Clinical and molecular characteristics of HNSCC patients with brain metastases: a retrospective study.

Among the metastasis patterns of head and neck squamous cell carcinoma (HNSCC), intracranial spread is a rare but dreaded event. To date only very few cases have been reported and clinical and molecular data are sparse. We screened our archives for HNSCC patients from 1992 to 2005 who were diagnosed with brain metastases (BM). For retrospective analysis, all clinico-pathological data including disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) were compiled. Additionally, we assessed the mutational status of the TP53 gene and the prevalence of HPV serotypes by PCR and Sanger sequencing. Immunohistochemistry was applied to detect p16INK4A expression levels as surrogate marker for HPV infection. The prevalence rate of BM in our cohort comprising 193 patients with advanced HNSCC was 5.7 %. Of 11 patients with BM, 3 were female and 9 were male. Seven of the primary tumors were of oropharyngeal origin (OPSCC). LPFS of the cohort was 11.8 months, DFS was 12.1 months and OS was 36.0 months. After the diagnosis of BM, survival was 10.5 months. Five tumors showed a mutation in the TP53 gene, while five of the seven OPSCC tumors had a positive HPV status displaying infection with serotype 16 in all cases. Compared with patients who harbored TP53wt/HPV-positive tumors, patients with TP53 mutations showed a poor prognosis. Compared with the whole cohort, the interval between diagnosis of the primary and the detection of BM was prolonged in the HPV-infected OPSCC subgroup (26.4 vs. 45.6 months). The prognosis of HNSCC patients with BM is poor. In our cohort, most tumors were OPSCC with the majority being HPV positive. Our study points toward a putatively unusual metastatic behavior of HPV-positive OPSCC.

Pretreatment and outcome correlates of sexual and physical trauma in an epidemiological cohort of first-episode psychosis patients.

OBJECTIVES: High prevalence of trauma has been reported in psychosis. While role of trauma as a risk factor for developing psychosis is still debated, its negative impact on outcome has been described. Few studies have explored this issue in first-episode psychosis (FEP) patients. We assessed rate of stressful events, as well as premorbid and outcome correlates of past sexual and/or physical abuse (SPA) in an epidemiological FEP patients cohort. METHODS: The Early Psychosis Prevention and Intervention Centre admitted 786 FEP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. A total of 704 files were available, 43 excluded because of a nonpsychotic diagnosis at end point and 3 due to missing data regarding past stressful events; 658 patients were analyzed. RESULTS: A total of 83% patients had been exposed to at least one stressful event and 34% to SPA. SPA patients were more likely to have presented other psychiatric disorders before psychosis onset (posttraumatic stress disorder, substance use disorder), to have made suicide attempts in the past, and to have had poorer premorbid functional levels. Additionally, SPA patients had higher rate of comorbid diagnosis at program entry and were more likely to attempt suicide during treatment. CONCLUSIONS: SPA prevalence is high in FEP patients and must be explored by clinicians considering its durable impact on psychological balance and link with long-lasting suicidal risk. More research is warranted to better understand mechanisms involved between trauma and its potential consequences, as well as to develop psychological interventions adapted to this very sensitive and complex issue.

A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss.

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Preoperative assessment and classification of benign laryngotracheal stenosis: a consensus paper of the European Laryngological Society.

Adult and pediatric laryngotracheal stenoses (LTS) comprise a wide array of various conditions that require precise preoperative assessment and classification to improve comparison of different therapeutic modalities in a matched series of patients. This consensus paper of the European Laryngological Society proposes a five-step endoscopic airway assessment and a standardized reporting system to better differentiate fresh, incipient from mature, cicatricial LTSs, simple one-level from complex multilevel LTSs and finally "healthy" from "severely morbid" patients. The proposed scoring system, which integrates all of these parameters, may be used to help define different groups of LTS patients, choose the best treatment modality for each individual patient and assess distinct post-treatment outcomes accordingly.

