Efficacy and safety of biologics in erythrodermic psoriasis: a multicentre, retrospective study.

BACKGROUND: Even though efficacy of biologics has been extensively studied in psoriasis vulgaris, studies in erythrodermic psoriasis, the most severe form of the disease, have been scarcely reported. OBJECTIVES: To address the efficacy and safety of biologics in patients with erythrodermic psoriasis. METHODS: A multicentre national retrospective study was performed using the French Psoriasis Group network. Patients showing psoriasis involving at least 90% of body surface area (BSA), and in whom severity of the disease had been evaluated before and after 3 and/or 6 months of treatment with biologics, were enrolled in the study. Results were expressed using intention-to-treat analysis. RESULTS: We included 28 patients, representing 42 flares of erythrodermic psoriasis treated with infliximab (n=24), adalimumab (n=7), etanercept (n=6), ustekinumab (n=3) or efalizumab (n=2). A 75% improvement of BSA or Psoriais Area and Severity Index 12-14 weeks after treatment onset was reached in 48% of flares treated with infliximab, in 50% of those treated with adalimumab and in 40% of those treated with etanercept. Twelve serious adverse events, consisting of bacterial infection in seven of them, were observed. Biological treatment was discontinued for safety concern in 19% of cases. A given biologic was administered for up to 48 weeks in 34% of flares. CONCLUSIONS: Biologics show overall good short-term efficacy, but treatment switch due to lack of efficacy or side-effects is frequently observed on a longer term, with only one-third of patients still receiving the same drug after 1 year. The most significant safety concern consists of severe infections.

Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointment.

Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2-15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of >or=60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was -11.8%, exceeding the non-inferiority limit of -15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 +/- 5.0 and 8.6 +/- 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep.

Superiority of tacrolimus 0.1% ointment compared with fluticasone 0.005% in adults with moderate to severe atopic dermatitis of the face: results from a randomized, double-blind trial.

BACKGROUND: No specific data are available on tacrolimus ointment as a second-line treatment in adults with facial eczema. OBJECTIVES: To compare tacrolimus 0.1% and fluticasone 0.005% ointments in adults with moderate to severe atopic dermatitis (AD) of the face in whom conventional treatment was ineffective or poorly tolerated. METHODS: Patients were randomized to double-blind treatment of facial AD with twice-daily tacrolimus ointment (n = 288) or fluticasone ointment (n = 280) for 3 weeks or until clearance. After day 21, patients could continue without the study treatment, apply the same ointment once daily, or switch to the other medication twice daily, depending on lesion clearance and patient/physician satisfaction. The primary endpoint was the day-21 response [> or = 60% reduction in the modified Local Eczema and Severity Index (mLEASI) score]. Secondary endpoints included facial erythema and pruritus, global clinical response, treatment switching at day 21 and safety. RESULTS Response with tacrolimus ointment (93%) was superior to that with fluticasone (88%; P = 0.026). Improvements in mLEASI components were also greater with tacrolimus ointment. Facial erythema and pruritus improved in both groups. Global clinical response was rated 'marked improvement' or better in 88% and 79% of patients in the tacrolimus ointment and fluticasone groups, respectively. At day 21, 9% of patients switched from fluticasone to tacrolimus ointment, while 4.5% switched from tacrolimus ointment to fluticasone. Adverse events were more frequent with tacrolimus ointment as a result of the higher incidence of application-site skin burning sensation. Safety of both drugs was in line with their respective summary of product characteristics. CONCLUSIONS: Tacrolimus 0.1% ointment has superior efficacy to fluticasone 0.005% ointment for twice-daily treatment of adults with moderate to severe facial AD in whom conventional therapy was inadequately effective or not tolerated. Tacrolimus 0.1% ointment is a safe and effective second-line treatment for the control of moderate to severe AD of the face.

Gemcitabine treatment in cutaneous T-cell lymphoma: a multicentre study of 23 cases.

