tbuckley/cabot-search huggingface dataset:
The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities
Authors: Evelyn Ramberger, Valeriia Sapozhnikova, Yuen Lam Dora Ng, Anna Dolnik, Matthias Ziehm, Oliver Popp, Eric Sträng, Miriam Kull, Florian Grünschläger, Josefine Krüger, Manuela Benary, Sina Müller, Xiang Gao, Arunima Murgai, Mohamed Haji, Annika Schmidt, Raphael Lutz, Axel Nogai, Jan Braune, Dominik Laue, Christian Langer, Cyrus Khandanpour, Florian Bassermann, Hartmut Döhner, Monika Engelhardt, Christian Straka, Michael Hundemer, Dieter Beule, Simon Haas, Ulrich Keller, Hermann Einsele, Lars Bullinger, Stefan Knop, Philipp Mertins, Jan Krönke
Journal: Nature Cancer (2024)

Abstract Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.
H15 Inflammation of the hair follicle: multiple eponyms!
Authors: Ji Fung Yong, Orla McFeely, Laoise Griffin
Journal: British Journal of Dermatology (2024)

Abstract Hidradenitis suppurativa (HS) had several different names in the past due to the bewildering history of conflicting bodies of knowledge and pathogenesis. In 1833, it was referred to as Velpeau disease, named after Alfred-Armand-Louis-Marie Velpeau, a French anatomist and surgeon, who was the first person who noted an unusual inflammatory process of the sebaceous follicle. He first described a ‘phlegmon tubériforme’ (tuberiform phlegmon) of the axilla, characterized by superficial abscess formation and often resulting in pain and suppuration. Velpeau then discovered painful induration and tumours, as a similar clinic aspect of HS, naming it ‘phlegmon érysipélateux’ (erysipelas phlegmon). In 1864, Verneuil renamed the disease to hidrosadénite phlegmoneuse, the French term for ‘hidradenitis suppurativa’, and defines it as a condition caused by inflammation of the sweat glands (hidradenitis) with pus collection (suppurativa). Later, Aristide Auguste Stanislas Verneuil, a French surgeon with special interest in skin and sudoral (sweat gland) tumours, found Velpeau’s discovery. He conducted the first clinical studies regarding this inflammatory condition from 1854 to 1865 and recognized that it was a disorder of sweat glands, earning it the name of Verneuil disease. In 1891, ‘acnitis’ and ‘folliclis’ were new terms introduced to describe HS as part of folliculitis, by French physician Barthélémy. However, these were soon rejected by French dermatologist William Auguste Dubreuilh, in favour of ‘hydrosadenitis’. In 1956, Pillsbury came up with the term ‘follicular occlusion triad’ as a group disorder consisting of HS, acne conglobata and dissecting cellulitis of the scalp. This decision was made on common features of follicular hyperkeratinization, with keratin retention complicated with bacterial infection in these conditions. Nineteen years later in 1975, Plewig and Kligman added pilonidal sinus to the follicular occlusion triad and introduced the new term ‘acne tetrad’. Histopathologically, all four entities are identical, with evidence of follicular occlusion causing inflammation of sweat glands. Given the inverse localizations of HS compared with the acne tetrad, Plewig suggested the term ‘acne inversa’ instead in 1989. In 2005, American dermatologists Sellheyer and Krahl observed histopathological evidence of hair follicle occlusion and noted clinical and therapeutic similarities to acne. They insisted on abandoning the name ‘HS’, replacing it with ‘acne inversa’. However, adversaries of the name ‘acne inversa’ contended that more research should be conducted, as histology alone does not define dermatology. HS is currently the recognized name of this disease, as agreement on its terminology has yet to be reached, despite centuries of research.
SG06 (P013) Eruptive seborrhoeic keratoses in late-onset constitutional mismatch repair deficiency
Authors: William Fostier, Georgie Holt, Akhtar Husain, James Tellez, Katharina Wimmer, Richard Martin, John Burn, Richard Gallon, Neil Rajan
Journal: British Journal of Dermatology (2024)

