Immunotherapeutics for head and neck squamous cell carcinoma stem cells.

Cancer stem cell (CSC)-related therapy resistance has become a new obstacle to the successful application of cancer treatment and head and neck squamous cell carcinoma (HNSCC) is no exception to this finding. Head and neck squamous cell carcinoma is highly immune-suppressive, and recently the immune suppression and invasion of HNSCC-CSCs have been characterized. These characteristics have received research and clinical attention because they would enable the stratification of patients into specific cancer subtypes and, consequently, the establishment of new therapeutic approaches with improved efficacy. This review discusses the feasibility of CSC-targeted strategies and their incorporation with nanotechnology to improve the efficacy of cancer immunotherapy.

HPV vaccination of immunocompromised hosts.

It is well-established that immunocompromised people are at increased risk of HPV-related disease compared with those who are immunocompetent. Prophylactic HPV sub-unit vaccines are safe and immunogenic in immunocompromised people and it is strongly recommended that vaccination occur according to national guidelines. When delivered to immunocompromised populations, HPV vaccines should be given as a 3-dose regimen.

Predicting Outcome in Subarachnoid Hemorrhage (SAH) Utilizing the Full Outline of UnResponsiveness (FOUR) Score.

BACKGROUND: Existing scoring systems for aneurysmal subarachnoid hemorrhage (SAH) patients fail to accurately predict patient outcome. Our goal was to prospectively study the Full Outline of UnResponsiveness (FOUR) score as applied to newly admitted aneurysmal SAH patients. METHODS: All adult patients presenting to Health Sciences Center in Winnipeg from January 2013 to July 2015 (2.5 year period) with aneurysmal SAH were prospectively enrolled in this study. All patients were followed up to 6 months. FOUR score was calculated upon admission, with repeat calculation at 7 and 14 days. The primary outcomes were: mortality, as well as dichotomized 1- and 6-month Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) values. RESULTS: Sixty-four patients were included, with a mean age of 54.2 years (range 26-85 years). The mean FOUR score upon admission pre- and post-external ventricular drain (EVD) was 10.3 (range 0-16) and 11.1 (range 3-16), respectively. There was a statistically significant association between pre-EVD FOUR score (total, eye, respiratory and motor sub-scores) with mortality, 1-month GOS, and 6-month GOS/mRS (p < 0.05 in all). The day 7 total, eye, respiratory, and motor FOUR scores were associated with mortality, 1-month GOS/mRS, and 6-month GOS/mRS (p < 0.05 in all). The day 14 total, eye, respiratory, and motor FOUR scores were associated with 6-month GOS (p < 0.05 in all). The day 7 cumulative FOUR score was associated with the development of clinical vasospasm (p < 0.05). CONCLUSIONS: The FOUR score at admission and day 7 post-SAH is associated with mortality, 1-month GOS/mRS, and 6-month GOS/mRS. The FOUR score at day 14 post-SAH is associated with 6-month GOS. The brainstem sub-score was not associated with 1- or 6-month primary outcomes.

Immunohistochemical Investigation of Metastasis-Related Chemokines in Deep-Infiltrating Endometriosis and Compromised Pelvic Sentinel Lymph Nodes.

Endometriosis is a prevalent benign disease, despite sharing several similarities with malignancies, such as the possibility of lymphatic spread. In malignancies, chemokines play a sovereign role in the process of metastasis. Metastasis-related chemokine axes have not yet been assessed in deep-infiltrating endometriosis (DIE), and this investigation was the aim of our study. The expression of these chemokines was investigated by immunohistochemistry in rectovaginal DIE lesions and in matched pelvic sentinel lymph nodes (PSLNs) of patients with endometriosis (n = 27), and their expression in the eutopic endometrium (EE) of endometriosis-free women (n = 20) was used as controls. Their staining pattern in rectovaginal DIE, in endometriotic lesions affecting the PSLN as well as in the EE of patients without endometriosis was characterized for the first time. Overall, these chemokines were highly expressed in DIE and endometriosis in PSLN. Chemokines might be involved in the spread of endometriosis and should be further investigated.