BACKGROUND: Primary cutaneous T-cell lymphomas (CTCLs) are malignancies characterized by a clonal T-cell infiltrate involving the skin. CTCLs often show resistance to conventional antineoplastic chemotherapy. Gemcitabine is a pyrimidine analogue which has shown efficacy and a favourable safety profile in solid tumours and haematological malignancies. OBJECTIVES: We report a multicentre retrospective study of 23 patients who received gemcitabine for advanced-stage CTCL and emphasize the high incidence of serious unusual adverse events. METHODS: We collected data from 23 patients with refractory CTCL (14 mycosis fungoides, six Sézary syndrome and three other CTCL). Gemcitabine was given weekly within a 21- or 28-day schedule. Response was evaluated after three and six cycles of chemotherapy. For each patient, all adverse events were recorded. RESULTS: Of the 16 patients who received at least three cycles of gemcitabine, 10 achieved a response (62.5%). Only five patients reached the sixth cycle of treatment and four still had a favourable response. Haematological toxicity was recorded in 15 cases with severe grade 3 or 4 neutropenia in seven patients (30%) and six serious infections (26%). Other serious adverse events were observed in six cases (26%): one haemolytic-uraemic syndrome, one severe capillary leak syndrome, one acute heart failure related to cardiac arrhythmia, two bullous and erosive dermatitis, and one recurrent influenza-like syndrome with altered general condition. CONCLUSIONS: Our study confirms the early efficacy of gemcitabine in advanced-stage CTCL. However, our results contradict the safety profile of gemcitabine previously reported and underline the high incidence of severe complications including visceral and cutaneous involvement.

Psoriatic fibroblasts induce hyperproliferation of normal keratinocytes in a skin equivalent model in vitro.

A skin equivalent model has been used to fabricate tissues with psoriatic and normal cells. Psoriatic fibroblasts can induce hyperproliferative activity in normal keratinocytes. The psoriatic epidermis from lesions continues to proliferate at high rates for at least 15 days in this model, and normal fibroblasts are unable to suppress this hyperproliferation. The primary defect in psoriatic skin may reside in the dermal fibroblast.

European S3-guidelines on the systemic treatment of psoriasis vulgaris.

Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

[Atorvastatin-induced drug reaction with eosinophilia and systemic symptoms (DRESS)]. / Syndrome d'hypersensibilité médicamenteuse induit par l'atorvastatine.

BACKGROUND: Atorvastatin is a widely-used therapeutic statin given for hypercholesterolaemia and for prevention of cardiovascular events. We report herein the occurrence of a drug reaction with eosinophilia and systemic symptoms (DRESS) secondary to intake of this drug. CASE REPORT: A 58-year-old woman presented with a febrile skin rash and facial oedema, appearing 6weeks after the start of atorvastatin for dyslipidaemia. The clinical features associated disseminated polymorphic lesions, oral mucosa involvement and systemic symptoms (fever, abdominal pain, diarrhoea, polyarthralgia and adenomegaly). Blood tests showed hypereosinophilia up to 11,540/mm(3), inflammatory syndrome and anicteric cholestasis without cytolysis. Serological tests for hepatitis B and C, HIV, EBV, HHV-6, HHV-8, CMV and human Parvovirus B-19 were negative. Cutaneous histology was unspecific. A diagnosis of DRESS secondary to atorvastatin was suspected. The clinical outcome was favourable after atorvastatin discontinuation. DISCUSSION: To our knowledge, this is the first description of atorvastatin inducing DRESS, a severe life-threatening drug eruption. Atorvastatin has previously been implicated in various cutaneous adverse events. Because of their potentially serious side effects, prescription of statins must be carefully evaluated.

[Pneumatosis cystoides intestinalis complicating paraneoplastic dermatomyositis]. / Pneumatose kystique intestinale compliquant une dermatomyosite paranéoplasique.