Abstract Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive condition typically diagnosed in childhood. It is caused by biallelic inheritance of pathogenic variants within the MLH1, MSH2, MSH6 and PMS2 genes (DNA mismatch repair pathway). It confers a high risk of cancer, with many patients developing brain, gastrointestinal or haematological malignancy in the first two decades of life. The cutaneous features of CMMRD share similarities with neurofibromatosis, with café au lait macules, Lisch nodules, neurofibromas and axillary/inguinal freckling reported. Herein, we report a case of a 31-year-old woman with colorectal polyposis and multiple primary cancers presenting with an eruption of seborrhoeic keratoses (SKs), consistent with the paraneoplastic sign of Leser–Trélat sign (LTS). Aged 23 years, the proband underwent a prophylactic subtotal colectomy for multiple adenomatous large-bowel polyps. During colectomy, analysis of an enlarged mesenteric lymph node revealed a synchronous diffuse large B-cell lymphoma. This was treated with excision and chemotherapy. When she was aged 24 years, an ampulla of Vater adenoma was excised. Aged 29 years, she developed triple-negative invasive ductal carcinoma of the breast, treated with surgery and chemotherapy. The proband also developed basal cell carcinoma on her forehead and the tarsal edge of her right eye at ages 28 and 31 years, respectively. Her family history revealed that her father died at age 33 years of colorectal cancer, while her mother died at age 60 years due to cerebral haemorrhage. Concurrently to the proband’s breast cancer diagnosis, cutaneous examination revealed widespread small skin-coloured and brown plaques, which were confirmed on biopsy to be SKs in a predominantly acral distribution, with sparing of the trunk. Immunohistochemical assessment of the SKs demonstrated loss of expression of PMS2, with loss of expression also seen in normal perilesional skin. Microsatellite instability (MSI) analysis of peripheral leucocyte DNA revealed high levels of constitutional MSI, indicative of CMMRD. Germline genetic testing revealed compound heterozygous pathogenic variants in PMS2, confirming the diagnosis. LTS is characterized by an eruption of SKs in association with concurrent development of cancers arising from the breast, lung and gastrointestinal tract. A putative mechanism is that tumour-secreted factors, such as epidermal growth factor, drive SK growth. The responsible tumour may be difficult to determine in patients with multiple primary cancers; however, temporally, the breast cancer in our patient was most closely linked to her presentation of LTS. This case emphasizes the importance of recognizing the sign of LTS, a novel feature in the context of CMMRD.
H18 Scabies: can we repurpose treatments from the past?
Authors: Musfira Shakeel, William Price, Manu Shah
Journal: British Journal of Dermatology (2024)

Abstract The UK is currently in the grip of a scabies epidemic. Current treatments seem to be either unavailable or ineffective, with multiple cases of permethrin resistance being reported. The British Association of Dermatologists has highlighted the shortage of scabies treatments and the lack of national tracking of cases. Scabies is not new, so can we learn from experiences and treatments of the past to help us in the present and the future? Scabies has irritated mankind for hundreds of thousands of years. The first treatments were based on sulfur and have been used for at least 5000 years. Sulfur is an irritant; it is unpleasant to use but can be effective. Lindane, created in 1825 but not used commercially until the 20th century is rarely used now due to its neurotoxicity and possible carcinogenic nature. It is still available but is banned in many countries. More treatments became available in the early 20th century due to the explosion of scabies cases associated with World War I. Benzyl benzoate, balsam of Peru and beta-naphthol were all successfully used to treat thousands of afflicted infantrymen. All have their limitations: benzyl benzoate and balsam of Peru commonly cause allergic reactions, and beta-naphthol may cause death. A reformulation of benzyl benzoate may be possible (its cure rate is a remarkable 86%), but overuse can lead to neurotoxicity. Dermatologists in World War II experimented with their own recipes. John Ingram reported in 1942 that a benzyl benzoate lotion of ‘equal parts soft soap and spirit’ gave ‘excellent results and caused no skin irritation’. New uses of old medicines may be one way forward. Tea tree oil has scabicide properties and is undergoing investigations for possible topical use. Oral ivermectin (discovered in 1975), although currently not licensed for scabies in humans, will probably be used in thousands of patients if the current surge of cases continues. There is the possibility that the topical form of ivermectin could be equally effective, and further studies are needed. Better formulation of old drugs may be possible to make them less irritant and cause fewer allergic reactions. Our current reliance on a tiny range of ‘safe’ topical therapies for treating scabies is clearly not working as the incidence of cases continues to rise. While work on developing new treatments and ways of dealing with this timeless problem continue, we also need to explore old treatments and reformulate irritant therapies.
BT03 A picture paints a thousand words: simple solutions for optimizing the flow of urgent skin cancer referrals
Authors: Jessie Felton
Journal: British Journal of Dermatology (2024)

