Morpho-functional analysis of patient-derived xenografts reveals differential impact of gastric cancer and chemotherapy on the tumor ecosystem, affecting immune check point, metabolism, and sarcopenia.

OBJECTIVES: Gastric cancer (GC) is an aggressive disease due to late diagnosis resulting from the lack of easy diagnostic tools, resistances toward immunotherapy (due to low PD-L1 expression), or chemotherapies (due to p53 mutations), and comorbidity factors, notably muscle atrophy. To improve our understanding of this complex pathology, we established patient-derived xenograft (PDX) models and characterized the tumor ecosystem using a morpho-functional approach combining high-resolution imaging with molecular analyses, regarding the expression of relevant therapeutic biomarkers and the presence of muscle atrophy. MATERIALS AND METHODS: GC tissues samples were implanted in nude mice. Established PDX, treated with cisplatin or not, were imaged by magnetic resonance imaging (MRI) and analyzed for the expression of relevant biomarkers (p53, PD-L1, PD-1, HER-2, CDX2, CAIX, CD31, a-SAM) and by transcriptomics. RESULTS: Three well-differentiated, one moderately and one poorly differentiated adenocarcinomas were established. All retained the architectural and histological features of their primary tumors. MRI allowed in-real-time evaluation of differences between PDX, in terms of substructure, post-therapeutic changes, and muscle atrophy. Immunohistochemistry showed differential expression of p53, HER-2, CDX2, a-SAM, PD-L1, PD-1, CAIX, and CD31 between models and upon cisplatin treatment. Transcriptomics revealed treatment-induced hypoxia and metabolic reprograming in the tumor microenvironment. CONCLUSION: Our PDX models are representative for the heterogeneity and complexity of human tumors, with differences in structure, histology, muscle atrophy, and the different biomarkers making them valuable for the analyses of the impact of platinum drugs or new therapies on the tumor and its microenvironment.

Chondroblastoma of the thoracic spine: a rare location. Case report with radiologic-pathologic correlation.

Chondroblastoma is a rare benign cartilage neoplasm that arises from the appendicular skeleton in the vast majority of the cases (80%). Chondroblastoma of the spine is an even more rare condition (30 cases reported), and vertebral chondroblastomas, unlike chondroblastomas of the extremities, present with the appearance of an aggressive tumor on CT and MR imaging and occur at least a decade later. Even though vertebral chondroblastomas are very uncommon tumors, they should nonetheless be included in the differential diagnosis when encountered with an aggressive vertebral mass, and a histological confirmation should be performed. We present a case of chondroblastoma of the thoracic spine of a 27-year-old female for which detailed radiologic-pathologic correlation was obtained.

Methylene blue protects liver oxidative capacity after gut ischaemia-reperfusion in the rat.

OBJECTIVES: Mesenteric ischaemia/reperfusion (IR) may lead to liver mitochondrial dysfunction and multiple organ failure. We determined whether gut IR induces early impairment of liver mitochondrial oxidative activity and whether methylene blue (MB) might afford protection. DESIGN: Controlled animal study. MATERIALS AND METHODS: Rats were randomised into three groups: controls (n = 18), gut IR group (mesenteric ischaemia (60 min)/reperfusion (60 min)) (n = 18) and gut IR + MB group (15 mg kg(-1) MB intra-peritoneally) (n = 16). Study parameters were: serum liver function markers, blood lactate, standard histology and DNA fragmentation (apoptosis) on intestinal and liver tissue, maximal oxidative capacity of liver mitochondria (state 3) and activity of complexes II, III and IV of the respiratory chain measured using a Clark oxygen electrode. RESULTS: Gut IR increased lactate deshydrogenase (+982%), aspartate and alanine aminotransferases (+43% and +74%, respectively) and lactate levels (+271%). It induced segmental loss of intestinal villi and cryptic apoptosis. It reduced liver state 3 respiration by 30% from 50.1 ± 3 to 35.2 ± 3.5 µM O(2) min(-1) g(-1) (P < 0.01) and the activity of complexes II, III and IV of the mitochondrial respiratory chain. Early impairment of liver mitochondrial respiration was related to blood lactate levels (r(2) = 0.45). MB restored liver mitochondrial function. CONCLUSIONS: MB protected against gut IR-induced liver mitochondria dysfunction.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Post-transplant lymphoproliferative disorders: determination of donor/recipient origin in a large cohort of kidney recipients.

