Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest. Understanding p53 regulation remains a crucial goal to design broadly applicable anticancer strategies based on this pathway. This Review of in vitro studies, human tumour data and recent mouse models shows that p53 post-translational modifications have modulatory roles, and MDM2 and MDM4 have more profound roles for regulating p53. Importantly, MDM4 emerges as an independent target for drug development, as its inactivation is crucial for full p53 activation.

Regulating the p53 pathway: in vitro hypotheses, in vivo veritas

Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol–SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol–SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol–SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) (P < 10–7). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol–SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4–9780.9); corrected P value = 4.7 × 10–24] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23–6665.26); corrected P value = 8.1 × 10–18]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol–SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.

/pdf/hla-b-5801-allele-as-a-genetic-marker-for-severe-cutaneous-19wf591t8q.pdf

HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

TFOS DEWS II pathophysiology report

Mutant PIK3CA promotes cell growth and invasion of human cancer cells

The DRESS Syndrome: A Literature Review

Stevens-Johnson syndrome and the related disease toxic epidermal necrolysis are life-threatening reactions of the skin to particular types of medication. Here we show that there is a strong association in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures. It should be possible to exploit this association in a highly reliable test to predict severe adverse reaction, as well as for investigation of the pathogenesis of Stevens-Johnson syndrome.

/pdf/medical-genetics-a-marker-for-stevens-johnson-syndrome-1vie3b9vki.pdf

Medical genetics: A marker for Stevens-Johnson syndrome

Background: Syringoma of the vulva has been rarely reported. No effective treatment modality has been documented. Objective: The purpose of this study was to describe the clinicopathologic features of vulvar syringoma, to investigate the hormonal influence on its growth, and to establish an effective treatment modality. Methods: A total of 18 cases of vulvar syringoma were selected from the surgical pathologic file at Chang Gung Memorial Hospital. In all, 15 formalin-fixed, paraffin-embedded specimens were examined by immunohistochemical staining for estrogen receptor and progesterone receptor. Results: The age of first presentation at our vulvar clinic ranged from 21 to 60 years with a median age of 29.5 years. Of patients, 13 (72%) had vulvar pruritus and 7 noticed aggravation during summer or during menstruation. The most common clinical appearance was multiple flesh-colored or brownish papules on bilateral sides of the vulva (9 of 18). One third of our series was found to have coexisting eyelid syringoma and 4 of them also had a family history of periorbital syringoma. Immunohistochemical stainings for estrogen receptor and progesterone receptor were all negative on the 15 cases studied. Of our patients, 7 with intense pruritus were treated with carbon dioxide laser vaporization. Their lesions resolved and pruritus subsided. Conclusion: Vulvar syringoma is not very rare and should be considered in the differential diagnosis of vulvar pruritus. In our study, estrogen receptor and progesterone receptor were not detected in vulvar syringoma. Carbon dioxide laser was an effective therapeutic modality in treating patients with intractable symptoms. (J Am Acad Dermatol 2003;48:735-9.)

https://www.jaad.org/article/S0190-9622(03)00357-8/pdf

Vulvar syringoma: a clinicopathologic and immunohistologic study of 18 patients and results of treatment

Kikuchi's disease (KD) or Kikuchi's lymphadenitis (KL) is a self-limiting disease mostly affecting the cervical lymph nodes of young individuals. Whether the reported cases of KL associated with systemic lupus erythematosus (SLE) were genuine KL or lupus lymphadenitis (LL) simulating KL in SLE patients is not clear. We analyzed six cases of KD-like lymphadenitis occurring in SLE patients and 12 reported cases to clarify the relationship between KL and SLE. We found that not all cases occurred simultaneously with SLE. Eight cases occured either before or after SLE. These cases might have true KL independent of SLE with the exception of two cases that occurred after SLE, but the patients still had lupus activity. The 10 cases that coexisted with SLE most likelty had LL rather than KL. This was supported by the immunohistochemical finding of sparse cytotoxic T cells in those lymph nodes in contrast to abundant cytotoxic T cells usually seen in a typical KL. We conclude that KL is not related to SLE, and KD-like lymphadenitis coexisting with SLE should be regarded as LL. Pathologists should be aware of the possibility that LL can mimic KL in patients with SLE, especially necrotizing-type KL.

Lupus lymphadenitis simulating Kikuchi's lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature.

Drug hypersensitivity syndrome (DHS) is an idiosyncratic and life-threatening adverse drug reaction characterized by skin rash and multiorgan involvement. In rare cases, fulminant type1 diabetes mellitus (DM) may develop after DHS. Among proposed pathogenesis, human herpesvirus 6 (HHV-6) infections may play a role in the development of DHS. We report a case of DHS associated with HHV-6 reactivation, complicated with a rare sequela of irreversible fulminant type 1 DM. No diabetes-related autoantibodies were detected. Early detection and intervention for this serious complication should be given in patients with DHS. Fulminant type1 DM associated with DHS is reviewed. The role of HHV-6 in DHS associated with fulminant type 1 DM is also discussed.

Fulminant type 1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection

BACKGROUND
Cutaneous Rosai-Dorfman disease (RDD) is a rare entity of unknown origin and is not well documented, especially in Asian populations.


OBJECTIVE
The purpose of this study was to evaluate the clinical manifestation, diagnostic histopathology, clinical course, and response to treatment of cutaneous RDD in Taiwan.


MATERIALS AND METHODS
This study included 21 patients with cutaneous RDD who presented at our institution from 1995 to 2003. Pathologic examinations with both hematoxylin-eosin and immunohistochemical stains were reviewed, as were associated clinical features and therapeutic methods.


RESULTS
None of the 21 patients with cutaneous RDD had nodal lesions. The clinical manifestation was variable, but most commonly involved a central noduloplaque with satellite papules. One patient manifested as an ulcerated nodule, something not reported previously. Multifocal involvement only occurred in 4 patients. Concurrent involvement of uvea or vocal cord occurred in two patients. The most prominent histologic feature was a florid and mixed inflammatory infiltration. The phagocytosis of inflammatory cells into the cytoplasm of histiocytes, a process called "emperipolesis," is a characteristic finding of nodular RDD but usually only focally presented in cutaneous ones. Positivity for S-100 protein helped to confirm the diagnosis. The most effective treatment was surgical excision of solitary lesions. High-dose thalidomide (300 mg/d), but not low-dose, was effective to control the extensive cutaneous diseases in two patients. A total of 3 patients experienced spontaneous remission 1 to 2 years after diagnosis.


CONCLUSIONS
Cutaneous RDD appeared more frequently in Asian populations than in reports from Western countries. The incidence of multifocal involvement in this series is much lower than in other literature. Although treatment of disseminated cutaneous RDD is difficult, high-dose thalidomide (300 mg/d), which was effective in two patients in this series, may be helpful.

Hong-Shang Hong

Papers

Medical genetics: A marker for Stevens-Johnson syndrome

Vulvar syringoma: a clinicopathologic and immunohistologic study of 18 patients and results of treatment

Lupus lymphadenitis simulating Kikuchi's lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature.

Fulminant type 1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection

Iconography : Clinical and histopathologic spectrum of cutaneous Rosai-Dorfman disease in Taiwan