Search

While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development., Author summary The childhood brain cancer high-grade glioma is a devastating disease that almost invariably ends in the death of the patient. The discovery that mutations in histone H3 variants are predominant in this type of cancer created great interest into the mechanism of transformation of these so-called oncohistones. Yet whereas most research is directed at understanding the role of mutant H3 in deregulating gene expression, we studied if and how it contributes to genomic instability–a research avenue that remains mostly unexplored. We discovered that the H3.3K27M oncohistone increases sensitivity to replication stress during S-phase, ultimately leading to mitotic aberrancies. This can explain why childhood high-grade glioma is among the most genomically unstable cancers.

Summary Background Cost‐effective use of biologicals is important. As drug concentrations have been linked to clinical outcomes, monitoring drug concentrations is a valuable tool to guide clinical decision‐making. A concentration–response relationship for ustekinumab at trough is uncertain owing to the contradictory results reported. Objectives To investigate the relationship between 4‐week postinjection ustekinumab concentrations and clinical response in patients with psoriasis. Methods Forty‐nine patients with moderate‐to‐severe psoriasis treated with 45 mg or 90 mg ustekinumab every 12 weeks for ≥ 16 weeks were included. Ustekinumab serum concentrations and anti‐ustekinumab antibodies were measured at week 4 after injection and disease severity was assessed by Psoriasis Area and Severity Index (PASI). Results At week 4 after injection, a significantly negative correlation was observed between ustekinumab concentrations and absolute PASI score up to 5·9 μg mL −1 (ρ = –0·357, P = 0·032). Ustekinumab concentrations were higher in optimal responders (PASI ≤ 2) than in suboptimal responders (PASI > 2) (4·0 vs 2·8 μg mL −1, P = 0·036). The ustekinumab concentration threshold associated with optimal response was determined to be 3·6 μg mL −1 (area under the curve 0·71, sensitivity 86%, specificity 63%). Only one patient (2%) had anti‐ustekinumab antibodies. Psoriatic arthritis was identified as an independent predictor of higher PASI scores and higher ustekinumab concentrations (P = 0·003 and P = 0·048, respectively). Conclusions A concentration–response relationship at week 4 after injection was observed for patients with psoriasis treated with ustekinumab. Monitoring 4‐week postinjection ustekinumab concentrations could timely identify underexposed patients who might benefit from treatment optimization. What's already known about this topic? Monitoring drug concentrations is a valuable tool that can guide clinical decision‐making when drug concentrations are linked to clinical outcomes.The presence of a concentration–response relationship for ustekinumab at trough is still debated owing to the contradictory results reported. What does this study add? A concentration–response relationship at week 4 after injection for ustekinumab‐treated patients with psoriasis was demonstrated.Monitoring 4‐week postinjection ustekinumab concentrations could timely identify underexposed patients who might benefit from treatment optimization.Based on the findings of this study, a treatment algorithm for patients with a suboptimal response is proposed., Linked Comment: https://doi.org/10.1111/bjd.18709. https://doi.org/10.1111/bjd.18709 available online

Neutrophilic eccrine hidradenitis (NEH) is a rare distinct entity that usually presents as asymptomatic erythematous papules that disappear spontaneously in 1-3 weeks. However, its appearance may be polymorphic, pruritic, recurrent or even chronic as is described in this case. The histological combination of neutrophilic infiltration in and necrosis of the eccrine secretory gland epithelium is highly characteristic for NEH. It typically occurs in patients receiving chemotherapeutic drugs for malignancies, but other associations have also been reported. To our knowledge, we report the first case of NEH in a patient with Behçet's disease (BD). Cutaneous manifestations of BD, an inflammatory systemic disorder of unknown origin, include neutrophilic dermatoses such as Sweet's syndrome and pyoderma gangrenosum, although these are unusual in BD. NEH could be another neutrophilic dermatosis related to BD. This observation suggests that NEH is not strictly related to chemotherapeutic drugs and malignancies. It appears to be a reactive dermatosis associated with other factors as well, including BD. Treatment was successful with dapsone 100 mg daily.