Although in previous studies most post-transplant lymphoproliferative disorders (PTLD) were reported to derive from recipient cells, some cases derived from donor lymphocytes have been reported. To provide a better description of the features and outcome of PTLD according to the origin of the lymphoma, we performed histologic and molecular studies of PTLD in kidney recipients. Forty-three specimens were analyzed by histochemistry, fluorescent hybridization of the Y chromosome and analysis of multiple short tandem repeat microsatellite loci. Sixteen tumors were shown to be of donor origin and 27 of recipient origin. Time to PTLD was shorter in donor-derived PTLDs (20 ± 27 vs. 69 ± 67 months, p = 0.013). Ten-year patient survival was similar among patients with recipient- and donor-derived PTLD, but when PTLD-related mortality was analyzed, there was a trend to better survival in patients with donor lymphomas. Among the 21 PTLDs localized in the allograft, 14 lymphomas were of donor origin and seven of recipient origin. No difference was found between the two groups. Our analysis of the origin of PTLDs in the largest cohort studied to date with a description of the clinical and histological characteristics of donor and recipient PTLDs should lead to a better understanding of lymphomagenesis.

Histopathological features in fatal COVID-19 acute respiratory distress syndrome.

Background: COVID-19 acute respiratory distress syndrome (ARDS) shares the common histological hallmarks with other forms of ARDS. However, the chronology of the histological lesions has not been well established. Objective: To describe the chronological histopathological alterations in the lungs of patients with COVID-19 related ARDS. Design: A prospective cohort study was carried out. Setting: Intensive Care Unit of a tertiary hospital. Patients: The first 22 consecutive COVID-19 deaths. Measurements: Lung biopsies and histopathological analyses were performed in deceased patients with COVID-19 related ARDS. Clinical data and patient course were evaluated. Results: The median patient age was 66 [63-74] years; 73% were males. The median duration of mechanical ventilation was 17 [8-24] days. COVID-19 induced pulmonary injury was characterized by an exudative phase in the first week of the disease, followed by a proliferative/organizing phase in the second and third weeks, and finally an end-stage fibrosis phase after the third week. Viral RNA and proteins were detected in pneumocytes and macrophages in a very early stage of the disease, and were no longer detected after the second week. Limitation: Limited sample size. Conclusions: The chronological evolution of COVID-19 lung histopathological lesions seems to be similar to that seen in other forms of ARDS. In particular, lung lesions consistent with potentially corticosteroid-sensitive lesions are seen.

Antecedentes: El síndrome de dificultad respiratoria aguda (SDRA) asociado a la COVID-19 comparte características histológicas con otros tipos de SDRA. Sin embargo, no se ha establecido adecuadamente la cronología de las lesiones histológicas. Objetivo: Describir las alteraciones histopatológicas cronológicas en los pulmones de los pacientes con síndrome de dificultad respiratoria aguda asociado a COVID-19. Diseño: Estudio prospectivo de cohortes. Ámbito: Unidad de cuidados intensivos de un hospital terciario. Pacientes: Las primeras 22 muertes consecutivas por COVID-19. Intervenciones: Se llevaron a cabo biopsias pulmonares y análisis histopatológicos en pacientes fallecidos por SDRA asociado a COVID-19. Se evaluaron los datos clínicos y la evolución médica. Resultados: La mediana de edad de los pacientes fue de 66 (63-74) años y el 73% eran varones. La mediana de la duración de la ventilación mecánica fue de 17 (8-24) días. La lesión pulmonar inducida por COVID-19 se caracterizó por una fase exudativa durante la primera semana de la enfermedad, seguida de una fase proliferativa/organizativa en la segunda y tercera semana y, por último, una fase de fibrosis en fase terminal tras la tercera semana de evolución. Se detectaron proteínas y ARN vírico en neumocitos y macrófagos en una fase muy temprana de la enfermedad, pero estos ya no se volvieron a detectar a partir de la segunda semana. Limitación: Tamaño limitado de la muestra. Conclusión: La evolución cronológica de las lesiones histopatológicas pulmonares asociadas a la COVID-19 parece ser similar a la de otras formas de SDRA. En particular, se observan daños pulmonares coherentes con las lesiones potencialmente sensibles a los corticosteroides.

