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1.
Breast Cancer Res ; 22(1): 51, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32430040

RESUMO

BACKGROUND: The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). METHODS: MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 µg/day), tamoxifen (500 µg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. RESULTS: In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo. CONCLUSION: In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.

2.
J Orthop Res ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134136

RESUMO

The dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically-induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra-articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra-articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition.

3.
J Pathol ; 250(5): 667-684, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32129476

RESUMO

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

4.
Acta Neurochir (Wien) ; 162(5): 1137-1146, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31897730

RESUMO

INTRODUCTION: Desmoid-type fibromatosis (DTF) frequently arises in patients with neuromuscular choristoma (NMC). We hypothesize that NMC-associated DTF occurs in soft tissues innervated by the NMC-affected nerve, and arises from CTNNB1-mutated (myo) fibroblasts within or directly adjacent to the NMC. MATERIALS AND METHODS: A retrospective review of patients treated at our institution was performed for patients with biopsy-confirmed diagnosis of NMC-DTF. Clinical presentation, physical examination, electrodiagnostic findings and radiological features (MR and FDG PET/CT images for each NMC-DTF) and pathologic re-review of available materials were analyzed. A literature review was also performed. RESULTS: Eight patients from our institution met the inclusion criteria. All patients presented with neuropathic symptoms and soft tissue or bone changes in the nerve territory innervated by the NMC. All MR images (N=8 cases) showed the characteristic features of NMC, and also showed direct contact between unifocal (N=5) or multifocal (N=3) DTF(s) and the NMC-affected nerve NMC. FDG PET/CT (N=2 cases) showed diffuse, increased FDG uptake along the entire affected nerve segment, contiguous with the FDG-avid DTF. In all cases, the DTFs arose in the soft tissues of the NMC-affected nerve's territory. No patient developed DTF at any other anatomic site. CONCLUSIONS: These data demonstrate that NMC-DTF arises solely within the NMC-affected nerve territory, and has direct contact with the NMC itself. Based on all these findings and the multifocality of NMC in several cases, we recommend imaging and surveillance of the entire NMC-affected nerve (from spine to distal extremity) to identify clinically-occult DTF in patients with NMC.

5.
Breast Cancer Res Treat ; 179(1): 241-249, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31571071

RESUMO

PURPOSE: Significant controversy exists regarding the expression patterns of estrogen receptor beta (ERß) in normal and diseased breast tissue. To address this issue, we have validated two ERß antibodies, optimized the IHC protocols for both antibodies and now report the expression patterns of ERß in normal and malignant breast tissues. METHODS: ERß antibody specificity was determined using western blot and IHC analysis. ERß protein expression patterns were assessed via IHC in normal breast tissue and invasive breast carcinoma. Further, we report the detailed protocol of the ERß IHC assay developed in our CAP/CLIA certified laboratory to provide a standardized method for future studies. RESULTS: We have confirmed the specificity of two independent ERß monoclonal antibodies, one that detects total (i.e., full length plus splice variants 2-5, which do not include the ligand binding domain) ERß protein (PPZ0506) and one that detects only the full-length form, which includes the ligand binding domain, of ERß (PPG5/10). Using these two antibodies, we demonstrate that ERß is highly expressed in normal human breast tissue as well as in 20-30% of invasive breast cancers. Further, these two antibodies exhibited similar staining patterns across multiple different tissues and were highly concordant with regard to determining ERß positivity in breast cancers. CONCLUSIONS: ERß protein was shown to be abundant in the majority of normal breast epithelial cells and is present in 20-30% of breast cancers. Use of these two antibodies, along with their standardized IHC protocols, provide a reference for future studies aimed at determining the utility of ERß as a prognostic and/or predictive biomarker in various tissues of benign or malignant states.

