Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts.

Resistance to endocrine therapy is a major complication of luminal breast cancer and studies of the biological features of hormonal resistance are limited by the lack of adequate preclinical models. The aim of this study is to establish and characterize a panel of primary human luminal breast carcinoma xenografts, and to evaluate their response to endocrine therapies. Four hundred and twenty-three tumor fragments obtained directly from patients have been grafted in the interscapular fatpad of Swiss nude mice. After stable engraftment with estradiol supplementation, xenografted tumors have been validated by conventional pathology and immunohistochemistry examination, and additional molecular studies. In vivo tumor growth and response to different endocrine treatments were evaluated. We have engrafted 423 tumors including 314 ER+ tumors, and 8 new luminal breast cancer xenografts have been obtained (2.5%). Tumor take was much lower for luminal tumors than for non-luminal tumors (2.5 vs. 24.7%, P < 0.0001), and was associated with two independent criteria, i.e., ER status (P < 0.0001) and a high grade tumor (P = 0.05). Histological and immunohistochemical analyses performed on patient's tumors and xenografts showed striking similarities in the tumor morphology as well as in the expression level of ER, PR, and HER2. Response to hormone therapy, evaluated in 6 luminal models, showed different sensitivities, thus exhibiting heterogeneity similar to what is observed in the clinic. We have established a panel of primary human luminal breast cancer xenografts, recapitulating the biological and clinical behaviors of patient tumors, and therefore suitable for further preclinical experiments.

Internalization and recycling pathways of the thyrotropin receptor.

Scant information is available to date on the intracellular trafficking of the TSH receptor. In the present study we have used stably transfected L cells that express the TSH receptor, 225I-labeled TSH, and antireceptor antibodies as well as gold-conjugated antireceptor monoclonal antibodies and hormone. The latter allowed us to study, by electron microscopy, the cellular distribution and endocytosis of TSH receptor. The receptor was initially localized on the plasmalemma proper and in clathrin-coated pits but was excluded from smooth vesicles open to the cell surface. It was internalized through clathrin-coated vesicles. Constitutive endocytosis represented 10% of cell surface receptor molecules. Endocytosis was increased 3-fold by incubation with hormone. The majority of internalized receptor molecules (90%) was recycled to the cell surface, whereas the hormone was degraded in lysosomes. This recycling of receptor was inhibited by administration of monensin. Electron microscopic and confocal microscopic studies were repeated in primary cultures of human thyroid cells and showed a distribution, and endocytosis pathways, very similar to those observed in transfected L cells. A previous study has shown the LH receptor to be endocytosed in high proportion and to be degraded in lysosomes. Confocal microscopy and colocalization studies with transferrin receptor confirmed that the highly homologous LH and TSH receptors exhibit, when expressed in the same cells, very different cellular trafficking properties. The use of LH/TSH receptor chimeras showed that transmembrane-intracellular domains contain information orienting the protein toward recycling or degradative pathways. The extracellular domain seems to play a role in the extent of intemalization. These observations should now allow the identification of the molecular signals involved.

[Cutaneous ulcerations and osteolysis in the carpal tunnel syndrome]. / Ulcérations cutanées et ostéolyse dans le syndrome du canal carpien.

A case of carpal tunnel syndrome with skin ulcerations and osteolysis is reported. Such cases are unusual. There was a sensory and motor deficit with chronic ulcerations on the palmar surface of the third phalanx of the medius. The distal phalanx of the forefinger had been lost due to osteolysis. Surgical treatment is said to be followed by a healing of the ulcerations.

[Thrombopenia caused by pentosan polysulfate]. / Thrombopénies au polysulfate de pentosane.

Two case-reports of thrombopenias induced by pentosane polysulfate (PSP) are reported. PSP may play a direct role in the genesis of the thrombopenia appearing between the 5th and 15th day of treatment, or a sensitizing role where the thrombopenia occurs quite rapidly following heparin treatment. The clinical complications are haematomas, arterial or venous thromboses and haemorrhages. The platelet aggregation test is always positive in the presence of PSP. The immunological origin is probable. Monitoring of the platelet count is recommanded with this treatment.

[Primary cutaneous monomelic B-cell lymphoma]. / Lymphome B cutané à début monomélique.

