early as 4 weeks from commencing therapy. Disclosures El-Sharkawi: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Other: Conference fees. OffLabel Disclosure: Use of BRAF inhibitor Dabrafenib in BRAF V600E mutation positive classical Hairy Cell Leukemia.

Abstract Background: Erdheim-Chester disease (ECD) is characterized by multi-organ infiltration of clonal histiocytes bearing activating mutations predominantly in the MAPK pathway. The diagnosis of ECD is clinico-pathologic; histopathologic findings alone are often non-specific. Characteristic pathognomonic finding of ECD is the symmetric osteosclerosis of the distal femur and proximal tibia/fibula, seen in &gt;90% of cases, and referred to herein as classic ECD (C-ECD). There is a paucity of data on the phenotypic and mutational differences between C-ECD and non-classic ECD (NC-ECD). Determining phenotypic patterns may allow for earlier suspicion and diagnosis. Methods: Patients who met the revised ECD criteria proposed by Haroche J et al (Blood 2020;135:1311-1318) and had full body imaging that included the lower legs (18-FDG-PET/CT or CT/bone scan) were included. ECD diagnosis was made when &gt;1 major criteria plus &gt;1 minor criteria were present. Major criteria: 1) symmetric meta-diaphyseal osteosclerosis in legs; 2) "hairy kidneys"; "coated aorta", right atrial pseudotumor, xanthelasma, exophthalmos; or osteosclerosis of paranasal sinuses. Minor criteria: 1) histologic finding of typical foamy histiocytes (CD68+/CD163+/CD1a-) associated with fibrosis; 2) mutation/gene fusion of BRAF, CSF1R, or MAPK/PI3K pathways. We compared the organ involvement and BRAF V600Emutational status between C-ECD and NC-ECD. Results: A total of 105 patients were included. The median age at diagnosis was 57 years (range, 38-81) and most were males (62%). Majority had 18-FDG-PET/CT (83%) and BRAF V600E testing (65%). The main organ systems involved were skeletal (83%), renal (64%), adrenal (44%), and pulmonary (42%). Central diabetes insipidus (DI), "hairy kidneys", and "coated aorta" were present in 27 (26%), 54 (51%), and 44 (42%) patients, respectively. Among those tested, BRAF V600E mutation was found in 48/67 (72%) by immunohistochemistry. In our cohort, most patients (n=87. 83%) had C-ECD. NC-ECD had significantly lower number of organs/systems involved compared with C-ECD (median 3 vs 6, p=0.002). C-ECD had significantly higher rates of involvement of paranasal sinuses (51%/7%, p=0.002), DI (26%/0%, p=0.02), and similar rates of lung (44%/43%), cardiac (34%/14%), and skin (14%14%) involvement when compared to NC-ECD. BRAF V600E was significantly more common in C-ECD (88%/30%, p=0.004). Thirty-nine (37%) patients underwent next generation sequencing, of whom 33 (31%) had successful testing. In C-ECD, 3 patients had mutations other than BRAF V600E, these included: NRAS, MAP2K1, and MEF2C-FLT3 fusion. In NC-ECD, 5 patients had mutations other than BRAF V600E, these included: MAP2K1, KRAS, and NF1. Conclusions: Our study suggests distinct differences in clinical presentation and molecular findings exist between C-ECD and NC-ECD. C-ECD has a higher degree of organ involvement and harbor BRAF V600E more frequently than NC-ECD. Further analysis of histopathologic findings and outcomes in this cohort may provide insights into these ECD subsets that can optimize future management of this disease. Figure 1: Sites of involvement of classical Erdheim-Chester Disease (C-ECD) versus non-classical Erdheim-Chester Disease (NC-ECD) Figure 1 Figure 1. Disclosures Vassallo: Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding; Pfizer: Research Funding. Tobin: Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding; National Institutes of Health: Research Funding. Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Vividion: Consultancy, Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board.

<p class="abstract"><strong>Background:</strong> <span lang="EN-IN">Mucocutaneous manifestations in patients positive for HIV are helpful in the diagnosis as well as treatment of the disease. Consequent to the introduction of Highly Active Anti-Retroviral Therapy (HAART), there seems to be an increase in the presentation of non-infective diseases. It was aimed to analyse the mucocutaneous manifestations in HIV infected patients taking HAART and correlate with age and CD4 lymphocyte count.</span></p><p class="abstract"><strong>Methods:</strong> A retrospective analysis of 125 People Living With HIV (PLWH) having mucocutaneous manifestations receiving HAART who attended a tertiary care city hospital over a period of ten months from January 2016 to October 2016 was carried out. The findings were correlated with CD4 count and age. The data were collected from the patient follow up cards maintained by qualified Dermatovenereologist.<strong></strong></p><p class="abstract"><strong>Results:</strong> <span lang="EN-IN">There was no major gender difference in our study. The trans genders presented with only non-infectious skin diseases. Younger patients had a higher CD4 count (p=0.01%) which was statistically significant. Candidiasis and pruritic papular eruption were the commonest infective and non-infective diseases observed respectively. The mean CD4 count comparison was statistically significant (p=0.04). The count was highest for insect bite allergy and lowest for oral hairy leukoplakia. The mean age of disease manifestation was highest for Herpes zoster and lowest for aphthous ulcers 45 and 29 years respectively. All the adverse reactions observed were to efavirenz. </span></p><p class="abstract"><strong>Conclusions:</strong> <span lang="EN-IN">With the improvement of CD4 count in PLWH receiving HAART, the proportion of non-infectious inflammatory disease manifestations are on the rise. Awareness about this fact is very important for effective management.</span></p>

<p class="abstract"><strong>Background:</strong> Psoriasis, a common chronic disfiguring inflammatory and proliferative papulosquamous disorder of the skin in which both genetic and environmental influences have a critical role. Scalp becomes the most common site of involvement, both at the time of onset of the disease and also throughout the course of the disease. This prospective study is designed to have a thorough insight into the etiological factors, clinical types and to unearth the factors behind the recalcitrant nature of scalp psoriasis.</p><p class="abstract"><strong>Methods:</strong> A prospective study, conducted in the Department of Dermatology, Chengalpattu Medical College, Tamilnadu. 50 patients of scalp psoriasis enrolled between April 2017 and March 2018 were included in the study.<strong></strong></p><p class="abstract"><strong>Results:</strong> It was found in our study that lesions of scalp psoriasis took longer time (on an average 6-8 weeks more) to resolve than lesions of psoriasis elsewhere in the body following treatment with systemic drugs like methotrexate and topical agents like 0.1% betamethasone + salicylic acid ointment and liquid paraffin. Out of 50 patients, 30 were female (60%) and 20 were male (40%). Following were the clinical types of scalp psoriasis encountered in our study. Chronic plaque psoriasis- 25 (50%), sebopsoriasis- 13 (26%), erythrodermic scalp psoriasis- 8 (16%), pityriasis amiantaceae- 4 (8%), pustular psoriasis of scalp- 0.</p><p class="abstract"><strong>Conclusions:</strong> The density of scalp hair leading to reduced absorption of topical treatment and the social reasons affecting the quality of life of patients are crucial factors that determine treatment outcome. All these inconveniences result in non compliance of treatment. Hairy scalp, rich vascular supply, patient’s non-compliance, adverse effects of topical agents-all throw a challenge to the treating dermatologist where it poses recalcitrant nature to treatment.</p>

An alkaloid compound from the hairy root culture of Eurycoma longifolia has been isolated and characterised as 9-methoxycanthin-6-one. The aims of these studies were to investigate the in vitro anti-cancer activities of 9-methoxycanthin-6-one against ovarian cancer (A2780, SKOV-3), breast cancer (MCF-7), colorectal cancer (HT29), skin cancer (A375) and cervical cancer (HeLa) cell lines by using a Sulphorhodamine B assay, and to evaluate the mechanisms of action of 9-methoxycanthin-6-one via the Hoechst 33342 assay and proteomics approach. The results had shown that 9-methoxycanthin-6-one gave IC50 values of 4.04 ± 0.36 µM, 5.80 ± 0.40 µM, 15.09 ± 0.99 µM, 3.79 ± 0.069 µM, 5.71 ± 0.20 µM and 4.30 ± 0.27 µM when tested in A2780, SKOV-3, MCF-7, HT-29, A375 and HeLa cell lines, respectively. It was found that 9-methoxycanthin-6-one induced apoptosis in a concentration dependent manner when analysed via the Hoechst 33342 assay. 9-methoxycanthine-6-one were found to affect the expressions of apoptotic-related proteins, that were proteins pyruvate kinase (PKM), annexin A2 (ANXA2), galectin 3 (LGAL3), heterogeneous nuclear ribonucleoprotein A1 (HNRNP1A1), peroxiredoxin 3 (PRDX3), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the differential analysis of 2-DE profiles between treated and non-treated 9-methoxycanthine-6-one. Proteins such as acetyl-CoA acyltransferase 2 (ACAA2), aldehyde dehydrogenase 1 (ALDH1A1), capping protein (CAPG), eukaryotic translation elongation factor 1 (EEF1A1), malate dehydrogenase 2 (MDH2), purine nucleoside phosphorylase (PNP), and triosephosphate isomerase 1 (TPI1) were also identified to be associated with A2780 cell death induced by 9-methoxycanthine-6-one. These findings may provide a new insight on the mechanisms of action of 9-methoxycanthin-6-one in exerting its anti-cancer effects in vitro.

