Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition.

Imatinib targets the Bcr-Abl oncogene that causes chronic myelogenous leukemia (CML) in humans. Recently, we demonstrated that besides triggering apoptosis in K562 cells, imatinib also mediated their erythroid differentiation. Although both events appear to proceed concomitantly, it is not known at present whether or not imatinib-induced apoptosis and differentiation are interdependent processes. Hence, we investigated the requirements for Bcr-Abl inhibitor-mediated apoptosis and erythroid differentiation in several established and engineered CML cell lines. Imatinib triggered apoptosis and erythroid differentiation of different CML cell lines, but only apoptosis exhibited sensitivity to ZVAD-fmk inhibition. Conversely, the p38 mitogen-activated protein (MAP) kinase inhibitor, SB202190, significantly slowed down erythroid differentiation without affecting caspase activation. Furthermore, imatinib and PD166326, another Bcr-Abl inhibitory molecule, triggered erythroid differentiation of K562 cell clones, nevertheless resistant to Bcr-Abl inhibitor-induced apoptosis. Finally, short hairpin RNA inhibitor (shRNAi) silencing of caspase 3 efficiently inhibited caspase activity but had no effect on erythroid differentiation, whereas silencing of Bcr-Abl mimicked imatinib or PD166326 treatment, leading to increased apoptosis and erythroid differentiation of K562 cells. Taken together, our findings not only demonstrate that Bcr-Abl inhibitor-mediated apoptosis and differentiation are fully distinguishable events, but also that caspases are dispensable for erythroid differentiation of established CML cell lines.

Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML.

Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.

Non-AIDS-associated Kaposi's sarcoma (classical and endemic African types): treatment with low doses of recombinant interferon-alpha.

In the treatment of the classical and endemic African forms of Kaposi's sarcoma (KS), radiation therapy and chemotherapy have been widely used with varying degrees of success and morbidity. We here report our preliminary experiences with low doses of recombinant interferon alfa-2b (rIFN alpha-2b) in the treatment of these types of KS, non-linked to the acquired immunodeficiency syndrome (AIDS). Ten consecutive patients (eight patients with classical and two with endemic KS) with a median age of 62 years were treated long-term with 5 X 10(6) units of rIFN alpha-2b (Introna) given subcutaneously three times weekly for at least 6 months. Of the 10 patients, six presented with cutaneous disease only, and four had additional visceral involvement. After 6 months of treatment, seven of the 10 patients had a major response of the cutaneous lesions, and three patients showed stable skin diseases. Of the four patients with additional visceral disease, one patient showed a complete regression of an intramyocardial tumor involving the right atrium and ventricle, whereas in the three other patients stabilization of the visceral lesions with marked symptomatic improvement occurred. On the whole, the long-term results over a median duration of 12 months (range, 7 to 30) are also satisfactory: IFN-alpha continued to control KS in all patients. The treatment was generally well tolerated; no serious side effects were observed. Our preliminary data suggest that low-dose rIFN alpha-2b regimens are effective in classical and endemic African KS. However, further studies are needed to establish the exact role for IFN-alpha as alternative to radiation and chemotherapy.

Papillon-Lefèvre syndrome. Ultrastructural study and successful treatment with acitretin.

Four siblings affected by Papillon-Lefèvre syndrome (PLS) ranged in age from 2 to 11 years. The parents were unaffected and parental consanguinity was present. The 2-year-old girl showed the early manifestations of PLS; that is, slight gingival swelling and erythema occurring simultaneously with minimal scaling of palms and soles. The other siblings, aged 5, 8, and 11 years, showed severe periodontopathy with tooth loss and marked palmoplantar keratoderma with a centripetal extension of the keratoses to the limbs and trunk. These three older siblings were treated with acitretin (Ro 10-1670), the free acid of etretinate, with complete clearing of the skin and healing of gingival pockets. Treatment was given for 16 months; teeth that erupted during therapy were free of periodontopathy and remained firmly anchored to the alveolar bone. In two of the children ultrastructural examination of involved skin was performed before and during acitretin treatment. Before treatment a large number of lipidlike vacuoles were found in corneocytes and in granulocytes; tonofilaments were reduced in number, and keratohyaline granules frequently showed a rectangular or globular shape. During treatment with acitretin these abnormalities diminished markedly. Thus, etretin is effective in treating PLS and, if treatment is started at an early age, should allow patients with PLS to have normal adult dentition.