BACKGROUND: Cutaneous B cell lymphomas, especially when appearing as a monomelic papulonodular eruption, are rare. PATIENT: Ms H. 87-year-old, consulted for a papulonodular eruption of the left lower limb which developed during the past 5 months. This limb had been the site of a lymphedema since a traumatism 8 years ago. Histopathological analysis and immunostaining of a nodule showed that it was a large cell lymphoma of follicular stem cells. There was no extracutaneous involvement and the patient was successfully treated with radiotherapy. Two months after the completed radiotherapy a cutaneous relapse on the trunk and the upper limbs was treated with cyclophosphamide-vincristine-prednisone chemotherapy. DISCUSSION: Lymphedema probably played a role in the genesis of this lymphoma presumably by reducing the local immune response. It may have harmed endothelial cells and maintained an antigenic stimulation leading first to lymphocyte hyperplasia and eventually to a true lymphoma, in the same way this has been proved for some MALT lymphomas.

[Oral ulcers induced by nicorandil: prevalence and clinicopathological aspects]. / Ulcérations buccales induites par le nicorandil: prévalence et aspects clinicopathologiques.

INTRODUCTION: The first observations of "giant buccal aphthosis" induced by nicorandil were published in 1996. Nicorandil is a potassium channel activator used in the treatment of angina pectoris, which seems to induce specific buccal ulcerations. The purpose of this study was to analyze the clinicopathologic data of patients with aphthosis induced by nicorandil and to study the prevalence of this side effect. PATIENTS AND METHODS: We have seen 3 patients who spontaneously consulted, and 5 patients who were addressed to us after a telephone survey. We have then examined 100 consecutive patients treated by nicorandil for at least 1 month, who were hospitalized in 3 departments of cardiology in Strasbourg, and 100 age- and sex-matched controls who were treated by other antianginal drugs. RESULTS: Our 8 patients suffered from large, chronic and painful ulcerations of a 4-week duration, located on the tongue, the gingiva and the cheeks despite various symptomatic treatments. In one case, histopathologic data were consistent with an eosinophilic ulcer. Prospective study: among 100 patients treated by nicorandil, 5 had unusual chronic buccal ulcerations, whereas none of the 100 controls had aphthosis (p = 0.03). The confidence interval (99 p. 100) of this side effect prevalence was therefore 1 p. 100 to 14 p. 100. DISCUSSION: Nicorandil can induce large and painful buccal ulcerations with severe dysphagia, weight loss, and depression. Dermatologists should be aware of this particular side-effect, since our study showed a high prevalence, and because lesions heal rapidly after withdrawal of nicorandil. Why nicorandil may be associated with mouth ulcers remains unanswered. A past history of aphthae could be a cofactor of this side-effect.

[Does subcutaneous cellular tissue exist?]. / Le tissu cellulaire sous-cutané existe-t-il?

BACKGROUND: The definition of the "subcutaneous cellular tissue" is still debated. METHODS: In order to establish the localisation and composition of this tissue, or, merely its existence, we interviewed French dermatologists and conducted a bibliographic study on the historical definitions of the so-called "subcutaneous cellular tissue". A questionnaire was sent to French professors of dermatology to assess their definition of the "subcutaneous cellular tissue". They were also asked to make a simple cartoon showing the anatomy of the skin and "subcutaneous cellular tissue". RESULTS: We obtained 37 answers which could be classified in three main categories: 1) "subcutaneous cellular tissue" and hypodermis are synonymous, 2) "subcutaneous cellular tissue" is an autonomous tissue which separates the hypodermis from the tissues below and 3) "subcutaneous cellular tissue" designates all structures located below the hypodermis. In an historic perspective, the "cellular system" was a macroscopic concept described in the eighteenth century as whitish fibrils delimitating "cells". It was renamed loose connective tissue in the twentieth century and thus "cellular" became obsolete. The definition of skin, and of "subcutaneous cellular tissue" in particular, has greatly changed over time. In the eighteenth century, only epidermis and dermis were considered as belonging to the skin, although some included the tela subcutanea. In the twentieth century, the "subcutaneous cellular tissue" is considered either as a part of the hypodermis, or as the hypodermis itself or as a tissue located between the hypodermis and the fascia. DISCUSSION: The difficulty in defining "subcutaneous cellular tissue" is the result of a French semantic problem. The "cellular tissue" became loose connective tissue. For French dermatologists, the skin is composed of epidermis, dermis and hypodermis and the hypodermis can therefore not be subcutaneous. In order to check whether an autonomous tissue could be evidenced under the skin, we conducted an histologic study, which is presented in a second article.

[Cellular subcutaneous tissue. Anatomic observations]. / Le tissu cellulaire sous-cutané. Observations anatomiques.