Abstract BACKGROUND: Hairy cell leukemia (HCL) is a rare lymphoid neoplasm with an incidence of 1,000 new cases per year and accounting for 2% of all leukemias in the United States. There is a lack of data on the spectrum of second primary malignancies (SPMs) and cause-specific mortality in the era of targeted therapies (anti-CD20, anti-CD22, and BRAF-inhibitors). We undertook this study to address the gaps in knowledge using a national registry from the United States. METHODS: We estimated the incidence of SPMs and cause-specific mortality among two-month survivors of hairy cell leukemia (HCL) using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 registries. We included patients from 2003-2018 with ICD-O-3 code 9940/3 from the registry. We calculated the risk of SPMs using standardized incidence ratios (SIRs), and cause-specific mortality by standardized mortality ratios (SMRs) and absolute excess risk (AER)/10,000 population. We also reported survival analysis using relative survival rates (RSRs). RSR was calculated as ratio of observed to expected survival compared to the 2000 US standard population and adjusted for age, sex, and race. Overall survival (OS) analysis was reported using Kaplan-Meier (KM) method. RESULTS: We included a total of 4,261 patients with Hairy cell leukemia in this study. The median age at diagnosis was 59 yrs (range 21-85). The median follow-up duration for entire cohort was 68 months (range 0-191 mo). A total of 538 (12.6%) patients developed SPMs at last follow-up, of which 75% were solid organ malignancies, and 25% were hematologic neoplasms. The SPM risk for cohort was significantly elevated (SIR 1.33, 95% confidence interval [CI] 1.22 - 1.45) compared with the general population. The median latency period for SPM development was 3 yrs (range 1-15 yrs). The SPM risk was statistically higher than general population among Whites with HCL (SIR 1.33, 95% CI 1.22 - 1.45), but not significant among Blacks (SIR 1.31, 95% CI 0.76 - 2.09). The SIR was slightly higher in females (SIR 1.39, 95% CI 1.12 - 1.71) when compared to males (SIR 1.32, 95% CI 1.20 - 1.45). The SIR according to age groups were as follows: age &lt; 65 years (SIR 1.36, 95% CI 1.21 - 1.52), age &gt; 65 years (SIR 1.31, 95% CI 1.15 - 1.48). The risk for hematopoietic SPMs was higher (SIR 2.82, 95% CI 2.31 - 3.41) compared with solid organ tumors (SIR 1.16, 95% CI 1.05 - 1.28). Specific SPMs with highest risk included non-epithelial skin cancers (SIR 5.20, 95% CI 2.59 - 9.30), Hodgkin lymphoma (SIR 4.68, 95% CI 1.52 - 10.91), non-Hodgkin lymphoma [NHL] (SIR 3.91, 95% CI 3.04 - 4.95), myeloid and monocytic leukemia (SIR 2.23, 95% CI 1.15 - 3.90), melanoma (SIR 1.60, 95% CI 1.12 - 2.20), and prostate cancer (SIR 1.45, 95% CI 1.21 - 1.72). Although the risk of developing secondary NHL was significantly high throughout the follow-up period, risk for Hodgkin lymphoma was only significant &gt;10 yr of follow-up (SIR 9.71, 95% CI 1.18 - 35). 5-year RSR for the cohort was 94.6%. On KM analysis, the mean OS for entire cohort was 11.8 yr, but the median OS was not reached (Figure 1). At last follow-up, 770 (18%) patients had died, of which 49% were due to malignant neoplasms. There was statistically significant risk of mortality due to all malignant cancers combined (SMR 2.41, 95% CI 2.17 - 2.66), largely due to mortality from leukemia (SMR 32.62, 95% CI 28.41 - 37.25, AER 70.2) and NHL (SMR 5.49, 95% CI 3.78 - 7.71, AER 9.01) (Table 1). Interestingly, risk of mortality from non-neoplastic causes was lower than general population: cardiovascular disease (SMR 0.70, 95% CI 0.58 - 0.83), pulmonary diseases (SMR 0.44, 95% CI 0.26 to 0.70), and infectious diseases (SMR 1.27, 95% CI 0.55 - 2.51). The risk of death from leukemia was highest within first year of diagnosis of HCL and continued to slowly decline thereafter, although remained statistically significantly elevated more than other causes of death (SMR 1yr 112, AER 214; SMR 1-5 yrs 36, AER 72; SMR 5-10 yrs 20, AER 43; SMR &gt;10 yrs 17, AER 43). CONCLUSION: Our study reveals that despite therapeutic advances in HCL, hematologic neoplasms (including leukemia) remain the leading cause of death in last two decades. Additionally, the risk of developing SPMs remains elevated in patients with HCL, and is significantly high in Whites compared with Blacks. Further studies are needed to better define the healthcare needs of HCL patients beyond initial treatment to reduce the burden of mortality from HCL and other SPMs. Figure 1 Figure 1. Disclosures Narkhede: Gilead: Research Funding; Genentech/Roche: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding.

Abstract Hairy cell leukemia (HCL) is a rare B-cell neoplasm generally responsive to Cladribine. Cladribine is generally administered intravenously either as a continuous weekly infusion or as a 2-hour daily or weekly infusion for 7 days. Subcutaneous Cladribine is an alternative route with 100% bioavailability and with efficacy similar to intravenous 2CdA at the dose of 0.7 mg/kg/cycle. In indolent non-Hodgkin lymphomas other than HCL, reduction to 0.5 mg/kg/cycle determined equivalent efficacy and lower toxicity. In a national multicentre clinical trial (protocol EudraCT code: ICGHCL 2004), we have evaluated efficacy and toxicity of subcutaneous Cladribine given 0.1mg/kg/die for 5 (total dose 0.5 mg/kg, arm A) or for 7 days (total dose 0.7 mg/kg, arm B) as a single course in newly diagnosed HCL requiring treatment. Responses to treatment were assessed on day 60 and day 180 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were considered as beneficial responses, while minor Responses (mR) and No Responses (NR) were rated as treatment failures. Toxicity was assessed from day 0 to day 60 after treatment, according to the 2003 NCI/CTCAE v3 criteria. In this interim analysis, 92 of the 132 patients currently recruited (45 patients in arm A and 47 in arm B) were evaluated for toxicity and response to treatment. 2CdA was administered at the proposed regimen with no modifications in all patients. Eighty-five of 92 patients (92%) had a beneficial response to treatment (57/92 CR, 62%; 28/92 PR, 30%). The 7/92 treatment failures scored as 3/92 mR (3%) and 4/92 (5%) NR. Responses were equivalent in the two arms (p=0.7), with 41/45 (91%) beneficial responses (27/45 CR, 60%; 14/45 PR, 31%; 2/45 mR, 4% and 2/45 NR, 4%) in arm A versus 44/47 (94%) beneficial responses in arm B (30/47 CR, 64%; 14/47 PR, 30%; 1/47 mR, 2%; 2/47 NR, 4%). Overall grade 3–4 toxicity was recorded in 16/92 (17%) patients (8/92 FUO, 9%; 4/92 documented infections, 6%, 3/92 skin rashes, 3%; 1/92 hepatic toxicity, 1%) and appeared less frequent in arm A (4/45, 9%) than in arm B (12/47, 25%) (p=0.05). Analysis of distribution of toxicities in the two arms (arm A: 2/45 FUO, 4%; 0/45 documented infections; 1/45 skin rash, 1%; 1/45 hepatic toxicity, 1%; arm B: 6/47 FUO, 13%; 4/47 documented infections, 9%; 2/47 skin rashes, 4%) revealed a significantly lower frequency of FUO and infections in arm A (2/45, 4%) than in arm B (10/47, 22%) (p=0.02), to suggest a higher risk of infection in the 7 day regimen. The present data indicate that overall activity of subcutaneous 2CdA is similar to the intravenous formulation (Cheson, 1998). Furthermore, the current interim analysis suggests that subcutaneous 2CdA given at 25% reduced doses (0.5 mg/kg) has equivalent activity and lower toxicity than subcutaneous 2CdA at standard doses (0.7 mg/kg) and is easy to give in an outpatient setting.

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p &lt; 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p &lt; 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