Monoclonal gammopathy in Sézary syndrome. Report of three cases and review of the literature.

Three patients with Sézary syndrome had monoclonal gammopathy: two had gammopathy of unknown significance and one had myeloma. The frequency of the association of Sézary syndrome and monoclonal gammopathy seems to be lower than previously suggested. However, it does emphasize that the presence of T-cell cutaneous disease does not preclude B-cell clonal proliferation.

Pachydermoperiostosis with gastric hypertrophy, anemia, and increased serum bone Gla-protein levels.

We evaluated a patient in whom pachydermoperiostosis occurred in conjunction with anemia and gastric hypertrophy. The mechanism of the anemia appears multifactorial because, besides a myelofibrosis, a serum inhibitor of the late stage of erythropoiesis was detected. The elevated serum bone Gla-protein (osteocalcin) favors the hypothesis that primary hypertrophic osteoarthropathy represents an imbalance between increased osteoblastic bone formation and normal bone resorption.

Severe acne due to chronic amineptine overdose.

We report six women with severe acne lesions associated with taking amineptine, a tricyclic antidepressant. The lesions appeared after self-administration of high doses of the drug over long periods of time. They mainly occurred on the face, back, and thorax, but were also found on the extremities and in the perineal region. In five of the six cases, severity of cutaneous lesions appeared to be correlated with degree of overdose. The sixth patient never admitted having taken amineptine. Most of the patients had been unsuccessfully treated with isotretinoin for 18 months. In all six cases, chromatography of urinary 17-ketosteroids showed abnormal peaks and retention times which were different from those usually found for known steroids. In addition, the areas under these peaks were found to be a function of the degree of intoxication and of the clinical severity of the lesions. Mass spectrometry was used to qualitatively study urinary amineptine metabolites, disclosing compounds normally found only in trace amounts, as well as certain others heretofore not described in man. In two of the three patients who stopped taking amineptine, cutaneous lesions subsequently diminished, totally disappearing in the least severe case.

Particular clinical features of psoriasis in infants and chidren.

The onset of psoriasis is observed before the age of 10 years in 15% of all patients. The clinical pattern often takes on a peculiar form. Psoriasis guttata--or less frequently nummular psoriasis--is the initial phase during childhood. It is very difficult to establish a diagnosis on the basis of incipient features when childhood psoriasis is located on the head, palms, soles, or on the fingers, toes and nails. Intertriginous or flexural psoriasis, psoriasis spinulosa and oral psoriasis is also described. The onset of napkin psoriasis starts at the age of 3 months. Occasionally, Leiner's disease may develop into a typical, chronic psoriasis. We have concentrated our studies on the less common features of childhood psoriasis: the generalized pustular infantile form, congenital psoriatic erythroderma, acquired psoriatic erythroderma, and infantile arthropathic psoriasis.

[Establishment of a 2-stage prognostic classification of primary malignant melanoma derived from a multidimensional analysis and from an agreement study]. / Etablissement d'une classification pronostique en 2 stades du mélanome malin primitif à partir d'une analyse multidimensionnelle et d'une étude de concordance.

Slides of 198 patients with primary malignant melanoma have been reevaluated independently by three pathologists; considered parameters were histologic type, Clark's level and tumor thickness. The agreement between pathologists is excellent, especially for histologic type and thickness. The use of the Cox's regression model, dealing with disease free interval as response criterion, shows that the main prognostic factor is tumor thickness, whatever the pathologist. A prognostic staging is thus proposed, based only on the tumor thickness, less than 2 mm, greater than 2 mm. The prognostic value of this staging is confirmed on a new sample of 145 patients. This classification is used as decision tool in a new randomized clinical trial.

[Lichen striatus with nail involvement. Report of 4 cases and review of the 4 cases in the literature (author's transl)]. / Le lichen striatus onychodystrophique. A propos de 4 cas avec revue de la littérature (4 cas).