Addition of MCP-1 and MIP-3ß to the IL-8 appraisal in peritoneal fluid enhances the probability of identifying women with endometriosis.

Chemokines have been associated with endometriosis. Our study was aimed at evaluating the levels of six chemokines--CXCL8 (IL-8), CXCL12 (SDF-1), CCL2 (MCP-1), CCL5 (RANTES), CCL19 (MIP-3ß), and CCL21 (6-Ckine)--in the peritoneal fluid (PF) of patients with and controls without endometriosis by multiplexed cytokine assay. In this retrospective case-control study conducted at the Charité University Hospital, patients (n = 36) and controls (n = 27) were enrolled. The patients were separated into groups according to stage of the disease: I-II (n = 21), III-IV (n = 1 5), and according to clinical findings: peritoneal endometriosis (PE; n = 7), deep-infiltrating endometriosis (DIE) affecting the retrocervical area (n = 13) or the bowel/rectovaginal site (n = 14). The subjects were also separated according to the cycle phase: follicular (n = 14) or luteal (n = 8) and the previous use (n = 25) or not (n = 38) of hormones. PF was collected from all subjects (n = 63) consecutively during laparoscopy. The concentration of chemokines in the PF was assessed using Luminex(®) x-MAP(®) technology. Sensitivity and specificity were calculated. A model of multiple logistic regressions estimated the odds of endometriosis for each combination of the chemokines detected. We observed significantly higher concentrations of IL-8 (p < 0.001), MCP-1 (p = 0.014), and MIP-3ß (p = 0.022) in the PF of women with endometriosis than in the controls. A joint evaluation revealed that elevated levels of the three chemokines had a positive endometriosis prediction value of 89.1%. The combined assessment of MCP-1, MIP-3ß, and IL-8 concentration in PF improved the likelihood of identifying patients with endometriosis. Future studies should investigate this panel in peripheral blood samples.

Norepinephrine as a potential aggravator of symptomatic cerebral vasospasm: two cases and argument for milrinone therapy.

Background. During hypertensive therapy for post-subarachnoid hemorrhage (SAH) symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI) post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140-150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130-140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH.

Feasibility and acceptance of cervicovaginal self-sampling within the German National Cohort (Pretest 2).

BACKGROUND AND OBJECTIVES: Within the German National Cohort (GNC) 100,000 adult women in Germany will be comprehensively interviewed and examined. While women's health is addressed in the basic interview, direct detection of cervicovaginal microbial colonisation or infection is not part of the examination protocol. In a pilot project the feasibility of female study participants of the GNC collecting a cervicovaginal lavage at home without having to involve a gynecologist or other medical personnel was thus investigated. The ability of the procedure to detect vaginal microbes and conditions including human papillomavirus (HPV), Chlamydia trachomatis and bacterial vaginosis (BV) were also explored. METHODS: This cross-sectional study was conducted in two study centers (Hamburg and Hanover) of the GNC during Pretest 2 in 2012 as an add-on module to the main program of the National Cohort. Participants were randomly selected through the population registration office. After providing written informed consent at the study center, participants self-collected a cervicovaginal lavage (Delphi Screener™) at home following written instructions. Participants mailed samples and acceptability questionnaires to the laboratory and the study center, respectively. Acceptability of self-sampling was categorized as consent, partial consent and rejection. The samples were analyzed by multiplex HPV genotyping for the presence of 27 mucosal HPV subtypes. To detect other pathogens "Sexually Transmitted Infection Profiling" (STIP) was used, a novel multiplex polymerase chain reaction (PCR) for various vaginally occurring pathogens/conditions coupled with subsequent bead-based Luminex(®) hybridization. Human beta-globin and DNA polymerase alpha (PolA) sequences were used as positive controls for the detection of human DNA during HPV detection and STIP, respectively. RESULTS: The participation based on the proportion of all women in Pretest 2 who could take part in the add-on Pretest 2 was 67.3 % (109 out of 162). The age of participants ranged from 20 to 69 years. The self-reported median duration of the collection of the lavage was 5 min. Analysis of the questionnaires (n = 108) revealed that the self-sampling of a cervicovaginal lavage was acceptable to 98 % of women (106 out of 108), and considered to be easy by 89 % (96 out of 108) as well as user-friendly by 96 % of the women (104 out of 108). Human beta-globin and PolA as markers for human DNA and sample quality were detected in all samples analyzed while HPV as a marker for pathogen detectability was identified in 18 out of 109 samples. Of the 107 samples tested with STIP as a second marker for pathogen detectability, 5 samples were excluded from statistical analyses on bacterial colonization because of signs in the laboratory results of the use of antibiotics. For the computation of the possible occurrence of bacterial vaginosis and candidiasis 7 and 8 samples, respectively, were excluded because of low signal intensities resulting in an evaluation of 95 or 94 samples, respectively. Ureaplasma parvum was detected in 22 out of 102 samples, BV in 14 out of 95 samples and candidiasis in 13 out of 94 samples. Chlamydia trachomatis was not detected in any sample. CONCLUSION: The feasibility study on cervicovaginal self-sampling indicates that this form of biosampling was very well accepted within the framework of the GNC and feasible in terms of pathogen detection. Its further application in the GNC would allow investigation of transience and persistence, or long-term effects of vaginal (co)infections and colonization.

[Cancer stem cell phenotypes and miRNA: therapeutic targets in head and neck squamous cell carcinoma]. / Tumorstammzellphänotypen und miRNA : Therapietargets bei Kopf-Hals-Plattenepithelkarzinomen.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HNSCC is caused by persistent high-risk human papillomavirus (HR-HPV) infection or excessive consumption of alcohol or tobacco. The persistently low survival rates result from local recurrences and metastases, which are probably caused by so-called tumor stem cells (TSCs). The epithelial-mesenchymal transition (EMT) or transformation is a key event in metastasis initiation and is being increasingly associated with TSCs. OBJECTIVES: This review describes new therapeutic targets in HNSCC, focusing on the TSC hypothesis and EMT regulation. MATERIALS AND METHODS, RESULTS: TSCs and EMT are regulated directly and indirectly via transcription factors and microRNAs (miRNAs). These miRNAs regulate multiple cellular processes and may serve as new therapeutic targets, whose modulation could increase the effectiveness of HNSCC treatments. Post-transcriptionally, miRNAs regulate transcription factors associated with EMT (ZEB1/2, EZH2, Bmi-1), tumor suppressors (p53), TSC markers (ALDH, CD44, EpCAM, p63) and both epithelial (E-cadherin) and mesenchymal markers (vimentin). CONCLUSION: Alterations in HNSSC TSC miRNA expression before and after chemotherapy could potentially serve as a therapeutic control. In the long term, knowledge of a patient's individual protein expression pattern may permit application of specific chemotherapy. Such individualized therapy might prohibit the development of metastases and potentially unresectable recurrences with a high resistance to radiation and chemotherapy, thus improving the prognosis in HNSCC patients.

[Role of miRNA in malignoma of the head and neck]. / Die Rolle von miRNA bei Kopf-Hals-Malignomen.

Despite optimized therapeutic strategies, the long-term survival of head and neck squamous cell carcinomas (HNSCC) has improved in recent years only slightly. Most studies on the tumor cell genome focus on protein-coding genes (exons). Data on changes within the non-coding sequences (introns) are limited. miRNAs (microRNA, miR) are small non-coding single-stranded RNAs that control gene expression at the posttranscriptional level by interacting with the mRNA. miRNA functions include many biological processes and control up to 50 % of human genes. They can have oncogenic or tumor suppressive functions. Altered expression patterns of miRNAs are involved in carcinogenesis and tumor progression even in HNSCC, or those processes (increased resistance to radiation or chemotherapy) that could be responsible for the poor long-term prognosis by forming metastases and inoperable local recurrences. Therefore, we here present miRNA groups, which are involved in these processes and may serve as new potential therapeutic treatment targets. miRNAs may also serve as biomarkers for early diagnosis, evaluation and monitoring of treatment and tumor recurrence. Alterations in miRNA expression before and after chemotherapy are therefore of high interest. In the long run, this knowledge could lead to more effective therapies with improved therapeutic outcome of HNSCC.