Abstract Background: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytic disorder that almost exclusively affects adults. Reports of pediatric-onset ECD are only anecdotal. Additionally, a comprehensive clinical and molecular characterization of pediatric ECD is lacking. Methods: All prevalent and incident cases followed at three ECD referral centers in Italy and France were considered eligible when they had: a) an age &lt;18y at disease onset; b) a clinical presentation consistent with ECD (i.e., at least one of the following localizations: bilateral, sclerotic bone involvement; sclerotic bone lesions of facial sinuses; hairy kidneys; coated aorta; xanthelasma; tumoral atrial involvement); c) pathology consistent with ECD or mixed ECD-Langerhans cell histiocytosis (LCH); d) available data on molecular studies. Results: Ten patients were included (4 boys and 6 girls); their median age at diagnosis was 4.5 years (IQR 3-9). Bone pain, diabetes insipidus, and exophthalmos were the predominant clinical manifestations at onset. The most commonly involved sites were the hypothalamic/pituitary axis (8/10, 80%), the maxillary/facial structures (8/10, 80%), the bone (6/10, 60%), and the central nervous system (CNS; 7/10, 70%). Other less frequent localizations included the skin (3/10, 30%), the retroperitoneum (2/10, 20%), the lymph nodes (2/10, 20%), the large vessels (1/10, 10%), the heart (1/10, 10%), and the lung (1/10, 10%). The median number of involved sites was four (IQR 4-4). Four patients (of whom three were younger than nine years) had clinical or pathological features consistent with mixed histiocytosis (ECD-LCH). Molecular analysis of tissue biopsies revealed the BRAF V600E mutation in 6 patients (60%). As compared with adult series, the retroperitoneum, the heart, the lungs, and the skin seemed to be less frequently involved. Conversely, hypothalamic/pituitary and maxillary/facial involvement were apparently more frequent in our pediatric cohort. Treatments were heterogeneous. First-line regimens mainly consisted of chemotherapy deriving from LCH-based regimens: six out of the eight treated patients received chemotherapy, but only two of them achieved a transient response. Interferon-alpha was used in five patients (as first-line treatment in two and as a rescue treatment in three), with a partial response in two. Four patients with the BRAF V600E mutation received the BRAF inhibitor vemurafenib at some point (partial responses were obtained in all, in one case requiring a combination with cobimetinib). All patients were alive at last follow up (median 94 months, IQR 12-108). Chronic sequelae included end-stage kidney disease in one patient, growth retardation in two, and endocrine abnormalities in seven. Conclusions: The clinical phenotype of ECD differs between children and adults. The hypothalamic/pituitary axis and the maxillary/facial area are frequently involved in pediatric cases, whereas other localizations typically seen in adults (i.e., retroperitoneum, heart, lung, and skin) are rarer. An overlap with LCH is frequent, especially in younger patients. As for LCH, targeted treatments can be highly effective in children carrying the BRAF V600Emutation. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction : Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with a very indolent clinical course and patients may survive for many decades. First-line treatment with purine analogues such as cladribine (Cld) is considered standard of care since it is very efficient and induces profound remissions. However, patients with HCL often relapse after purine analogues and repeated treatment may increase morbidity and mortality. Despite good clinical evidence of long term control of the disease by several mainly single center studies of patients treated with purine analogues, there is only one study analyzing mainly subcutaneous (sc) treated patients based on registry data. We therefore performed a pooled long-term follow-up analysis of our prospective multicenter studies treating patients with sc Cld focusing on survival, secondary malignancy and retreatment. Materials and Methods : The SAKK included patients treated for HCL in 4 studies between 1993 and 2005. Three studies focused on first-line regimens with sc Cld, whereas the fourth protocol focused on the effect of Rituximab monotherapy in patients pretreated with Cld. Classical morphologic, immunohistochemistry and flow cytometry criteria were used as inclusion criteria and response was assessed by established criteria. Treatment algorithms in the 4 studies were as follows: 1) 5 days of Cld 0.14mg/kg sc followed by max 2 cycles of 7 days of Cld 0.1mg/kg sc in case of minor response or no response (SAKK 32/93); 2) Single shot of Cld 0.25mg/kg sc followed by a maximum of 2 cycles of 0.14mg/kg sc for 5 day in case of minor response, no response or relapse (SAKK 32/95); 3) 5 consecutive days of Cld 0.14mg/kg sc versus the same dose in 5 weekly applications (SAKK 32/98); 4) Rituximab 375 mg/m2iv weekly for 4 weeks in relapsed patients (SAKK 31/98). SAKK 32/93 included 63, SAKK 32/95 74 and SAKK 32/98 100 patients. Of the 26 patients registered in 31/98 20 were already in SAKK 32/93, 32/95 and 32/98. Therefore, we also included the treatment information and follow-up data of these 20 patients. All patients were subject to life-long follow-up within the clinical trials. Further information including secondary malignancies and retreatments were obtained by sending out questionnaires to the treating physicians of the study patients. Of the 237 patients 4 patients were in two of the studies and 10 patients have been excluded because of non-classical HCL phenotype. Therefore, a total of 223 patients were included in the analysis. Overall survival and follow-up time were assessed by Kaplan-Meier and reverse Kaplan-Meier method, respectively. Results : The median age of patients at the time of diagnosis was 55 (range 21 to 96) years, 50 patients were female (22.4%) and 173 (77.6%) male. At the time of data analysis, the median follow-up time was 12.1 (95%-CI 10.0 to 14.0) years. A total of 129 (57.8%) patients had the last follow-up information more than two years prior to the data cut-off in May 2016, however, the available information of all patients was used for the sub-analyses including secondary malignancies or retreatment. By the cut-off date, 49 patients have died, 14 (28.6%) due to secondary malignancies and 7 (14.3%) due to HCL progression. Median overall survival from diagnosis was 31.6 (95%-CI 31.6 to 37.8) years. Retreatment was necessary in 53 (23.7%) patients after a mean of 6 (0.2 to 20.4) years and first retreatment was mainly Cld (64%), rituximab (19%) or Cld and rituximab (13%). 21 patients (9.4%) required more than one retreatment with a mean number of 1.57 (range 1 to 5) treatments. A total of 42 (18.8%) patients developed secondary malignancies with an average time to occurrence of 7.1 (range: 0.1 to 17.7) years. The majority of the secondary malignancies were of non-hematological origin (85.9%), most frequently skin cancer (31.0%), followed by prostate cancer (19.0%) and colorectal cancer (16.7%). Six patients (14.4%) developed hematological secondary malignancies with a predominance of B-lymphoid neoplasms. Conclusion : Long-term overall survival in HCL patients treated with sc Cld was excellent and comparable to studies using iv Cld. Despite the long follow-up, sc Cld had a curative potential and relapses requiring re-treatment were observed only in a minority of patients. Secondary malignancies were predominantly non-hematological. These data indicate that patients need to be followed carefully with a special focus on secondary malignancies. Disclosures Chalandon: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Abstract Abstract 536 Long-term outcomes following novel therapies for CLL have rarely been reported. Between 10/90 and 12/94, 509 eligible, untreated patients (pts) with symptomatic CLL were enrolled by 4 cooperative groups onto study C9011; 179 were randomized to F, 193 to C, and 137 to F+C. After slightly more than 5 years median follow up, with the time of last follow-up in June 1999, we reported in 2000 (NEJM 343:1750) that F provided significantly higher response rates and longer remission duration and progression-free survival (PFS) than C (p<0.001 for all 3 endpoints). The combination arm with F+C was stopped early because of high morbidity and mortality. There was no difference in overall survival (OS) among the 3 groups. Nearly 10 years have now elapsed since this report. Therefore, with the time of last follow-up in January 2009, we analyzed the long term outcomes of pts enrolled on the study. PFS was defined as the time between randomization and the occurrence of progressive disease or death due to any cause. Results: Of the 509 pts, 85% have now died; among pts on the F and C arms, 92% have progressed. We found that F treatment resulted in significantly longer PFS than did C (p < 0.001), with notable differences in PFS at 2, 3, and 4 years (Table). While the F and C arms had the same OS during the initial 5 years following randomization, our current analysis with longer follow-up shows that pts treated on the F arm had better survival than did those on the C arm during the ensuing years (Figure). The p-values for this difference are 0.04 (unadjusted for covariates) and 0.07 (covariate-adjusted). The emergence of improved survival following initial F treatment, appearing only after 5-6 years, is an unexpected and noteworthy finding. Reporting second malignancies was required on this study. There were 27 epithelial cancers reported (9 on F, 11 on C, 7 on F+C), involving colon, lung, breast, prostate, pancreas, liver, bladder and skin (6 squamous, 2 melanoma). Seven therapy-related myeloid neoplasms (t-MN) were reported; 6 were on F+C; 1 on F. Richter's transformation to non-Hodgkin lymphoma was reported in 34 pts; prolymphocytic leukemia occurred in 10; Hodgkin lymphoma in 6; myeloma in 2; hairy cell leukemia in 1. These cases were distributed with 18 on F, 18 on C, and 17 on F+C. Thus, the overall incidence of second malignancies reported was 17%. Conclusion: Initial treatment with F provides better long-term outcomes than initial treatment with C. Second malignancies are common, but the overall incidence is not increased on the F-containing treatment arms except for t-MN. Disclosures: No relevant conflicts of interest to declare.

Abstract Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis with a broad, non-specific clinical spectrum. Here, we retrospectively evaluated the clinical and pathologic characteristics, presence of the BRAF V600E mutation, treatment options and outcomes of Chinese patients diagnosed with ECD at our center. Methods Patients diagnosed with ECD between January 2010 and April 2015 at Peking Union Medical College Hospital were included for study. We evaluated baseline characteristics, reviewed histological material, and tested for the presence of the BRAF V600E mutation using immunohistochemistry and polymerase chain reaction (PCR). Results Sixteen patients were diagnosed with ECD. Median age at diagnosis was 47 years (range, 22-61 years). Median disease duration (from the first symptom to diagnosis) was 22.5 months (range, 3-100 months). The main sites of involvement included bone (93.8%), cardiovascular region (43.8%), skin (31.3%), central nervous system (25.0%), and ¡°hairy kidney¡± (25%). Thirteen patients displayed characteristic histological features, including foamy histiocyte infiltration of polymorphic granuloma and fibrosis or xanthogranulomatosis, with CD68-positive and CD1-¦Á- negative immunostaining. Three patients (designated 3, 5 and 10) displayed CD68-positive and CD1¦Á- negative histiocyte infiltration, but not the above histological characteristics, and were thus initially misdiagnosed as Rosai-Dorfman disease. All three cases were BRAFV600E mutation-positive, leading to revision of diagnosis as ECD. Diagnosis of ECD in each case was additionally supported by typical radiographic findings. The BRAF V600E mutation was detected in 68.8% patients using PCR and 50.0% patients with immunohistochemistry. Ten patients (62.5%) received IFN-¦Á as first-line treatment, 3 patients showed improvement, 3 remained stable, 3 were too early for evaluation and 1 died. Three patients (5, 10 and 11) underwent transsphenoidal pituitary lesion surgery but were not subjected to systemic treatment, owing to the absence of symptoms and disease activity post-surgery and remained stable after a median of 16 months (range, 6-30 months) from diagnosis. Thirteen patients (81.3%) were still alive at median follow-up of 14.5 months. Conclusion ECD remains a largely overlooked disease, and increased recognition by clinicians and pathologists is necessary for effective diagnosis and treatment. The presence of the BRAF V600E mutation may facilitate discrimination of ECD from other non-Langerhans cell histiocytoses. Table 1. Characteristics and treatment of 16 patients with ECD Patient Sex/ age, years Disease duration, mo Main sites of involvement BRAF IH BRAF V600E Therapy Vital Status OS£¬mo 1 M/33 5 B N/A - IFN-6 MIU 3/wk Alive 15 2 M/22 43 S, B - - IFN-3 MIU 3/wk Alive 11 3 M/25 18 B, LN, CNS - + Pred Dead 13 4 F/28 3 S, B + + None Alive 16 5 M/60 27 B, PIT + + Surgery Alive 15 6 F/61 5 B, H, LV, R£¬CNS, MS, S N/A + IFN-6 MIU 3/wk Dead 25 7 F/23 67 S, B, H, LV - - IFN-3 MIU 3/wk Alive 19 8 M/60 43 B, P, LV, R N/A + IFN-6 MIU 3/wk Alive 14 9 M/46 84 CNS, B + + IFN-6 MIU 3/wk Alive 22 10 F/51 7 PIT + + Surgery Alive 6 11 F/36 72 PIT, B + + Surgery Alive 30 12 M/55 100 B, S, CNS, PIT - + IFN-6 MIU 3/wk Alive 3 13 F/50 11 B, H N/A + IFN-6 MIU 3/wk Alive 5 14 F/46 8 B, LV, P + + IFN-6 MIU 3/wk Alive 1 15 M/52 30 B, LV, R, P£¬E - - IFN-6 MIU 3/wk Alive 1 16 M/47 4 B, LV, R, LN - - None Dead 36 Age is at diagnosis£»disease duration is from the first symptom to diagnosis IH, immunohisochemistry; B, long bones; LN, lymph nodes; LV, large vessels; H, heart; S, skin; CNS, central nervous system; MS, maxillary sinus; PIT, pituitary gland; R, retroperitoneal; P, pericardial effusion; E, Exophthalmos; MIU, million international units; N/A, not available Disclosures No relevant conflicts of interest to declare.

Viral diseases with oral manifestations are common in the practice of pedodontist, however, sometimes their diagnosis is complicated due to the similar clinical manifestations. A huge number of viruses are present in oral cavity, especially from Herpesviridae family, however, the most of them are asymptomatic. Cold, systemic diseases and stress provoke the activation of viruses with different clinical manifestations. Therefore, a dentist can be the first who diagnoses not only herpetic gingivostomatitis, but also other viral diseases. The aim of the article was to analyse the oral manifestations of viral diseases in children in order to optimize their diagnostics. This article analyses clinical cases and reviews of diseases in English in Google database from 2011 to May 2020 (and earlier publications) by Keywords: «herpetic gingivostomatitis», «recurrent aphthous stomatitis», «oral manifestations of infectious mononucleosis», «herpetic angina», «oral manifestations of cytomegalovirus infection», «recurrent herpetic gingivostomatitis», «oral manifestations of varicella virus», «oral manifestations of herpes zoster», «roseola infantum», «herpangina», «hand, foot and mouth disease», «oral manifestations of measles», «rubella», «oral manifestations of papillomavirus», and «oral manifestations of human immunodeficiency virus». Viruses which have oral manifestations were characterized by transmission. Mostly airborne viruses are represented by Herpesviridae family. The differential diagnosis of primary herpetic gingivostomatitis includes recurrent aphthous stomatitis which forms ulcers on non-keratinised oral mucosa without a vesicle phase. Recurrent herpetic infection doesn’t have difficulties in diagnostics, but could be complicated by erythema multiform with clear target lesions. Vesicles, erosions in oral cavity associated with vesicles on hear part of head help to distinguish chickenpox from herpetic infection. Compared to Herpes simplex virus infection, Herpes zoster has a longer duration, a more severe prodromal phase, unilateral vesicles and ulceration, with abrupt ending at the midline and postherpetic neuralgia. Roseola is characterized by small papules on skin and palate which appears when severe fever in prodromal period subsides and disappears after 1-2 days. Oral vesicles associated with foot and hand rush differentiate enterovirus stomatitis from chickenpox and roseola. The distribution of the lesions of herpangina (palate, tonsils) differentiates it from primary herpetic gingivostomatitis, which affects the gingivae. Comparing with roseola and rubella, measles has a bigger size of rush and specific oral localization on buccal mucosa. Mild fever and skin rush which appears on face and extensor surfaces of body and extremities help to distinguish rubella from measles and roseola. Viruses transmitted through biological liquids are represented in oral cavity by infectious mononucleosis and cytomegalovirus. The vesicles and ulcers on the tonsils and posterior pharynx in case of these infections can resemble herpetic stomatitis, but liver and spleen enlargement allows to exclude this diagnose; also cytomegalovirus erosions heal for long time. Cervical lymphoadenopathy differentiates them from herpetic angina. Laboratory diagnostics is based on detection of antibodies to virus or virus DNA in blood helps to make diagnosis of infectious mononucleosis and cytomegalovirus infections. Viruses transmitted through direct contact with mucosa and biological liquids represented by human papillomavirus (HPV) and human immunodeficiency virus (HIV). HPV in oral cavity represent by benign epithelial hyperplasia which might persist and transform to malignant. Therefore, histological examination plays important role in diagnostics of HPV. Oral manifestations such as candidiasis, herpes labialis, and aphthous stomatitis represent some of the first signs of HIV immunodeficiency. Oral lesions also associated with HIV in children are oral hairy leukoplakia, linear gingival erythema, necrotizing ulcerative gingivitis, and Kaposi’s sarcoma. Rapid necrotization and long-term healing of oral lesions help to suspect HIV and prescribe the blood test for the detection of antibodies to the virus. Oral mucosa is often the first to be affected by viral infections. A thorough anamnesis and examination is the key to accurate diagnostics of the most oral viral lesions and their adequate treatment. Biopsy, examination of antibodies to the virus in the blood or polymeraze-chain reaction to the virus in the bioptate or blood are performed in case of diagnostic difficulties. Laboratory methods had to use more widely for the diagnostics of recurrent or unclear lesions of the oral mucosa in children.

