Endoscopic treatment of inverted papilloma attached in the frontal sinus/recess.

BACKGROUND: Inverted papilloma (IP) is a benign sinonasal tumour for which endoscopic surgery, with complete removal of the underlying and surrounding mucoperiosteum at the attachment site followed by drilling and/or coagulation of this area, is the treatment of choice. This can be challenging in the frontal sinus. OBJECTIVES: To report on the outcome of treatment for IPs involving the frontal sinus. To propose the possible use of topical 5-fluorouracil 5% (5-FU) in the postoperative management of challenging IPs. METHODS: This is a retrospective cohort evaluation of patients with IPs attached in the frontal sinus or in the frontal recess and growing into the frontal sinus. Data on primary or revision surgery, uni- or bilaterality, attachment site, surgical procedure, 5-FU usage, recurrence and follow-up are provided. The end points are disease-free follow-up in months and recurrence. RESULTS: Twenty cases, including fifteen revision cases, were retrieved over a period of ten years. All cases were treated endoscopically. Two cases recurred (10%) and the intervention was repeated. In eight cases, 5-FU was applied at the end of surgery. None of these cases recurred. The mean follow-up after the last intervention was 42 months (standard deviation (SD) 22.1). CONCLUSION: IP involving the frontal sinus is a surgical challenge that can be successfully addressed endoscopically. The topical application of 5-FU could have a place in postoperative treatment when it is difficult to be absolutely sure that all diseased mucoperichondrium or mucoperiosteum at the attachment site(s) has been completely removed.

Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of blindness of 24 hours due to acute sinusitis based on CLL localisation in a patient with undiagnosed CLL. Emergency endoscopic sinus surgery and intra- and extra-ocular orbital decompression were performed. The sinusitis resolved after surgery and intravenous antibiotics. Her vision improved within 24 hours and eventually recovered completely after six months. Her CLL remained in an indolent state, needing no active treatment. This case illustrates that blindness from a lymphoproliferative disorder may be treated with emergency endoscopic sinus surgery instead of conventional chemotherapy in order to salvage the vision first, even if the vision is lost for more than 24 hours.

Initial experiences with endoscopic rhino-neurosurgery in Amsterdam.

Endoscopic surgery of the skull base has been on the rise for several years. Endoscopic access for surgery can be achieved from the frontal sinus anteriorly along the skull base to the odontoid process posterior inferiorly. An endoscope is inserted through one nasal corridor and allows visualization of the working field and up to three surgical instruments can be used to address the lesion. This is called the "two nostrils-four hands technique". This is a retrospective study of 67 cases. Setting of the study is an Amsterdam University hospital. Cases were identified in the department of otorhinolaryngology and department of neurosurgery database. All patients operated between 1 January, 2008 and 1 February, 2012 with pituitary tumours that extend beyond the sella, sinonasal tumours and all non-pituitary skull-base tumours were included. Mean tumour diameter was 3.8 cm. We performed a near-to-gross total resection in 92% of cases where we intended to perform a total resection. The most frequent complication was CSF leakage. This study demonstrates that this technique is safe and reliable. What is needed is a dedicated team, which includes a dedicated anesthesiologist, endocrinologist, ophthalmologist, and radiation oncologist.

Long-term results of functional endoscopic sinus surgery in children with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is rare in children and has a major impact on Quality of Life (QoL). Functional endoscopic sinus surgery (FESS) has proven to be an effective treatment, but it is still unclear what long-term outcomes are in children with CRSwNP. The objective of this study was to assess long-term results of FESS in children with CRSwNP. METHODOLOGY: We performed a combined prospective and retrospective study. A QoL questionnaire was send to all children with CRSwNP who received FESS between the year 2000-2010. Almost half of these children also filled in this questionnaire preoperatively. RESULTS: Forty-four Children underwent FESS. From 18 patients, we also prospectively collected preoperative QoL questionnaires. The mean follow-up period was 4.0 years (+- 2.9). The mean age at surgery was 13 years (+-2.9). Of these children, 9 had CF and 10 children asthma. R-SOM scores showed a significant improvement both in general symptoms as well as several different domains when comparing pre- and postoperative questionnaires. Only 5 of 44 patients needed a subsequent intervention. In children with CF this was 3 of 9. CONCLUSION: This study demonstrates that long-term results of FESS in children with CRSwNP are good. QoL has improved significantly, especially in nasal symptoms, showing that FESS is a good treatment in children with CRSwNP. Furthermore, even children with CF show good results.

Effects of alvocidib and carboplatin on ovarian cancer cells in vitro.

AIM: Failure of platinum chemotherapy is an unresolved issue in ovarian cancer. Targeted therapy has been added to the treatment options in solid cancers. Alvocidib is a cyclin dependent kinase inhibitor. MATERIALS AND METHODS: This study evaluated the effects of alvocidib together with carboplatin on ovarian cancer cells (BG-1 and Skov-3) in vitro applying proliferation assays, cell cycle distribution analyses, apoptosis induction assays, and drug accumulation assay. RESULTS: Proliferation of both cell lines was inhibited by carboplatin and alvocidib. The interaction index revealed drug synergism at distinct drug concentrations. Cell cycle distribution was altered. Alvocidib induced apoptosis in Skov-3 cells, and necrosis in BG-1 cells. Rhodamine accumulation was increased by alvocidib or both compounds together. CONCLUSION: These data provide evidence for antiproliferative effects of alvocidib on human ovarian cancer cells in vitro associated with changes in cell cycle distribution, the induction of apoptosis, and modulation of intracellular drug accumulation. Alvocidib and carboplatin showed some cooperative activity.