Gamma knife radiosurgery for high grade glial neoplasms: a Canadian experience.

OBJECT: To review our institutional experience with Gamma Knife (GK) stereotactic radiosurgery in treating focally recurrent high grade glial neoplasms of World Health Organization (WHO) grade III or IV. METHODS: We conducted a retrospective cohort review of all patients treated with GK for focally recurrent high grade gliomas at our institution between November 2003 and April 2013. Data on age, sex, tumor volume, location and maximal diameter, presenting clinical status, complications and clinical outcome was recorded. RESULTS: A total of 33 patients were identified. Four were lost to follow-up. Average post-GK and overall survival was 20.4 months (range: 3­72) and 63.3 months (range: 10­214) respectively. For WHO grade IV gliomas, the average post-GK and overall survival was 15.8 months (range: 3­77) and 40.1 months (range: 13­148) respectively. Similarily, for WHO grade III gliomas, the average post-GK and overall survival was 34.9 months (range: 6­72) and 136.4 months (range: 22­214) respectively. Twenty-two patients (75.9%) had post-GK edema, with 14 requiring dexamethasone and eight being asymptomatic. Four patients (13.8%) had imaging defined radiation necrosis. CONCLUSIONS: Gamma Knife SRS affords an extension of local tumor control, acceptable morbidity, and potentially prolonged survival, for highly selected patients with focally recurrent high grade glial neoplasms.Radiochirurgie par scalpel gamma pour les néoplasies gliales de haut grade de malignité : une expérience canadienne.

Ketamine for medically refractory status epilepticus after elective aneurysm clipping.

BACKGROUND: Medically refractory status epilepticus, without an identifiable cause, post elective aneurysm clipping is a rare event. OBJECTIVE: To describe the two cases of refractory status epilepticus post elective aneurysm clipping, without an identifiable cause, and discuss the potential role for early consideration of ketamine. METHODS: Retrospectively reviewed two patients at our institution who developed refractory status epilepticus post elective aneurysm clipping, without a defined cause. RESULTS: Two patients who underwent elective aneurysm clipping developed medically refractory status epilepticus post-craniotomy. No structural, vascular, infectious, or metabolic cause was identified. Seizure control failed with multiple medications and intravenous sedatives over the period of weeks in both. Ketamine was instituted at 20 and 40 mg/kg/min in these patients. Within hours of starting ketamine, burst suppression was obtained in both. Medications were all tapered over the next month, and both the patients recovered to be cognitively normal, with mild residual morbidity secondary to critical care polyneuropathy. CONCLUSIONS: Refractory status epilepticus, in the absence of an identifiable etiology, in elective aneurysm clipping is a rare event. Consideration should be given for the early use of ketamine in refractory status epilepticus.

Estimating the long-term effects of HPV vaccination in Germany.

In Germany, vaccination against the most oncogenic HPV types 16/18 is recommended by the Standing Committee on Vaccination (STIKO) for 12-17 year old girls since March 2007. We developed a dynamic mathematical model for the natural history and transmission of HPV infections to estimate the impact of vaccination on incidence and mortality of cervical cancer and its pre-stages, and on anogenital warts. We focused on an extensive model calibration to epidemiologic data for all stages of the natural history model as well as on a detailed implementation of cervical cancer screening modalities in Germany. Our model predicts first a substantial reduction of cervical cancer incidence and mortality over the next 30 years, which is mainly attributable to an increase in screening participation in the 1990s and not to HPV vaccination, followed by a further reduction attributable to vaccination. Over the next 100 years, HPV vaccination will prevent approximately 37% of cervical cancer cases even if vaccination coverage is only 50% (as currently observed in Germany). Consideration of cross-protection results in a further reduction of approximately 7% of all cervical cancer cases for the bivalent and about 5% for the quadrivalent vaccine in our model. Vaccination of boys was only reasonable if moderate to high vaccination coverage in girls was not achieved. Strategies should be implemented in Germany to increase HPV vaccination coverage among girls thereby making better use of the demonstrated benefits of the vaccine.