Abstract Few studies have compared treatment outcomes and disease complications between classical and variant hairy cell leukemia (HCL). We reviewed records of patients (pts) with HCL treated at Memorial Sloan Kettering Cancer Center between 1983 and 2013 and identified 331 pts. To reduce bias we limited analysis to the 183 pts who were reviewed and treated at MSKCC within 3 months of diagnosis (table 1). The median follow-up was 46.8 months. Median overall survival (OS) for the entire cohort was not reached and 5 and 10 year OS was 94% and 83% respectively. Median OS for classical and variant HCL was not reached in either group (Fig 1) while 5 and 10 year OS appeared equal. The time to next treatment (TNT) following initial therapy was longer for classical HCL (Fig 2). Pts with classical HCL were also more likely to achieve remission with first therapy and required fewer individual lines of therapy (Table 1). Cladribine was used first line in 122 pts and resulted in a median TNT of 138 months (97.1-NA), pentostatin was used in 9 pts and resulted in similar remission duration as cladribine with TNT of 81 months (80.5-NA) (p=0.82). 5 pts had abnormal cytogenetics at diagnosis and this did not influence OS when compared to the 62 pts who had a normal karyotype with estimated 5 year OS of 100% and 97%, respectively. 31 pts required treatment for disease relapse. The median time to 3rd therapy was not reached however 72% and 52% of all pts were estimated to require a 3rd treatment at 5 and 10 years, respectively. Cladribine was used to treat 1st relapse in 18 pts while 5 were treated with the combination of cladribine and rituximab. This resulted in a median TNT of 66.3 (37.2-NA) months in the cladribine group, median TNT was not reached for the combination group. We found that initial treatment of HCL with cladribine appeared to result in a longer disease remission when compared with the second treatment with a median TNT of 138 and 66 months respectively. 22 pts died during follow up, with 2 deaths due to HCL, 6 due to secondary malignancy, the remainder were unknown. 27 Secondary cancers were identified the most common were non-melanoma skin cancer (5), prostate cancer (5), melanoma (4) and other lymphoproliferative disorders (4). The most common reasons for needing retreatment varied depending on disease type with the recurrence of cytopenias accounting for 23/25 pts with classical HCL and only 1 with variant HCL. Symptomatic splenomegaly prompted re-treatment in 4/5 with variant and 3/25 classical HCL. B symptoms were uncommon occurring in 1 pt with classical and 1 with variant disease at relapse. The major complication of 1st therapy was febrile neutropenia necessitating admission for intravenous antibiotics, which occurred in 40/139 pts. There were no mortalities due to bacterial sepsis following 1st therapy. We conclude that OS of pts with HCL variant is equal to that of classical disease; however patients with classical HCL have a far longer duration of first remission and a greater chance of complete remission. Patients with variant HCL have different clinical features at relapse and appear to require more lines of therapy to maintain disease control. We found that responses to cladribine following first treatment appear longer than for second treatment. The combination of cladribine and rituximab may result in a longer second remission. We did not find a higher incidence of secondary malignancy in patients with variant HCL. Table 1. Comparison of patients with classical and variant HCL. Classical HCL (N=146) Variant HCL (N=10) Median age (range) 52 (27-84) 67 (39-78) P=0.005 Men (%) 114 (78%) 6 (60%) Median WBC at diagnosis 3.7x10^9/L 9.7x10^9/L CD25 expression 146/146 0/10 BRAF* (V600E mutated/ assessed) 3/6 1/2 Number needing therapy 109 10 Indication for re-treatment 25 5 Cytopenia 23/25 1/5 splenomegaly 3/25 4/25 Median OS Not reached Not reached 5 year OS 94% 100% 10 year OS 84% 67% TNT following 1st treatment (months) 120 20 P=0.002 CR to 1st therapy 87/109 5/10 Median number of therapies (range) 1 (0-7) 4 (2-7) Splenectomy 1 3 Secondary cancers 27 0 Deaths 15 1 *BRAF mutation was infrequently assessed as we analyzed patients up to 2013. Figure 1. OS for classical and variant HCL is equal despite the shorter remission duration and more frequent need for re-treatment in HCL variant. Figure 1. OS for classical and variant HCL is equal despite the shorter remission duration and more frequent need for re-treatment in HCL variant. Figure 2. Remission duration following first therapy is significantly longer in patients with classical than variant HCL. Figure 2. Remission duration following first therapy is significantly longer in patients with classical than variant HCL. Disclosures Park: Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy.

Burrows can provide refuge for both burrowing and non-burrowing species within harsh environments through protection from climatic extremes, water loss and predation. In Australia, however, despite having a rich diversity of burrowing mammals, little is known about the use of burrows by non-burrowing species. This study aimed to identify the extent of co-use of southern hairy-nosed wombat (Lasiorhinus latifrons) burrows on Wedge Island off the coast of South Australia. Burrow use was monitored using 34 motion-activated cameras placed outside wombat burrows between March and September 2015. Eleven species were found to use burrows, with six commensal species observed using burrows on numerous occasions. These included two mammal species (black-footed rock-wallaby, Petrogale lateralis pearsoni; brush-tailed bettong, Bettongia penicillata), three reptile species (peninsula dragon, Ctenophorus fionni; southern sand-skink, Liopholis multiscutata; White’s skink, Liopholis whitii), and one avian species (little penguin, Eudyptula minor). The most common species observed using burrows was the black-footed rock-wallaby, which was recorded using burrows 1795 times. Observations of wombats using burrows were made 1674 times. The prevalent use of burrows on Wedge Island by species other than wombats is an observation with potentially important and broad ecological, conservation, and management implications across Australia’s arid and semiarid zones.

Abstract Introduction Response to treatment for multiple myeloma (MM) patients is variable and often unpredictable, which may be attributed to the heterogeneous genomic landscape of the disease. However, the effect of recurrent molecular alterations on drug response is unclear. To address this, we systematically profiled 50 samples from 43 patients to assess ex vivo sensitivity to 308 anti-cancer drugs including standard of care and investigational drugs, with results correlated to genomic alterations. Our results reveal novel insights about patient stratification, therapies for high-risk (HR) patients, signaling pathway aberrations and ex-vivo-in-vivo correlation. Methods Bone marrow (BM) aspirates (n=50) were collected from MM patients (newly diagnosed n=17; relapsed/refractory n=33) and healthy individuals (n=8). CD138+ plasma cells were enriched by Ficoll separation followed by immunomagnetic bead selection. Cells were screened against 308 oncology drugs tested in a 10,000-fold concentration range. Drug sensitivity scores were calculated based on the normalized area under the dose response curve (Yadav et al, Sci Reports, 2014). MM selective responses were determined by comparing data from MM patients with those of healthy BM cells. Clustering of drug sensitivity profiles was performed using unsupervised hierarchical ward-linkage clustering with Spearman and Manhattan distance measures of drug and sample profiles. Somatic alterations were identified by exome sequencing of DNA from CD138+ cells and skin biopsies from each patient, while cytogenetics were determined by fluorescence in situ hybridization. Results Comparison of the ex vivo chemosensitive profiles of plasma cells resulted in stratification of patients into four distinct subgroups that were highly sensitive (Group I), sensitive (Group II), resistant (Group III) or highly resistant (Group IV) to the panel of drugs tested. Many of the drug responses were specific for CD138+ cells with little effect on CD138- cells from the same patient or healthy BM controls. We generated a drug activity profile for the individual drugs correlating sensitivity to recurrent alterations including mutations to KRAS, DIS3, NRAS, TP53, FAM46C, and cytogenetic alterations del(17p), t(4;14), t(14;16), t(11;14), t(14;20), +1q and -13. Cells from HR patients with del(17p) exhibited the most resistant profiles (enriched in Groups III and IV), but were sensitive to some drugs including HDAC and BCL2 inhibitors. Samples from patients with t(4;14) were primarily in Group II and very sensitive to IMiDs, proteasome inhibitors and several targeted drugs. Along with known recurrently mutated genes in myeloma, somatic mutations were identified in genes involved in several critical signaling pathways including DNA damage response, IGF1R-PI3K-AKT, MAPK, glucocorticoid receptor signaling and NF-κB signaling pathways. The predicted impact of these mutations on the activity of the pathways often corresponded to the drug response. For example, all samples bearing NF1 (DSS=21±7.9) and 67% with NRAS (DSS=15±4.35) mutations showed higher sensitivity to MEK inhibitors compared to healthy controls (DSS=5±.21). However, sensitivity was less predictable for KRAS mutants with modest response only in 47% samples (DSS=7±2.14) . One sample bearing the activating V600E mutation to BRAF showed no sensitivity to vemurafenib, which otherwise has good activity towards V600E mutated melanoma and hairy-cell leukemia. Comparison of the chemosensitive subgroups with survival showed patients in Groups I and IV had high relapse rate and poor overall survival. The ex vivo drug sensitivity results were used to decide treatment for three HR patients with results showing good ex vivo -in vivo correlation. Summary Our initial results suggest that ex vivo drug testing and molecular profiling of MM patients aids stratification. Grouping of patients based on their ex vivo chemosensitive profile proved extremely informative to predict clinical phenotype and identify responders from non-responders. While some molecular markers could be used to predict drug response, others were less predictive. Nevertheless, ex vivo drug testing identified active drugs, particularly for HR and relapsed/refractory patients, and is a powerful method to determine treatment for this group of patients. Disclosures Silvennoinen: Genzyme: Honoraria; Sanofi: Honoraria; Janssen: Research Funding; Celgene: Research Funding; Research Committee of the Kuopio University Hospital Catchment Area for State Research Funding, project 5101424, Kuopio, Finland: Research Funding; Amgen: Consultancy, Honoraria. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Heckman:Celgene: Honoraria, Research Funding.