BACKGROUND: Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by the presence of gas-filled cysts within the wall of the digestive tract. Classically, it occurs in lung or colon diseases but rarely in patients with collagen disorders. We report a new case of PCI occurring during the course of paraneoplastic dermatomyositis. PATIENTS AND METHODS: A 53-year-old woman was diagnosed with dermatomyositis two years ago. Relapse of dermatomyositis preceded the discovery of metastases for which chemotherapy was initiated with 5-fluorouracil and vinorelbine. Three months later, she was admitted to our department for abdominal pains. On physical examination, the abdomen was distended with normal peristalsis. There was no evidence in favour of active dermatomyositis. Abdominal computed tomography scan showed gas collection in the mesentery, revealing the PCI. There was also pneumoperitoneum. The patient slowly improved with symptomatic treatment. DISCUSSION: PCI is uncommon in systemic diseases and extremely rare in dermatomyositis. The pathogenesis and aetiology of PCI are unknown in most cases. In collagen diseases, several hypotheses have been suggested: digestive hypokinesia, corticosteroid-induced ulceration and intestinal vasculitis. In our patient, two factors contributed to PCI: corticosteroid administration and a chemotherapeutic agent (vinorelbine), resulting in severe constipation. Diagnosis of PCI is based on abdominal computed tomography. Pneumoperitonitis is frequent. Although rare, the diagnosis of PCI must be evoked in collagen disorder patients presenting nonspecific abdominal symptoms.

[Relapsing annular erythema following streptococcal throat infection in an adult patient: Adult erythema marginatum associated with rheumatic fever]. / Erythème annulaire récidivant après angine streptococcique : érythème marginé rhumatismal de l'adulte.

BACKGROUND: Erythema marginatum is one of the main Jones diagnostic criteria for rheumatic fever. However, since it rarely occurs in industrialized countries, this diagnosis is seldom suspected, especially in adult patients. CASE REPORT: We report a case of an annular facial eruption associated with fever and polyarthralgia seen twice in a 30-year-old woman following episodes of streptococcal throat infection. DISCUSSION: This case report underlines the fact that the rheumatic fever has not completely disappeared in the highly developed countries. Dermatologists should be careful not to overlook its clinical manifestations and should be vigilant about potential cardiac complications.

[Systematic screening for methicillin-resistant Staphylococcus aureus (MRSA) in the nasal cavities of patients hospitalized in the dermatology departments of the Saint-Louis Hospital]. / Dépistage systématique du portage nasal du Staphyloccocus aureus résistant à la méticilline (SARM) chez les patients hospitalisés en dermatologie : expérience de l'hôpital Saint-Louis.

OBJECTIVES: In a bid to combat methicillin-resistant Staphylococcus aureus (MRSA) more efficiently in our department, we performed a study to 1) clarify the MRSA carriage rate in patients hospitalized in the department; 2) evaluate the rate of MRSA acquisition during hospitalization; 3) describe the MRSA carrier profile; 4) study the morbidity and mortality associated with MRSA. PATIENTS AND METHODS: We conducted a three-month prospective study in all patients hospitalized for more than 24hours in the dermatology department of the Saint-Louis Hospital. Nasal swab cultures were performed on the day of admission, once a week thereafter and on the day of discharge. Clinical and epidemiological data were individually reviewed by means of a standardized questionnaire. RESULTS: In 310 patients, the prevalence of nasal MRSA carriage at admission was 6.5%. During hospitalization, 1.9% of our patients became colonized with MRSA. MRSA carriers were significantly older than non-carriers and had been hospitalized more frequently over the previous 12 months, principally in intensive care or in intermediate or long-term care facilities, and erosive and/or ulcerated dermatitis was more common in this population. Of the 27 patients colonized with MRSA, only three had MRSA infections, and these were successfully treated with antibiotics. DISCUSSION: The observed rate of MRSA carriage was close to that seen in intensive care units (7%). While systematic screening for MRSA in patients with erosive and/or ulcerated dermatitis would allow detection of twice as many cases of MRSA than the usual screening recommendations, this would be associated with little tangible benefit and high costs, and we therefore decided not to change the usual MRSA screening politic in our dermatology department.

[Presenting skin disorders in black Afro-Caribbean patients: a multicentre study conducted in the Paris region]. / Motifs de consultation en dermatologie des sujets de peau noire d'origine africaine et antillaise: enquête multicentrique en région parisienne.