Epidemiology and injury patterns of patients consulting following assault by nightclub security agents in a university hospital emergency service and an associated specialised forensic consultation

Introduction: The Violence Medical Unit (VMU), a specialised forensic medical consultation, was created at the Lausanne university Hospital in 2006. All patients consulting at the ED for interpersonal violencerelated injury are referred to the VMU, which provides forensic documentation of the injury and referral to the relevant community based victim-support organisations within 48 hours of the ED visit. This frees the ED medical staff from forensic injury documentation and legal/social referral, tasks for which they lack both time and training. Among community violence, assaults by nightclub security agents against patrons have increased from 6% to 10% between 2007 and 2009. We set out to characterise the demographics, assault mechanisms, subsequent injuries, prior alcohol intake and ED & VMU costs incurred by this group of patients. Methods: We retrospectively included all patients consulting at the VMU due to assault by nightclub security agents from January 2007 to December 2009. Data was obtained from ED & VMU medical, nursing and administrative records. Results: Our sample included 70 patients, of which 64 were referred by the CHUV ED. The victims were typically young (median age 29) males (93%). 77% of assaults occurred on the weekend between 12 PM and 4 AM, and 73% of the victims were under the influence of alcohol. 83% of the patients were punched, kicked and/or head-butted; 9% had been struck with a blunt instrument. 80% of the injuries were in the head and neck area and 19% of the victims sustained fractures. 21% of the victims were prescribed medical leave. Total ED & VMU costs averaged 1048 SFr. Conclusion: Medical staff treating this population of assault victims must be aware of the assault mechanisms and injury patterns, in particular the high probability of fractures, in order to provide adequate diagnosis and care. Associated inebriation mandates liberal use of radiology, as delayed or missed diagnosis may have medical, medicolegal and legal implications. Emergency medical services play an important role in detecting and reporting of such incidents. Centralised management of the forensic documentation facilitates referral to victim support organisations and epidemiological data collection. Magnitudes and trends of the different types of violence can be determined, and this information can be then impact public safety management policies.

Clinical and biochemical responses after Gamma Knife surgery for a dopamine-secreting paraganglioma: case report.

The efficacy of Gamma Knife surgery (GKS) in local tumor control of non-secreting paragangliomas (PGLs) has been fully described by previous studies. However, with regard to secreting PGL, only one previous case report exists advocating its efficacy at a biological level. The aims of this study were: 1) to evaluate the safety/efficacy of GKS in a dopamine-secreting PGL; 2) to investigate whether the biological concentrations of free methoxytyramine could be used as a marker of treatment efficacy during the follow-up. We describe the case of a 62-year-old man diagnosed with left PGL. He initially underwent complete surgical excision. Thirty months after, he developed recurrent biological and neuroradiological disease; the most sensitive biomarker for monitoring the disease, concentration of plasma free methoxytyramine, started to increase. GKS was performed at a maximal marginal dose of 16 Gy. During the following 30 months, concentration of free methoxytyramine gradually decreased from 0.14 nmol/l (2*URL) before GKS to 0.09 nmol/l, 6 months after GKS and 0.07 nmol/l at the last follow-up after GKS (1.1*URL), confirming the efficacy of the treatment. Additionally, at 30 months there was approximately 36.6% shrinkage from the initial target volume. The GKS treatment was safe and effective, this being confirmed clinically, neuroradiologically and biologically. The case illustrates the importance of laboratory tests taking into account methoxytyramine when analyzing biological samples to assess the biochemical activity of a PGL. In addition, the identification of methoxytyramine as a unique positive biomarker could designate it for the monitoring of tumor relapse after treatments, including Gamma Knife surgery.

Fusion of Multi-Atlas Segmentations with Spatial Distribution Modeling

In recent years, multi-atlas fusion methods have gainedsignificant attention in medical image segmentation. Inthis paper, we propose a general Markov Random Field(MRF) based framework that can perform edge-preservingsmoothing of the labels at the time of fusing the labelsitself. More specifically, we formulate the label fusionproblem with MRF-based neighborhood priors, as an energyminimization problem containing a unary data term and apairwise smoothness term. We present how the existingfusion methods like majority voting, global weightedvoting and local weighted voting methods can be reframedto profit from the proposed framework, for generatingmore accurate segmentations as well as more contiguoussegmentations by getting rid of holes and islands. Theproposed framework is evaluated for segmenting lymphnodes in 3D head and neck CT images. A comparison ofvarious fusion algorithms is also presented.