Abstract In the face of increasing urgent skin cancer (USC) referrals from primary care, innovative solutions are needed. We present a low-cost, low-burden solution. Alternative pathways such as ‘rapid access lesion clinics’ build up waiting lists. In some areas photos are not assessed for 4 months (unpublished data) and the pathway is redundant. USC referrals are traditionally not triaged by a consultant, but non-USC referral are. We use consultant triage of some USC referrals, to support the USC teledermatology service. This ensures patients are appropriate, and correct numbers of patient are seen via teledermatology each week to avoid build-up of a waiting list. We present data from a 1-week snapshot survey of 66 USC referrals from primary care to a National Health Service hospital. We recorded the following: (i) whether a photo of any type accompanied the referral; (ii) whether the patient was suitable for teledermatology; this was established using criteria agreed by our local network with exclusions (e.g. immunosuppressed) and (iii) whether the consultant undertaking triage was confident to either downgrade off the USC pathway or discharge the patient based on the information provided in the USC referral. The results showed that 35 of 66 (53%) were suitable for teledermatology, and 31 of 66 (47%) were for face-to-face review. Ten of 66 referrals (15%) had a photograph but no dermoscopic images provided. Six of 66 (9%) were considered suitable for removal from the USC pathway or for discharge to the general practitioner (GP). Of these patients, five of six (83%) had a photograph attached to the referral. This indicates that use of USC consultant triage has the potential to reduce the number of patients entering the USC pathway. A macroscopic picture can be sufficient. This is a low-cost change that can be implemented quickly in most services. One clear referral pathway for the GP is used, USC referral, but patients are diverted at an early stage. USC triage also ensures that appropriate patients enter into the teledermatology pathway, avoiding duplication. The number of patients triaged to teledermatology matches the image-taking capacity, to eliminate waiting lists. USC triage allows for low-risk patients to be sent for artificial intelligence (AI) analysis, but can select out high-risk patients and unusual tumours. Many AI skin cancer services do not use metadata in their process and are not sufficiently trained on rare tumours. USC triage places additional burden on dermatology consultants but this is balanced against USC breaches and unrestricted numbers of patients entering the USC pathway.
SG03 A case of Bazex–Dupré–Christol syndrome (BDCS)
Authors: Oliver Reed, Schaida Schirwani
Journal: British Journal of Dermatology (2024)

Abstract A 36-year-old man presented to the dermatology department in 2013 with a pink papule on his neck. He had no significant past medical history and took no regular medications. He was born with sparse hair and had milia on his face, neck and ears since childhood. His nonidentical twin daughters were born with milia confined to the head and neck. His mother and maternal aunt had histories of multiple basal cell carcinomas (BCCs), hypotrichosis and follicular atrophoderma and were subsequently diagnosed with Bazex–Dupré–Christol syndrome (BDCS). On examination, he had a superficial BCC on his right posterior neck, with prominent follicular atrophoderma affecting the dorsum of his hands, elbows and feet. He had milia on his ears bilaterally. The BCC was successfully treated with imiquimod 5% cream. The initial genetic testing was uninformative. He was subsequently lost to follow-up but presented again in 2021 with a BCC on his lower eyelid. In 2022 a pertinent paper was published in the British Journal of Dermatology by Liu et al. (Liu Y, Banka S, Huang Y et al. Germline intergenic duplications at Xq26.1 underlie Bazex–Dupré–Christol basal cell carcinoma susceptibility syndrome. Br J Dermatol 2022; 187: 948–61). This revealed new insights into the genetic aetiology for the syndrome, and hence the patient was contacted to consider further genetic testing. Whole-genome sequencing was performed, which identified the same duplications in noncoding sections of chromosome Xq26.1 as highlighted by Liu et al. BDCS is a rare X-linked dominant condition characterized by a triad of BCC, follicular atrophoderma and hypotrichosis. It may also be accompanied by milia, hypohidrosis and trichoepithelioma (AlSabbagh M, Baqi M. Bazex–Dupré–Christol syndrome: review of clinical and molecular aspects. Int J Dermatol 2018; 57: 1102–6). It has been previously thought that there is no single gene solely responsible for BDCS; however, in 2022, Liu et al. suggested that dysregulation of the gene ARHGAP36, resulting from duplications in noncoding sections of chromosome Xq26.1, might be implicated. ARHGAP36 is a flanking centromeric gene near the control hair follicular stem cell compartment (Liu et al.). Our case highlights the importance of considering BDCS as a differential diagnosis in patients presenting with early-onset BCC. Having a confirmed diagnosis enables tailored clinical management with early preventative measures and the opportunity for genetic counselling for future generations of affected individuals.
PA11 An indolent course of paediatric primary cutaneous γ/δ T-cell lymphoma
Authors: Pierce Deng, Ingrid Polcari, Daniel Miller
Journal: British Journal of Dermatology (2024)