The case is presented of a man with allergic contact dermatitis and occupational asthma due to triglycidylisocyanurate (TGIC), which is used as a hardener in thermosetting powder paint. The contact dermatitis was confirmed by patch testing (TGIC 0.5% and 5% in petrolatum), and the occupational asthma was confirmed by bronchial provocation testing: two challenges to an aerosol of lactose containing TGIC (0.05% and 0.1%, w/w, each for 0.5+1+2+4 min) led to a maximal decrease in FEV1 of 22% and 31% after 6 and 4 h, respectively. Skin prick tests with unconjugated TGIC were possibly positive. This case confirms that exposure to TGIC in powder paints may cause not only contact dermatitis, but also occupational asthma.

Two corticosteroid-treated patients with cutaneous cryptococcal infection are described. One patient had pustulous lesions on the back of his left hand and cellulitis of his left forearm, the other patient had ulcerous lesions of the right forearm and cellulitis of the right lower leg. In both cases diagnosis was suggested by histopathological examination of a biopsy and confirmed by culture. One patient may have had disseminated cryptococcal disease as suggested by a positive cryptococcal capsular antigen test, the other had no evidence of dissemination. Treatment consisted of oral fluconazole for six weeks. One patient died of an unrelated cause after four weeks treatment. Secondary antifungal prophylaxis was not given. Cutaneous cryptococcal infections are described in AIDS patients, but only seldom observed in other immunocompromised patients. Early recognition of the cutaneous lesions is important, as they can be the first sign of disseminated cryptococcosis. Untreated, the mortality of this disease is high. Therapy consists of amphotericin B with or without flucytosine. Fluconazole may be valuable alternative. The optimal treatment regimen and duration are not defined yet. Contrary to AIDS patients with cryptococcal infection, who need life-long secondary antifungal prophylaxis in order to prevent relapses, suppressive treatment is not indicated for immunocompromised non-AIDS patients.

Topical ketoprofen (KP) is widely used because of its anti-inflammatory effect. However, photocontact dermatitis is a side-effect. Between May 2001 and June 2002, the Belgian Contact & Environmental Dermatitis Group conducted a prospective, open patch and photopatch test study in 20 patients suspected of KP dermatitis. Severe skin symptoms requiring systemic corticotherapy occurred in 47%. 5 patients were hospitalized. 1 patient showed prolonged photosensitivity. All patients were tested with KP and the other constituents of KP gel. Attribution to KP was demonstrated in all cases. Patch and photopatch tests with KP 2% in petrolatum showed contact photoallergy in 17 patients, contact allergy in 1 patient and photoaggravated contact allergy in 2 patients. 5 patients also reacted to the fragrance components lavender (Lavandula augustifolia) oil and/or neroli (Citrus aurantium dulcis) oil 5% in alcohol. However, in 4 of these, irritant reactions to the ethanolic dilutions could not be ruled out. Additional tests with 3 non-steroidal anti-inflammatory drugs without benzophenone structure ibuprofen, naproxen and diclofenac identified only 1 contact allergic reaction to diclofenac. Cross-reactivity to the substituted benzophenones, oxybenzone and sulisobenzone occurred only to the first in less than 30% of the patients. A high frequency (69%) of contact allergy to fragrance mix was found. Dermatologists should be aware of the severity of photoallergic reactions to KP and the risk of cross-sensitization.

In the past few years, thalidomide is experiencing a revival in many different fields as a last therapeutic option, because of the potential severe adverse drug reactions (ADR) induced by this drug (teratogenicity, peripheral neuropathy and sedation). Taking into consideration the increased use, we should focus on the prevalence of these and other ADR as well on their management. We describe a patient with multiple myeloma who presented with a morbilliform rash induced by thalidomide. Reintroduction of the drug confirmed the diagnosis. Nevertheless we continued the thalidomide treatment, although combined with methylprednisolone 64 mg. There was no recurrence of the cutaneous drug reaction (CDR). To the best of our knowledge, this is the first case showing that systemic steroids can help to ‘treat through’ a thalidomide CDR.