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Thyroglossal duct cysts are the most common congenital abnormality in the neck, accounting for 70-75% of midline neck masses in children [1]. Late in the 4th week of gestation, the thyroid anlage develops as a small, solid mass of endoderm proliferating at the foramen cecum. As the thyroid anlage descends caudally in the neck, it maintains an attachment to the site of origin at the level of the foramen cecum of the tongue via the thyroglossal duct [2]. The thyroglossal duct typically involutes and atrophies between 7 and 10 weeks of gestation by the time the thyroid gland reaches its final position inferior to the cricoid cartilage [2]. The source of TGDC is believed to be persistent remnants of the thyroglossal duct. Due to the communication of the duct to the mouth via the foramen cecum, thyroglossal cysts can become infected with oral flora. One-third of patients of all ages will present with a concurrent or prior infection, and one-quarter will present with a draining sinus from spontaneous or incisional drainage of an abscess [3]. The cysts occur almost equally in both sexes [4,5].

OBJECTIVES/HYPOTHESIS The effects of different electrocautery power settings on mucosal contraction and margin status in the oral cavity have not been well established. The aim of this study was to examine how different levels of electrocautery energy outputs affect oral mucosal tissue margins. STUDY DESIGN Animal model. METHODS A model of 23 adult rats was used (two specimens per rat). After anesthetizing the animals, a 6-mm biopsy punch marked the resection margin on the buccal mucosa (one per cheek). The specimens were excised by means of three energy levels, a cold knife, and monopolar diathermy that was set on either 20 W or 30 W cut modes. The specimens were evaluated for extent of contraction. RESULTS A total of 45 samples were obtained and measured, including 15 specimens in the cold-knife group, 15 specimens in the 20 W group, and 15 specimens in the 30 W group. The median diameters of the specimens after resection were 4.5 mm for the cold-knife group (interquartile range [IQR] = 4.0-5.0), 3.5 mm for the 20 W group (IQR = 3.5-4.0), and 2.8 mm for the 30 W group (IQR = 2.5-3.0). Specimen contraction was 25.0%, 41.7%, and 53.3%, respectively. The difference in shrinkage between each pair was statistically significant: cold knife versus 20 W, P = .001; cold knife versus 30 W, P

Cancer-Associated Fibroblasts (CAFs) were shown to orchestrate tumour-promoting inflammation in multiple malignancies, including breast cancer. However, the molecular pathways that govern the inflammatory role of CAFs are poorly characterised. In this study we found that fibroblasts sense damage-associated molecular patterns (DAMPs), and in response activate the NLRP3 inflammasome pathway, resulting in instigation of pro-inflammatory signalling and secretion of IL-1β. This upregulation was evident in CAFs in mouse and in human breast carcinomas. Moreover, CAF-derived inflammasome signalling facilitated tumour growth and metastasis, which was attenuated when NLRP3 or IL-1β were specifically ablated. Functionally, CAF-derived inflammasome promoted tumour progression and metastasis by modulating the tumour microenvironment towards an immune suppressive milieu and by upregulating the expression of adhesion molecules on endothelial cells. Our findings elucidate a mechanism by which CAFs promote breast cancer progression and metastasis, by linking the physiological tissue damage response of fibroblasts with tumour-promoting inflammation., Cancer associated fibroblasts (CAFs) are known to promote pro-tumorigenic inflammation. Here, the authors show that CAFs sense tissue damage and activate NLRP3 inflammasome and pro-inflammatory IL-1β secretion, and CAF-derived inflammasome signalling promotes breast tumour growth and metastasis.

Aims The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. Methods A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. Results Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). Conclusions A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

Cancer-associated fibroblasts (CAFs) are highly prominent in breast tumors, but their functional heterogeneity and origin are still largely unresolved. We report that bone marrow (BM)–derived mesenchymal stromal cells (MSCs) are recruited to primary breast tumors and to lung metastases and differentiate to a distinct subpopulation of CAFs. We show that BM-derived CAFs are functionally important for tumor growth and enhance angiogenesis via up-regulation of Clusterin. Using newly generated transgenic mice and adoptive BM transplantations, we demonstrate that BM-derived fibroblasts are a substantial source of CAFs in the tumor microenvironment. Unlike resident CAFs, BM-derived CAFs do not express PDGFRα, and their recruitment resulted in a decrease in the percentage of PDGFRα-expressing CAFs. Strikingly, decrease in PDGFRα in breast cancer patients was associated with worse prognosis, suggesting that BM-derived CAFs may have deleterious effects on survival. Therefore, PDGFRα expression distinguishes two functionally unique CAF populations in breast tumors and metastases and may have important implications for patient stratification and precision therapeutics.

Background A positive margin is among the most significant factors that affects the outcome in head and neck squamous cell carcinoma (SCC). The purpose of this study was to compare the negative margin rates between 2 methods of intraoperative margin assessment in patients with oral cavity SCC. Methods A prospective, randomized controlled trial comparing 2 methods of intraoperative margin assessment: specimen-driven margins and patient-driven margins. Results The final analysis included 71 patients, 20 (29%) in the patient-driven margin arm. Frozen section analysis revealed positive/close surgical margins that led to an extension of the surgical resection in 22 of 51 patients (43%) in the specimen-driven margin arm, and 2 of 20 patients (10%) in the patient-driven margin arm (p = .01). After final pathological analysis, the wide negative margin rate was 84% in the specimen-driven margin arm, compared to 55% in the patient-driven margin arm (p = .02). Extension of the surgical resection prevented escalation of adjuvant treatment in 19 patients (38%) in the specimen-driven margin arm and 10% in the patient-driven margin arm. Conclusion Specimen derived margin assessment led to significant improvement in the rate of negative margins. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1803–E1809, 2016

Tumor spread along nerves, a phenomenon known as perineurial invasion, is common in various cancers including pancreatic ductal adenocarcinoma (PDAC). Neural invasion is associated with poor outcome, yet its mechanism remains unclear. Using the transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we investigated the mechanism of neural invasion in PDAC. To detect tissue-specific factors that influence neural invasion by cancer cells, we characterized the perineurial microenvironment using a series of bone marrow transplantation (BMT) experiments in transgenic mice expressing single mutations in the Cx3cr1, GDNF and CCR2 genes. Immunolabeling of tumors in KPC mice of different ages and analysis of human cancer specimens revealed that RET expression is upregulated during PDAC tumorigenesis. BMT experiments revealed that BM-derived macrophages expressing the RET ligand GDNF are highly abundant around nerves invaded by cancer. Inhibition of perineurial macrophage recruitment, using the CSF-1R antagonist GW2580 or BMT from CCR2-deficient donors, reduced perineurial invasion. Deletion of GDNF expression by perineurial macrophages, or inhibition of RET with shRNA or a small-molecule inhibitor, reduced perineurial invasion in KPC mice with PDAC. Taken together, our findings show that RET is upregulated during pancreas tumorigenesis and its activation induces cancer perineurial invasion. Trafficking of BM-derived macrophages to the perineurial microenvironment and secretion of GDNF are essential for pancreatic cancer neural spread.

The chemokines RANTES (CCL5) and MCP-1 (CCL2) were suggested to contribute, independently, to breast malignancy. In the present study, we asked if the two chemokines are jointly expressed in clinical samples of breast cancer patients, and do they interact in breast tumor cells. We found that RANTES and MCP-1 were expressed by breast tumor cells in primary tumors of Ductal Carcinoma In Situ and of Invasive Ductal Carcinoma, but minimally in normal breast epithelial duct cells. The chemokines were also detected in metastases and pleural effusions. Novel findings showed that co-expression of RANTES and MCP-1 in the same tumor was associated with more advanced stages of disease, suggesting that breast tumors "benefit" from interactions between the two chemokines. Accordingly, MCP-1 significantly promoted the release of RANTES from endogenous pre-made vesicles, in an active process that depended on calcium from intracellular and extracellular sources, and on intracellular transport of RANTES towards exocytosis. Our findings show a chemokine-triggered release of stored pro-malignancy chemokine from breast tumor cells. These observations support a major tumor-promoting role for co-expression of the chemokines in breast malignancy, and agree with the significant association of joint RANTES and MCP-1 expression with advanced stages of breast cancer.

Two patients evaluated for metamorphopsia were noted to have inferotemporal retinal pigment epithelium elevations formed by a yellowish lesion. Fluorescein angiography showed granular hyperfluorescence with late leakage, which was interpreted as an occult choroidal neovascularization. One patient underwent photodynamic therapy. In both patients, neither vitreous cells nor neurologic manifestations were evident on presentation. Subsequent neurological signs appeared that prompted performance of brain imaging, which confirmed a space-occupying lesion. In both patients, the tumor was proven on histopathologic examination of brain tissue to be central nervous system lymphoma. Awareness of other possible underlying pathologies is warranted in cases of atypical choroidal neovascularization.

Considerable progress has been made during the last decade in our understanding of the complex anatomy of the anterior skull base. Anatomical and clinical studies have contributed extensively to the development of new surgical approaches, while new imaging tools have significantly increased the accuracy of preoperative evaluation and postoperative follow-up of our patients. Finally, the concept of cooperation between multidisciplinary teams was adopted for the treatment of these tumors allowing complete eradication of large tumors involving the skull base and craniofacial regions. When tumors arising in the anterior skull base invade both soft and hard tissues of the skull base, tumor resection may create extensive skull base defects and produce a free conduit between the paranasal sinuses and the intracranial space. Following tumor extirpation, skull base cranial base defects require precise and durable reconstruction to (1) form a watertight dural seal, (2) provide a barrier between the contaminated sinonasal space and the sterile subdural compartment, (3) prevent airflow into the intracranial space, (4) maintain a functional sinonasal system, and (5) provide a good cosmetic outcome. A variety of approaches have been developed to accomplish these goals. A split calvarial bone graft, hydroxyapatite paste, or titanium mesh may be utilized for bony reconstruction. Autologous flaps (pericranial or galeal flaps) and artificial substitutions are often used for reconstruction of the skull base. Unfortunately, these methods bear significant disadvantages. Local flaps are often insufficient in size for reliable restoration of extensive anterior skull base defects.1 Synthetic substitutions of dura and bone can induce chronic inflammation, carry high risk of infection, and are inferior to biological sources in terms of strength and sealing quality.2 Recent progress in microvascular and surgical techniques has enabled the development and implementation of free tissue transfer. Following skull base resection, free flaps may be used for massive defects, with excellent surgical results and low complication rates.1,3,4 Free tissue transfer is, however, a relatively complex surgical procedure that requires high technical qualifications. Another drawback of this method is the bulk of the muscular free flap, which may mask local recurrence and make radiological follow-up more difficult.5 Auto grafts, such as fascia lata and temporalis fascia, had been used in the past for skull base reconstruction, but they were usually covered with a vascularized flap (i.e., free muscular flaps, pericranial or galeal flaps), assuming that an overlying vascular tissue is essential to preserve long-term viability of the fascial graft.6 In any situation, failure to create adequate reconstruction harbors significant complications, among them cerebrospinal fluid (CSF) leak, meningitis, brain herniation, and tension pneumocephalus.7 Although the subcranial or craniofacial approaches have become established procedures for management of anterior skull base tumors,8 surgeons commonly use combinations of methods to accomplish satisfactory anterior skull base reconstruction. Thus, there is no single gold standard technique that is both simple and reliable for reducing the morbidity and mortality associated with anterior cranial base operations. Here we present a large series of patients who had undergone extirpation of tumors via the subcranial approach followed by reconstruction of anterior skull base defects. We present a reliable and reproducible algorithm for cranial base reconstruction, with low rates of intra- and extracranial complications. We describe the healing process of the double-layer free fascial grafts and provide evidence to show that long-term viability of the fascia is achievable without an overlying vascularized flap.

Pediatric low-grade gliomas (LGGs) are the largest group of central nervous system neoplasms in children. Although these tumors are generally benign, 5 to 10% of patients with pediatric LGGs present with leptomeningeal dissemination. The genetic and biological nature of these tumors is poorly understood. The authors looked for certain molecular abnormalities that may differentiate disseminated gliomas from the other pediatric LGGs.Comparative genomic hybridization (CGH) was applied to 18 pediatric LGGs. Six cases featuring disseminated pediatric LGGs were compared with 12 control cases involving nondisseminated pediatric LGGs. Fluorescence in situ hybridization (FISH) analysis and immunohistochemical analysis were used to highlight further specific genetic targets. The CGH revealed multiple chromosomal abnormalities in five of six cases with disseminated gliomas and in six of 12 control cases. No correlation was found between the number of chromosomal abnormalities and dissemination status. Amplification of chromosome 7 was noted in four of six cases with disseminated gliomas as opposed to one of 12 control cases (p = 0.02). The FISH analysis revealed epidermal growth factor receptor (EGFR) amplification in one case negative to chromosome 7 amplification by CGH, raising the amplification cases to five of six (p = 0.0038). Immunohistochemical analysis for EGFR was positive in six of six cases and in two of 12 control cases (p = 0.0015). At the end of a mean follow-up period of 7.2 years, all patients with disseminated gliomas are alive with variable but slow disease progression.The high rate of EGFR gene amplification and protein expression in disseminated pediatric LGGs is intriguing and may have implications for our understanding of the role of EGFR in glioma genesis. Targeted therapies may be available for these children. Larger-scale studies are needed to establish further these findings.

Chordoma is an uncommon malignant neoplasm derived from remnants of the embryonal notochord. The tumor arises in the sacrococcygeal region in most cases. Cytogenetic information on clival chordomas is scarce due to the low incidence of these tumors. In this study, we applied the G-banding and spectral karyotyping techniques to compare the karyotypes of three variants of clival chordoma: conventional, chondroid, and dedifferentiated. We describe a normal karyotype of a chondroid chordoma and a complex karyotype of a conventional chordoma involving chromosomes 1, 2, 3, 5, 8, 9, 11, 15, 19, 20, and X. The cytogenetic analysis of the dedifferentiated chordoma showed a polyploid complex karyotype of 71-123 chromosomes with double minutes that originated from chromosome 17.

Object The goal of this study was to demonstrate the efficacy of a simple and reliable technique for anterior skull base and craniofacial reconstruction in patients who have undergone excision of tumors via the subcranial approach. Methods There were 63 patients who had undergone 71 anterior skull base resections of tumors via the aforementioned approach. Twenty-nine cases (41%) involved malignant tumors and 42 (59%) involved benign tumors. Reconstruction of the anterior skull base was performed by a single team who used double-layer fascial graft. Limited dural defects were reconstructed using the temporalis fascia, whereas large anterior skull base defects were reconstructed using a fascia lata sheath. Reconstruction was achieved without the support of bone graft or titanium mesh and without pericranial, galeal, or free flaps. Pericranial flap wrapping of the frontonasoorbital segment was performed to prevent osteoradionecrosis if postoperative radiotherapy was planned. The incidence of cerebrospinal fluid (CSF) leakage, intracranial infection, and tension pneumocephalus was 5.6%. Histopathological examination of fascia lata grafts obtained in patients who had undergone a second procedure demonstrated integration of vascularized fibrous tissue to the graft, as well as local proliferation of a newly formed vascular layer embedding the fascial sheath. Conclusions The use of a double-layer fascial graft alone was adequate for prevention of CSF leakage, meningitis, tension pneumocephalus, and brain herniation. The double-layer fascial flap provided a simple and reliable means for anterior skull base reconstruction after en bloc resection of both malignant and benign tumors.

Introduction Breast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES). Methods Chemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-α (and IL-1β). The roles of AP-1 and NF-κB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers. Results TNF-α (and IL-1β) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-α (and IL-1β) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-α-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF-κB but not via the AP-1 pathway. Exposure of MSCs to TNF-α led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors. Conclusions Our novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-κB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0080-7) contains supplementary material, which is available to authorized users.

β-catenin is a cytoskeleton-associated signaling molecule shown to be elevated in various carcinomas but mostly in colon cancer owing to its impaired degradation. In contrast, its close homologue plakoglobin was shown to suppress the tumorigenicity of certain tumor cells. In the present study, we have used a semiquantitative immunohistochemical approach to evaluate the extent of nuclear localization of β-catenin in human colonic adenocarcinomas and adenomas and compared it to the distribution of plakoglobin in the same tissues. We show that β-catenin accumulates in the nuclei of the epithelium of primary and metastatic colonic adenocarcinoma as well as in colonic adenomas. In contrast, nuclear plakoglobin levels in these tissues were low, even compared to those found in epithelial cells of normal colon. These results support the view that the increase in β-catenin levels in colon cancer cells occurs early in the tumorigenic process, leading to its nuclear localization, not only in invasive adenocarcinoma, but also in colonic adenoma with mild dysplasia.

Protein phosphatase (PP2Calpha) is a member of the mammalian serine threonine-specific protein phosphatases family. We produced monoclonal antibodies against the recombinant PP2Calpha and evaluated the immunoreactivity of normal human tissues. The reactivity was strong in normal skin, the digestive tract, lung, kidney, breast, prostate, endocrine glands, and brain, while it was moderate in the ovary, testis, and liver. Epithelial cells revealed high levels of PP2Calpha expression, but stromal cells, including fibroblasts and endothelial cells, showed no or little PP2Calpha expression. Given the broad reactivity in endocrine and secreting epithelial cells, we propose that PP2Calpha expression might contribute to secretory cell function.

RBM (RNA-binding motif) protein is a marker of male germ cells. This protein is encoded by the Azoospermia factor region-b (AZF-b) of the human Y chromosome and is expressed exclusively in the male germ cell line, that is, spermatogonia, spermatocytes, and round spermatids. The authors analyzed the expression of the RBM gene in germ cell tumors and in the seminiferous tubules in the vicinity of these tumors to identify the presence of IGCN. Sections from testicular germ cell tumors of 21 patients were stained with anti-RBM antibody by using an immunohistochemical method. Distal tubules showing spermatogenesis were immunopositive for RBM protein. All of the germ cell tumors studied were completely immunonegative for RBM. Defined areas of IGCN also showed an absence of RBM expression. Tubules with spermatocyte-like cells, which were expected to express RBM, did not express this protein. This result enabled the identification of tubules as being IGCN. RBM is a novel marker consistently expressed in normal male germ cells but not in malignant germ cell tumors or IGCN. Thus, the absence of RBM expression in germ cells provides a new diagnostic tool of preinvasive malignancy of the testis.

Background We investigated the risk of neck metastases in patients undergoing salvage total laryngectomy in association with previous radiotherapy. Methods The medical records of 42 patients (51 neck specimens) with clinical N0 classification who underwent salvage total laryngectomy in 2 cancer centers were reviewed. Fourteen patients had previous radiotherapy to the central neck and 28 to the central and lateral neck. Results Staging before salvage total laryngectomy was similar in both groups. The risk of neck metastases in the central and central/lateral radiation groups was 12% and 18%, respectively (p = .69). Subgroup analysis revealed that 4 of 8 patients initially presenting with clinically N+ had neck metastases before surgery, versus 2 of 26 for those with clinically N0 (p = .015; relative risk [RR] = 4.67). The risk or metastases in the contralateral neck was 0 of 9. Conclusion The risk of neck metastases in patients who undergo either central or central/lateral neck radiotherapy is similar. Elective neck dissection seems appropriate in patients undergoing SLR. © 2012 Wiley Periodicals, Inc. Head Neck 35: 1392–1396, 2013

Benign sinonasal tumours are relatively common, with an overall incidence of 3–5 %. These tumours may be divided into fibro-osseous lesions and soft tissue tumours. Many of them are asymptomatic and are discovered incidentally on imaging studies or nasal endoscopy; for example, osteomas present as an incidental finding in up to 1 % of plain sinus radiographs, and in 3 % of sinus computerized tomograms (CTs) [1, 2]. Other tumours may cause symptoms, such as nasal obstruction, epistaxis, deformation and orbit-related problems. Soft tissue tumours will usually require biopsy and surgical resection, whereas fibro-osseous lesions may be followed radiologically if they are not associated with symptoms or signs. The indication for surgical treatment should be based on pathological findings and symptoms; this should be weighed against the adverse effects of treatment. Many of these tumours can be removed endoscopically, while others may require open approaches. In this chapter, we review the major histological types of benign sinonasal tumours, as well as their clinical presentation and management (Box 3.1). The radiological features of each tumour are further discussed in Chap. 5.

Malignant tumours of the paranasal sinuses and skull base are relatively rare (~3 % of all malignant tumours of the head and neck) [1]. The salient features of such tumours are male predominance, increased incidence among Caucasians, and an age of over 50 years of most of the patients at the time of diagnosis [2]. Tumours located in the anterior skull base may be of epithelial, neuronal or mesenchymal origin. Lymphomas and plasmocytomas are relatively rare in this area.

The World Health Organization (WHO) classification of ovarian tumors, which first appeared in 1983 and since then has undergone a number of revisions, is based on morphologic features as well as on the concept that each category of ovarian tumors develops from a specific ovarian cell. According to this histogenetic classification, all the epithelial ovarian neoplasms are derived from the ovarian surface epithelium and/or from ovarian inclusion cysts, which are lined by the above epithelial cells. In recent years, a new approach to morphologic data, increasing presumptive evidence that the cell of origin of most, if not all, ovarian epithelial tumors may be extraovarian, especially from fallopian tube and uterine endometrial cells, the recognition of precursor lesions, the emergence of certain key immunomarkers as well as molecular and genetic factors have brought about a reevaluation of the traditional approach to these tumors. This has resulted in attempts of reclassification or subclassification of ovarian epithelial neoplasms as well as new diagnostic criteria for these tumors. It should also be stressed that in most cases these new concepts correlate with the clinical course of the disease and eventually may also have an impact on the therapeutic approach to these tumors.

Background The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course. Methods The expression of CCL2, CCL5, TNFα and IL-1β was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments. Results CCL2, CCL5, TNFα and IL-1β were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNFα & IL-1β in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse. Conclusions Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.

Objective: This pilot double-blind randomized study evaluated the efficacy of 780-nm laser phototherapy on the acceleration of axonal growth and regeneration after peripheral nerve reconstruction by polyglycolic acid (PGA) neurotube. Background Data: The use of a guiding tube for the reconstruction of segmental loss of injured peripheral nerve has some advantages over the regular nerve grafting procedure. Experimental studies have shown that laser phototherapy is effective in influencing nerve regeneration. Methods: The right sciatic nerve was transected, and a 0.5-cm nerve segment was removed in 20 rats. A neurotube was placed between the proximal and the distal parts of the nerve for reconnection of nerve defect. Ten of 20 rats received post-operative, transcutaneous, 200-mW, 780-nm laser irradiation for 14 consecutive days to the corresponding segments of the spinal cord (15 min) and to the reconstructed nerve (15 min). Results: At 3 months after surgery, positive somato-sensory evoked responses were found in 70% of the irradiated rats (p � 0.015), compared to 30% of the non-irradiated rats. The Sciatic Functional Index in the irradiated group was higher than in the non-irradiated group (p � 0.05). Morphologically, the nerves were completely reconnected in both groups, but the laser-treated group showed an increased total number of myelinated axons. Conclusion: The results of this study suggest that postoperative 780-nm laser phototherapy enhances the regenerative process of the peripheral nerve after reconnection of the nerve defect using a PGA neurotube.

Necrotizing fasciitis is a rapidly progressing, life-threatening soft tissue bacterial infection found more frequently in immunocompromised subjects and rarely in the head and neck. We report a rare case of a patient with acquired immunodeficiency syndrome (AIDS) and non-Hodgkin's lymphoma (NHL) who presented with a high fever and supraorbital cellulitis 1 week after undergoing chemotherapy. He received intravenous antibiotic therapy but soon developed dyspnea and trismus with rapid extension of the cellulitis to the face, ipsilateral infratemporal fossa (ITF), and bilateral neck. An awake tracheotomy was followed by surgical exploration and drainage and debridement of the supraorbital and ITF areas, parotid gland, and bilateral neck. He received intravenous antibiotic therapy and the surgical wound was regularly debrided for 10 days. Following a gradual recovery, the patient was discharged 2 weeks later. Early antibiotic therapy, wide surgical exploration, and a secured airway are the therapeutic mainstay for necrotizing fasciitis of the skull base and neck.

Purpose: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers. Experimental Design: The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed. Results: Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5+), the absence of ER-α (ER-α−), and the lack of PR expression (PR−) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-α−, improved by combining them together (CCL5+/ER-α−: P = 0.0001), being highly evident in the stage IIA subgroup [CCL5+/ER-α− (P = 0.0003); ER-α− (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5−/ER-α+ and CCL5−/PR+ were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-α and CCL5 were independent predictors of disease progression. Conclusions: CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5+/ER-α− combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.

Rituximab, a chimeric anti-CD20 monoclonal antibody, is commonly being used to treat indolent and aggressive B-cell non-Hodgkin's lymphoma. Rituximab is considered a relatively safe drug, but recently, severe and fatal adverse effects related to this drug have been reported. In this regard, we report an 80-year-old patient with follicular grade 3 non-Hodgkin's lymphoma who developed a fatal interstitial pneumonitis related to treatment with a rituximab/CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) regimen. The pneumonitis was diagnosed on a routine midtreatment positron emission tomography/computed tomography scan when the patient was almost asymptomatic. Pulmonary deterioration occurred as the treatment with rituximab/CHOP was continued. In this article, we also review the literature on rituximab-associated pneumonitis, and we discuss the differential diagnosis with cyclophosphamide-induced lung injury.

Background. Recurrences in the neck after neck dissections occur even in previously operated fields. Although the pathogenesis is unclear, it is well established that recur- rences commonly occur at the jugular chain of nodes close to the carotid artery. We investigated the carotid sheath as possibly responsible for such regional recurrences. Methods. Patients undergoing therapeutic or elective neck dissections were prospectively enrolled. Following surgery, the carotid sheath was resected throughout its entire length, fixated in formalin, and histologically examined. Results. Pathologic assessment of carotid sheaths har- vested from 34 patients who underwent 40 uncomplicated neck dissections revealed fibro-fatty tissue and scarce neutrophilic infiltration in all 40 specimens. Four lymphoid aggregates composed almost exclusively of B cells were found at the carotid bifurcation level in three patients. No cancer cells were detected. Conclusion. The absence of cancer cells in patients with metastatic nodes argues against the need to resect the ca- rotid sheath as part of a routine neck dissection. The occurrence of lymphoid aggregates within it, however, may indicate its par- ticipation in the pathogenesis of nodal recurrence following neck dissection. A 2004 Wiley Periodicals, Inc. Head Neck 26: 594-597, 2004

Background. Mucormycosis is a potentially lethal disease caused by an opportunistic fungal infection. It occurs mostly in diabetic or immunosuppressed patients and usually involves the lungs or paranasal sinuses. Methods. We report a rare case of a patient with diabetic ketoacidosis who presented with progressive cough and dyspnea. CT of the neck and chest showed an intraluminal soft-tissue mass extending from the first tracheal ring to the thoracic inlet, causing severe destruction of the trachea. Direct laryngoscopy and biopsy demonstrated hyphal invasion with architecture typical of invasive mucormycosis. Results. The patient underwent resection of the upper trachea and prolonged amphotericin B therapy and is disease free at 24 months after surgery. Conclusions. In patients with diabetes presenting with progressive hoarseness, dyspnea, and endobronchial mass, a fungal infection should be considered. In case of invasive tracheal mucormycosis, prompt diagnosis and early surgical resection may help improve survival. © 2004 Wiley Periodicals, Inc. Head Neck26: 541–543, 2004

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2mnull mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.

Background & Aims: Impaired mucosal barrier, cytokine imbalance, and dysregulated CD4 + T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA, are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation. Methods: The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate–induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. Similarly, these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice. Results: In all models of experimental and spontaneous colitis examined, ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metalloproteinases in both dextran sodium sulfate– and hapten–induced colitis. Conclusions: As the colon is continuously exposed to bacterial DNA, these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease. GASTROENTEROLOGY 2002;122:1428-1441

Importance Squamous cell carcinoma of the oral cavity (OSCC) is a common malignant tumor worldwide. Objective To determine if regional failure in patients with OSCC and pathologically negative neck nodes (pN–) is due to an incomplete sampling procedure during surgery. Design, Setting, and Participants We retrospectively reviewed the medical records of 2258 patients from 11 cancer centers worldwide who underwent neck dissection for OSCC (1990-2011) and who were pN−. Of those, 345 had clinical evidence of nodal metastases (cN+) on radiologic workup. The neck specimens were available for reanalysis in 193 patients. Survival rates were calculated using the Kaplan-Meier graphs and analyzed by multivariable analysis. Main Outcomes and Measures Five-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Results Resectioning and analysis of the neck dissection specimens in the cN+/pN− subgroup revealed false-negative results in 29 (15%) of 193 patients. The negative predictive value of the initial pathologic examination was 85%. The 5-year OS and DSS in the cN−/pN− group were 77.6% and 87.2%, respectively. The 5-year OS and DSS of the cN+/pN− group were 62.6% and 78.5%, respectively ( P P = .03) and poor DSS (HR, 1.46; 95% CI, 1.1-4.1; P = .04). A cN+ classification was associated with lower DFS (66.3% vs 76.2%; P = .05) and lower regional recurrence–free survival (68.6% vs 78.8%; P = .02) but not with local ( P = .20) or distant recurrence ( P = .80). Conclusions and Relevance Pathologic staging underestimates the incidence of nodal metastases in cN+ disease. After correction for pathologically missed nodal metastases, radiologic evidence of neck nodes is an independent predictor of outcome, suggesting that traditional sampling during surgery might miss metastases, and this fact might explain the origin of treatment failure in these patients.

The incidence of testicular neoplasia has increased, and its early detection has become a pressing clinical issue. The strong association between male subfertility and risk of testicular neoplasia is consistent with the existence of common pathogenetic factors. Most forms of testicular germ tumors are believed to stem from a common precursor, intratubular germ cell neoplasia (ITGCN), also known as testicular carcinoma in situ. Identification of ITGCN cells in testicular biopsies, however, is a diagnostic challenge and markers are sorely needed to assist in the accurate identification of the lesion.

The present report of a 25 year old woman with a primary ovarian angiosarcoma is supplemented by histochemical and ultrastructural studies and reviews the literature of this extremely rare neoplasm. Since this ovarian tumor, especially in young women, may constitute a diagnostic pitfall, problems relating to differential diagnosis are emphasized. Although the origin of this neoplasm appears to occur most likely from the rich ovarian vasculature, other less conventional histogenetic theories such as a possible origin in mixed mullerian tumor, in teratoma or in other ovarian germ cell tumors have also been proposed and are considered in this paper.

Background Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells. Methods and Findings A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors. Conclusions This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies., Gideon Rechavi and colleagues describe the case of a boy with ataxia telangiectasia who developed a brain tumor after neural stem cell therapy., Editors' Summary Background. Most of the cells in the human body are highly specialized (“differentiated”). The brain and the spinal cord, for example, contain two main cell types—neurons, which transmit electrical signals to and from the brain, and glial cells, which support and protect the neurons. If these essential neural cells become damaged or diseased, the body cannot replace them. Scientists think, however, that it might be possible to use “neural stem cell” transplants to replace the neural cells that are lost in neurodegenerative diseases (for example, Parkinson's disease) or damaged by strokes or trauma. Stem cells are undifferentiated cells that replicate indefinitely and that have the potential to develop into many different specialized cells. Pluripotent stem cells (which are able to develop into any kind of specialized cell) can be isolated from early human embryos; “multipotent” stem cells (which develop into only a few cell types) can be isolated from many differentiated tissues, including the brain. Human fetuses (unborn offspring from the end of the 8th week after conception) are thought to be a particularly good source of neural stem cells because many new neural cells are made in fetal brains. Why Was This Study Done? Although stem cell transplantation might provide treatments for many debilitating diseases, some concerns have been raised over its safety. In particular, some experts fear that tumors might sometimes develop from transplanted stem cells. Tumor cells actually behave very much like stem cells—they divide indefinitely and they tend to be undifferentiated. It is very important, therefore, that every patient who receives a human stem cell transplant is carefully followed up to see whether any tumors develop as a result. In this study, the researchers describe a case in which multiple, slow-growing, donor-derived brain tumors formed in a patient after the transplantation of human fetal neural stem cells. What Did the Researchers Do and Find? Beginning in 2001, fetal neural stem cells were injected several times into the brain and the fluid surrounding it of a boy with ataxia telangiectasia at a Moscow hospital. Ataxia telangiectasia, a rare disorder characterized by degeneration of the brain region that controls movement and speech, occurs when both copies of the ATM gene (human cells contain two copies of most genes) contain a genetic change that stops the production of functional ATM protein. In 2005, the boy had a magnetic resonance imaging scan at the Sheba Medical Center (Israel) because of recurrent headaches. The scan revealed abnormal growths in his brain and spinal cord. In September 2006, when the boy was 14, the spinal cord growth was surgically removed. This growth has never reappeared but the mass in the boy's brain has continued to grow slowly. The material removed from the boy's spinal cord contained both neurons and glial cells, the researchers report, and resembled a glioneuronal tumor. In addition, it contained both XX (female) and XY (male) cells and the tumor cells had two normal copies of the ATM gene. Finally, a technique called HLA typing showed that the tumor contained cells from at least two donors. What Do These Findings Mean? These findings indicate that the growth in the patient's spinal cord was donor-cell derived and contained cells from two or more donors, at least one of whom was female. Although the growth in the patient's brain has not been examined, the multiple masses seen in this patient probably arose independently from transplanted cells injected at different sites, suggest the researchers. Importantly, the slow growth of the tumors and the well-differentiated appearance of the cells removed from the patient suggest that the tumors are relatively benign. Donor-derived cells might have been able to establish tumors in this particular patient because people with ataxia telangiectasia often have an impaired immune system and the immune system normally helps to reject tumor cells. Nevertheless, this first example of a donor-derived brain tumor developing after fetal neural cell transplantation is worrying and suggests that further work should be done to assess the safety of this therapy. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000029. The US National Institutes of Health provides information about stem cells and their potential uses The International Society for Stem Cell Research also provides information about all aspects of stem cells for the public and for professionals The US National Human Neural Stem Cell Resource provides specific information about neural stem cells for the public and for scientists The US National Cancer Institutes has a fact sheet about ataxia telangiectasia