Histopathological features in fatal COVID-19 acute respiratory distress syndrome.

BACKGROUND: COVID-19 acute respiratory distress syndrome (ARDS) shares the common histological hallmarks with other forms of ARDS. However, the chronology of the histological lesions has not been well established. OBJECTIVE: To describe the chronological histopathological alterations in the lungs of patients with COVID-19 related ARDS. DESIGN: A prospective cohort study was carried out. SETTING: Intensive Care Unit of a tertiary hospital. PATIENTS: The first 22 consecutive COVID-19 deaths. MEASUREMENTS: Lung biopsies and histopathological analyses were performed in deceased patients with COVID-19 related ARDS. Clinical data and patient course were evaluated. RESULTS: The median patient age was 66 [63-74] years; 73% were males. The median duration of mechanical ventilation was 17 [8-24] days. COVID-19 induced pulmonary injury was characterized by an exudative phase in the first week of the disease, followed by a proliferative/organizing phase in the second and third weeks, and finally an end-stage fibrosis phase after the third week. Viral RNA and proteins were detected in pneumocytes and macrophages in a very early stage of the disease, and were no longer detected after the second week. LIMITATION: Limited sample size. CONCLUSIONS: The chronological evolution of COVID-19 lung histopathological lesions seems to be similar to that seen in other forms of ARDS. In particular, lung lesions consistent with potentially corticosteroid-sensitive lesions are seen.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

The mouse one P-domain (pS2) and two P-domain (mSP) genes exhibit distinct patterns of expression.

We have previously shown that the human pS2 gene, which codes for a secreted peptide of 60 amino acids, is expressed in a number of human carcinomas, including carcinomas of the breast, the pancreas, and the large bowel. Strong pS2 gene expression was also observed in the normal gastric mucosa and in the regenerative tissues surrounding ulcerous lesions of the gastrointestinal tract. A number of pS2 similar peptides, designated as P-domain peptides, have been described, notably the porcine (PSP), murine (mSP), and human (hSP) spasmolytic polypeptides, which correspond to duplicated pS2 proteins. We have now cloned a mouse homolog of the human pS2 cDNA to dispose of an animal model to study the pS2 protein function, which remains unknown at the present time. We show that the mouse putative pS2 protein sequence and the physiological pattern of expression of the mouse pS2 gene are well conserved. The mouse pS2 gene is highly expressed in the stomach mucosa cells, whereas no pS2 gene expression could be detected in the mouse mammary gland, even during postnatal development processes dependent on growth factors or hormones. Using in situ hybridization, we show that although coexpressed in the fundus, the antrum and the antrum-pyloric regions of the stomach, the mouse pS2 and mSP genes exhibit distinct and complementary cellular patterns of expression.

In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.

Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.

Breast cancer-associated pS2 protein: synthesis and secretion by normal stomach mucosa.