Four cases of lichen striatus (L.S.) with nail involvement were studied and the four cases published previously reviewed. There are several types of nail dystrophy: fraying, longitudinal ridging, splitting and shredding, onycholysis, and total nail loss. All of them are transient and can be explained by the pathologic changes observed, particulary the transitory disruption of the basal layer. Lichen striatus must be differentiated from systematized eruptions such as lichen planus (the simultaneous occurrence of L.S. and lichen planus is extremely rare and the resemblance of one dermatosis to the other can be so pronounced that a differential diagnosis is difficult) linear localized neurodermatitis, linear psoriasis (almost always associated with more typical lesions of psoriasis elsewhere on the body), linear keratosis follicularis (histologically typical of Darier's disease) and linear epidermal nevus which occasionaly does not appear at birth but later in life and may present nail involvement. In some cases, however, clinical similarity of the inflammatory linear verrucose epidermal nevus to lichen striatus is striking.

[Antenatal diagnosis of hereditary epidermolysis bullosa]. / Le diagnostic anténatal des épidermolyses bulleuses héréditaires.

Among the genetic disorders of the skin, the heterogeneous group of epidermolysis bullosa includes some of the most severe. Prenatal diagnosis is of considerable importance to the families who have had an affected child, or in which one of the parents is affected. The prenatal diagnosis is performed using fetoscopy and fetal skin biopsy. Fetal skin samples are taken at 20 weeks of gestation and are examined by light and electron microscopy to determine whether the fetus is affected. We report here the French experience on prenatal diagnosis of the severe inherited epidermolysis bullosae. Given the severity and frequency of Herlitz syndrome, it is not surprising that this is the most frequently encountered disease in our series of prenatal diagnosis (14 of 21 epidermolysis bullosae), followed by Hallopeau-Siemens (6 cases), and Pasini type (1 case). Our exclusion diagnosis of a Pasini fetus was the first prenatal diagnosis of this type of epidermolysis bullosa performed and reported in the literature. We stress here in this paper that observing the site of separation in the epidermal dermal junction is not sufficient to make a positive prenatal diagnosis. Prenatal diagnosis depends on the observation of the specific ultrastructural marker of the disease such as: hypoplasia and absence of hemidesmosomes and sub-basal dense plate in junctional epidermolysis bullosa-Herlitz, collagenolysis in recessive dystrophic epidermolysis bullosa-Hallopeau-Siemens, and absence and hypoplasia of anchoring fibrils in dominant dystrophic epidermolysis bullosa-Pasini. Until biochemical defects are clarified and suitable tests become available, electron microscopy remains the only current means for reliable, genetically useful, diagnosis of epidermolysis bullosa. In 62 per cent of cases of our series a prenatal diagnosis of exclusion of disease was made and we would stress that in high risk families repeated fetoscopies for prenatal diagnosis are possible in consecutive pregnancies thus allowing the family to have only normal children.

[Dosage and modulation of cutaneous steroid receptors during antihormonal therapy in a case of Stewart-Treves syndrome]. / Dosage et modulation des récepteurs stéroïdiens cutanés sous thérapeutique anti-hormonale dans le cas d'un syndrome de Stewart-Trèves.

We report a case with clinical symptoms of a Stewart-Treves syndrome 2 years after homolateral mastectomy for carcinoma. The mammary origin of the syndrome was found at histology and confirmed by assays of hormone receptors in skin biopsies before and during anti-hormone therapy. This treatment rapidly attenuated the clinical signs of both the lymphedema and the pseudo-Kaposi cutaneous lesions. Hormone receptor determinations are suggested as useful tools for the diagnosis and for surveillance of therapeutic efficacy. CASE HISTORY. This 68-year old patient whose right breast was removed in April, 1985 for scirrhous carcinoma was hospitalized in February, 1987 for lymphedema, pain and functional impotence of the right arm accompanied by Kaposi-like skin lesions in the homolateral mammary region, the right shoulder and the upper third of the right arm. Tamoxifen administration in doses of 30 mg/day was started on the day of the first biopsies at sites of the cutaneous lesions and continued for 60 days. Additional biopsies were taken on days 30 and 60 of therapy. Under therapy clinical improvement was noted with decrease in the lymphadenopathy and in the size of the nodular skin lesions. PATHOLOGY AND STEROID HORMONE ASSAYS. Standard histological studies were performed on one of the biopsies. The remaining tissues were flash frozen and assayed for estrogen and progesterone receptors. ER was determined by radio-ligand assay (RLA) to measure the free binding sites of the hormone or anti-hormone and by enzyme immunoassay (EIA) to detect both free and occupied antigenic sites.(ABSTRACT TRUNCATED AT 250 WORDS)

[The practice of judo and the risk of fungal contamination]. / Pratique du judo et risque de contamination fongique.