Abstract A 16-year-old girl with a history of antinuclear antibody (ANA) positivity, Raynaud phenomenon, arthralgias and night sweats presented to our paediatric dermatology clinic for relapsing and remitting tender subcutaneous nodules on the trunk and extremities over the past year. The nodules arise spontaneously within a couple of days and resolve over a few days or up to a month later without overlying skin changes or ulceration. At one time, she had six nodules altogether, but typically she has one to four nodules that come and go every month. Prior rheumatology evaluation had considered systemic lupus erythematosus; however, multiple repeated autoimmune serologies had returned negative, including repeat ANAs, extractable nuclear antigen antibody panels, and DNA double-stranded antibodies. Physical exam at the initial dermatology visit demonstrated a single small deep subcutaneous nodule on the left buttock. Inflammatory panniculitis was suspected and a biopsy was considered, but it was ultimately deferred given that the present nodule was very deep and already resolving. The patient returned to clinic a year later given continued formation of subcutaneous nodules. An incisional punch biopsy from her right flank was performed, which revealed a subcutaneous, predominantly lobular infiltrate of mostly CD3-positive T cells with prominent atypia, high Ki-67 labelling, significant positivity on T-cell receptor δ immunostaining and cytotoxic markers, and a positive T-cell gene rearrangement study. These findings were consistent with primary cutaneous γ/δ T-cell lymphoma (PCGD-TCL). The patient was subsequently referred to haematology and oncology. Peripheral blood smear, positron emission tomography scan, and bone marrow biopsy were reassuring, with no evidence of haemophagocytic syndrome or malignancy. Treatment with methotrexate was initiated and the patient experienced some mild improvement initially; however, the nodules soon returned to the same frequency and intensity as before. Interestingly, she did report resolution of her night sweats since starting methotrexate. Currently, she is seeking additional expert opinions with consideration for a repeat biopsy, as well as second-line therapies such as ciclosporin, mycophenolate or bexarotene. PCGD-TCL is a rare lymphoma of γ/δ T cells that usually presents with generalized subcutaneous nodules or ulceronecrotic plaques, and is classically associated with a poor prognosis. The apparent indolent course in this patient supports the notion that PCGD-TCL may be more heterogeneous than traditionally described, and a subset of PCGD-TCL follows a more indolent course analogous to the α/β phenotype of subcutaneous panniculitis-like T-cell lymphoma. This case also highlights a rare paediatric presentation of PCGD-TCL and the often overlapping clinical and microscopic features of the panniculitic cutaneous lymphomas with lupus panniculitis.
BG07 Once in a blue moon?
Authors: Vidya Madhwapathi, Simon Tso
Journal: British Journal of Dermatology (2024)

Abstract An 80-year-old woman with a background of Hodgkin disease, hypertension and arthritis was diagnosed with bullous pemphigoid (BP) following skin biopsy. She was managed as a dermatology outpatient with skin-directed therapies (clobetasol propionate ointment and emollients) and doxycycline 100 mg once daily (due to renal function). Following a flare of BP, the accident and emergency department added oral prednisolone 40 mg once daily with proton pump inhibitor cover, which was gradually weaned down, but disease control remained suboptimal at prednisolone 20 mg once daily. She was later admitted as an inpatient due to new-onset delirium and acute chronic renal impairment attributable to hyponatraemia and steroid-induced delirium. Despite supervised weaning of oral prednisolone (with cortisol monitored to avoid Addisonian crisis) and commencement of oral dapsone 50 mg once daily (on a background of normal glucose-6-phosphate dehydrogenase level and baseline methaemoglobin level), the delirium persisted. Full-body computed tomography was performed, showing small-vessel ischaemia. A methaemoglobin level performed after dermatology review showed an increased level of 14.2%. Methylene blue was commenced and dapsone stopped. The patient continued to deteriorate despite ward-based care. She was discharged for palliation and passed away a few weeks later. Dapsone is a drug with immunosuppressive properties, used in a wide variety of dermatological conditions including BP, pyoderma gangrenosum and vasculitis. Methaemoglobinaemia is a well-known, but uncommon side-effect. Attributing causation for this patient’s symptoms to prednisolone alone is difficult, as her symptoms started 4 weeks after, at a dose of 20 mg. Fully attributing them to dapsone is also difficult, as the symptoms had started before its initiation. However, it is likely multifactorial. BP itself, addition of immunosuppressive BP treatment, polypharmacy and subsequent methaemoglobinaemia tipped the delicate balance in a patient of advancing age, with known small-vessel ischaemia and other comorbidities. This difficult case highlights the challenges and complexities of managing dermatological conditions and the use of immunosuppression in an increasingly older population. The number of people aged ≥ 85 years in the UK was estimated to be 1.7 million in 2020 (2.5% of the UK population) and this is projected to almost double to 3.1 million by 2045 (4.3% of the UK population). The issues arising in this case will become more commonplace for dermatologists. This case emphasizes the need for working closely with colleagues caring for older patients, and for consideration of rare side-effects of medications as a contributor to delirium.