Touch is perceived most pleasant when delivered at velocities known to optimally activate the C-Tactile afferent system. At the group level, pleasantness ratings of touch delivered at velocities in the range between 0.3 and 30 cm/s follows an inverted-U shape curve, with maximum pleasantness between 1 and 10 cm/s. However, the prevalence, reliability, and stability of this function at the individual level and across skin types based on hair density remains unknown. Here, we tested a range of seven velocities (0.3, 1, 3, 6, 9, 18, 27 cm/s) delivered with a soft brush, on both hairy (forearm and dorsal hand) and non-hairy skin (palm) in 123 participants. Our results suggest that the relationship between pleasantness and velocity of touch is significantly best described by a negative quadratic model at the individual level in the majority of participants both on hairy (67.1%) and non-hairy (62.6%) skin, a larger extent than previously reported. Higher interoceptive accuracy and self-reported depression were related to a better fit of the quadratic model and to the steepness of the curve, respectively. The prevalence of the quadratic model at the individual level was stable across body sites (62.6%, Experiment 1), across two experimental sessions (73-78%, Experiment 2), and regardless of the number of repetitions of each velocity (Experiment 3). Thus, the individual perception of tactile pleasantness follows a characteristic velocity-dependent function across skin types and shows trait characteristics. Future studies can investigate further the possibility to use affective touch as a behavioural biomarker for mental health disorders.

AbstractWe developed a non-destructive and rapid whole-mount bone staining method for small fish, Xenopus laevis, and rodent fetuses (RAP-B). RAP-B does not require skin or soft tissue removal. However, RAP-B requires hair removal from hairy animals, such as adult mice and rats. In the present study, we investigated hair removal chemical treatments that did not result in soft tissue destruction. The hair removal effectiveness was investigated using a calcium mercaptoacetate or sodium mercaptoacetate solution on skin fragments obtained from the back of adult mice. A mixture of 2% sodium mercaptoacetate in 3% potassium hydroxide was found to be the most effective in complete hair removal from the skin. Using this hair removal treatment as a pretreatment for RAP-B, the preparation of fast-acting artifact-free whole-mount bone staining was possible without skin and soft tissue removal (RAP-B/HR). We performed a seamless observation from a low magnification wide-view to a high magnification without artifactacting artifacts using fluorescence zoom microscopy. Therefore, the combination of RAP-B/HR and fluorescent zoom microscopy is a novel platform for three-dimensional, wide-field, high-resolution pathological anatomical analysis.

BACKGROUND: Endothelial dysfunction and microvascular disturbances are suggested to play a key role in higher morbidity and worse prognosis in patients with COVID-19 and cardiometabolic diseases. OBJECTIVE: Study was aimed to establish relationships between the skin microcirculation parameters and various clinical and laboratory indicators. METHODS: The study included 18 patients with moderate disease according to WHO criteria. Skin microcirculation measurements were performed by laser Doppler flowmetry using a heating test on the hairy skin of the right forearm. RESULTS: Baseline perfusion only correlated with C-reactive protein (Rs = 0.5, p = 0.034). Microcirculation indices characterising the development of hyperaemia during the first minute of heating (LTH1 and AUC60) showed significant correlations (Rs from 0.48 to 0.67, p < 0.05) with indices of general blood analysis and blood coagulation (fibrinogen, D-dimer, haemoglobin, erythrocyte count and haematocrit). Indexes characterising the dynamics of hyperaemia development over longer time intervals showed correlation with the glomerular filtration rate (Rs = 0.6, p = 0.009). CONCLUSION: Known COVID-19 risk factors (haemorheological parameters, age) are correlated with the microvascular reactivity to heating in patients with COVID 19. We suggest that, prospectively, the method of laser Doppler flowmetry could be used for non-invasive instrumental assessment of microcirculatory disorders in patients with COVID-19.

Aim: To present the first report of a large congenital melanocytic nevus with satellite nevi in an apparently healthy child from Sokoto, North-Western Nigeria. Presentation of Case: A three year old girl was brought to the paediatric out-patient clinic of Paediatrics department of Usmanu Danfodiyo University Teaching Hospital (UDUTH) Sokoto with complaints of darkened skin colour on the left side of the face and scalp, the left arm, lower back, buttocks, and thighs, and excessive hair growth over the same side of the face since birth. There were no neurological symptoms Physical examination findings revealed a well-nourished, not ill looking child. She had a hyper pigmented patch on the left side of the face extending from the lower jaw to the scalp, measuring 21 cm in its longest length, with hypertrichosis on the same site, and two distinct, firm, painless nodular lesions on the left temporal region measuring 3 mm and 4mm respectively. On the lower one-third of the left arm was a hairy, velvety area of hyperpigmentation measuring 2X3 cm in diameter. Other affected sites were the lower back, the gluteal region and the thighs. Her neurologic and other systemic examinations were normal. A diagnosis of large congenital facial melanocytic hairy nevus with multiple satellite nevi was made. Discussion: Congenital melanocytic nevi are benign proliferations of melanocytic cells said to be present at birth or in the first two years of life. Large lesions are rare, they measure 20 cm or more and are said to occur more commonly on the trunk and thighs. The exact pathogenesis of congenital melanocytic nevi is yet, unknown. It is thought to occur as a result of a morphological error in the neuroectoderm during embryogenesis. Treatment of patients with large congenital melanocytic nevus may include surgical or non-surgical procedures as well as psychological interventions. Large lesions, multiple satellite lesions or paravertebral and axial locations are sometimes associated with the risk of neurological complications and malignant transformation. Conclusion: Large congenital melanocytic nevi are uncommon skin lesions that can occur in apparently healthy children. Individualization of the patients with regards to treatment options and long term monitoring are imperative.

Objective: Alopecia aretea is associated with an increase in free radicals causing damage to hair follicles. Superoxide dismutase (SOD) with sufficient penetration through hair follicles, can prevent their death by its strong antioxidant effects. SOD with high molecular weight underwent limitation in follicular delivery. The aim of this study was the improvement of SOD localization into hair follicles. Methods: SOD-loaded niosomes were prepared by thin layer hydration method and were used as a vehicle for delivery to hair follicles through guinea pig skin and the synthetic membrane. Particle size, entrapment efficiency, drug release, and permeability parameters through hairly and non-hairly pig skin compared with a synthetic membrane were evaluated. Results: Niosomes demonstrated 152-325 nm particle size and the SOD burst and sustained release from niosomes were mainly controlled by diffusion and dissolution phenomena. SOD was protected against degradation by niosomes and after six months, enzyme content and activity decreased less than 5%. In comparison with free SOD, niosomes increased SOD affinity to penetration through follicles by interaction with sebum. Likewise, niosome's characters such as type of surfactant, solid lipid/liquid lipid ratio played critical roles on SOD deposition on hair follicles. Conclusion: Synthetic membrane and hairy guinea pig skin demonstrated similar barrier property against free-SOD thereby implying that free SOD does not interact with guinea pig sebum. Niosomes can introduce a suitable carrier for SOD localization into the hair follicles.

1.1. Purpose: Making the surgeons aware of the significance of penile chordee, need of optimal straightening of penile shaft (orthoplasty) and appropriate use of well-developed prepucial hood for re-construction of an ideal neo-urethral plate and a near normal neo-urethra by its tubularization and finally re-enforcement of the neo-urethra by prepucial dartos fascial flap to minimize post-operative morbidities. 1.2. Aims and Objectives: Exact assessment of characteristics of chordee by artificial erection of penis, achieving acceptable orthoplasty before commencing upon final neo-urethroplasty and making maximum use of prepucial hood skin in (i) formation of neo-urethral plate and to have an ideal near normal non-hairy and resistance free neo-urethra and or (ii) designing and harvesting various types of skin and or water proofing flaps because of its axial vascularity. 1.3. Material and Methods: Material related to the penile chordee, orthoplasty and appropriate utilization of prepucial hood was collected from the photographic record of hypospadias patients who attended “Hypospadias and VVFs Clinic” between 2004- 2016. Based upon the characteristics of penile shaft and its chordee, various surgical techniques used for acceptable correction of the chordee (orthoplasty) were circum-coronal degloving of penile shaft up to its root, excision of chordee, Dorsal Tunica Albuginea Plication (DTAP), Double Dorsal Tunica Albuginea Plication (DDTAP), Ventral Tunica Albuginea Plication (VTAP), Inner Prepucial Full Thickness Skin Graft (IPFTSG), outer Prepucial Full Thickness Skin Graft (OPFTSG), Dermal Graft (DG), Tunica Vag inalis Graft (TVG) and Tunica Vaginalis Flap (TVF). Accidental breach in Tunica Albuginea (TA) was identified and repaired in water tight fashion. Special care was taken to prevent injury to Dorsal Neuro-Vascular Bundle (DNVB). Hypospadiacs with Bala- clinicsofsurgery.com 2 nitis Xerotica Obliterans (BXO) were excluded from study. 1.4. Observations: Neo-urethroplasty in an uncorrected chordee is deemed to be associated with subsequent anatomical, functional and aesthetic problems, thereby warranting re-do orthoplasty and neo-urethroplasty including total dismantling of the previous surgical repair. The presence of fully developed prepucial hood proved to be a boon to the surgeon in repairing both the fresh as well as re-do cases of neo-urethroplasty and also in harvesting water-proofing flaps to decrease post-operative morbidities. Presence of Undescended Testis (UDT), Inguinal Hernia (IH) and Ano-Rectal Malformation (ARM) are to be corrected on priority.

Abstract In this study, we sought to enhance the cutting properties of the various blades by coating them with Zr- and Fe-based thin film metallic glasses (TFMGs) to a thickness of 234–255 nm via sputter deposition. In oil-repellency/sliding tests on kitchen blades, the sliding angle and friction forces were as follows: bare blades (31.6°) and (35 µN), Ti-coated blades (20.3°) and (23.7 µN), and Z-TFMG coated blades (16.2°) and (19.2 µN). Comparisons were conducted with bare blades and those with a Teflon coating (a low-friction material commonly used for the coating of microtome blades). We also found that the Teflon coating reduced the cutting forces of an uncoated microtome blade by ~80%, whereas the proposed Z-TFMG achieved a ~51% reduction. The Z-TFMG presented no indications of delamination after being used 30 times for cutting; however, the Teflon coating proved highly susceptible to peeling and the bare blade was affected by surface staining. These results demonstrate the efficacy of the TFMG coating in terms of low friction, non-stick performance, and substrate adhesion. The performance of Z-TFMG and F-TFMG was also evaluated in split-thickness skin graft surgery using dermatome blades aimed at elucidating the influence of TFMG coatings on the healing of surgical incisions. When tested repeatedly on hairless skin, the surface roughness of uncoated blades increased by approximately 70%, whereas the surface roughness of TFMG-coated blades increases by only 8.6%. In the presence of hair, the surface roughness of uncoated blades increased by approximately ~108%, whereas the surface roughness of TFMG-coated blades increases by only ~23%. By Day 7, the wounds produced using TFMG-coated blades were noticeably smaller than those produced using uncoated blades, and these effects were particularly evident in hairy samples. This is a clear demonstration of the efficacy of TFMG surface coatings in preserving the cutting quality of surgical instruments.