Over one hundred judokas, a large training tatami, the ground of shower rooms were examined by various methods. Cultures showed that Trichophyton rubrum, though being as frequent as Trichophyton interdigitale on the feet of sportsmen is much less frequent on the training tatami and was never isolated in great quantity from the shower rooms. The problem of fungus contamination in this kind of sportsmen is obvious. Some prophylactic measures are proposed.

[Acquired localized epidermolysis bullosa. A case with scalp involvement and immunoelectron microscopic study]. / Epidermolyse bulleuse acquise localisée. Un cas avec atteinte du cuir chevelu étudié en immunomicroscopie électronique.

The case of a 59-year old man who had a clinical Brunsting-Perry pemphigoid localized to the scalp is described. Direct immunoelectron microscopy demonstrated IgG and C3 immune deposits in the anchoring fibril zone, as in epidermolysis bullosa acquisita. No circulating antibodies were detected by Western immunoblotting on epidermal and dermal extracts. These findings show that Brunsting-Perry pemphigoid is not an immunological entity and that it widens the clinical spectrum of epidermolysis bullosa acquisita.

[Type IV Ehlers-Danlos syndrome of acrogeria type]. / Syndrome d'Ehlers-Danlos type IV à type d'Acrogeria.

A familial case of acrogeria, occurring in a mother and her daughter, is reported. A 12-year old mentally retarded girl was seen with a history of repeated ecchymoses despite normal hemostasis. On clinical examination, the skin was diffusely atrophic with atrophy and wrinkling most pronounced on the extremities. The venous pattern was noticeable on the upper aspect of the anterior trunk and the extremities. The feet were small and the nose was pinched. "Cigarette paper" scars and molluscoid pseudotumors were seen over the elbows and the knees. Some skin hyperextensibility was noted and loose-jointedness of the fingers was demonstrated. The fingernails, hair, dentition, and bone roentgenograms were normal. The mother, a 34-year old woman, presented with the same abnormalities and reported the same condition in her mother. A younger brother was normal and there was no history of consanguinity. In both cases, the skin biopsy specimens showed dermal atrophy with irregular increase of the elastic staining material in the mid dermis. Ultrastructural studies showed a widened endoplasmic reticulum within the fibroblasts. Biochemical studies, performed in the daughter, showed complete lack of collagen III in the dermis. This, together with the visceral complications occurring in the mother and in previously reported patients, suggests that acrogeria represents a clinical variant of Ehlers-Danlos type IV. Its association with phenylketonuria in the daughter is considered to be coincidental.

[Digestive symptoms of scleroderma (author's transl)]. / Les symptômes digestifs de la sclérodermie.

The authors successively study the oral, peri-oral, esophageal, intestinal and anal manifestations of systemic scleroderma. They point out that dental, salivary, and esophageal involvement is of great interest for diagnosis and prognosis. They particularly describe the malabsorption syndrome including anatomical and ultrastructural lesions of the smooth muscle fibers. They present an original study of arrector pili in clinically and histologically non-involved skin of patients undergoing scleroderma. Finally they state that any suspected or diagnosed scleroderma needs a digestive check-up as follows: radiologic examination of the teeth, biopsy of the minor salivary glands of the lower lip, radiologic study of esophageal motility and radioactive C 14 glycocholate test.

[Epithelioid hemangioendothelioma: disease course in 3 cases]. / Hémangioendotheéliome épithélioïde: évolution dans 3 cas.

