Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates.

Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation.

Loss of H3K27 trimethylation is not suitable for distinguishing malignant peripheral nerve sheath tumor from melanoma: a study of 387 cases including mimicking lesions.

The diagnosis of malignant peripheral nerve sheath tumor remains challenging, especially in the sporadic setting. Malignant peripheral nerve sheath tumor is a rare malignancy, and owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, in particular melanoma. Recently, inactivation of the polycomb repressive complex 2 (PRC2), induced by inactivating mutations in two of its critical constituents SUZ12 and EED, was reported in a large subset of malignant peripheral nerve sheath tumors. Homozygous PRC2 inactivation induces complete loss of trimethylation at lysine 27 of histone 3 (H3K27me3). Recent studies suggest that complete loss of H3K27me3 is highly specific for malignant peripheral nerve sheath tumor and may be a useful immunohistochemical diagnostic marker. Therefore, to determine the specificity of the complete loss of H3K27me3 expression in the context of the differential diagnosis of malignant peripheral nerve sheath tumor from melanoma (its major potential mimic), we performed H3K27me3 immunohistochemistry in a pathologically and genetically well-characterized cohort of primary (neurofibromatosis type 1 (NF1), radiation-associated and sporadic context) malignant peripheral nerve sheath tumors (n=122) and in a cohort or primary (desmoplastic) and metastatic melanomas (n=265). In total, 88 (72%) malignant peripheral nerve sheath tumors, including 46 (71%) NF1-associated, 4 (100%) radiation-associated, and 38 (72%) sporadic tumors, showed complete loss of H3K27me3. We observed increased loss of H3K27me3 with increasing histological grade. Interestingly, we found complete loss of H3K27me3 in 37% (n=98) of all melanomas, including 25% (n=9) of primary desmoplastic melanomas. Moreover, partial loss ('mosaic' pattern) was observed in 23 (19%) of all malignant peripheral nerve sheath tumors and in 136 (51%) of all melanomas. Complete loss of H3K27me3 detected by immunohistochemistry is not specific for malignant peripheral nerve sheath tumor and cannot be used safely when distinguishing malignant peripheral nerve sheath tumor from melanoma.

Oncologic Phenotype of Peripheral Neuroblastic Tumors Associated With PHOX2B Non-Polyalanine Repeat Expansion Mutations.

BACKGROUND: Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. METHODS: We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. RESULTS: Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years. CONCLUSIONS: Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling.

A new mutation in the C-SH2 domain of PTPN11 causes Noonan syndrome with multiple giant cell lesions.

Noonan syndrome (NS), an autosomal dominant multisystem disorder, is caused by the dysregulation of the RAS-MAPK pathway and is characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism and facial dysmorphism. We here present the clinical and molecular characterization of a family with NS and multiple giant cell lesions (MGCLs). The proband is a 12-year-old girl with NS and MGCL. Her mother shows typical NS without MGCL. Whole-exome sequencing of the girl, her mother and her healthy maternal grand parents revealed a previously unobserved mutation in exon 5 of the PTPN11 gene (c.598 A>T; p.N200Y), transmitted from the mother to the proband. As no other modification in the RAS-MAPK pathway genes as related to Rasopathies was detected in the proband, this report demonstrates for the first time that a unique mutation affecting this, otherwise unaffected signaling route, can cause both NS and NS/MGCL in the same family. This observation further confirms that NS/MGCL is not a distinct entity but rather that MGCL represents a rare complication of NS. Moreover, the localization of the p.N200Y mutation suggests an alternative molecular mechanism for the excessive phosphatase activity of the PTPN11-encoded protein.

Phaeohyphomycosis due to Alternaria infectoria: a single-center experience with utility of PCR for diagnosis and species identification.