6.
Mod Pathol ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481664

RESUMO

Lipomatosis of nerve is a rare malformation characterized by a fibrolipomatous proliferation within peripheral nerve. Lipomatosis of nerve most frequently involves the median nerve, and manifests clinically as a compressive neuropathy. However, 30-60% of cases are associated with tissue overgrowth within the affected nerve's territory (e.g., macrodactyly for lipomatosis of nerve in the distal median nerve). Somatic activating PIK3CA mutations have been identified in peripheral nerve from patients with lipomatosis of nerve with type I macrodactyly, which is now classified as a PIK3CA-related overgrowth spectrum disorder. However, the PIK3CA mutation status of histologically confirmed lipomatosis of nerve, including cases involving proximal nerves, and cases without territory overgrowth, has not been determined. Fourteen histologically confirmed cases of lipomatosis of nerve involving the median (N = 6), brachial plexus (N = 1), ulnar (N = 3), plantar (N = 2), sciatic and superficial peroneal nerves (N = 1 each) were included. Ten cases had nerve territory overgrowth, ranging from macrodactyly to hemihypertrophy; and four cases had no territory overgrowth. Exome sequencing revealed "hotspot" activating PIK3CA missense mutations in 6/7 cases. Droplet digital polymerase chain reaction for the five most common PIK3CA mutations (p.H1047R, p.H1047L, p.E545K, p.E542K, and p.C420R) confirmed the exome results and identified an additional six cases with mutations (12/14 total). PIK3CA mutations were found in 8/10 cases with territory overgrowth (N = 7 p.H1047R and N = 1 p.E545K), including two proximal nerve cases with extremity overgrowth, and 4/4 cases without territory overgrowth (p.H1047R and p.H1047L, N = 2 each). The variant allele frequency of PIK3CA mutations (6-32%) did not correlate with the overgrowth phenotype. Three intraneural lipomas had no detected PIK3CA mutations. As PIK3CA mutations are frequent events in lipomatosis of nerve, irrespective of anatomic site or territory overgrowth, we propose that all phenotypic variants of this entity be classified within the PIK3CA-related overgrowth spectrum and termed "PIK3CA-related lipomatosis of nerve".

7.
BMC Genomics ; 20(1): 689, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477010

RESUMO

BACKGROUND: Archived formalin fixed paraffin embedded (FFPE) samples are valuable clinical resources to examine clinically relevant morphology features and also to study genetic changes. However, DNA quality and quantity of FFPE samples are often sub-optimal, and resulting NGS-based genetics variant detections are prone to false positives. Evaluations of wet-lab and bioinformatics approaches are needed to optimize variant detection from FFPE samples. RESULTS: As a pilot study, we designed within-subject triplicate samples of DNA derived from paired FFPE and fresh frozen breast tissues to highlight FFPE-specific artifacts. For FFPE samples, we tested two FFPE DNA extraction methods to determine impact of wet-lab procedures on variant calling: QIAGEN QIAamp DNA Mini Kit ("QA"), and QIAGEN GeneRead DNA FFPE Kit ("QGR"). We also used negative-control (NA12891) and positive control samples (Horizon Discovery Reference Standard FFPE). All DNA sample libraries were prepared for NGS according to the QIAseq Human Breast Cancer Targeted DNA Panel protocol and sequenced on the HiSeq 4000. Variant calling and filtering were performed using QIAGEN Gene Globe Data Portal. Detailed variant concordance comparisons and mutational signature analysis were performed to investigate effects of FFPE samples compared to paired fresh frozen samples, along with different DNA extraction methods. In this study, we found that five times or more variants were called with FFPE samples, compared to their paired fresh-frozen tissue samples even after applying molecular barcoding error-correction and default bioinformatics filtering recommended by the vendor. We also found that QGR as an optimized FFPE-DNA extraction approach leads to much fewer discordant variants between paired fresh frozen and FFPE samples. Approximately 92% of the uniquely called FFPE variants were of low allelic frequency range (< 5%), and collectively shared a "C > T|G > A" mutational signature known to be representative of FFPE artifacts resulting from cytosine deamination. Based on control samples and FFPE-frozen replicates, we derived an effective filtering strategy with associated empirical false-discovery estimates. CONCLUSIONS: Through this study, we demonstrated feasibility of calling and filtering genetic variants from FFPE tissue samples using a combined strategy with molecular barcodes, optimized DNA extraction, and bioinformatics methods incorporating genomics context such as mutational signature and variant allelic frequency.


Assuntos
Neoplasias da Mama/genética , Análise Mutacional de DNA/métodos , DNA de Neoplasias/isolamento & purificação , Mama/química , Feminino , Fixadores , Formaldeído , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inclusão em Parafina , Fixação de Tecidos
8.
J Orthop Res ; 37(12): 2609-2620, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31410880

RESUMO

Arthrofibrosis is a common complication following total knee arthroplasty caused by pathologic fibroblast activation and excessive collagen deposition around a synovial joint leading to debilitating loss of motion. Treatment options are limited because the pathologic mechanisms remain to be characterized. Dysregulation of the inflammatory cascade may lead to communication between myofibroblasts and immune cells triggering tissue metaplasia, and excessive collagen deposition described clinically as arthrofibrosis. We explored the novel use of celecoxib (selective cyclooxygenase-2 [COX-2] inhibitor) to disrupt the downstream effects of the post-traumatic inflammatory cascade and inhibit scar tissue formation in a validated rabbit model of arthrofibrosis combined with new parameters for quantifying the stiffness of the posterior capsule. Biomechanical and molecular analyses, of contracted rabbit knee posterior capsule tissue after COX-2 inhibition revealed increased maximal passive extension and down-regulation of collagen messenger RNA compared with controls. Histopathologic examination suggested a trend of decreased quantities of dense fibrous connective tissue with COX-2 inhibition. These data may suggest that inhibiting the inflammatory cascade could potentially reduce pathologic myofibroblast activation, thereby reducing scar tissue formation and increasing the range of motion in arthrofibrotic joints. Implementing a multi-modal pharmacologic approach may simultaneously target numerous cellular components contributing to the complex process of arthrofibrogenesis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2609-2620, 2019.


Assuntos
Contratura/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/farmacologia , Articulações/patologia , Animais , Artroplastia do Joelho/efeitos adversos , Fenômenos Biomecânicos , Celecoxib/farmacologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Miofibroblastos/fisiologia , Coelhos
9.
World Neurosurg ; 129: e761-e766, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203072

RESUMO

INTRODUCTION: The natural history of growth and radiologic progression of neuromuscular choristomas (NMCs) remain unknown. The purpose of this study was to describe the radiologic growth pattern of NMCs and to determine how the pattern of growth relates to clinical progression. METHODS: A retrospective review was performed for patients with a confirmed diagnosis of NMC and at least 2 years of radiologic (magnetic resonance imaging [MRI]) follow-up. Medical records, including physical examinations and radiologic studies, were reviewed in detail. The NMC length and transverse dimensions were compared between serial MRI examinations. RESULTS: Eleven patients with a mean radiologic follow-up time of 5.6 years (range 2-19 years) were identified. Motor deficits occurred in 10 patients (90%), sensory deficits in 5 patients (45%), and neuropathic pain in 4 (36%) patients. Eight patients (73%) presented with manifestations of limb undergrowth, 2 (18%) with congenital hip dysplasia, and 1 with a cavus foot deformity. Progression of motor and sensory deficits was observed in 5 (45%) and 1 (9%) patients, respectively. The maximal length and height of the NMC was significantly (P < 0.05) longer (initial 218 ± 118 mm vs. follow-up 270 ± 135 mm) and larger (20 ± 10 mm vs. 24 ± 14 mm) on the follow-up scan. MRI demonstrated abnormalities that were in continuity along the longitudinal extent of the NMC. CONCLUSIONS: According to this small but relatively long-term follow-up cohort, the growth pattern of this lesion is slow but progressive. We found a longitudinal continuity pattern of growth in all MRI scans, often spanning a great distance.


Assuntos
Plexo Braquial/diagnóstico por imagem , Coristoma/diagnóstico por imagem , Músculo Esquelético , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Nervo Isquiático/diagnóstico por imagem , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
World Neurosurg ; 129: e555-e560, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31154102

RESUMO

BACKGROUND: Diverse adipose lesions can affect peripheral nerves, including an intrinsic disorder known as lipomatosis of nerve (LN). This condition leads to massive nerve enlargement and has often been associated with nerve territory overgrowth. Although LN has been well documented as a peripheral lesion, it is uncertain whether LN can occur or extend intradurally. METHODS: In the present 2-part study, we searched our institutional database and the world literature to identify any case of LN occurring or extending intradurally. Strict pathognomonic imaging and histopathologic features of LN were required to be present. RESULTS: We did not identify any case of LN that had occurred or extended intradurally in our institution. Specifically, in our database, we found no case of intradural LN, and an evaluation of the imaging studies of proximal examples of LN did not show any extension proximal to the spinal foramen. Our literature search identified 208 reports of potential interest, of which only 3 had reported on spinal LN. Although 2 of the 3 cases showed some similarities to LN, none had demonstrated features diagnostic for LN and none had demonstrated nerve territory overgrowth. A review of 16 cases of LN in proximal locations summarized in a recently reported systematic review did not reveal any cases with LN proximal to the foramen or in an intradural location. CONCLUSION: A review of our institutional cases and reported cases did not show any example of LN extending or occurring intradurally. It appears that LN is a benign tumor-like nerve lesion that is without a central location, unlike more well-known tumors such as schwannomas.


Assuntos
Lipomatose/patologia , Nervos Periféricos/patologia , Adulto , Idoso , Feminino , Humanos , Lipomatose/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nervos Periféricos/diagnóstico por imagem , Estudos Retrospectivos , Adulto Jovem
11.
Acta Neurochir (Wien) ; 161(4): 679-684, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30798481

RESUMO

BACKGROUND: Lipomatosis of nerve (LN) is a peripheral nerve disorder characterized by fibroadipose proliferation within the epineurium. It has been associated with nerve-territory overgrowth affecting soft tissue and/or bony structures. We sought to understand if there is an anatomical relationship associated with nerve-territory overgrowth. METHODS: A review of the literature and our institutional LN cases was performed to determine the prevalence of nerve-territory overgrowth. Only cases with sufficient clinical and/or imaging data were selected. The cases were then subdivided into two groups and analyzed: (1) motor (mixed) nerve and (2) predominant sensory nerve, based on the anatomical location of the LN lesion. Subgroup analysis was performed on median nerves affected by LN, for a more homogenous population. RESULTS: We identified 329 LN cases with sufficient information for analysis. Motor (mixed) nerve group (M) consisted of 287 cases (155 with overgrowth and 132 without overgrowth). Sensory nerve group (S) revealed group of 42 cases (4 cases with overgrowth and 38 without overgrowth). Statistical analysis comparing overgrowth status in the M and S nerve groups showed a statistically significant difference in overgrowth, favoring the M group for overgrowth (p < 0.0001). The analysis of median nerve group consisted of 225 cases in the M group (106 with overgrowth and 119 without overgrowth) and 20 cases in the S group (3 with overgrowth and 17 cases without overgrowth). A statistically significant difference in nerve-territory overgrowth status was present in the M vs. the S group, again favoring the M group for overgrowth. (p = 0.0083). Cases from our institution included 44 cases for this analysis. Forty-two cases in the M group (28 with overgrowth and 14 without overgrowth) and 2 cases in the S group (all 2 without overgrowth). CONCLUSION: We believe the association of LN and nerve-territory overgrowth might be explained by involvement of mixed motor nerves; however, the exact underlying mechanism is not known.

13.
Hum Pathol ; 91: 123-128, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30496800

RESUMO

Adamantinoma of the long bones is a rare, typically low-grade malignant tumor that frequently involves the tibia. Radiographically, adamantinoma is characteristically a lytic, intracortical, and expansile lesion with variable margins. Histologically, adamantinoma is a bimorphic neoplasm, composed of epithelial and osteofibrous elements. Herein, we describe a 72-year-old man with a long-standing tibial mass that, on imaging, rapidly developed cortical destruction with soft tissue extension. Imaging revealed no evidence of a distant site of origin. Needle core biopsy demonstrated high-grade squamous cell carcinoma, and metastasis was initially favored. However, the combined clinicoradiologic and pathologic features were most compatible with a high-grade squamous cell carcinoma arising in adamantinoma. The diagnosis was confirmed in the resection specimen. Both the age at presentation and histologic features make this case unusual and highlight a potential for misdiagnosis in the evaluation of squamous cell carcinoma-containing lesions of the tibia, reinforcing the importance of clinicoradiologic correlation in bone pathology.

14.
Oper Neurosurg (Hagerstown) ; 16(1): E17, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800277

RESUMO

Neuromuscular choristoma (NMC) is a rare congenital nerve lesion that is classified by the presence of heterotopic muscle fibers intercalated within nerve fascicles.1 The presence of NMC typically causes progressive neuropathy and bony/soft tissue undergrowth, often leading to a shortened atrophic limb.2,3 The typical appearance of NMC on magnetic resonance imaging is an enlarged fusiform nerve that exhibits minimal gadolinium enhancement.4 While there is increasing documentation of pathognomonic clinical and radiographic features for various diffuse fusiform peripheral nerve lesions, nerve biopsy is still occasionally required for some patients given the rarity of these diseases and progressive neuropathic features.The intraoperative appearance of NMC and its unique electrical stimulation properties are quite interesting. Intrafascicular replacement of nerve by skeletal muscle gives the nerve a red beefy color and causes the fascicles to contract with electrical stimulation.5 In this video, we demonstrate the intraoperative appearance and contractile properties of NMC in a 60-yr-old woman with progressive sciatic neuropathy. Histologic and immunohistochemical studies identified a gradient of intralesional mature skeletal muscle within the NMC, with substantially fewer desmin-positive skeletal muscle fibers in the distal aspect. A gradient of contractility with intraoperative stimulation seemed to correlate with this pathology. These findings suggest that the lesional extent of NMC may not be clinically or grossly evident, reflecting a varying distribution of skeletal muscle within the affected nerve.The Mayo Clinic Institutional Review Board Office for Human Research Protection does not require approval for single participant case studies. The subject involved in this study was not identifiable and the general surgical consent form included permission for intraoperative photos and video.

15.
Am J Surg Pathol ; 42(12): 1708-1714, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30303818

RESUMO

Perineuriomas are rare nerve sheath tumors, divided into intraneural and extraneural (soft tissue) types. Intraneural perineuriomas frequently contain TRAF7 mutations, and rarely, chr22q12 deletions. While chr22q losses can occur in soft tissue perineuriomas, comprehensive high-resolution molecular profiling has not been reported in these tumors and TRAF7 status is unknown. We used whole-exome sequencing and OncoScan single nucleotide polymorphism (SNP) array to evaluate 14 soft tissue perineuriomas. Thirteen cases showed 2 or more chromosomal abnormalities, composed primarily of large deletions. Recurrent chr22q deletions, containing the NF2 locus (n=6) and the previously unreported finding of chr17q deletions, with the NF1 locus (n=4) were frequent events and were mutually exclusive in all but1 case. In addition, 5 cases had varying chr2 deletions; and 4 cases had chr6 deletions. A chr10 deletion (previously reported in the sclerosing variant of soft tissue perineurioma) was observed in one case and another case had chr7 chromothripsis as the sole chromosomal abnormality. No TRAF7 mutations or alterations were identified in any case and no other evaluated gene (MAF<0.0001) had recurrent, deleterious mutations in >2 cases. The molecular genetic profiles showed no association with patient sex, age, tumoral histology or anatomic site. OncoScan SNP array analysis was performed on 10 cases and showed high concordance with the whole exome data, validating the large-scale deletions, duplications, and chr7 chromothripsis findings. In soft tissue perineuriomas, recurrent 22q12 deletions (with NF2) and 17q11 deletions (with NF1) appear to be mutually exclusive events, and alterations in NF1 or NF2 likely contribute to perineurioma pathogenesis, similar to other nerve sheath tumors. Moreover, the lack of TRAF7 mutations in soft tissue perineuriomas indicates divergent pathogenetic mechanisms from those of intraneural perineuriomas.


Assuntos
Biomarcadores Tumorais/genética , Deleção Cromossômica , Cromotripsia , Neoplasias da Bainha Neural/genética , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Neoplasias de Tecidos Moles/genética , Adulto , Idoso de 80 Anos ou mais , Criança , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Bainha Neural/patologia , Neurofibromina 1/genética , Neurofibromina 2 , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Neoplasias de Tecidos Moles/patologia , Transcriptoma , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Sequenciamento Completo do Exoma , Adulto Jovem
16.
J Neurosurg ; 131(1): 175-183, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30168738

RESUMO

OBJECTIVE: Desmoid-type fibromatosis (DTF) presents a therapeutic dilemma. While lacking metastatic potential, it is a locally aggressive tumor with a strong propensity for occurrence near nerve(s) and recurrence following resection. In this study, the authors introduce the association of an occult neuromuscular choristoma (NMC) identified in patients with DTF. METHODS: After experiencing a case of DTF found to have an occult NMC, the authors performed a retrospective database review of all other cases of biopsy-proven DTF involving the extremities or limb girdles in patients with available MRI data. Two musculoskeletal radiologists with expertise in peripheral nerve imaging reviewed the MRI studies of the eligible cases for evidence of previously unrecognized NMC. RESULTS: The initial case of a patient with an occult sciatic NMC is described. The database review yielded 40 patients with DTF-18 (45%) in the upper limb and 22 (55%) in the lower limb. Two cases (5%) had MRI findings of NMC associated with the DTF, one in the proximal sciatic nerve and the other in the proximal tibial and sural nerves. CONCLUSIONS: The coexistence of NMC may be under-recognized in a subset of patients with extremity DTF. This finding poses implications for DTF treatment and the likelihood of recurrence after resection or biopsy. Further study may reveal crucial links between the pathogenesis of NMC and DTF and offer novel therapeutic strategies.

17.
NPJ Breast Cancer ; 4: 26, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131975

RESUMO

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice.

18.
Cryobiology ; 84: 69-76, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30076796

RESUMO

We have developed a novel, intraluminal preservation solution that is tailored to the metabolic requirements of the intestine. This organ-specific solution addresses many of the problems associated with low temperature organ storage including energy, oxidative and osmotic stresses. However, conservation of energy levels remains one of the most difficult obstacles to overcome due to the inherent sensitivity of the mucosa to ischemia. Creatine-loading has become a popular and scientifically proven method of augmenting energy reserves in athletes performing anaerobic burst work activities. We hypothesized that if we could develop a method that was able to augment cellular energy levels, the structure and function of the mucosa would be more effectively preserved. The purpose of this study was to determine if creatine-loading is a feasible and effective strategy for preserving the intestine. Our data indicate that creatine loading has significant impact on energy levels during storage with corresponding improvements in mucosal structure and function. Both of our rodent models, a) continuous perfusion for 4 h and b) a single flush with our intraluminal preservation solution supplemented with 50 mM creatine, demonstrated significant improvements in creatine phosphate, ATP, Energy Charge and ATP/AMP following cold storage (P < 0.05). Notably, after 10 h creatine phosphate was 324% greater in Creatine-treated tissues compared to Controls (P < 0.05). Preferential utilization of glutathione in the Creatine group was effective at controlling oxidative injury after 10 h storage (P < 0.05). Improvements in barrier function and electrophysiology with creatine-treatment reflected superior mucosal integrity after 10 h storage; Permeability and Transepithelial resistance measurements remained at fresh tissue values. This was in stark contrast to Control tissues in which permeability rose to >300% of fresh tissue values (P < 0.005) and transepithelial resistance dropped by 95% (P < 0.005). After 10 h storage, Park's grading of histologic injury reflected extensive villus denudation (grade 4) in control tissues compared to healthy tissue (grade 0) in the Creatine group. This study demonstrates that a strategy of creatine supplementation of our intraluminal preservation solution facilitates the preservation of the intestinal mucosa during storage.


Assuntos
Creatina/farmacologia , Criopreservação/métodos , Intestino Delgado , Soluções para Preservação de Órgãos/química , Preservação de Órgãos/métodos , Animais , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Masculino , Soluções para Preservação de Órgãos/farmacologia , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
19.
J Clin Oncol ; 36(18): 1840-1846, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29676945

RESUMO

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.


Assuntos
Neoplasias da Mama/epidemiologia , Mama/patologia , Adulto , Biópsia , Doenças Mamárias/epidemiologia , Doenças Mamárias/patologia , Neoplasias da Mama/patologia , Calibragem , Estudos de Casos e Controles , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Humanos , Hiperplasia/epidemiologia , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Retrospectivos , Risco
20.
Am J Clin Pathol ; 149(3): 222-233, 2018 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-29425276

RESUMO

Objectives: Most giant cell tumors of bone (GCTs) occur in patients aged 20 to 40 years. We analyzed features of GCT in patients 55 years or older. Methods: GCTs were examined for fibrosis, matrix, cystic change, histiocytes, mitoses, and necrosis. Clinical/radiologic data were collected. Results: Thirty-four (5%) of 710 GCTs occurred in patients older than 55 years (14/20 male/female; 56-83 years) in long bones (n = 24), vertebrae (n = 6), pelvis (n = 3), and metacarpal (n = 1). Imaging was classic in 26 of 27 cases; one case appeared malignant. Morphologic patterns included fibrosis (n = 29), bone formation (n = 19), cystic change (n = 8), necrosis (n = 8), foamy histiocytes (n = 7), and secondary aneurysmal bone cyst formation (n = 1). Mitoses ranged from 0 to 18 per 10 high-power fields. Six recurred; one patient developed metastasis. Four of five cases harbored H3F3A mutations. Conclusions: GCTs in patients 55 years or older share pathologic characteristics with those arising in younger adults. Fibrosis and reactive bone are common, potentially leading to diagnostic confusion in this population. No histologic features correlate with adverse outcome.


Assuntos
Tumor de Células Gigantes do Osso/diagnóstico , Tumor de Células Gigantes do Osso/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
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