Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Use of mesenchymal stem cells for cutaneous repair and skin substitute elaboration.

Human mesenchymal stem cells (MSCs) are a heterogeneous population of fibroblast-like cells, which are present in different locations, including bone marrow, adipose tissue, extra-foetal tissues, gingiva and dermis. MSCs, which present multipotency capacities, important expansive potential and immunotolerance properties, remain an attractive tool for tissue repair and regenerative medicine. Currently, several studies and clinical trials highlight the use of MSCs in cutaneous repair underlining that their effects are essentially due to the numerous factors that they release. MSCs are also used in skin substitute development. In this study, we will first discuss the different sources of MSCs actually available. We will then present results showing that bone marrow-derived MSCs prepared according to Good Manufacturing Practices and included in a dermal equivalent are able to promote appropriate epidermis growth and differentiation. These data demonstrate that bone marrow-derived MSCs represent a satisfactory alternative to dermal fibroblasts in order to develop skin substitute. In addition, MSCs could provide a useful alternative to sustain epidermis development and to promote wound healing.

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.

[Occupational physicians and occupational cancers: attitudes, opinions, practices. A qualitative study in South Eastern France]. / Médecins du travail et cancers professionnels : attitudes, opinions et pratiques. Une recherche qualitative dans le Sud-Est de la France.

BACKGROUND: A qualitative study was conducted in 2008 of occupational physicians (OPs) in south-eastern France to document their attitudes, opinions and practices on prevention and screening of occupational cancers. This was done to provide elements to prepare the questionnaire of a quantitative study in 2009. METHODS: Semi-structured interviews were conducted using a structured interview guide with 20 OPs. The data collected were subjected to an analysis of thematic content type. RESULTS: The analysis revealed that OPs face many difficulties when preventing occupational cancers. For most of OPs, these difficulties appeared related to "external factors": lack of involvement of employers and minimization of risks by employers and employees. Lack of time, overload and, for some OPs, perceived lack of independence towards employers, were also mentioned as barriers to cancer prevention. This study also suggested hypotheses related to OPs themselves (internal factors): perceived lack of effectiveness and, trend to minimize the risks of occupational cancer in their geographical area. Finally, the results suggest a significant heterogeneity of OPs' practices regarding occupational cancer screening. CONCLUSION: These results raise several hypotheses that will be addressed further in the quantitative survey. They warn about the difficulties of a profession that seems to encounter a demographic and identity crisis.

Empirical nonparametric bootstrap strategies in quantitative trait loci mapping: conditioning on the genetic model.

Several nonparametric bootstrap methods are tested to obtain better confidence intervals for the quantitative trait loci (QTL) positions, i.e., with minimal width and unbiased coverage probability. Two selective resampling schemes are proposed as a means of conditioning the bootstrap on the number of genetic factors in our model inferred from the original data. The selection is based on criteria related to the estimated number of genetic factors, and only the retained bootstrapped samples will contribute a value to the empirically estimated distribution of the QTL position estimate. These schemes are compared with a nonselective scheme across a range of simple configurations of one QTL on a one-chromosome genome. In particular, the effect of the chromosome length and the relative position of the QTL are examined for a given experimental power, which determines the confidence interval size. With the test protocol used, it appears that the selective resampling schemes are either unbiased or least biased when the QTL is situated near the middle of the chromosome. When the QTL is closer to one end, the likelihood curve of its position along the chromosome becomes truncated, and the nonselective scheme then performs better inasmuch as the percentage of estimated confidence intervals that actually contain the real QTL's position is closer to expectation. The nonselective method, however, produces larger confidence intervals. Hence, we advocate use of the selective methods, regardless of the QTL position along the chromosome (to reduce confidence interval sizes), but we leave the problem open as to how the method should be altered to take into account the bias of the original estimate of the QTL's position.

A nonparametric bootstrap method for testing close linkage vs. pleiotropy of coincident quantitative trait loci.

A novel method using the nonparametric bootstrap is proposed for testing whether a quantitative trait locus (QTL) at one chromosomal position could explain effects on two separate traits. If the single-QTL hypothesis is accepted, pleiotropy could explain the effect on two traits. If it is rejected, then the effects on two traits are due to linked QTLs. The method can be used in conjunction with several QTL mapping methods as long as they provide a straightforward estimate of the number of QTLs detectable from the data set. A selection step was introduced in the bootstrap procedure to reduce the conservativeness of the test of close linkage vs. pleiotropy, so that the erroneous rejection of the null hypothesis of pleiotropy only happens at a frequency equal to the nominal type I error risk specified by the user. The approach was assessed using computer simulations and proved to be relatively unbiased and robust over the range of genetic situations tested. An example of its application on a real data set from a saline stress experiment performed on a recombinant population of wheat (Triticum aestivum L. ) doubled haploid lines is also provided.