INTRODUCTION: Epithelioid hemangioendothelioma is an uncommon vascular neoplasm, one of intermediate-grade malignancy. Cutaneous epithelioid hemangioendothelioma is rare and often associated with multiple site involvement. CASES: Three patients with cutaneous EHE without systemic involvement in one case, with skin, liver and lung tumoral lesions in two others cases are reported. One patient is in complete remission after one year. The second patient is stable without treatment after ten years. In the third patient, alpha interferon given for one year don't produce effective results and the lesions do not progress without treatment after eight years of follow-up. DISCUSSION: Cutaneous presentation of EHE is quite variable. After the diagnosis is done, systemic involvement must be detected specially in bone, liver or lung. Metastatic spread or mulitcentric origin of the tumor are a matter of controversy. The pathobiologic behavior of EHE is not clearly recognized. Little data are available regarding the results of treatment with alpha interferon.

[Coexistence of lichen planus and bullous pemphigoid (an immunofluorescence study of a "lichen pemphigoides") (author's transl)]. / Coexistence d'un lichen plan et d'une pemphigoide bulleuse étude en immunofluorescence d'un "lichen pemphigoïde".

A 35 year old black man presented with a generalized eruption of lichen planus; subsequently tense blisters appeared within the lichenoid lesions and on clinically normal skin. Histopathological characteristics of lichen planus were present in the papules, and those of bullous pemphigoid were seen in the bullae taken from non-lichenoid skin. Direct immunofluorescence studies revealed immunological characteristics of lichen planus in skin and mucosal lesions of L. P. Bound IgG and beta1 C/beta1 A with tubular patterns were detected at the dermo-epidermal junction in all the skin fragments (clinically normal skin, bullous lesions lichenoid skin and mucous lesions). Indirect immunofluorescence studies showed at several intervals that the patient had circulating antibasement membrane zone antibodies (IgG; titres 1/50). This is the third published case in which immunofluorescence studies have established the "pemphigoid" nature of some bullous lichen planus. These findings are in favour of an immune disorder in lichen planus.

[Anticytoplasmic antibodies of human epidermal cells (author's transl)]. / Anticorps anticytoplasme des cellules de l'épiderme humain

Antibodies reacting with the cytoplasm of epidermal cells (E. C. A.) were defected by indirect immunofluorescence (I.I.F.) studies of 255 sera in various dermatoses (8 p. 100) and significantly more frequently (46 p. 100) in bone marrow transplanted patients having skin lesions. Bound E.C.A. were only found in two cases. E.C.A. were found to be devoided of any diagnostic value. E.C.A. were interpreted as the result of a skin injury liberating skin antigens which stimulated their production. The reaction of E.C.A. in I.I.F. on human skins substrates showed three different patterns; in some cases only the basal cell layer was stained; in others only the supra basal layers were stained; in other all the layers were stained. A serum was shown to be able to give the three patterns of reaction (or no reaction at all) if different human skins were used as substrate. Autologous skins never gave a basal cell layer staining. These findings support the facts that (I) there is antigenic differences between the basal cell layer and the supra basal layers (with regard to the cytoplasmic antigens) (II) these antigens may be different from one subject to the other, supporting the allogeneic nature of this system. Therefore, E.C.A. are regarded as a useful marker of the human skin cytoplasmic antigens.

[Cutaneous localizations of disseminated Histoplasma capsulatum histoplasmosis in a case of acquired immunodeficiency]. / Localisations cutanées d'une histoplasmose disséminée à Histoplasma capsulatum au cours d'un cas d'immunodéficience acquise.

A widespread maculo-papular cutaneous rash appeared on a HIV-positive young bisexual Cambodian man. He was treated for Mycobacterium tuberculosis and Pneumocystis carinii infections. He had been residing in France for seven years. Histology showed, within the dermis, abundant extracellular and intramacrophagic yeast-like organisms suggestive of histoplasmosis. Cultured specimens produced a growth of colonies after three weeks on Sabouraud 4 p. 100 dextrose agar at 25 degrees C. Numerous macroconidia were found which made the species diagnosis of Histoplasma capsulatum possible. Despite initiation of therapy with amphotericin B the patient died. Cutaneous involvement with or without specific features is uncommon in disseminated histoplasmosis. The specific cutaneous lesions are protean. They rarely are the presenting sign of initial infection. Disseminated histoplasmosis has a poor prognosis in acquired immunodeficiency syndrome: amphotericin B is not curative. Maintenance suppressive therapy with ketoconazole has been recommended following amphotericin B completion, although break-through has been reported.