The human pS2 gene is specifically expressed under estrogen transcriptional control in a subclass of estrogen receptor-containing human breast cancer cells. The pS2 gene encodes an 84-amino acid protein that is secreted after signal peptide cleavage. The distribution of pS2 protein in normal human tissues was studied with antibodies to pS2; pS2 was specifically expressed and secreted by mucosa cells of the normal stomach antrum and body of both female and male individuals. Moreover, no estrogen receptor could be detected in these cells, indicating that pS2 gene expression is estrogen-independent in the stomach. The function of the pS2 protein in the gastrointestinal tract is unknown. However, the pS2 protein is similar in sequence to a porcine pancreatic protein that has been shown to inhibit gastrointestinal motility and gastric secretion.

Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein.

To determine the function of the pS2 trefoil protein, which is normally expressed in the gastric mucosa, the mouse pS2 (mpS2) gene was inactivated. The antral and pyloric gastric mucosa of mpS2-null mice was dysfunctional and exhibited severe hyperplasia and dysplasia. All homozygous mutant mice developed antropyloric adenoma, and 30 percent developed multifocal intraepithelial or intramucosal carcinomas. The small intestine was characterized by enlarged villi and an abnormal infiltrate of lymphoid cells. These results indicate that mpS2 is essential for normal differentiation of the antral and pyloric gastric mucosa and may function as a gastric-specific tumor suppressor gene.

Type 1 diabetes and idiopathic retroperitoneal fibrosis: case report.

Retroperitoneal fibrosis is characterized by the presence of a retroperitoneal tissue, consisting of chronic inflammation and marked fibrosis, which entraps the retroperitoneal organs. In two-thirds of cases, the retroperitoneal fibrosis is idiopathic. The pathogenic mechanism is not clearly identified. We report a case of idiopathic retroperitoneal fibrosis associated with type 1 diabetes mellitus. A 61-year-old woman with C peptide negative insulindependent diabetes developed retroperitoneal fibrosis revealed by bilateral hydronephrosis. Anti-GAD 65 antibodies were positive. There were no signs of autoimmune pancreatitis: no steatorrhea, normal IgG4 isotype levels, and absence of pancreas morphological abnormalities.

[Thoracic manifestations of Castleman's disease]. / Maladie de Castleman à expression thoracique.

INTRODUCTION: Castleman's disease is a rare orphan disease. The prevalence is estimated at less than 1/100 000. Respirologists may encounter this disease when its thoracic manifestations occur. CASE REPORT: The authors report two cases of Castleman's disease with two different thoracic involvements. The first patient was a 20-year-old man without a previous medical history. A chance chest X-ray revealed right basal opacity. A lung biopsy demonstrated giant lymph node polyclonal hyperplasia leading to the diagnosis of a thoracic form of Castleman's disease. Since the patient was completely symptom free, no treatment was proposed. The patient was stable after 10months of medical supervision. The second patient, a 34-year-old woman, had a medical history of myasthenia gravis, autoimmune thrombopenic purpura and haemolytic anaemia. Her general condition deteriorated and upper mediastinal enlargement was noted. A diagnosis of multicentric Castleman's disease was established by means of the biopsy of an axillary lymph node. As the symptoms persisted, she was treated by rituximab. The clinical response was dramatic. CONCLUSION: The authors call to mind the difficult diagnostic features and therapeutic strategies of Castleman's disease, a rare disease which may involve the thorax.

[A case of bronchiectasis due to light chain deposition disease]. / Histoire naturelle d'une forme bronchectasiante de la maladie à dépôts de chaînes légères.

INTRODUCTION: The natural history of orphan lung diseases is often unclear. We report the long-term follow-up of a case of bronchiectasis due to pulmonary non amyloid light chain deposition disease (LCDD). CASE REPORT: A 50-year-old woman who was a smoker, was diagnosed with diffuse thin walled bronchiectasis of uncertain origin after presenting with a respiratory tract infection. Ten years later, the combination of bronchiectasis, the appearance of pulmonary cysts and the identification of increased kappa free light chains evoked the diagnosis of pulmonary LCDD. The diagnosis was confirmed by lung biopsy. No immunoproliferative disorder was identified. During the 12 years follow-up, dyspnea worsened progressively and bronchiectasis and lung cysts extended leading to multicystic lung disease. Pulmonary function tests did not show any ventilatory defect but a small decrease in carbon monoxide transfer factor occurred. CONCLUSION: We describe the evolution of a rare presentation of isolated pulmonary LCDD, characterized by cystic diffuse atypical bronchiectasis with thin walls, associated with progressive cystic destruction of the lung parenchyma. The possibility of pulmonary LCDD should be considered in cases of atypical bronchiectasis of unknown etiology.