BACKGROUND: There have been few studies in France concerning the specific features of dermatological practice regarding dark skin (Fitzpatrick's phototype V and VI) or the special requirements of black African and Afro-Caribbean patients. AIM: To determine the principal reasons for dermatological consultation among black patients of African or Afro-Caribbean descent in the Paris region. METHODS: This was a prospective clinical study conducted between 15 February and 15 May 2004. The diagnoses of cutaneous conditions leading to dermatological consultation for all black patients of phototype V to VI were recorded by 10 dermatologists practicing in 14 centres within the Paris region. LIMITS: The method used did not allow any conclusions to be drawn regarding the incidence of the presenting conditions among the global population nor did it allow comparison between populations of different phototypes. The absence of any preset list of diagnoses or of precise inclusion criteria regarding evaluation of skin colour left individual investigators with a broad margin of interpretation. RESULTS: In 836 adults and 228 children (half of whom were from Africa and half from the West Indies), diagnoses were as follows: acne in 29.2% of adults and 13.2% in children, and eczema in 6.8% of adults and 27.2% of children. Among dermatoses more specific to black subjects, scalp conditions were frequently seen in both adults (alopecia 7% of diagnoses) and children (tinea capitis 9.6% and alopecia 3.6% of diagnoses). In at least 25% of cases, consultation was associated with dyschromia. Clinical signs suggesting the use of skin lightening products were seen in 95 patients. CONCLUSION: In France, as in other industrialized countries, black patients consult dermatologists essentially for common benign dermatoses also seen amongst white people. Nevertheless, it is important to emphasise the presence of skin problems specific to black patients such as dyschromia and pigmentary disorders, hair and scalp dermatoses, and side effects associated with the use of skin lightening products.

Oligoclonal expansion of HIV-specific cytotoxic CD8 T lymphocytes in the skin of HIV-1-infected patients with cutaneous pseudolymphoma.

A massive infiltration of the skin by activated CD8+ T lymphocytes involving both the dermis and the epidermis has been found in HIV-1-infected patients presenting with a chronic skin rash. We characterized the T cell receptor (TCR) BV-BJ junctional diversity of the skin-infiltrating lymphocytes (SILs) in four patients. The SILs expressed a limited set of TCRBV gene segments. Complementarity determining region 3 length analysis further emphasized their oligoclonality, suggesting that antigen stimulation might be responsible for the cutaneous T cell expansion. Furthermore, independent skin biopsies obtained from the same individual were shown to harbor distinct T cell repertoires, possibly reflecting the spatial heterogeneity of the antigenic stimuli. The CD8+ cytotoxic T lymphocyte (CTL) lines isolated from the skin rash in one patient exhibited a specific, class I MHC-restricted cytotoxic activity against HIV-1 Gag- and Pol-expressing target cells, whereas CTL lines derived from the skin lesions of a second patient were shown to be predominantly Env-specific. Taken together, these data demonstrate the infiltration of HIV-specific CTLs in the skin of HIV-infected patients, and suggest that in addition to their known role in controlling the retroviral infection, these CTLs may also be involved in the pathogenesis of cutaneous inflammatory disorders occurring during the course of HIV infection.

Exclusion of linkage between the collagenase gene and generalized recessive dystrophic epidermolysis bullosa phenotype.

Generalized recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited autosomal disease characterized by dermolytic blister formation. Enhanced collagenase and/or abnormal collagenase have been reported in skin from affected patients, suggesting that collagenase could be responsible for the absence of anchoring fibrils in this disorder. We used a genetic linkage approach to test the hypothesis that this disease is due to a defect in the collagenase gene in nine affected families. Analysis of amplified genomic DNA fragments of the collagenase gene by means of denaturing gradient gel electrophoresis (DGGE) allowed us to detect intragenic polymorphisms, which were subsequently characterized by direct genomic sequencing. Segregation analysis of these polymorphic sites showed exclusion of linkage between the collagenase gene and generalized RDEB phenotype in a family with consanguineous parents and three affected children. However, the possibility of linkage with the collagenase gene in the other eight families tested could not be excluded. The genetic markers described here provide a tool for investigating genetic linkage in other affected families. Overall, our results show that generalized RDEB can be caused by a defect in a gene other than the collagenase gene, and support the hypothesis that the genetic defect lies in abnormal anchoring fibril formation.

Genetic linkage of recessive dystrophic epidermolysis bullosa to the type VII collagen gene.