Sawhorse-type diruthenium tetracarbonyl complexes containing porphyrin-derived ligands as highly selective photosensitizers for female reproductive cancer cells.

Diruthenium tetracarbonyl complexes of the type [Ru2(CO)4(l2-g2-O2CR)2L2] containing a Ru-Ru backbone with four equatorial carbonyl ligands, two carboxylato bridges, and two axial two-electron ligands in a sawhorse-like geometry have been synthesized with porphyrin-derived substituents in the axial ligands [1: R is CH3, L is 5-(4-pyridyl)-10,15,20-triphenyl-21,23H-porphyrin], in the bridging carboxylato ligands [2: RCO2H is 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23H-porphyrin, L is PPh3; 3: RCO2H is 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23H-porphyrin, L is 1,3,5-triaza-7-phosphatricyclo [3.3.1.1]decane], or in both positions [4: RCO2H is 5-(4-carboxyphenyl)-10,15,20-triphenyl-21,23H-porphyrin, L is 5-(4-pyridyl)-10,15,20-triphenyl-21,23H-porphyrin]. Compounds 1-3 were assessed on different types of human cancer cells and normal cells. Their uptake by cells was quantified by fluorescence and checked by fluorescence microscopy. These compounds were taken up by human HeLa cervix and A2780 and Ovcar ovarian carcinoma cells but not by normal cells and other cancer cell lines (A549 pulmonary, Me300 melanoma, PC3 and LnCap prostate, KB head and neck, MDAMB231 and MCF7 breast, or HT29 colon cancer cells). The compounds demonstrated no cytotoxicity in the absence of laser irradiation but exhibited good phototoxicities in HeLa and A2780 cells when exposed to laser light at 652 nm, displaying an LD50 between 1.5 and 6.5 J/cm2 in these two cell lines and more than 15 J/cm2 for the others. Thus, these types of porphyric compound present specificity for cancer cell lines of the female reproductive system and not for normal cells; thus being promising new organometallic photosensitizers.

Bisphosphonate-related osteonecrosis of the jaws: how to manage cancer patients.

Bisphosphonate related osteonecrosis of the jaw (BRONJ) is defined as exposed necrotic bone appearing in the jaws of patients treated by systemic IV or oral BPs never irradiated in the head and neck area and that has persisted for more than 8 weeks. More than 90% of cases of osteonecrosis of the jaw have been in patients with cancer who received IV-BPs. The estimate of cumulative incidence of BRONJ in cancer patients with IV-BPs ranges from 0.8% to 18.6%. The pathogenesis of BRONJ appeared related to the potent osteoblast-inhibiting properties of BPs which act by blocking osteoclast recruitment, decreasing osteoclast activity and promoting osteoclast apoptosis. Dental extractions are the most potent local risk factor. Cancer patients wearing a denture could also be at increased risk of BRONJ. Non-healing mucosal breaches caused by dentures could be a portal for the oral flora to access bone, while the oral mucosa of patients on IV-BPs could also be defective. Whether periodontal disease is a risk factor for BRONJ remains controversial. Preventive measures are fundamental. Nevertheless, some teams have questioned its cost-effectiveness. The perceived limitations of surgical therapy of BRONJ led to the restriction of aggressive surgery to symptomatic patients with stage 3 BRONJ. The evidence-based literature on BRONJ is growing but there are still many controversial aspects.

Descriptive epidemiology of skin cancer in the Swiss Canton of Vaud.

Incidence registration and survival data for non-melanocytic skin neoplasms and cutaneous melanoma have been abstracted from the population-based system of the Cancer Registry of the Swiss Canton of Vaud, which has been operating in a particularly favourable environment, since the large majority of cutaneous lesions resected in the area are examined by a pathologist. Among the 5,712 cases registered, 66.7% were basal-cell carcinomas, 20.6% squamous-cell cancers, 9.3% cutaneous melanomas and 3.4% other miscellaneous histological types. The distribution by histological type did not differ appreciably in the 2 sexes, but there were marked inter-sex differences as regards anatomical site. In both sexes, head and neck was by far the commonest localization for non-melanomatous neoplasms (69 to 81% of all incident cases), followed by trunk for basal-cell cancers (18% in males, 15% in females) and upper limb for squamous-cell (10% in males, 17% in females). The distribution of skin melanomas differed considerably between the 2 sexes, by far the commonest site being the trunk for males (45% of cases) and lower limbs for females (40%), followed by head and neck (22% in both sexes). Incidence rates for both basal- and squamous-cell cancers increased with age, and rates were higher in males for each localization except the lower limb. In contrast, incidence for melanoma was higher in females, and incidence rates did not increase with age above 55 years for all sites except head and neck. This can be interpreted in terms of cohort effect, since mortality from melanoma has substantially increased in Switzerland across subsequent birth cohorts. Although this study is essentially descriptive, accurate inspection of these data provides some support for the major aetiological hypotheses of skin carcinogenesis, i.e., the observation that the large majority of basal- and squamous-cell cancers arise on the head and neck confirms the importance of long-term ultraviolet exposure; the relative excess of squamous-cell as compared to basal-cell neoplasms on the upper limb may suggest the role of exposure to other (chemical) carcinogens; and the proportional excess of melanomas on the trunk in males and lower limb in females further indicates that intermittent exposure to sunlight is probably the relevant aetiologic factor for melanocytic skin neoplasms.

The Rare Cancer Network: achievements from 1993 to 2012.

The Rare Cancer Network (RCN), founded in 1993, performs research involving rare tumors that are not common enough to be the focus of prospective study. Over 55 studies have either been completed or are in progress.The aim of the paper is to present an overview of the 30 studies done through the RCN to date, organized by disease site. Five studies focus on breast pathology, including sarcoma, lymphoma, phyllodes tumor, adenoid cystic carcinoma, and ductal carcinoma in situ in young women. Three studies on prostate cancer address prostatic small cell carcinoma and adenocarcinoma of young and elderly patients. Six studies on head and neck cancers include orbital and intraocular lymphoma, mucosal melanoma, pediatric nasopharyngeal carcinoma, olfactory neuroblastoma, and mucosa-associated lymphoid tissue lymphoma of the salivary glands. There were 4 central nervous system studies on patients with cerebellar glioblastoma multiforme, atypical and malignant meningioma, spinal epidural lymphoma and myxopapillary ependymoma. Outside of these disease sites, there is a wide variety of other studies on tumors ranging from uterine leiomyosarcoma to giant cell tumors of the bone. The studies done by the RCN represent a wide range of rare pathologies that were previously only studied in small series or case reports. With further growth of the RCN and collaboration between members our ability to analyze rare tumors will increase and result in better understanding of their behavior and ultimately help direct research that may improve patient outcomes.

Trends in cancer mortality in Brazil, 1980-2004.

Scanty information, limited to selected areas of the country, is available on cancer mortality in Brazil. Age-standardized (world population) mortality rates between 1980 and 2004, derived from the WHO database, were computed for all cancers and 24 major cancer sites in Brazil. Joinpoint regression analyses were used to identify the significant changes in trends and estimate annual percent change (APC) in rates. Total cancer mortality rates increased over the last decade in men (APC = 0.5) to reach 101.2/100 000, and in women (APC = 0.3) to reach 71.3/100 000. In men, upward trends were observed for cancers of the oral cavity and pharynx with a rate of 5.9/100 000 in 2000-2004, intestines (whose rate, however was low, i.e. 7.6), prostate (12.2), and leukemias (3.4). Male lung cancer increased until 1993 (APC = 1.39) and decreased thereafter (APC = -0.29), with a relatively low rate of 16.2/100 000 in 2000-2004. In women, there were steady upward trends for cancers of the lung (APC = 2.3), reaching 6.2/100 000 in 2000-2004, and leukemias (2.5). Breast cancer mortality leveled off at around 10/100 000 in the last decade, whereas declines were observed for cancers of the uterus, whose rate (8.3) however, remained comparatively high. Declines were observed for stomach cancer in both sexes, with rates of 11.1 in men and 4.6 in women. In conclusion, the key issues of cancer mortality in Brazil are the high rates of head and neck cancers in men and (cervix) uterine cancer in women, that is, in principle cancers that are largely avoidable through prevention, screening, and early diagnosis.