Pilonidal disease is a common anorectal problem that typically affects young people. Pilonidal sinus describes a hair-filled cavity in the subcutaneous fat of the post sacral intergluteal region known as the natal cleft. the pilonidal sinus, presented with boil with slight seropurulent foul discharge from post anal region in the natal cleft. The most commonly used surgical techniques for pilonidal sinus includes excision with primary closure and excision with reconstructive flap with their own limitation(PNS).In Ayurveda acharya Sushruta has considered it under shalyaj nadi vrana ( sinus or fistula due to foreign body). Sushruta mentioned the chedana as well as ksharkarma in the management of Nadivrana. Hence the study concluded that excision & ksharkarma in pilonidal sinus is one of the potential treatment option to avoid recurrence. Nowadays Pilonidal Sinus (PNS) is becoming common disease in between 20-50 years of age, in men and mostly dense hairy persons. Commonly it occurs midline over the coccyx. It results in purulent discharge, pain and discomfort. In Ayurvedic practice, there are many surgeons who are practicing classical Ksharasutra management to treat PNS, which is very effective but there are some problems using classical Kshara in the management of PNS, such as discomfort, burning sensation, itching and irritation due to Snuhi-ksheera. So patients can do their daily routine work without any pain or discomfort. In Ayurveda, Shastra and Anushstra Karma are described in detail. Kshara is best among Shastra and Anushastras. Two types of Kshara are there - Paneeya and Pratisarneeya. Pratisarneeya Kshara is of three types- Mridu, Madhyama and Teekshana. Kshara Karma include - Pratisarneeya Kshara application, Kshara Sutra therapy and Kshara Varti. Pratisaraniya Kshara is mainly used in wound management, various anorectal disorders such as Arsha (Haemorrhoids), kushtha, Arbuda, Dushta Nadivrana, Guda Bhramsha (Rectal prolapse). Kshara is a caustic material. It causes chemical burn on the area where it is applied. It helps in sloughing of necrosed and infected tissues. Kshara Sutra therapy is used specially in Bhagandara (Fistula in Ano), Nadivrana (Pilonidal sinus) and various benign growth of skin such as papilloma, warts etc. Kshara Varti is used in chronic non healing wounds for debridement and in sinuses or fistula in ano. Ksahra Karma has been very much effective non surgical means in the management of various disorders especially in anorectal disorders.

Background: Squamous cell carcinoma is a malignant neoplasm that originates from the keratinized stratified squamous epithelium and predominantly affect light-skinned animals. In dogs, breeds such as American Staffordshire Terriers, white or speckled Bull Terriers, and Beagles have a higher predisposition. Squamous cell carcinoma presents in the skin, at slightly pigmented or hairy sites, especially in digits, but also may occur in the nasal planum, oral mucosa, and rarely, in the eye. Considering that few reports have been published on eye neoplasms, the aim of this paper is to describe a dog with a lesion in the third eyelid of his right eye which was diagnosticated with squamous cell carcinoma. Case: A 10-year-old male American Staffordshire dog was admitted to the Veterinary Medical Teaching Hospital of the Veterinary Medicine and Zootechnics College, Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Brazil with injury to the right eye. During the physical examination, there was also a non-adhered lump near the foreskin, measuring 1.5 cm in diameter. In addition, there was another lump in the third eyelid of the right eye, approximately 3 mm in diameter. Cytology of the dermal nodule was performed by fine-needle aspiration cytology; however, the sample was insufficient for cytological evaluation. Therefore, the animal was placed under general anesthesia for skin lump excision and for fine-needle aspiration cytology of the third eyelid nodule. The histopathological exam revealed high cellularity of epithelial cells, intense anisocytosis and pleomorphism, cytoplasmic basophilia and vacuolation, multiple evident nucleoli, and anisocariosis and coarse chromatin. These finds were compatible with squamous cell carcinoma, which was the same result suggested by fine-needle aspiration cytology of the third eyelid sample. Based on these results, the dog underwent a surgical procedure for enucleation and subsequent histopathological evaluation of the nodule in the third eyelid, which confirmed the squamous cell carcinoma diagnosis.Discussion: Squamous cell carcinoma is an extremely aggressive tumor with low metastatic potential, characterized by invasion of the dermis by proliferation of malignant epithelial cells from the prickly layer. It is most common in elderly animals, and American Staffordshires are among the breeds that are predisposed to develop this tumor. The clinical presentation is highly variable, depending on the tissue involved. In this case, the dermal nodule was an elevated area on the skin and the third eyelid nodule resembled an ulcerative mass. Cytological examination from the lesion located on the third eyelid, showed malignancies cytoplasmic changes frequently found in carcinomas such as anisocytosis, cytoplasmic basophilia, and cell pleomorphism. In addition, nuclear changes had also occurred, such as crass chromatin, multiple evident nucleoli, and multinucleated cells. A presumptive diagnosis was made based on cytology and was confirmed after biopsy and histopathological examination. Because it is uncommon in dogs, squamous cell carcinoma of the third eyelid may be misdiagnosed, delaying correct treatment, and accelerating the development of the tumor. Currently, various therapeutic approaches are available, such as surgical excision, electrosurgery, cryosurgery, radiation, and hyperthermia. The choice of treatment depends on the location and stage of the lesions. Surgical treatment should be aimed at removing sufficient tissue to leave surgical margins free of neoplastic cells.

Abstract The formation of hair follicles, a landmark of mammals, requires complex mesenchymal–epithelial interactions and it is commonly believed that embryonic epidermal cells are the only cells that can respond to hair follicle morphogenetic signals in vivo. Here, we demonstrate that epithelial stem cells of non-skin origin (e.g. that of cornea, oesophagus, vagina, bladder, prostate) that express the transcription factor Tp63, a master gene for the development of epidermis and its appendages, can respond to skin morphogenetic signals. When exposed to a newborn skin microenvironment, these cells express hair-follicle lineage markers and contribute to hair follicles, sebaceous glands and/or epidermis renewal. Our results demonstrate that lineage restriction is not immutable and support the notion that all Tp63-expressing epithelial stem cells, independently of their embryonic origin, have latent skin competence explaining why aberrant hair follicles or sebaceous glands are sometimes observed in non-skin tissues (e.g. in cornea, vagina or thymus).