Gamma Knife radiosurgery of cavernous sinus meningiomas: an institutional review.

INTRODUCTION: Stereotactic radiosurgery offers a unique and effective means of controlling cavernous sinus meningiomas with a low rate of complications. METHODS: We retrospectively reviewed all cavernous sinus meningiomas treated with Gamma Knife (GK) radiosurgery between November 2003 and April 2011 at our institution. RESULTS: Thirty patients were treated, four were lost to follow- up. Presenting symptoms included: headache (9), trigeminal nerve dysesthesias/paresthesias (13), abducens nerve palsy (11), oculomotor nerve palsy (8), Horner's syndrome (2), blurred vision (9), and relative afferent pupillary defect (1). One patient was asymptomatic with documented tumor growth. Treatment planning consisted of MRI and CT in 17 of 30 patients (56.7%), the remainder were planned with MRI alone (44.3%). There were 8 males (26.7%) and 22 females (73.3%). Twelve patients had previous surgical debulking prior to radiosurgery. Average diameter and volume at time of radiosurgery was 3.4 cm and 7.9 cm3 respectively. Average dose at the 50% isodose line was 13.5 Gy. Follow-up was available in 26 patients. Average follow-up was 36.1 months. Mean age 55.1 years. Tumor size post GK decreased in 9 patients (34.6%), remained stable in 15 patients (57.7%), and continued to grow in 2 (7.7%). Minor transient complications occurred in 12 patients, all resolving. Serious permanent complications occurred in 5 patients: new onset trigeminal neuropathic pain (2), frame related occipital neuralgia (1), worsening of pre-GK seizures (1), and panhypopituitarism (1). CONCLUSION: GK offers an effective treatment method for halting meningioma progression in the cavernous sinus, with an acceptable permanent complication rate.

[Biology and relevance of stem cells in squamous head and neck cancer: latest insights and review of literature]. / Biologie und Bedeutung von Tumorstammzellen in der HNO: Neueste Erkenntnisse und Zusammenfassung der aktuellen Literatur.

The initiation, growth, recurrence and metastasis of head and neck squamous cell carcinomas (HNSCC) and other cancers have recently been related to the presence of cancer stem cells (CSC). Cancer stem cells have some characteristics in common with tissue stem cells like unlimited self renewal and the expression of stem cell factors. CSC express specific markers that vary considerably depending on tumor type or tissue of origin--the discovery of an universal marker has not yet been made. Compared to the bulk tumor mass, CSC are less sensitive to chemo- and radiotherapy and also have a lower immunogenicity. Another concept that explains the seeding of metastases is the epithelial-mesenchymal transition of CSC. CSC-targeted therapies may change the prognosis of patients with HNSCC in the future. Recent knowledge on the role of CSC in HNSCC is reviewed, and known CSC markers as well as possible therapeutic targets are described.

[Prophylactic and therapeutic vaccines against human papilloma virus]. / Prophylaktische und therapeutische Vakzinen gegen humane Papillomviren.

Infection with human papilloma virus (HPV) has been identified as the cause of recurrent papillomatosis and of a subgroup of squamous cell carcinomas of the head and neck. A change in prevalence of these lesions, especially for oropharyngeal carcinoma, can be expected as a consequence of the introduction of prophylactic HPV vaccines for young women, targeting the most frequent high- and low-risk HPV subtypes. Vaccination for the major low-risk HPV types has proven to be highly effective against genital warts and activity against papillomatosis can be expected. The possibilities of prophylactic HPV vaccination as well as new developments and the rationale for therapeutic vaccines are discussed on the basis of the current literature.