The term phaeohyphomycosis refers to a rare group of fungal infections characterized by the presence of dark-walled hyphae or yeast-like cells in affected tissues. Herein, we report on the clinical and epidemiological characteristics of six cases of phaeohyphomycosis due to Alternaria spp. that occurred in our hospital over a 30-month period (from January 2008 to June 2010). Interestingly, whereas histopathological examinations were positive and fungal cultures yielded molds in all cases, mycological identification using conventional phenotypic methods was never possible despite prolonged incubation of the isolates. Identification of Alternaria infectoria species complex was obtained for each isolate by amplification and sequencing of the internal transcribed spacer of the ribosomal DNA (ITS rDNA). All patients had favourable outcomes following the introduction of azole-based antifungal therapy. This case series describes the clinical course of these six patients and highlights the utility of molecular identification to help in the identification of the etiologic agent when classical mycological methods have failed.

[Place of the pathologist in the management of primary bone tumors (osteosarcoma and Ewing's family tumors after neoadjuvant treatment)]. / Rôle du pathologiste dans la prise en charge des tumeurs osseuses primitives malignes : ostéosarcomes et tumeurs de la famille Ewing après traitement néoadjuvant.

The survival of osteosarcoma and Ewing family tumours has been improved by the introduction of neoadjuvant chemotherapy. The response to preoperative chemotherapy is evaluated on the microscopic analysis of the surgical resection, by the percentage of tumour necrosis according to the Huvos and Rosen's grading. It remains the only reliable prognostic factor for patients and is used to guide the choice of post-operative chemotherapy. The macroscopic and microscopic management of the surgical resection (cf. supra) is essential and is the subject of a specific protocol. Several studies have been conducted to identify news factors able to predict the response to chemotherapy, the tumour aggressiveness and its ability to develop metastases. Inhibitors of mTOR and/or regulators of the balance RANKL/OPG are promising therapeutics. The study's expression of these new factors could be performed on the biopsy and will offer new therapeutic strategy.

Non image-guided core needle biopsies can be used safely to improve diagnostic efficiency for soft tissue tumors.

INTRODUCTION: Front-line biopsy remains the rule in the management of soft tissue mass syndromes. Although open biopsy has long been considered the gold standard, it has recently been shown that a percutaneous biopsy is associated with a reduction in the rate of complications and cost, while maintaining high diagnostic accuracy. Though there is much literature regarding the diagnostic accuracy of image-guided and open biopsies for soft tissue tumors, the accuracy of percutaneous non image-guided biopsies has not been well documented. The objective of this study was to compare the failure rate of non image-guided biopsies, image-guided biopsies and open biopsies for the diagnosis of soft tissue tumors. We also attempted to identify the failure risk factors for non image-guided biopsies and we compared the diagnostic delay of the three types of biopsy. MATERIALS AND METHODS: This was a continuous, single-center retrospective study. We reviewed the results from 337 patients managed with a biopsy (percutaneous or open) for a soft tissue tumor, all carried out in our center between January 2010 and December 2015. Biopsy technique was chosen by the treating orthopedic surgeon, according to the clinical and radiological characteristics of the mass. 141 patients (41.8%) had a non-image-guided biopsy as the first-line diagnostic procedure, 81 (24.0%) had an image-guided biopsy, and 115 (34.1%) an open biopsy. Diagnostic failure was defined either by a non-contributory biopsy, the need for repeat biopsy, or a major histological discordance obtained from the resected tumor piece. The risk factors studied were tumor characteristics, patient' characteristics and sampling modalities. Diagnostic delay was defined as the period between the day of the first external consultation at the hospital and the day of the notification of the diagnosis by the physician. RESULTS: We obtained a failure rate of 9.9% (14 patients) for non image-guided biopsies. Eleven were non-contributive and three were considered as errors of diagnosis. The failure rate for image-guided biopsies was 18.5% (15 patients), with no significant difference compared with non image-guided biopsies. The open biopsies were associated with a failure rate of 6.9% (eight patients). We found no failure risk factors for non image-guided biopsies. Diagnostic delay was significantly shorter for non image-guided biopsies (p = 0.001). CONCLUSION: When performed in a referral center by the patient's surgeon, a non-image-guided core needle biopsy is a safe procedure which ensures equivalent diagnostic accuracy for soft tissue tumors, while reducing the diagnostic delay.