Introduction In a 2019 report for the International Journal of Communication, Baym et al. positioned distributed blockchain ledger technology, and what would subsequently be referred to as Web3, as a convening technology. Riffing off Barnett, a convening technology “initiates and serves as the focus of a conversation that can address issues far beyond what it may ultimately be able to address itself” (403). The case studies for the Baym et al. research—early, aspirant projects applying the blockchain concept to music publishing and distribution—are described in the piece as speculations or provocations concerning music’s commercial and social future. What is convened in this era (pre-2017 blockchain music discourse and practice) is the potential for change: a type of widespread, broadly discussed, reimagination of the 21st-century music industries, productive precisely because near-future applications suggest the realisation of what Baym et al. call dreams. In this article, we aim to examine the Web3 music field as it lies some years later. Taking the latter half of 2021 as our subject, we present a survey of where music then resided within Web3, focussing on how the dreams of Baym et al. have morphed and evolved, and materialised and declined, in the intervening years. By investigating the discourse and functionality of 2021’s current crop of music NFTs—just one thread of music Web3’s far-reaching aspiration, but a potent and accessible manifestation nonetheless—we can make a detailed analysis of concept-led application. Volatility remains throughout the broader sector, and all of the projects listed here could be read as conditionally short-term and untested, but what they represent is a series of clearly evolved case studies of the dream, rich precisely because of what is assumed and disregarded. WTF Is an NFT? Non-fungible tokens inscribe indelible, unique ledger entries on a blockchain, detailing ownership of, or rights associated with, assets that exist off-chain. Many NFTs take the form of an ERC-721 smart-contract that functions as an indivisible token on the Ethereum blockchain. Although all ERC-721 tokens are NFTs, the inverse is not true. Similar standards exist on other blockchains, and bridges allow these tokens to be created on alternative networks such as Polygon, Solana, WAX, Cardano and Tezos. The creation (minting) and transfer of ownership on the Ethereum network—by far the dominant chain—comes with a significant and volatile transaction cost, by way of gas fees. Thus, even a “free” transaction on the main NFT network requires a currency and time investment that far outweighs the everyday routines of fiat exchange. On a technical level, the original proposal for the ERC-721 standard refers to NFTs as deeds intended to represent ownership of digital and physical assets like houses, virtual collectibles, and negative value assets such as loans (Entriken et al.). The details of these assets can be encoded as metadata, such as the name and description of the asset including a URI that typically points to either a file somewhere on the Internet or a file hosted via IPFS, a decentralised peer-to-peer hosting network. As noted in the standard, while the data inscribed on-chain are immutable, the asset being referred to is not. Similarly, while each NFT is unique, multiple NFTs could, in theory, point to a single asset. In this respect ERC-721 tokens are different from cryptocurrencies and other tokens like stable-coins in that their value is often contingent on their accurate and ongoing association with assets outside of the blockchain on which they are traded. Further complicating matters, it is often unclear if and how NFTs confer ownership of digital assets with respect to legislative or common law. NFTs rarely include any information relating to licencing or rights transfer, and high-profile NFTs such as Bored Ape Yacht Club appear to be governed by licencing terms held off-chain (Bored Ape Yacht Club). Finally, while it is possible to inscribe any kind of data, including audio, into an NFT, the ERC-721 standard and the underpinning blockchains were not designed to host multimedia content. At the time of writing, storing even a low-bandwidth stereo audio file on the ethereum network appears cost-prohibitive. This presents a challenge for how music NFTs distinguish themselves in a marketplace dominated by visual works. The following sections of this article are divided into what we consider to be the general use cases for NFTs within music in 2021. We’ve designated three overlapping cases: audience investment, music ownership, and audience and business services. Audience Investment Significant discourse around NFTs focusses on digital collectibles and artwork that are conceptually, but not functionally, unique. Huge amounts of money have changed hands for specific—often celebrity brand-led—creations, resulting in media cycles of hype and derision. The high value of these NFTs has been variously ascribed to their high novelty value, scarcity, the adoption of NFTs as speculative assets by investors, and the lack of regulatory oversight allowing for price inflation via practices such as wash-trading (Madeline; Das et al.; Cong et al.; Le Pennec, Fielder, and Ante; Fazil, Owfi, and Taesiri). We see here the initial traditional split of discourse around cultural activity within a new medium: dual narratives of utopianism and dystopianism. Regardless of the discursive frame, activity has grown steadily since stories reporting the failure of Blockchain to deliver on its hype began appearing in 2017 (Ellul). Early coverage around blockchain, music, and NFTs echoes this capacity to leverage artificial scarcity via the creation of unique digital assets (cf Heap; Tomaino). As NFTs have developed, this discourse has become more nuanced, arguing that creators are now able to exploit both ownership and abundance. However, for the most part, music NFTs have essentially adopted the form of digital artworks and collectibles in editions ranging from 1:1 or 1:1000+. Grimes’s February 2021 Mars NFT pointed to a 32-second rotating animation of a sword-wielding cherubim above the planet Mars, accompanied by a musical cue (Grimes). Mars sold 388 NFTs for a reported fixed price of $7.5k each, grossing $2,910,000 at time of minting. By contrast, electronic artists Steve Aoki and Don Diablo have both released 1:1 NFT editions that have been auctioned via Sotheby’s, Superrare, and Nifty Gateway. Interestingly, these works have been bundled with physical goods; Diablo’s Destination Hexagonia, which sold for 600 Eth or approximately US$1.2 million at the time of sale, proffered ownership of a bespoke one-hour film hosted online, along with “a unique hand-crafted box, which includes a hard drive that contains the only copy of the high-quality file of the film” (Diablo). Aoki’s Hairy was much less elaborate but still promised to provide the winner of the $888,888 auction with a copy of the 35-second video of a fur-covered face shaking in time to downbeat electronica as an Infinite Objects video print (Aoki). In the first half of 2021, similar projects from high-profile artists including Deadmau5, The Weekend, Snoop Dogg, Eminem, Blondie, and 3Lau have generated an extraordinary amount of money leading to a significant, and understandable, appetite from musicians wanting to engage in this marketplace. Many of these artists and the platforms that have enabled their sales have lauded the potential for NFTs to address an alleged poor remuneration of artists from streaming and/or bypassing “industry middlemen” (cf. Sounds.xyz); the millions of dollars generated by sales of these NFTs presents a compelling case for exploring these new markets irrespective of risk and volatility. However, other artists have expressed reservations and/or received pushback on entry into the NFT marketplace due to concerns over the environmental impact of NFTs; volatility; and a perception of NFT markets as Ponzi schemes (Poleg), insecure (Goodin), exploitative (Purtill), or scammy (Dash). As of late 2021, increased reportage began to highlight unauthorised or fraudulent NFT minting (cf. TFL; Stephen), including in music (Newstead). However, the number of contested NFTs remains marginal in comparison to the volume of exchange that occurs in the space daily. OpenSea alone oversaw over US$2.5 billion worth of transactions per month. For the most part, online NFT marketplaces like OpenSea and Solanart oversee the exchange of products on terms not dissimilar to other large online retailers; the space is still resolutely emergent and there is much debate about what products, including recently delisted pro-Nazi and Alt-Right-related NFTs, are socially and commercially acceptable (cf. Pearson; Redman). Further, there are signs this trend may impact on both the willingness and capacity of rightsholders to engage with NFTs, particularly where official offerings are competing with extant fraudulent or illegitimate ones. Despite this, at the time of writing the NFT market as a whole does not appear prone to this type of obstruction. What remains complicated is the contested relationship between NFTs, copyrights, and ownership of the assets they represent. This is further complicated by tension between the claims of blockchain’s independence from existing regulatory structures, and the actual legal recourse available to music rights holders. Music Rights and Ownership Baym et al. note that addressing the problems of rights management and metadata is one of the important discussions around music convened by early blockchain projects. While they posit that “our point is not whether blockchain can or can’t fix the problems the music industries face” (403), for some professionals, the blockchain’s promise of eliminating the need for trust seemed to provide an ideal solution to a widely acknowledged business-to-business problem: one of poor metadata leading to unclaimed royalties accumulating in “black boxes”, particularly in the case of misattributed mechanical royalties in the USA (Rethink Music Initiative). As outlined in their influential institutional research paper (partnered with music rights disruptor Kobalt), the Rethink Music Initiative implied that incumbent intermediaries were benefiting from this opacity, incentivising them to avoid transparency and a centralised rights management database. This frame provides a key example of one politicised version of “fairness”, directly challenging the interest of entrenched powers and status quo systems. Also present in the space is a more pragmatic approach which sees problems of metadata and rights flows as the result of human error which can be remedied with the proper technological intervention. O’Dair and Beaven argue that blockchain presents an opportunity to eliminate the need for trust which has hampered efforts to create a global standard database of rights ownership, while music business researcher Opal Gough offers a more sober overview of how decentralised ledgers can streamline processes, remove inefficiencies, and improve cash flow, without relying on the moral angle of powerful incumbents holding on to control accounts and hindering progress. In the intervening two years, this discourse has shifted from transparency (cf. Taghdiri) to a practical narrative of reducing system friction and solving problems on the one hand—embodied by Paperchain, see Carnevali —and ethical claims reliant on the concept of fairness on the other—exemplified by Resonate—but with, so far, limited widespread impact. The notion that the need for b2b collaboration on royalty flows can be successfully bypassed through a “trustless” blockchain is currently being tested. While these earlier projects were attempts to either circumvent or fix problems facing the traditional rights holders, with the advent of the NFT in particular, novel ownership structures have reconfigured the concept of a rights holder. NFTs promise fans an opportunity to not just own a personal copy of a recording or even a digitally unique version, but to share in the ownership of the actual property rights, a role previously reserved for record labels and music publishers. New NFT models have only recently launched which offer fans a share of IP revenue. “Collectors can buy royalty ownership in songs directly from their favorite artists in the form of tokens” through the service Royal. Services such as Royal and Vezt represent potentially massive cultural shifts in the traditional separation between consumers and investors; they also present possible new headaches and adventures for accountants and legal teams. The issues noted by Baym et al. are still present, and the range of new entrants into this space risks the proliferation, rather than consolidation, of metadata standards and a need to put money into multiple blockchain ecosystems. As noted in RMIT’s blockchain report, missing royalty payments … would suggest the answer to “does it need a blockchain?” is yes (although further research is needed). However, it is not clear that the blockchain economy will progress beyond the margins through natural market forces. Some level of industry coordination may still be required. (18) Beyond the initial questions of whether system friction can be eased and standards generated without industry cooperation lie deeper philosophical issues of what will happen when fans are directly incentivised to promote recordings and artist brands as financial investors. With regard to royalty distribution, the exact role that NFTs would play in the ownership and exploitation of song IP remains conceptual rather than concrete. Even the emergent use cases are suggestive and experimental, often leaning heavily on off-chain terms, goodwill and the unknown role of existing legal infrastructure. Audience and Business Services Aside from the more high-profile NFT cases which focus on the digital object as an artwork providing a source of value, other systemic uses of NFTs are emerging. Both audience and business services are—to varying degrees—explorations of the utility of NFTs as a community token: i.e. digital commodities that have a market value, but also unlock ancillary community interaction. The music industries have a longstanding relationship with the sale of exclusivity and access tailored to experiential products. Historically, one of music’s most profitable commodities—the concert ticket—contains very little intrinsic value, but unlocks a hugely desirable extrinsic experience. As such, NFTs