Influence of human dermal fibroblasts on epidermalization.

Using a method that allowed the reconstruction of simplified living human skin in vitro, we investigated the effects of collagen texture and dermal fibroblasts on epidermal growth. Like in vivo skin, our in vitro model comprised two tissues: a dermal equivalent and an overlying epidermis. It permitted measurement of epidermal growth and therefore evaluation of the effect of the dermal equivalent on this growth. Epidermal growth was enhanced when the collagen matrix had previously been reorganized by fibroblasts, and was greatest when living fibroblasts persisted in this matrix. On cell-free collagen gel and on collagen matrices containing dead fibroblasts, epidermal growth increased when the medium was conditioned by fibroblasts grown in monolayers. We conclude that the function of the fibroblasts is not only to synthesize and degrade the extracellular matrix, but also to regulate epidermalization; on the one hand by remodeling the collagen fibers, and on the other by secreting diffusible factors that promote epidermal growth. These results underline the importance of fibroblasts in dermo-epidermal interactions, and show that the skin equivalent culture model provides a way to quantitatively study these interactions.

Neutrophil studies in psoriatics: in vivo migration, phagocytosis and bacterial killing.

A reproducible method for sequential study of migration out of human skin, phagocytosis and bactericidal activity of neutrophils is described. Untreated psoriatics exhibit an early increase of chemotactic activity (0-8 hr, p less than 0.02) and subsequently a strong inhibition of chemotaxis (8-24 hr, p less than 0.01), a slight decrease of phagocytosis and a decrease in bactericidal activity (20 min, p less than 0.02; 30 min, p less than 0.003); 60 min, p less than 0.001; 120 min, p less than 0.001) as compared with controls. After clearing of skin lesions, the early increased chemotactic activity returned to normal values but the subsequent chemotactic inhibition remains as strong as before treatment. Phagocytosis increased to normal values (p less than 0.02) and bactericidal activity also increased but remained significantly low. These abnormalities were more evident in migrating than in circulating neutrophils, underlining the sensitivity of the described method.

Human dermal fibroblasts modulate the effects of retinoids on epidermal growth.

We report the pharmacologic effects of retinoids in a human skin-equivalent model. This sophisticated culture system is composed, as in vivo, of a dermis and epidermis, and provides a unique in vitro system for studying dermal-epidermal interactions and thus, whether normal dermal fibroblasts influence the effects of retinoids on epidermal growth. Epidermalization was initiated on collagen substrates in which fibroblasts were either viable or lysed by osmotic shock. Retinoic acid, isotretinoin, and acitretin at 10(-6) M or 10(-7) M were added to the cultures just after epidermalization, then every two days. Epidermal growth was determined after 2 weeks in terms of the surface area, DNA content, and tritiated thymidine incorporation during the last 24 h of culture. In the absence of viable fibroblasts, retinoic acid and isotretinoin increased epidermal growth, whereas etretin inhibited it. In contrast, in the presence of viable fibroblasts, retinoic acid and isotretinoin inhibited epidermal growth, whereas etretin had no effect. Thus, retinoic acid and isotretinoin had a similar effect on keratinocyte proliferation that contrasted with that of etretin. Taken as a whole, these results show that fibroblasts, present within a collagen substrate, can modulate the pharmacologic effects of retinoids on epidermal growth.

Non-coherent near infrared radiation protects normal human dermal fibroblasts from solar ultraviolet toxicity.

The sun is the most important and universal source of non-ionizing radiation shed on human populations. Life evolved on Earth bathed by this radiation. Solar UV damages cells, leading to deleterious conditions such as photoaging and carcinogenesis in human skin. During the process of evolution, the cells selected dark- and light-dependent repair mechanisms as a defence against these hazardous effects. This study describes the induction by non-coherent infrared radiation (700-2000 nm), in the absence of rising temperature, of a strong cellular defense against solar UV cytotoxicity as well as induction of cell mitosis. Blocking mitoses with arabinoside-cytosine or protein synthesis with cycloheximide did not abolish the protection, leading to the conclusion that this protection is independent of cell division and of protein neosynthesis. The protection provided by infrared radiation against solar UV radiation is shown to be a long-lasting (at least 24 h) and cumulatif phenomenon. Infrared radiation does not protect the lipids in cellular membranes against UVA induced peroxidation. The protection is not mediated by heat shock proteins. Living organisms on the Earth's surface are bathed by infrared radiation every day, before being submitted to solar UV. Thus, we propose that this as yet undescribed natural process of cell protection against solar UV, acquired and preserved through evolutional selection, plays an important role in life maintenance. Understanding and controlling this mechanism could provide important keys to the prevention of solar UV damage of human skin.