Generalized mutilating recessive dystrophic epidermolysis bullosa (RDEB) is characterized by extreme skin fragility owing to loss of dermal-epidermal adherence. Immunohistochemical studies have implicated type VII collagen, the major component of anchoring fibrils, in the etiology of RDEB. In this study, we demonstrate genetic linkage of the type VII collagen gene and the generalized mutilating RDEB phenotype. We first identified a Pvull polymorphic site by digestion of an amplified product of the type VII collagen gene, which was shown to reside within the coding region. Genetic linkage analysis between this marker and the RDEB phenotype in 19 affected families which were informative for this polymorphism showed no recombination events, and gave a maximum lod score of 3.97 at a recombination fraction (theta) of 0, demonstrating that this DNA region is involved in this form of RDEB. These data provide strong evidence that the type VII collagen gene, which has also been linked with the dominant form of the disease, harbors the mutation(s) causing the generalized mutilating form of RDEB in these families, thus underscoring the major functional importance of type VII collagen in basement membrane zone stability.

[Erysipelas-like dermatitis of the legs revealing aspergilloma of the maxillary sinus]. / Dermatite érysipéloïde des membres inférieurs révélant un aspergillome du sinus maxillaire.

BACKGROUND: Skin signs is associated with Aspergillus are rare and are seen principally in immunodepressed patients. Distinction is generally made between primary skin aspergillosis, caused by direct cutaneous inoculation with the offending organism, and secondary skin aspergillosis, associated with peripheral emboli from an area of chronic pulmonary or sinus mycetoma. There have been rare reports of indirect satellite skin signs resulting from Aspergillus infection, and below we present such a case. PATIENTS AND METHODS: A 40 year-old immunocompetent man consulted for erysipeloid plaques on the lower limbs recurring over a period of seven months. X-rays and CAT scans of the sinus demonstrated asymptomatic axillary sinusitis probably caused by Aspergillus. The diagnosis was confirmed by surgery, which resulted in cure without additional antifungal treatment. The inflammatory syndrome subsided and after 15 months, there was no recurrence of lesions. DISCUSSION: The absence of relapse following treatment of the focus of aspergillosis forms a major argument in favour of a causal relationship between the erysipeloid dermatitis and the sinus mycotic infection. The hypothesis of a septic embologenic mechanism within the sinus was abandoned in favour of a mechanism similar to streptococcal nodular erythema, seen in diseases involving immune complexes, possibly caused by allergy to Aspergillus proteins. This case history demonstrates the existence of satellite skin signs of Aspergillus infection indicative of neither primary nor secondary aspergillosis.

[Confluent and reticulate papillomatosis of Gougerot and Carteaud: a retrospective study of 9 cases]. / Papillomatose confluente et réticulée de Gougerot et Carteaud: étude rétrospective de neuf cas.

BACKGROUND: Confluent and reticulate papillomatosis of Gougerot and Carteaud is a rare entity and a subject of controversy in terms of nosology. It has occasionally been regarded as a peculiar variant of acanthosis nigricans, pityriasis versicolor or amyloidosis. OBJECTIVES: To discuss confluent and reticulate papillomatosis and its diagnostic criteria as a distinct entity. METHODS: Retrospective study from 1994 to 2005 based on photographic files from 2 dermatology wards at the Saint Louis Hospital, Paris. Files containing a precise clinical description of the rash and at least one mycological element were included. RESULTS: Nine cases were included (6 females, 3 males). These patients showed clinical features comprising elementary lesion, distribution and topography corresponding to the classical description; histology was also consistent with confluent and reticulate papillomatosis, with no signs of amylosis and negative fungal samples or failure of antifungal treatment. One patient was presenting associated acanthosis nigricans. Doxycycline was efficacious in 4 cases in which it was evaluated. CONCLUSION: Confluent and reticulate papillomatosis is a definite entity and is not a superficial fungal disease. It must be distinguished from pityriasis versicolor as well as acanthosis nigricans and cutaneous amyloidosis. The therapeutic efficacy of oral cyclines (doxycycline or minocycline) appears to be an important distinguishing feature that can serve as a diagnostic criterion.

[Malassezia folliculitis: characteristics and therapeutic response in 26 patients]. / Folliculites à Malassezia: Caractéristiques et réponses thérapeutiques chez 26 malades.