have already found adoption as tools of music exclusivity; as gateways into fan experiences, digital communities, live events ticketing and closed distribution. One case study incorporating almost all of these threads is the Deathbats club by American heavy metal band Avenged Sevenfold. Conceived of as the “ultimate fan club”, Deathbats is, according to the band’s singer M. Shadows, “every single thing that [fans] want from us, which is our time, our energy” (Chan). At the time of writing, the Deathbats NFT had experienced expected volatility, but maintained a 30-day average sale price well above launch price. A second affordance provided by music NFTs’ ability to tokenise community is the application of this to music businesses in the form of music DAOs: decentralised autonomous organisations. DAOs and NFTs have so far intersected in a number of ways. DAOs function as digital entities that are owned by their members. They utilise smart contracts to record protocols, votes, and transactions on the blockchain. Bitcoin and Ethereum are often considered the first DAOs of note, serving as board-less venture capital funds, also known as treasuries, that cannot be accessed without the consensus of their members. More recently, DAOs have been co-opted by online communities of shared interests, who work towards an agreed goal, and operate without the need for leadership. Often, access to DAO membership is tokenised, and the more tokens a member has, the more voting rights they possess. All proposals must pass before members, and have been voted for by the majority in order to be enacted, though voting systems differ between DAOs. Proposals must also comply with the DAO’s regulations and protocols. DAOs typically gather in online spaces such as Discord and Zoom, and utilise messaging services such as Telegram. Decentralised apps (dapps) have been developed to facilitate DAO activities such as voting systems and treasury management. Collective ownership of digital assets (in the form of NFTs) has become commonplace within DAOs. Flamingo DAO and PleasrDAO are two well-established and influential examples. The “crypto-backed social club” Friends with Benefits (membership costs between $5,000 and $10,000) serves as a “music discovery platform, an online publication, a startup incubator and a kind of Bloomberg terminal for crypto investors” (Gottsegen), and is now hosting its own curated NFT art platform with work by the likes of Pussy Riot. Musical and cross-disciplinary artists and communities are also exploring the potential of DAOs to empower, activate, and incentivise their communities as an extension of, or in addition to, their adoption and exploration of NFTs. In collaboration with Never Before Heard Sounds, electronic artist and musical pioneer Holly Herndon is exploring ideological questions raised by the growing intelligence of AI to create digital likeness and cloning through voice models. Holly+ is a custom voice instrument that allows users to process pre-existing polyphonic audio through a deep neural network trained by recordings of Holly Herndon’s voice. The output is audio-processed through Holly Herndon’s distinct vocal sound. Users can submit their resulting audio to the Holly+ DAO, to whom she has distributed ownership of her digital likeness. DAO token-holders steward which audio is minted and certified as an NFT, ensuring quality control and only good use of her digital likeness. DAO token-holders are entitled to a percentage of profit from resales in perpetuity, thereby incentivising informed and active stewardship of her digital likeness (Herndon). Another example is LA-based label Leaving Records, which has created GENRE DAO to explore and experiment with new levels of ownership and empowerment for their pre-existing community of artists, friends, and supporters. They have created a community token—$GENRE—for which they intend a number of uses, such as “a symbol of equitable growth, a badge of solidarity, a governance token, currency to buy NFTs, or as a utility to unlock token-gated communities” (Leaving Records). Taken as a whole, the spectrum of affordances and use cases presented by music NFTs can be viewed as a build-up of interest and capital around the technology. Conclusion The last half of 2021 was a moment of intense experimentation in the realms of music business administration and cultural expression, and at the time of writing, each week seemed to bring a new high-profile music Web3 project and/or disaster. Narratives of emancipation and domination under capitalism continue to drive our discussions around music and technology, and the direct link to debates on ecology and financialisation make these conversations particularly polarising. High-profile cases of music projects that overstep norms of existing IP rights, such as Hitpiece’s attempt to generate NFTs of songs without right-holders’ consent, point to the ways in which this technology is portrayed as threatening and subversive to commercial musicians (Blistein). Meanwhile, the Water and Music research DAO promises to incentivise a research community to “empower music-industry professionals with the knowledge, network and skills to do more collaborative and progressive work with technology” through NFT tokens and a DAO organisational structure (Hu et al.). The assumption in many early narratives of the ability of blockchain to provide systems of remuneration that musicians would embrace as inherently fairer is far from the reality of a popular discourse marked by increasing disdain and distrust, currently centred on NFTs as lacking in artistic merit, or even as harmful. We have seen all this talk before, of course, when jukeboxes and player pianos, film synchronisation, radio, recording, and other new communication technologies steered new paths for commercial musicians and promised magical futures. All of these innovations were met with intense scrutiny, cries of inauthentic practice, and resistance by incumbent musicians, but all were eventually sustained by the emergence of new forms of musical expression that captured the interest of the public. On the other hand, the road towards musical nirvana passes by not only the more prominent corpses of the Digital Audio Tape, SuperAudio, and countless recording formats, but if you squint and remember that technology is not always about devices or media, you can see the Secure Download Music Initiative, PressPlay, the International Music Registry, and Global Repertoire Databases in the distance, wondering if blockchain might correct some of the problems they dreamed of solving in their day. The NFT presents the artistic and cultural face of this dream of a musical future, and of course we are first seeing the emergence of old models within its contours. While the investment, ownership, and service phenomena emerging might not be reminiscent of the first moment when people were able to summon a song recording onto their computer via a telephone modem, it is important to remember that there were years of text-based chat rooms before we arrived at music through the Internet. It is early days, and there will be much confusion, anger, and experimentation before music NFTs become either another mundane medium of commercial musical practice, or perhaps a memory of another attempt to reach that goal. References Aoki, Steve. “Hairy.” Nifty Gateway 2021. 16 Feb. 2022 <https://niftygateway.com/marketplace/collection/0xbeccd9e4a80d4b7b642760275f60b62608d464f7/1?page=1>. Baym, Nancy, Lana Swartz, and Andrea Alarcon. "Convening Technologies: Blockchain and the Music Industry." International Journal of Communication 13.20 (2019). 13 Feb. 2022 <https://ijoc.org/index.php/ijoc/article/view/8590>. Barnett, C. “Convening Publics: The Parasitical Spaces of Public Action.” The SAGE Handbook of Political Geography. Eds. K.R. Cox., M. Low, and J. Robinson. London: Sage, 2008. 403–418. Blistein, Jon. "Hitpiece Wants to Make Every Song in the World an NFT. But Artists Aren't Buying It." Rolling Stone 2022. 14 Feb, 2022 <https://www.rollingstone.com/music/music-news/hitpiece-nft-song-controversy-1294027/>. Bored Ape Yacht Club. "Terms & Conditions." Yuga Labs, Inc. 2020. 14 Feb. 2022 <https://boredapeyachtclub.com/#/terms>. Carnevali, David. "Paperchain Uses Defi to Speed Streaming Payments to Musicians; the Startup Gets Streaming Data from Music Labels and Distributors on Their Artists, Then Uses Their Invoices as Collateral for Defi Loans to Pay the Musicians More Quickly." Wall Street Journal 2021. 16 Feb. 2022 <https://www.wsj.com/articles/paperchain-uses-defi-to-speed-streaming-payments-to-musicians-11635548273>. Chan, Anna. “How Avenged Sevenfold Is Reinventing the Fan Club with Deathbats Club NFTs”. NFT Now. 2021. 16 Feb. 2022 <https://avengedsevenfold.com/news/nft-now-avenged-sevenfold-reinventing-fan-club-with-deathbats-club/>. Cong, Lin William, Xi Li, Ke Tang, and Yang Yang. “Crypto Wash Trading.” SSRN 2021. 15 Feb. 2022 <https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3530220>. Das, Dipanjan, Priyanka Bose, Nicola Ruaro, Christopher Kruegel, and Giovanni Vigna. "Understanding Security Issues in the NFT Ecosystem." ArXiv 2021. 16 Feb. 2022 <https://arxiv.org/abs/2111.08893>. Dash, Anil. “NFTs Weren’t Supposed to End like This.” The Atlantic 2021. 16 Feb. 2022 <https://www.theatlantic.com/ideas/archive/2021/04/nfts-werent-supposed-end-like/618488/>. Diablo, Don. “Destination Hexagonia.” SuperRare 2021. 16 Feb. 2022 <https://superrare.com/artwork-v2/d%CE%BEstination-h%CE%BExagonia-by-don-diablo-23154>. Entriken, William, Dieter Shirley, Jacob Evans, and Nastassia Sachs. “EIP-721: Non-Fungible Token Standard.” Ethereum Improvement Proposals, 2022. 16 Feb. 2022 <https://arxiv.org/abs/2111.08893>. Fashion Law, The. “From Baby Birkins to MetaBirkins, Brands Are Facing Issues in the Metaverse.” 2021. 16 Feb. 2022 <https://www.thefashionlaw.com/from-baby-birkins-to-metabirkins-brands-are-being-plagued-in-the-metaverse/>. Fazli, Mohammah Amin, Ali Owfi, and Mohammad Reza Taesiri. "Under the Skin of Foundation NFT Auctions." ArXiv 2021. 16 Feb. 2022 <https://arxiv.org/abs/2109.12321>. Friends with Benefits. “Pussy Riot Drink My Blood”. 2021. 28 Jan. 2022 <https://gallery.fwb.help/pussy-riot-drink-my-blood>. Gough, Opal. "Blockchain: A New Opportunity for Record Labels." International Journal of Music Business Research 7.1 (2018): 26-44. Gottsegen, Will. “What’s Next for Friends with Benefits.” Yahoo! Finance 2021. 16 Feb. 2022 <https://au.finance.yahoo.com/news/next-friends-benefits-204036081.html>. Heap, Imogen. “Blockchain Could Help Musicians Make Money Again.” Harvard Business Review 2017. 16 Feb. 2022 <https://hbr.org/2017/06/blockchain-could-help-musicians-make-money-again>. Herndon, Holly. Holly+ 2021. 1 Feb. 2022 <https://holly.mirror.xyz>. Hu, Cherie, Diana Gremore, Katherine Rodgers, and Alexander Flores. "Introducing $STREAM: A New Tokenized Research Framework for the Music Industry." Water and Music 2021. 14 Feb. 2022 <https://www.waterandmusic.com/introducing-stream-a-new-tokenized-research-framework-for-the-music-industry/>. Leaving Records. “Leaving Records Introducing GENRE DAO.” Leaving Records 2021. 12 Jan. 2022 <https://leavingrecords.mirror.xyz/>. LePenne, Guénolé, Ingo Fiedler, and Lennart Ante. “Wash Trading at Cryptocurrency Exchanges.” Finance Research Letters 43 (2021). Gottsegen, Will. “What’s Next for Friend’s with Benefits?” Coin Desk 2021. 28 Jan. 2021 <https://www.coindesk.com/layer2/culture-week/2021/12/16/whats-next-for-friends-with-benefits>. Goodin, Dan. “Really Stupid ‘Smart Contract’ Bug Let Hacker Steal $31 Million in Digital Coin.” ARS Technica 2021. 16 Feb. 2022 <https://arstechnica.com/information-technology/2021/12/hackers-drain-31-million-from-cryptocurrency-service-monox-finance/>. Grimes. “Mars.” Nifty Gateway 2021. 16 Feb. 2022 <https://niftygateway.com/itemdetail/primary/0xe04cc101c671516ac790a6a6dc58f332b86978bb/2>. Newstead, Al. “Artists Outraged at Website Allegedly Selling Their Music as NFTS: What You Need to Know.” ABC Triple J 2022. 16 Feb. 2022 <https://www.abc.net.au/triplej/news/musicnews/hitpiece-explainer--artists-outraged-at-website-allegedly-selli/13739470>. O’Dair, Marcus, and Zuleika Beaven. "The Networked Record Industry: How Blockchain Technology Could Transform the Record Industry." Strategic Change 26.5 (2017): 471-80. Pearson, Jordan. “OpenSea Sure Has a Lot of Hitler NFTs for Sale.” Vice: Motherboard 2021. 16 Feb. 2022 <https://www.vice.com/en/article/akgx9j/opensea-sure-has-a-lot-of-hitler-nfts-for-sale>. Poleg, Dror. In Praise of Ponzis. 2021. 16 Feb. 2022 <https://www.drorpoleg.com/in-praise-of-ponzis/>. Purtill, James. “Artists Report Discovering Their Work Is Being Stolen and Sold as NFTs.” ABC News: Science 2021. 16 Feb. 2022 <https://www.abc.net.au/news/science/2021-03-16/nfts-artists-report-their-work-is-being-stolen-and-sold/13249408>. Rae, Madeline. “Analyzing the NFT Mania: Is a JPG Worth Millions.” SAGE Business Cases 2021. 16 Feb. 2022 <https://sk-sagepub-com.ezproxy.lib.rmit.edu.au/cases/analyzing-the-nft-mania-is-a-jpg-worth-millions>. Redman, Jamie. “Political Cartoonist Accuses NFT Platforms Opensea, Rarible of Being 'Tools for Political Censorship'.” Bitcoin.com 2021. 16 Feb. 2022 <https://news.bitcoin.com/political-cartoonist-accuses-nft-platforms-opensea-rarible-of-being-tools-for-political-censorship/>. Rennie, Ellie, Jason Potts, and Ana Pochesneva. Blockchain and the Creative Industries: Provocation Paper. Melbourne: RMIT University. 2019. Resonate. "Pricing." 2022. 16 Feb. 2022 <https://resonate.is/pricing/>. Rethink Music Initiative. Fair Music: Transparency and Payment Flows in the Music Industry. Berklee Institute for Creative Entrepreneurship, 2015. Royal. "How It Works." 2022. 16 Feb. 2022 <https://royal.io/>. Stephen, Bijan. “NFT Mania Is Here, and So Are the Scammers.” The Verge 2021. 15 Feb. 2022 <https://www.theverge.com/2021/3/20/22334527/nft-scams-artists-opensea-rarible-marble-cards-fraud-art>. Sound.xyz. Sound.xyz – Music without the Middleman. 2021. 14 Feb. 2022 <https://sound.mirror.xyz/3_TAJe4y8iJsO0JoVbXYw3BM2kM3042b1s6BQf-vWRo>. Taghdiri, Arya. "How Blockchain Technology Can Revolutionize the Music Industry." Harvard Journal of Sports & Entertainment Law 10 (2019): 173–195. Tomaino, Nick. “The Music Industry Is Waking Up to Ethereum: In Conversation with 3LAU.” SuperRare 2020. 16 Feb. 2022 <https://editorial.superrare.com/2020/10/20/the-music-industry-is-waking-up-to-ethereum-in-conversation-with-3lau/>.