Prefabrication of composite grafts for long-segment tracheal reconstruction.

OBJECTIVE: To investigate the prefabrication of vascularized mucosa-lined composite grafts intended to replace circumferential tracheal defects. DESIGN: Plane grafts composed of ear cartilage and full-thickness oral mucosa were revascularized by the laterothoracic fascia. The use of meshed vs nonmeshed mucosa to improve the epithelial coverage was examined. We also investigated the creation of a vascular bed over the cartilage and the subsequent application of meshed mucosa. Macroscopic aspects, viability, and degree of mucosal lining were analyzed. SUBJECTS: Twenty male New Zealand white rabbits. INTERVENTIONS: Ten animals underwent placement of auricular cartilage under the laterothoracic fascia. Intact (group 1) or meshed mucosa (group 2) was applied over the fascia and protected by a silicone sheet. After 3 weeks, prefabricated grafts were removed for comparison. In 10 other animals, a sheet of perforated cartilage was placed under the laterothoracic fascia. Two weeks later, 5 grafts (group 3) were harvested. The remaining 5 grafts were reopened for mucosal application over the cartilage and revascularized for 3 additional weeks (group 4). RESULTS: Vascularized plane grafts were obtained in all groups. Mucosal lining increased significantly with meshed mucosa (14%-68%; mean, 40%) compared with nonmeshed mucosa (3%-15%; mean, 10%) (P = .008). Induction of a vascular bed over perforated cartilage was achieved, but survival of secondary implanted mucosa was variable. CONCLUSIONS: A reliable technique to prefabricate composite grafts with cartilaginous support and mucosal lining is presented. The use of meshed mucosa significantly improves epithelial coverage.

Neuropathie optique rétrobulbaire post-actinique [Post-actinic retrobulbar optic neuropathy]

BACKGROUND: Radiation optic neuropathy (RON) is a rare, unpredictable, late complication of radiotherapy secondary to obliterative endarteritis. Tumor recurrence has to be ruled out by a clinical and neuroradiological examination. METHODS: Five patients with RON were investigated by magnetic resonance imaging (MRI) during 1992. RESULTS: Radiation-induced lesions of the intracranial visual pathways were easily visible on MRI. Without Gadolinium, a sectorial swelling was detectable, which markedly enhanced with Gadolinium. Intracranial optic nerve was affected in 5/5 cases, optic chiasm in 3/5 cases, and optic tract in 2/5 cases. CONCLUSIONS: MRI is the examination of choice when RON is suspected: it will easily delineate the extent of the lesion, and compression/infiltration by a recurrent tumor will be formally ruled out. A segmental swelling of visual pathway with marked Gadolinium enhancement on MRI is highly suggestive of radionecrosis.

Weighted Shape-based Averaging with Neighborhood Prior Model for Multiple Atlas Fusion-based Medical Image Segmentation

In medical imaging, merging automated segmentations obtained from multiple atlases has become a standard practice for improving the accuracy. In this letter, we propose two new fusion methods: "Global Weighted Shape-Based Averaging" (GWSBA) and "Local Weighted Shape-Based Averaging" (LWSBA). These methods extend the well known Shape-Based Averaging (SBA) by additionally incorporating the similarity information between the reference (i.e., atlas) images and the target image to be segmented. We also propose a new spatially-varying similarity-weighted neighborhood prior model, and an edge-preserving smoothness term that can be used with many of the existing fusion methods. We first present our new Markov Random Field (MRF) based fusion framework that models the above mentioned information. The proposed methods are evaluated in the context of segmentation of lymph nodes in the head and neck 3D CT images, and they resulted in more accurate segmentations compared to the existing SBA.