Exercise-Induced Vasculitis: A Review with Illustrated Cases.

Although exercise-induced vasculitis (EIV) is usually misdiagnosed, it is not uncommon. Occurring mostly after prolonged exercise, especially in hot weather, EIV is an isolated cutaneous vasculitis with stereotypical presentation. This article reviews the clinical characteristics, treatments, and outcomes of EIV based on the published literature. We report 99 patients who developed EIV after walking, dancing, swimming, or hiking especially during hot weather, including the records of 16 patients with EIV treated at our hospital from 2007 to 2015. Erythematous or purpuric plaques arise on the lower legs, without the involvement of compression socks or stockings. Symptoms include itch, pain, and a burning sensation. EIV is an isolated cutaneous vasculitis. Lesions resolve spontaneously after 10 days. When triggering conditions persist, relapses are frequent (77.5 %). Histopathology demonstrates leukocytoclastic vasculitis in 95 % of cases with C3 or immunoglobulin M deposits in 88 and 46 % of cases, respectively. Blood investigations are negative. EIV appears to be a consequence of venous stasis induced by an acute failure of the muscle pump of the calf and thermoregulation decompensation. Both appear after prolonged and unusual exercise in hot weather. Treatment is not codified; topical corticosteroids may reduce symptoms and wearing light clothes might limit lesion occurrence.

A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification.

In contrast to long bone osteosarcoma, mandibular osteosarcoma is highly heterogeneous and morphologically overlaps with benign tumors, obscuring diagnosis and treatment selection. Molecular characterization is difficult due to the paucity of available specimens of this rare disease. We aimed to characterize the spectrum of mandibular osteosarcoma using immunohistochemistry and molecular techniques (quantitative polymerase chain reaction and sequencing) and compare them with benign fibro-osseous lesions. Forty-nine paraffin-embedded mandible osteosarcoma tissue samples were collected retrospectively and compared with 10 fibrous dysplasia and 15 ossifying fibroma cases. These were analyzed for molecular markers thought to differ between the different diseases and subtypes: MDM2 (murine double-minute type 2) overexpression, GNAS (guanine nucleotide-binding protein/α subunit) mutations, and amplification of MDM2 and/or RASAL1 (RAS protein activator like 1). Five fibroblastic high-grade osteosarcoma subtypes showed MDM2 amplification, including 2 with a microscopic appearance of high-grade osteosarcoma with part low-grade osteosarcoma (differentiated/dedifferentiated osteosarcoma) and MDM2 overexpression. The other 3 contained a coamplification of MDM2 and RASAL1, a signature also described for juvenile ossifying fibroma, with no overexpression of MDM2. These were of the giant cell-rich high-grade osteosarcoma, with areas mimicking juvenile ossifying fibroma (ossifying fibroma-like osteosarcoma). Our results show that some diagnosed high-grade osteosarcomas are differentiated/dedifferentiated osteosarcomas and harbor an overexpression and amplification of MDM2. In addition, juvenile ossifying fibromas can potentially evolve into giant cell-rich high-grade osteosarcomas and are characterized by a RASAL1 amplification (osteosarcoma with juvenile ossifying fibroma-like genotype). Thus, the presence of a RASAL1 amplification in ossifying fibroma may indicate a requirement for closer follow-up and more aggressive management.

The PPAR(gamma) K422Q mutation does not contribute to troglitazone inefficiency in colon cancer treatment.