INTRODUCTION: We showed in a companion paper that the definition of the French "subcutaneous cellular tissue" considerably varied from the 18th to the end of the 20th centuries and has not yet reached a consensus. To address the anatomic reality of this "subcutaneous cellular tissue", we investigated the anatomic structures underlying the fat tissue in normal human skin. METHODS: Sixty specimens were excised from the surface to the deep structures (bone, muscle, cartilage) on different body sites of 3 cadavers from the Institut d'Anatomie Normale de Strasbourg. Samples were paraffin-embedded, stained and analysed with a binocular microscope taking x 1 photographs. Specimens were also excised and fixed after subcutaneous injection of Indian ink, after mechanic tissue splitting and after performing artificial skin folds. RESULTS: The aspects of the deep parts of the skin greatly varied according to their anatomic localisation. Below the adipose tissue, we often found a lamellar fibrous layer which extended from the interlobular septa and contained horizontally distributed fat cells. No specific tissue below the hypodermis was observed. Artificial skin folds concerned either exclusively the dermis, when they were superficial or included the hypodermis, but no specific structure was apparent in the center of the fold. India ink diffused to the adipose tissue, mainly along the septa, but did not localise in a specific subcutaneous compartment. DISCUSSION: This study shows that the histologic aspects of the deep part of the skin depend mainly on the anatomic localisation. Skin is composed of epidermis, dermis and hypodermis and thus the hypodermis can not be considered as being "subcutaneous". A difficult to individualise, fibrous lamellar structure in continuity with the interlobular septa is often found under the fat lobules. This structure is a cleavage line, as is always the case with loose connective tissues, but belongs to the hypodermis (i.e. fat tissue). No specific tissue nor any virtual space was observed below the skin. Thus, the commonly used term "subcutaneous cellular tissue" is inappropriate.

[Macrophage activation syndrome disclosing leukemic transformation of mycosis fungoides]. / Syndrome d' activation macrophagique Révélateur de la transformation leucémique d' un mycosis fongoïde.

BACKGROUND: Mycosis fungoides can mimic pigmented purpuric dermatitis. We report such a case which progressed to peripheral T-cell lymphoma; progression was revealed by reactive hemophagocytic syndrome (RHS). CASE REPORT: A 65-year old male patient was hospitalized for a pigmented and purpuric eruption. The skin lesions appeared 2 years earlier and at that time biopsy had shown pigmented and purpuric dermatitis. One month before hospitalization, general signs appeared. On admission, he had papular and purpuric rash, mainly on the trunk, hepatosplenomegaly, enlarged axillar and inguinal lymph nodes, and fever at 38.2 degrees. A skin biopsy showed histologic changes typical of mycosis fungoides. He also had bicytopenia, hepatitis, and increased triglyceride and ferritin levels suggesting RHS which was proved by means of bone marrow biopsy. These tests also evidenced peripheral T-cell lymphoma. The patient was treated with two courses of chemotherapy (CHOP) but the disease progressed and he deceased. DISCUSSION: Mycosis fungoides can occasionally begin with an eruption very closely resembling pigmented purpuric dermatitis. Therefore, repeated biopsies should be done in case of widespread permanent pigmented purpuric dermatitis of no apparent origin. RHS is a life-threatening disease. The diagnosis should be suspected in any cytopenic patient with fever, increased triglyceride levels and abnormal liver tests. A search for an etiology must then be undertaken a prompt treatment is needed.

[Chloroquine-induced achromotrichia. An ultrastructural study]. / Achromotrichie due A la chloroquine. Etude ultrastructurale.

BACKGROUND: Electron microscopy examination of scalp biopsies from a patient with chloroquine achromotrichia gave elements concerning the pathogenesis of chloroquine-induced achromotrichia. CASE REPORT: A 21-year old light brown-haired patient developed achromotrichia after four months of treatment with chloroquine for subacute lupus erythematosus. Hair bleaching completely regressed 5 months after discontinuing chloroquine despite replacement with hydroxychloroquine. During the achromatrichia phase, many ultrastructural anomalies were observed in the hair root melanocytes: the nuclei were small and densified, and there was an accumulation of immature melanosomes in the cytoplasm; these melanosomes, mainly in stage II, were rarely transferred to keratinocytes. After recovery from the achromotrichia, melanocytes displayed a normal aspect. DISCUSSION: Pathophysiological disturbances leading to chloroquine induced achromotrichia are still unclear. The ultrastructural study of hair follicles in our patient show that under chloroquine action melanocytes become unable to perform complete melanin synthesis and to produce normally melanized melanosomes which may be transferred to keratinocytes. Non-melanized or poorly melanized melanosomes accumulate in the melanocytes which finally become inactive cells. These findings suggest that achromotrichia is induced by a toxic effect of chloroquine on the melanocyte.