Rapid localization of carbon 14-labeled molecules in biological samples by ion mass microscopy.

We report here on the ability of secondary ion mass spectrometry (SIMS) to provide rapid imaging of the intracellular distribution of 14C-labeled molecules. The validity of this method, using mass discrimination of carbon 14 atoms, was assessed by imaging the distribution of two molecules of well-known metabolism, [14C]-thymidine and [14C]-uridine, incorporated by human fibroblasts in culture. As expected, 14C ion images showed the presence of [14C]-thymidine in the nucleus of dividing cells, whereas [14C]-uridine was present in the cytoplasm as well as the nucleus of all cells, with a large concentration in the nucleoli. The time required to obtain the distribution images with the SMI 300 microscope was less than 6 min, whereas microautoradiography, the classical method for mapping the tissue distribution of 14C-labeled molecules, usually requires exposure times of several months. Secondary ion mass spectrometry using in situ mass discrimination is proposed here as a very sensitive method which permits rapid imaging of the subcellular distribution of molecules labeled with carbon 14.

[Intramedullary metastases of bronchogenic carcinoma. Two cases]. / Métastases intramédullaires d'un cancer bronchique. Deux observations.

Intramedullary metastases are uncommon. We report two cases in patients with small cell bronchogenic cancer. The clinical diagnosis was supported by T1 magnetic resonance imaging after gadolinium injection. A unique medullary metastasis associated with other metastatic localizations was observed in the first patient and multiple intramedullary metastases alone in the second. These secondary intramedullary localizations were highly sensitive to chemotherapy after the first monthly cure in the first patient and after the third in the second patient. We emphasize the importance of chemotherapy in such cases, usually associated with focal radiotherapy.

[Plication of the hip synovium above the femur neck]. / Le repli synovial supra-cervical de la hanche.

A 23 year old man, expert in karate, complained of sudden movements of right hip during "circular kicks", followed by persistent pain. Arthrography showed synovial plication in joint at upper border femoral neck, with a tongue-like projection from upper recess extending to head/neck junction and provoking bone erosion visible on standard images. Recovery followed resection of the fold. This is probably the first case of this type to be published. The lesion recalls the internal synovial plica of knee but differs from "frenula capsulae" and does not appear to have been described by anatomists. As in the knee it is probably an embryonic relic.

[Pulmonary digital subtraction angiography. A comparative study of 2 technics. Electrocardiographic servo-assistance versus 3 images per second]. / L'angiographie pulmonaire numérique. Etude comparée de deux techniques. Asservissement à l'électro-cardiogramme versus trois images par seconde.

A prospective study in 60 consecutive patients evaluated gain in quality of image using ECG servo-assistance during pulmonary digital subtraction angiography (PDSA). Two groups of 30 comparable patients were randomly allocated to examination with ECG servo-assistance or three images per second technique. Criteria for assessment of quality of image were defined and used to compare results. No significant difference were noted and ECG servo-assistance failed to improve images during PDSA.

[Desmoid tumors of the mesentery in Gardner's syndrome. Value of x-ray computed tomography]. / Les tumeurs desmoïdes du mésentère dans le cadre du syndrome de Gardner. Intérêt du scanner.

3 cases of desmoid tumours of the mesentery occurring as part of Gardner's syndrome are reported. In 2 cases, CAT scanning was carried out. We underline the value of this examination compared to other imaging methods. It allows the establishment of a diagnosis, investigation for complications, the operability to be assessed and is useful for monitoring patients. Its major value is in avoiding an unnecessary laparotomy, a factor certain to produce recurrence, in certain patients. Other alternative therapy may then be proposed.

[Cranial localizations of sarcoidosis. Apropos of a case. General review of the 21 reported cases]. / Localisations crâniennes de la sarcoïdose. A propos d'une observation. Revue générale des 21 cas décrits.

A case of sarcoidosis with lesions also localized to the cranial region is reported, and 21 similar cases published in the literature reviewed. Lesions are usually seen as small lacunae in the cranial vault, and are commonly associated with neurologic and cutaneous manifestations of the disease. They appear to be very rare but their frequency is probably underestimated. Their detection is facilitated by the use of technetium scintigraphy.

[Diffuse peritoneal lymphoma in AIDS]. / Lymphome péritonéal diffus au cours d'un SIDA.

We report an unusual observation of peritoneal localisation in a non-Hodgkin lymphoma, the only sign of digestive injury. This peritoneal injury may be more frequent with AIDS patients, as in our observation. Tomodensitometry was the best exam to visual this injury.