Stromelysin-3 expression promotes tumor take in nude mice.

Stromelysin-3 (ST3) is a matrix metalloproteinase expressed in human carcinomas in ways suggesting that it may play a role in tumor progression. To test this possibility, we have performed gene transfer experiments using both anti-sense and sense ST3 expression vectors, and malignant cells either expressing (NIH 3T3 fibroblasts) or not (MCF7 epithelial cells) endogenous ST3. We have compared the ability of parental and transfected cells to cause subcutaneous tumor development in nude mice. 3T3 cells expressing anti-sense ST3 RNA showed reduced tumorigenicity, and MCF7 cells expressing mouse or human ST3 were associated with reduced tumor-free period leading to a significant increased tumor incidence(P<10(-4)). However, once established, the ST3 expressing tumors did not grow faster than those obtained with the parental MCF7 cell line. In addition, tumors obtained after sub-cutaneous injection of ST3-expressing or nonexpressing cells did not exhibit obvious histological differences, and careful examination did not reveal any local invasive tissue areas nor systemic metastases. These in vivo observations were in agreement with those obtained in vitro showing that ST3 expression did not modify proliferative nor invasive properties of transfected cells. Altogether, these results indicate that ST3 expression promotes tumor take in nude mice, presumably by favoring cancer cell survival in a tissue environment initially not permissive for tumor growth. These findings represent the first experimental evidence showing that ST3 can modulate cancer progression.

[Diffuse uptake of brown fat on computed-tomography coupled positron emission tomoscintigraphy (PET-CT) for the exploration of extra-adrenal pheochromocytoma]. / Hyperfixation diffuse de la graisse brune à la tomoscintigraphie par émission de positons couplée à la tomodensitométrie (TEP-TDM) dans l'exploration d'un phéochromocytome extra surrénalien.

We report an observation of strong bilateral uptake on a PET-CT scan compatible with activation of brown adipose tissue in a patient with extra-adrenal pheochromocytoma. A 42-year-old man was hospitalized for hypersudation together with weight loss and palpitations. Heart rate was 120 bpm and fasting blood glucose 1.36 g/l. Endocrine explorations revealed elevated serum chromogranine which reached 517 ng/ml (19-38). The norepinephrine level reached 49.7 nmol/l (<4.00) and urinary norepinephrine and normetanephrine levels reached 13977 nmol/24h (<414) and 32 micromol/24h (0.4-2.5) respectively. The thoraco-abdominal and pelvic scan showed a 6 cm diameter paraaortic hypervascularized mass with an infiltrative lesion of both perirenal area and mediastinal tissue without adenopathies. The abdominal MRI revealed the mass with a low intensity signal in T1 and a slight high intensity signal in T2. MIBG and octreoscan scintigraphies were negative. 18F-DG PET showed intensed uptake in the tumor mass together with intense, diffuse and bilateral uptake above and below the diaphragm. The mass was resected. Histological examination of the surgical specimen confirmed the diagnosis of extra-adrenal pheochromocytoma with an index of 13% cellular proliferation without cell atypia. There was a hypervascularization with small islets of brown adipose tissue in the perirenal fat. Both plasmatic and urinary catecholamines decreased to the normal range after the operation and PET-scan normalized. Bilateral spread of the radiotracer uptake was probably due to brown adipose tissue activation by excessive sympathetic stimulation induced by catecholamines released by the tumor.