[Painful edema of the feet revealing ankylosing spondylitis]. / OEdèmes douloureux des pieds révélateurs d'une spondylarthrite ankylosante.

INTRODUCTION: Painful peripheral oligoarthritis can reveal ankylosing spondylitis. In some instances, an acral pitting edema can be the sign of this affection. CASE REPORT: A 39-year-old man, with no significant previous medical history, consulted in a dermatology department for acral pain and edema of both feet, which were exacerbated during the second part of the night. On examination, he had a pitting edema and a livedo of the distal part of the feet. Biological investigations revealed an inflammatory syndrome and the presence of the histocompatibility HLA-B27 antigen. Bone scintigraphy revealed distal hyperfixation on both feet. Diagnosis of ankylosing spondylitis was established. DISCUSSION: Late-onset ankylosing spondylitis, which appears in subjects older than 35 years, can manifest as peripheral arthritis with systemic signs, often in the absence of involvement of the axial skeleton. Peripheral pitting edema of lower limbs can be the presenting sign. Since cutaneous involvement can be the presenting sign, dermatologists should be aware of this entity.

[Pavlik's method of reduction treatment of congenital hip dislocation]. / Repositie behandeling van de congenitale heupluxatie volgens Pavlik.

In 68 patients with 101 congenital dysplasias of the hip results of treatment by Pavlik harness were retrospectively analysed. Of the 101 there were 61 dislocations. After six weeks of treatment with the Pavlik harness reduction was achieved in 48 of the 61 dislocated hips (80%). However, because of persisting dysplasia 50% of all cases had to be treated with an abduction device for a few months. There were no complications, in particular osteonecrosis of the femoral head was not observed. Provided well controlled, the Pavlik harness is a good, safe and easy method for treating congenital dislocation of the hip.

[Cockett's syndrome]. / Le syndrome de Cockett.

Two personal cases from the pretext for a short discussion on the syndrome defined by Cockett in 1965. The condition is a post-phlebitic syndrome localised to the left common iliac vein. This vein, which is crossed by the right common iliac artery, is in fact the site, at the level of this crossing, of intraluminal and extraluminal lesions whose nature and significance are controversial. The clinical manifestations are those of a severe post-phlebitic syndrome and the classical medical treatments are often inadequate. Surgery can bring about improvement, but its indications must be carefully assessed.

[Abnormal popliteal arteries]. / Les artères poplitées anormales

Arteriopathy restricted to the popliteal artery, except in cases of atheroma, must indicate three of four unusual diagnoses: the trapped popliteal artery and the dessicating haematoma are anatomo-clinical entities that have been identified only relatively recently. The popliteal artery may be trapped by the medial gastrocnomius muscle, round the tendon of which the artery passes (totally or partially). This results in compression of the artery and eventually in thrombosis. Clinically, intermittent claudication is seen that may deteriorate and lead to gangrene of the toes. Arteriography makes it possible to diagnose the condition as the condition as the artery is considerably displaced inwards. Surgical correction is simple: sectioning of the tendon and repositioning of the artery. Dessicating haematoma of the popliteal artery is due essentially to atheroma, associated with medianecrosis. A "egg-timer" stenosis is found by arteriography and this condition also progresses towards thrombosis. Arterial restoration is called for, usually by bridging.

[Thoraco-brachial outlet syndrome]. / Le syndrome de la traversée thoraco-brachiale

Under this name are included all the neurovascular disorders of ftthe upper limb caused by compression of the subclavian vessels and the vessels of the brachial plexus. There are three dangerous anatomical regions where trouble can arise: the now of scalene muscles, the costo-clavicular interspace, and the pulley of the smaller pectoral muscle. The clinical manifestations are fairly variable but often indicate the diagnosis. Certain clinical tests, in particular angiography with the arm in hyperabduction contribute towards confirmation. With minor forms of the syndrome rehabilitation should suffice. In other cases the cause of the sompression can be removed by surgery: sectioning of the anterior scalene, suppresion of a cervical rib, and particularly resection of the first rib, as this plays an important role.