Peroxisome proliferator-activated receptor gamma (PPAR(gamma)) ligands inhibit cell growth of colorectal cancer cells in most experimental models, but no significant effect could be observed in patients with colorectal cancer. We therefore, screened human colorectal tumors to determine the prevalence of the PPAR(gamma) K422Q loss-of-function mutation, recently identified in 50% of colonic cancer cell lines. A sensitive allele-specific real-time amplification assay was developed and 170 colorectal primary tumors and 12 liver metastasis were analyzed. We did not find the K422Q mutation in any of these samples. We can therefore exclude this alteration as a mechanism of resistance to PPAR(gamma) ligands in patients with colon cancer.

Postoperative interstitial brachytherapy for resectable squamous cell carcinoma of the tongue.

PURPOSE: To evaluate the efficiency and toxicity of postoperative brachytherapy (POBT) in the treatment of resectable mobile tongue squamous cell carcinoma. PATIENTS AND METHODS: This was a retrospective single-center study of patients with SSC of the mobile tongue who were treated between August 1992 and June 2013 by glossectomy and neck dissection followed by (192)Ir interstitial brachytherapy of the tumor bed. Endpoints were local control, cancer-specific survival (CSS), overall survival (OS), and morbidity. Independent prognostic factors were analyzed in a Cox regression model. RESULTS: A total of 112 patients were identified (median age, 55 years [range, 15-84]; 76% male). Patient and tumor characteristics were: T1T2N0 (85%), pN+ (13%), positive surgical margins (14%), negative margins <5 mm (29%), dysplasic margins (14%), lymphatic vessel invasion (5%), and perineural spread (5%). Median followup was 6.7 years (1.5 months to 17.7 years). Local control, CSS, and OS rates at 2 years were 79%, 81%, and 72%, respectively. The corresponding 5-year rates were 76%, 67%, and 56%, respectively. After POBT, 22% of patients presented grade ≥2 necrosis and 8% experienced chronic pain. Independent prognostic factors were positive surgical margins for poor local control and tumor recurrence and lymphatic vessel invasion for poor OS. CONCLUSION: POBT provided good local control and better CSS and OS than reported for surgery alone. Morbidity was higher than that reported for brachytherapy alone but may be considered acceptable in a well-selected patient population at high risk of local recurrence.

Life-threatening hemorrhaging in neonatal ulcerated congenital hemangioma: two case reports.

IMPORTANCE: Congenital hemangiomas (CHs) are rare benign vascular tumors that differ from common infantile hemangiomas in that they grow in utero and are fully developed at birth. While ulceration is a common, predominantly benign complication in infantile hemangioma, little is known about the prognosis of ulcerated CH. However, it has been observed that ulcerated CH may be complicated by life-threatening bleeding episodes. OBSERVATIONS: We report 2 cases of ulcerated rapidly involuting congenital hemangiomas (RICH) that were complicated by life-threatening bleeding episodes in the neonatal period. In both cases, the CHs were fed by high-flow vessels and the ensuing massive bleeding was due to superficial vessel wall erosion induced by the ulceration. Both patients were successfully treated with intravascular embolization; one patient underwent additional hemostatic surgery. CONCLUSIONS AND RELEVANCE: These 2 cases highlight the importance of closely monitoring children with ulcerated CH because of the risk of severe bleeding. Embolization is the treatment of choice in the case of severe bleeding, as the natural history of RICH is to spontaneously regress.

Uncommon perineal tumours: caution with aggressive surgical management.

An asymptomatic 66-year-old woman showed a large perineal mass extending close to pelvic organs on MRI. CT-guided needle biopsies revealed a desmoid tumour (DT). The patient refused radical surgery. Four years later, the tumour had marginally increased in size and was still asymptomatic. The revision of earlier biopsies then revealed typical aspects of aggressive angiomyxoma (AA). AA and DT are rare mesenchymal tumours of low-grade malignancy, usually of large size, that occurs in female pelvi-perineal region. Radical resection with wide margins is classically advocated in such tumours in order to prevent the high risk of recurrences. However, due to a slow growth, rare infiltration of adjacent organs and a very low metastatic potential, a watchful waiting policy can be proposed when high postoperative morbidity is expected. In order to propose the accurate treatment, frontline biopsies of the tumour are essential.