Identification of a new interferon-alpha-inducible gene (p27) on human chromosome 14q32 and its expression in breast carcinoma.

A new complementary DNA, p27, has been cloned and sequenced from estradiol-treated MCF7 human breast carcinoma cells. It encodes a putative highly hydrophobic protein of 122 amino acids which has a 33% overall sequence similarity to the product of the 6-16 gene (R. L. Friedman, S. P. Manly, M. McMahon, I. M. Kerr, and G. R. Stark, Cell, 38: 745-755, 1984), which is transcriptionally induced by interferons of the alpha/beta type. We demonstrate here that the p27 gene, which is located in band q32 of human chromosome 14, is also induced by interferon-alpha in human cell lines of different origin and that expression is independent of the presence of estradiol receptor in the cells. High levels of p27 RNA were found in vivo in approximately 50% of primary human breast carcinomas (21 were tested by Northern blotting). In situ hybridization to some of the p27-overexpressing tumors showed that the p27 RNA is localized in cancer cells and sometimes also in fibroblastic cells of tumor stroma. p27 RNA levels in the tumors did not correlate with the presence of estrogen receptor or with the expression of the estrogen-induced pS2 gene. Further studies are now necessary to elucidate the cause of p27 gene overexpression in breast carcinoma and in particular to determine whether it corresponds to chromosomal rearrangements in the 14q32 region and/or to induction by interferons of the alpha/beta type.

High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase.

Matrix metalloproteinases (MMPs) are extracellular enzymes. Some of them are known to be involved in tumor development and/or progression. Several cellular functions have been proposed for MMPs during malignant processes. Notably, they may be involved in tissue-remodeling processes through their ability to digest matrix components or to participate in tumor neoangiogenesis and, subsequently, in cancer cell proliferation. One of these MMPs, stromelysin-3 (ST3/MMP11), although devoid of enzymatic activity against the matrix components, is associated with human tumor progression and poor patient clinical outcome. Using several in vivo experimental models, it has been demonstrated that ST3 expression by the fibroblastic cells surrounding malignant epithelial cells promotes tumorigenesis in a paracrine manner. The present study was devoted to the identification of the cellular function underlying this ST3-induced tumor promotion using a syngeneic tumorigenesis model in mice. Our results show that ST3 exhibits a new and unexpected role for a MMP, because ST3-increased tumorigenesis does not result from increased neoangiogenesis or cancer cell proliferation but from decreased cancer cell death through apoptosis and necrosis. Thus, during malignancy, the cellular function of ST3 is to favor cancer cell survival in the stromal environment.

Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note.

INTRODUCTION: Diffuse intrinsic pontine gliomas (DIPG) constitute 10-15% of all brain tumors in the pediatric population; currently prognosis remains poor, with an overall survival of 7-14 months. Recently the indication of DIPG biopsy has been enlarged due to the development of molecular biology and various ongoing clinical and therapeutic trials. Classically a biopsy is performed using a stereotactic frame assisted procedure but the workflow may sometimes be heavy and more complex especially in children. In this study the authors present their experience with frameless robotic-guided biopsy of DIPG in a pediatric population. PATIENTS AND METHODS: Retrospective study on a series of five consecutive pediatric patients harboring DIPG treated over a 4-year period. All patients underwent frameless robotic-guided biopsy via a transcerebellar approach. RESULTS: Among the 5 patients studied 3 were male and 2 female with a median age of 8.6 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy in all patients. MRI imaging of the lesion showed typical DIPG features (3 of them located in the pons) with hypo-intensity on T1 and hyper-intensity signal on T2 sequences and diffuse gadolinium enhancement. The mean procedure time was 56minutes (range 45 to 67minutes). No new postoperative neurological deficits were recorded. Histological diagnosis was achieved in all cases as follows: two anaplastic astrocytomas (grade III), two glioblastomas, and one diffuse astrocytoma (grade III). CONCLUSION: Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis.