Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck.

OBJECTIVE: Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic disorder. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. We review less common imaging findings outside the head and neck. CONCLUSION: The imaging manifestations of RDD overlap with a variety of neoplastic and nonneoplastic conditions. Confirmation of an RDD diagnosis is based on specific histologic features. Radiologic assessment is used to rule out multifocality on initial workup and to evaluate treatment response.

[An attempt at defining the notion of wellbeing at work]. / Réflexion autour de la notion de bien-être au travail.

Feeling good at work means having the means to perform the tasks which are entrusted to us, feeling useful and receiving recognition. The many different types of suffering at work, known as psychosocial risks, are both social and psychological in nature. A management method which allows sharing and the search for meaning will undoubtedly help employees feel they are being treated well.

[Palliative care network, six reasons for early intervention]. / SLA: six raisons pour une intervention précoce des réseaux de soins palliatifs.

The benefits of early intervention on the part of a palliative care network are proven. Assisting both patients and their family, the aim is to support them through every stage of the disease. This article presents the example of the care provided by the NEPALE 91 palliative care network to a patient suffering from amyotrophic lateral sclerosis.

Utilization of cytologic cell blocks for targeted sequencing of solid tumors.

BACKGROUND: Targeted sequencing of cytologic samples has significantly increased in recent years. With increasing numbers of clinical trials for variant specific therapeutics, validating a comprehensive assay for cytologic samples has become clinically important. AIM: For this study, a retrospective review of cytologic cell blocks from fine needle aspirations and fluid specimens was performed. METHODS: Two hundred twenty six total cases of solid tumor malignancies were identified, of which 120 cases and 20 lymph node negative controls were sequenced for the Oncomine Comprehensive Assay. Cytology and surgical specimen correlation was performed in a subset of cases. Statistical analysis to determine variant concordance was performed. RESULTS: Within the 117 cases sequenced, a total of 347 pathogenic variants were detected. Of the 117 cases, 32 cases (27.4%) would qualify for FDA approved targeted therapy according to the current guidelines, and an additional 23 cases (19.7%) would qualify for clinical trial based on pathogenic variants detected. DISCUSSION: With over 27% of cases in our cohort qualifying for some form of targeted therapy, our study shows the importance of providing comprehensive molecular diagnostic options. Despite only half of the cytology cases in the review period having enough material to be sequenced, overall approximately 27% of patients in this cohort would have benefitted from this service.

Machine Learning for Digital Scoring of PRMT6 in Immunohistochemical Labeled Lung Cancer.

Lung cancer is the leading cause of cancer death in the U.S. Therefore, it is imperative to identify novel biomarkers for the early detection and progression of lung cancer. PRMT6 is associated with poor lung cancer prognosis. However, analyzing PRMT6 expression manually in large samples is time-consuming posing a significant limitation for processing this biomarker. To overcome this issue, we trained and validated an automated method for scoring PRMT6 in lung cancer tissues, which can then be used as the standard method in future larger cohorts to explore population-level associations between PRMT6 expression and sociodemographic/clinicopathologic characteristics. We evaluated the ability of a trained artificial intelligence (AI) algorithm to reproduce the PRMT6 immunoreactive scores obtained by pathologists. Our findings showed that tissue segmentation to cancer vs. non-cancer tissues was the most critical parameter, which required training and adjustment of the algorithm to prevent scoring non-cancer tissues or ignoring relevant cancer cells. The trained algorithm showed a high concordance with pathologists with a correlation coefficient of 0.88. The inter-rater agreement was significant, with an intraclass correlation of 0.95 and a scale reliability coefficient of 0.96. In conclusion, we successfully optimized a machine learning algorithm for scoring PRMT6 expression in lung cancer that matches the degree of accuracy of scoring by pathologists.

Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality.

This study aims to perform a comprehensive genomic analysis to assess the influence of overexpression of MYO1E in non-small cell lung carcinoma (NSCLC) and whether there are differences in survival and mortality risk in NSCLC patients depending on both DNA methylation and RNA expression of MYO1E. The DNA methylation probe cg13887966 was inversely correlated with MYO1E RNA expression in both LUAD and LUSC subpopulations showing that lower MYO1E RNA expression was associated with higher MYO1E DNA methylation. Late stages of lung cancer showed significantly lower MYO1E DNA methylation and significantly higher MYO1E RNA expression for LUAD but not for LUSC. Low DNA methylation as well as high RNA expression of MYO1E are associated with a shorter median survival time and an increased risk of mortality for LUAD, but not for LUSC. This study suggests that changes in MYO1E methylation and expression in LUAD patients may have an essential role in lung cancer's pathogenesis. It shows the utility of MYO1E DNA methylation and RNA expression in predicting survival for LUAD patients. Also, given the low normal expression of MYO1E in blood cells MYO1E DNA methylation has the potential to be used as circulating tumor marker in liquid biopsies.

[Palliative care networks, players in the 24-hour provision of care]. / Les réseaux de soins palliatifs, acteurs de la permanence des soins.

Palliative care networks ensure the coordination of patients' care in their homes and thereby contribute to the 24-hour provision of care. However, how is participation in round-the-clock care organised when the network's mobile coordination and expertise team does not perform care procedures?

Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity.

Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibition of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, virtually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas express B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and interferon (IFN)-gamma. T cells conditioned with the B7-H1-blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one approach for cancer immunotherapy.

ProEx C stain analysis in recurrent respiratory papillomatosis.

OBJECTIVES: We evaluated the presence and pattern of ProEx C stain, a marker for the proliferative capacity of cells, in laryngeal tissues, including benign, malignant, and recurrent respiratory papilloma (RRP) specimens, and compared it to hematoxylin and eosin staining for the presence of dysplasia. METHODS: We performed a retrospective study with chart review. RESULTS: A total of 26 specimens (9 benign, 7 malignant, 10 RRP) representing 21 patients were stained. ProEx C stained positive in the nuclei of laryngeal tissue, consistent with its localization in cervical cytology specimens. Seven of 9 benign and 7 of 10 RRP specimens stained positive. The benign specimens were mostly polyps. The malignant specimens were either well or moderately differentiated squamous cell carcinoma, and they stained strongly and diffusely. In benign and RRP specimens, the basal layer typically stained positive. Other areas of epithelium stained weakly in benign specimens and variably in RRP specimens. Current analysis of hematoxylin and eosin-stained RRP specimens revealed that 30% of specimens had at least moderate dysplasia and 80% exhibited viral changes (koilocytosis). CONCLUSIONS: ProEx C is a clean and reliable stain in laryngeal tissue, and stains positive in RRP. This study could not definitively correlate positive ProEx C staining in areas of greater dysplasia, although a trend was observed. Further studies are necessary to determine whether ProEx C can be used in triage of cases of clinically aggressive RRP for closer follow-up or frequent operative intervention.

PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages.

Increased expression of protein arginine methyl transferase 6 (PRMT6) correlates with worse prognosis in lung cancer cases. To interrogate the in vivo functions of PRMT6 in lung cancer, we developed a tamoxifen-inducible lung-targeted PRMT6 gain-of-function mouse model, which mimics PRMT6 amplification events in human lung tumors. Lung-targeted overexpression of PRMT6 accelerated cell proliferation de novo and potentiated chemical carcinogen (urethane)-induced lung tumor growth. To explore the molecular mechanism/s by which PRMT6 promotes lung tumor growth, we used proteomics-based approaches and identified interleukin-enhancer binding protein 2 (ILF2) as a novel PRMT6-associated protein. Furthermore, by using a series of in vitro gain-of-function and loss-of-function experiments, we defined a new role for the PRMT6-ILF2 signaling axis in alternate activation of tumor-associated macrophages (TAM). Interestingly, we have also identified macrophage migration inhibitory factor, which has recently been shown to regulate alternate activation of TAMs, as an important downstream target of PRMT6-ILF2 signaling. Collectively, our findings reveal a previously unidentified noncatalytic role for PRMT6 in potentiating lung tumor progression via the alternate activation of TAMs. IMPLICATIONS: This is the first study to demonstrate an in vivo role for PRMT6 in lung tumor progression via the alternate activation of TAMs.

EGFR/c-Met and mTOR signaling are predictors of survival in non-small cell lung cancer.

BACKGROUND: EGFR/c-Met activation/amplification and co-expression, mTOR upregulation/activation, and Akt/Wnt signaling upregulation have been individually associated with more aggressive disease and characterized as potential prognostic markers for lung cancer patients. METHODS: Tumors obtained from 109 participants with stage I-IV non-small cell lung cancer (NSCLC) were studied for EGFR/c-Met co-localization as well as for total and active forms of EGFR, c-Met, mTOR, S6K, beta-catenin, and Axin2. Slides were graded by two independent blinded pathologists using a validated scoring system. Protein expression profile correlations were assessed using Pearson correlation and Spearman's rho. Prognosis was assessed using Kaplan-Meier analysis. RESULTS: Protein expression profile analysis revealed significant correlations between EGFR/p-EGFR (p = 0.0412) and p-mTOR/S6K (p = 0.0044). Co-localization of p-EGFR/p-c-Met was associated with increased p-mTOR (p = 0.0006), S6K (p = 0.0018), and p-S6K (p < 0.0001) expression. In contrast, active beta-catenin was not positively correlated with EGFR/c-Met nor any activated proteins. Axin2, a negative regulator of the Wnt pathway, was correlated with EGFR, p-EGFR, p-mTOR, p-S6K, EGFR/c-Met co-localization, and p-EGFR/p-c-Met co-localization (all p-values <0.03). Kaplan-Meier analysis revealed shorter median survival in participants with high expression of Axin2, total beta-catenin, total/p-S6K, total/p-mTOR, EGFR, and EGFR/c-Met co-localization compared with low expression. After controlling for stage of disease at diagnosis, subjects with late-stage disease demonstrated shorter median survival when exhibiting high co-expression of EGFR/c-Met (8.1 month versus 22.3 month, p = 0.050), mTOR (6.7 month versus 22.3 month, p = 0.002), and p-mTOR (8.1 month versus 25.4 month, p = 0.004) compared with low levels. CONCLUSIONS: These findings suggest that increased EGFR/c-Met signaling is correlated with upregulated mTOR/S6K signaling, which may in turn be associated with shorter median survival in late-stage NSCLC.

Detection of Promoter DNA Methylation in Urine and Plasma Aids the Detection of Non-Small Cell Lung Cancer.

PURPOSE: Low-dose CT screening can reduce lung cancer-related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation-based detection of non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: This nested case-control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation-specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42). RESULTS: DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively. CONCLUSIONS: DNA methylation-based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.

Molecular Classification of Lymph Node Metastases Subtypes Predict for Survival in Head and Neck Cancer.

PURPOSE: In advanced stage head and neck squamous cell cancers (HNSCC), approximately half of the patients with lymph node metastases (LNM) are not cured. Given the heterogeneous outcomes in these patients, we profiled the expression patterns of LNMs to identify the biological factors associated with patient outcomes.Experimental Design: We performed mRNAseq and miRNAseq on 72 LNMs and 29 matched primary tumors from 34 patients with HNSCC. Clustering identified molecular subtypes in LNMs and in primary tumors. Prediction Analysis of Microarrays algorithm identified a 73-gene classifier that distinguished LNM subtypes. Gene-set enrichment analysis identified pathways upregulated in LNM subtypes. RESULTS: Integrative clustering identified three distinct LNM subtypes: (i) an immune subtype (Group 1), (ii) an invasive subtype (Group 2), and (iii) a metabolic/proliferative subtype (Group 3). Group 2 subtype was associated with significantly worse locoregional control and survival. LNM-specific subtypes were not observed in matched primary tumor specimens. In HNSCCs, breast cancers, and melanomas, a 73-gene classifier identified similar Group 2 LNM subtypes that were associated with worse disease control and survival only when applied to lymph node sites, but not when applied to other primary tumors or metastatic sites. Similarly, previously proposed prognostic classifiers better distinguished patients with worse outcomes when applied to the transcriptional profiles of LNMs, but not the profiles of primary tumors. CONCLUSIONS: The transcriptional profiles of LNMs better predict outcomes than transcriptional profiles of primary tumors. The LNMs display site-specific subtypes associated with worse disease control and survival across multiple cancer types.

Parotid gland fine-needle aspiration cytology: an approach to differential diagnosis.

Parotid glands can undergo a wide range of pathologic changes that may be difficult to characterize by clinical features alone. No single diagnostic modality is currently accepted unequivocally as the definitive approach to parotid gland enlargement or tumors. Although it is generally accepted that fine-needle aspiration (FNA) biopsy is useful in the preoperative setting, the accuracy is highly dependent on both operator experience and the interpretative skills of the cytopathologist. Results of FNA biopsy must be considered in a global context, in conjunction with clinical and radiographic findings. The objectives of this paper are threefold: (1) to define the clinical role of parotid FNA, such that pathologists performing and/or interpreting such specimens have a clearer understanding of the expectations of our surgical colleagues; (2) to clearly describe a protocol for the performance of parotid FNA biopsy, including a discussion of complications and pitfalls; and (3) to present the cytologic differential diagnoses of diverse clinicopathologic parotid gland processes that may present as generalized enlargement, cystic lesions, or discrete masses.

Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals.

CD4(+)CD25(+) regulatory T cells (Tregs) mediate peripheral T-cell homeostasis and contribute to self-tolerance. Their homeostatic and pathologic trafficking is poorly understood. Under homeostatic conditions, we show a relatively high prevalence of functional Tregs in human bone marrow. Bone marrow strongly expresses functional stromal-derived factor (CXCL12), the ligand for CXCR4. Human Tregs traffic to and are retained in bone marrow through CXCR4/CXCL12 signals as shown in chimeric nonobese diabetic/severe combined immunodeficient mice. Granulocyte colony-stimulating factor (G-CSF) reduces human bone marrow CXCL12 expression in vivo, associated with mobilization of marrow Tregs to peripheral blood in human volunteers. These findings show a mechanism for homeostatic Treg trafficking and indicate that bone marrow is a significant reservoir for Tregs. These data also suggest a novel mechanism explaining reduced acute graft-versus-host disease and improvement in autoimmune diseases following G-CSF treatment.

Synchronous Ipsilateral Parotid Tumors with Cytologic-Histologic Correlation.

Synchronous ipsilateral tumor formation within a major salivary gland is a very rare event. In this case, a 54-year-old female tobacco smoker presented with a slowly enlarging left parotid gland. Computed tomography of the neck demonstrated a solid mass superficial to a cystic mass in the deep lobe of the gland. Ultrasound-guided fine needle aspiration yielded oncocytic cells, lymphoid cells, and granular debris along with rare cohesive groups of basaloid cells. Parotidectomy was performed, and the resected gland was found to contain two adjacent but distinct masses. One mass, a predominantly solid, well-circumscribed lesion composed of ribbons of double-layered oncocytic cells and a lymphoid stroma with germinal center formation, was a Warthin tumor. The other mass, a predominantly cystic lesion composed of cords and nests of basaloid cells with associated deposits of basement membrane-like material, was a basal cell adenoma of the membranous type. To our knowledge, this is the first reported case of synchronous Warthin tumor and basal cell adenoma of the parotid gland with cytologic-histologic correlation attributable to each tumor.

Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage.

PURPOSE: Akt is a signal transduction protein that plays a central role in inhibiting apoptosis in a variety of cell types including human cancer cells. In cell lines derived from human non-small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by inhibition of apoptosis in response to different chemotherapeutic agents including platinum-based agents, which are often the first-line therapy for NSCLCs. Only 20% to 30% of patients with NSCLC treated with chemotherapy have clinical evidence of response. The purpose of this study is to determine whether or not overexpression of activated Akt [i.e., phosphorylated Akt (pAkt)] is correlated with survival. EXPERIMENTAL DESIGN: We studied tumors from 61 patients with NSCLC in three tissue microarrays. All patients were followed for a period of 10 years or until death. The arrays were studied immunohistochemically with antibodies against pAkt, p53, and Ki-67. RESULTS: There was a statistically significant difference in survival between the 14 patients with strong pAkt staining and the 47 patients with weak to absent pAkt staining both by log-rank (P = 0.0416) and Breslow analysis (P = 0.0446). Difference in survival time with respect to pAkt status was also statistically significant even after accounting for stage at diagnosis (P = 0.004). Neither p53 nor Ki-67 was a statistically significant prognostic factor. CONCLUSIONS: Overexpression of pAkt is an independent prognostic factor. Additional studies of human NSCLCs are warranted to drive the development of targeted tumor-specific antineoplastic therapies.

Spatial composition of prostate cancer spheroids in mixed and static cultures.

Aggregation of neoplastic cells produces multicellular spheroids resembling micrometastases. The objective of this study was to investigate the effects of mixing culture medium on the spatial composition of spheroids prepared from well (LNCaP) and poorly (DU 145) differentiated human prostate cancer cells. Spheroids were cultured in a mixed suspension within a high-aspect rotating wall vessel and static liquid-overlay plate. Results from this study demonstrate that mixed cultures consistently manifested differences in morphology and composition between DU 145 and LNCaP spheroids. For example, 40 +/- 12% of DU 145 cells were Ki-67 positive 100 microm from the surface within mixed spheroids versus 0% for LNCaP cells; there was no significant difference in this spatial profile for static cultures. The results suggest that poorly differentiated spheroids may be more likely to experience a change in composition from mixing culture medium than well-differentiated spheroids, due to low tissue density. Immunostaining for P-glycoprotein is representative of this trend; average staining intensity increased 50% for DU 145 spheroids on mixing but was unchanged for LNCaP spheroids. The effects of mixing on spheroid composition were attributed to faster interstitial mass transport. Applications include drug development and delivery, as well as basic research on drug action and resistance.

Unusual cases of metastases to the breast. A report of 17 cases diagnosed by fine needle aspiration.

BACKGROUND: Although nonmammary tumors metastatic to the breast are relatively uncommon, a correct diagnosis is essential to appropriate management. Radiologically these lesions are single, round, discrete lesions without the spiculations of primary malignancies. Fine needle aspiration biopsy (FNAB) may provide a definitive diagnosis, thereby sparing patients unnecessary surgery. CASES: Seventeen cases of nonmammary malignancies diagnosed by fine needle aspiration of the breast were identified in the cytopathology files at three different institutions from 1989 to 1999. Three of the cases are of particular interest, including a mucoepidermoid carcinoma of salivary gland origin and a small cell undifferentiated carcinoma of rectal origin, neither of which has been reported in the literature previously. The third case was a male with a breast mass that was originally thought to be primary based on clinical, cytologic and immunocytochemical features but subsequently was determined to be a metastasis from the lung. CONCLUSION: Virtually any malignancy may metastasize to the breast. FNAB is the best approach to the diagnosis of tumors that either clinically or radiographically are not typical of primary breast tumors. Extramammary neoplasms metastatic to the breast may be definitively diagnosed by FNAB, resulting in the most appropriate as well as cost-effective patient management.