Prognostic factors for T1-T2 squamous cell carcinomas of the mobile tongue: A retrospective cohort study.

BACKGROUND: The aim of this study was to identify factors predicting poor prognosis at the time of early oral tongue carcinoma diagnosis. METHODS: A retrospective cohort study was carried out on 70 patients with T1 or T2 squamous cell carcinoma of the mobile tongue treated with primary surgical treatment. RESULTS: In all, 47% of patients received adjuvant treatment. Local recurrence was observed in 29% and regional recurrence in 26%. With a median follow-up of 7.3 years for living patients, 5-year actuarial overall, disease-specific, and disease-free survival rates were 48%, 61%, and 42%, respectively. The presence of poor histological differentiation increased the overall risk of death. Tumor thickness and posterior lingual location independently increased overall and disease-specific risk of death. Concurrent or previous diagnosis of oral lichen significantly increased the risk of disease-specific death and disease recurrence. CONCLUSIONS: This study corroborates several known prognostic factors and indicates that diagnosis of oral lichen planus may be a risk factor for disease recurrence.

Pancreatic ductal and acinar cell neoplasms in Carney complex: a possible new association.

CONTEXT: Carney complex (CNC) is a rare disease inherited as an autosomal dominant trait, associated with various tumors, and caused most frequently by inactivation of the PRKAR1A gene. OBJECTIVES: In our recent investigation of a large cohort of CNC patients, we identified several cases of pancreatic neoplasms. This possible association and PRKAR1A's possible involvement in pancreatic tumor have not been reported previously. PATIENTS AND METHODS: Nine patients (2.5%) with CNC and pancreatic neoplasms in an international cohort of 354 CNC patients were identified; we studied six of them. Immunohistochemistry and PRKAR1A sequencing were obtained. RESULTS: Three men and three women with a mean age of 49 yr (range 34-75 yr) had acinar cell carcinoma (n = 2), adenocarcinoma (n = 1), and intraductal pancreatic mucinous neoplasm (n = 3). Five patients had a germline PRKAR1A mutation, including two patients with acinar cell carcinoma, for whom mutations were found in a hemizygous state in the tumor, suggesting loss of heterozygosity. PRKAR1A expression was not detected in five of the six pancreatic neoplasms from CNC patients, whereas the protein was amply expressed on other sporadic pancreatic tumors and normal tissue. CONCLUSION: An unexpectedly high prevalence of rare pancreatic tumors was found among CNC patients. Immunohistochemistry and loss-of-heterozygosity studies suggest that PRKAR1A could function as a tumor suppressor gene in pancreatic tissue, at least in the context of CNC. Clinicians taking care of CNC patients should be aware of the possible association of CNC with a potentially aggressive pancreatic neoplasm.

Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence.

BACKGROUND: Osteosarcoma is the most common malignant primary bone tumour in young adult treated by neo adjuvant chemotherapy, surgical tumor removal and adjuvant multidrug chemotherapy. For correction of soft tissue defect consecutive to surgery and/or tumor treatment, autologous fat graft has been proposed in plastic and reconstructive surgery. PRINCIPAL FINDINGS: We report here a case of a late local recurrence of osteosarcoma which occurred 13 years after the initial pathology and 18 months after a lipofilling procedure. Because such recurrence was highly unexpected, we investigated the possible relationship of tumor growth with fat injections and with mesenchymal stem/stromal cell like cells which are largely found in fatty tissue. Results obtained in osteosarcoma pre-clinical models show that fat grafts or progenitor cells promoted tumor growth. SIGNIFICANCE: These observations and results raise the question of whether autologous fat grafting is a safe reconstructive procedure in a known post neoplasic context.