BACKGROUND: Malassezia folliculitis is most often described in patients living in hot and humid countries or in immunocompromised patients. Its frequency in France is unknown. We report 26 cases diagnosed at Saint-Louis Hospital between May 2002 and April 2004. The clinical features, the contributing factors, the results of direct mycological examination and/or histology and the efficacy of antifungal treatments were compared to the literature. PATIENTS AND METHODS: The inclusion criteria were the presence of folliculitis on the trunk confirmed by direct microscopy and/or histopathology showing abundant yeast cells in the follicles. RESULTS: Patients comprised 22 men and 4 women (M/F sex ratio: 5: 5) with a mean age of 46 years. Five patients (19%) were immunocompromised. In normal patients, the duration of folliculitis was long with a mean of 61 months. The eruption was typical, with follicular papules and superficial pustules distributed predominantly on the trunk. Itching was frequent (70%). Direct microscopy was more often positive than histology (89% vs 33%). Some sixty-five percent of the patients had been previously treated by topical or systemic antibiotics or anti-acne drugs, which was ineffective in all cases. Cure with topical ketoconazole, oral ketoconazole alone or in combination with topical ketoconazole occurred respectively in 12%, 75% and 75% of patients, but with consistent recurrence within 3 to 4 months after cessation of treatment. DISCUSSION: Malassezia folliculitis is probably misdiagnosed, as suggested by the long time between onset and diagnosis and the high frequency of non-antifungal treatments prescribed. In our study, direct mycological examination provided more effective diagnosis than histology. Treatment is difficult especially because of the high frequency of relapses. CONCLUSION: A diagnosis of Malassezia folliculitis should be considered in young adults or immunocompromised patients with an itching follicular eruption. Further therapeutic trials are needed due to the frequency of relapse.

Mixed epidermal cell-lymphocyte reaction in prediction of acute graft-versus-host disease in bone marrow recipients.

Peripheral blood lymphocytes (PBL) and epidermal cells (EC) of 44 patients to be grafted with bone marrow from an HLA-identical sibling have been used as stimulator cells in primary cultures with effector PBL of one or several potential donors. Proliferative responses against PBL did not differ from those obtained with effector cells cultured in medium alone, whereas EC induced clearly positive proliferation in 21/53 (40%) of the pairs tested. Evaluation of 30 patients followed for more than 3 months after the graft shows that a high level of response in the mixed epidermal cell lymphocyte reaction is directly correlated with the incidence of acute graft-versus-host disease.

Association between INK4a-ARF and p53 mutations in skin carcinomas of xeroderma pigmentosum patients.

BACKGROUND: The INK4a-ARF locus encodes two tumor suppressor proteins, p16(INK4a) and p14(ARF), that act through the Rb-CDK4 and p53 pathways, respectively. Data from murine models and sporadic human skin carcinomas implicate p16(INK4a) and p14(ARF) in the development of skin carcinomas. We examined the frequency of INK4a-ARF, p53, and CDK4 mutations in skin carcinomas from patients with xeroderma pigmentosum (XP), a rare autosomal disease that is associated with a defect in DNA repair and that predisposes patients to skin cancer. METHODS: DNA from skin cancers of 28 unrelated XP patients was screened for mutations in p53, INK4a-ARF, and CDK4 coding exons by single-strand conformation polymorphism analysis and automated sequencing. Data were evaluated with the use of the exact unconditional test derived from Fisher's test. All statistical tests were two-sided. RESULTS: Eight of 28 XP-associated tumors had mutations in the INK4a-ARF locus. Three XP-associated tumors had multiple mutations at this locus. In all, 13 mutations in the INK4a-ARF locus were detected in XP-associated tumors, of which seven (54%) were signature UV radiation-induced mutations, i.e., tandem CC : GG-->TT : AA transitions. p53 mutations, mostly of the type induced by UV radiation, were present in 12 tumors (43%). Statistically significant positive associations were found between the frequency of mutations in p53 and in p16(INK4a) (P =.008) and between the frequency of mutations in p53 and in p14(ARF) (P<.001). No mutations were detected within the CDK4 gene. CONCLUSIONS: We have demonstrated for the first time the occurrence of UV radiation-induced mutations in INK4a-ARF in XP-associated skin carcinomas. The simultaneous inactivation of p53 and INK4a-ARF may be linked to the genetic instability caused by XP and could be advantageous for tumor progression.