Inverse PPARß/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.

Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARß/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARß/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor ß (TGFß)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARß/δ target in MDA-MB-231 cells, previously implicated in TGFß-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFß and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARß/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARß/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARß/δ-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARß/δ agonists is feasible.

Quality of life in extended endonasal approaches for skull base tumours.

OBJECTIVE: To assess the quality of life (QOL) impact of extended endonasal approaches and nasoseptal flap reconstruction for benign skull base tumours METHODS: A random sample of 110 patients undergoing either limited endonasal transphenoidal hypophysectomy or extended endonasal approaches (trans-cribriform, trans-sellar, trans-tuberculum, trans-pterygoid) for the removal of benign skull base tumours were asked to complete Rhinosinusitis Outcome Measure (RSOM-31) questionnaire. RESULTS: A total of 91 patients returned the completed questionnaire. All patients in the limited approach group had pituitary adenomas, while patients in the extended group had a variety of tumours including adenomas with suprasellar or cavernous extension, chordomas, meningiomas, craniopharyngiomas and dermoids. Median time to completion of questionnaire was 1104 days in the limited group and 142 days in the extended approaches group. Although smell and headache were significantly worse in the group undergoing reconstruction with Haddad flap, there was no significant difference in overall, nasal, general, emotional or sleep quality of life between the two groups. Both smell and headache showed significant improvement with time. In linear regression, the single most important factor independently associated with overall worse RSOM-31 total scores was the presence of secreting adenomas. CONCLUSION: The use of nasoseptal flap appears to have a limited negative impact in nasal quality of life, mainly related to heada- che and reduced smell, both of which tend to improve with time. Hormone-secreting tumours have the most important adverse effect in quality of life extending in general, emotional, sleep and overall wellbeing, as reflected in RSOM 31 subscales.

The microdebrider, a step forward or an expensive gadget?

BACKGROUND: Although the use of the microdebrider (shaver) is well known in endoscopic sinus surgery (FESS), there is lack of evidence from comparative studies focussing on the difference in operating time, intra-operative blood loss and user-friendliness between the microdebrider and traditional operating techniques. In this study we compared the use of the microdebrider to conventional instruments in FESS in these areas. METHODS: A prospective randomised double blind controlled trial in 60 patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) undergoing bilateral FESS. Each subject received FESS using only traditional instruments (Blakseley forceps) on one side and the other side with the additional use of the microdebrider, this way serving as their own control. The primary outcome was operation time, intra-operative blood loss and user friendliness and secondly safety and postoperative healing with a follow-up period at different time points up to three months postoperative. RESULTS: We found a 37% longer operating time when operating without a microdebrider. This difference was highly significant. The microdebrider scored significantly higher on every different parameter of user friendliness, except on the preparation of the instrument needed before surgery. For estimated blood loss during surgery we found no differences. Also there was no significant difference in postoperative healing at any point of time. CONCLUSIONS: This study demonstrates that operating patient with CRSwNP with the microdebrider is efficient and that the microdebrider at the same time is safe and easy to use.

Long-term low-dose antibiotics in recalcitrant chronic rhinosinusitis: a retrospective analysis.

INTRODUCTION: In recalcitrant Chronic RhinoSinusitis (CRS) treatment with intranasal corticosteroids, short-term antibiotics and even sinus surgery is frequently insufficient. Long-term low-dose administration of antibiotics has been suggested as a treatment option in these patients. We analysed the outpatient clinic population treated with different long-term low-dose antibiotics at the AMC Amsterdam. PATIENTS AND METHODS: Eligible patients, who were treated with trimethoprim-sulfamethoxazole or macrolides, were retrospectively identified from our outpatient clinic in 2009. The two main outcome measures were sinonasal complaints and nasal endoscopic findings. A 5-point grading scale was used to score the results compared with the pre-treatment situation. This was measured at several time-points during, and after the antibiotic course, and at the end of the follow-up term. RESULTS: Seventy-six patients were included, 53 per cent had asthma and all of them had undergone sinus surgery. Seventy-eight per cent showed improvement of the symptoms, and 84 per cent demonstrated improvement of the sinonasal mucosa at the end of the course. No significant difference was found between the trimethoprim-sulfamethoxazole and macrolide group. DISCUSSION: Long-term low-dose treatment with antibiotics seems to improve CRS symptoms and the appearance of the sinonasal mucosa on nasal endoscopy. However, at this stage, strong conclusions are immature because no placebo-group has been included. Despite increasing use of long-term low-dose treatment of recalcitrant CRS in referral centres, hard clinical evidence is lacking. More research is urgently required.

Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD.

Plasmacytoid dendritic cells (pDCs) are professional antigen-presenting cells with antiviral and tolerogenic capabilities. Viral infections and autoimmunity are proposed to be important mechanisms in the pathogenesis of chronic obstructive pulmonary disease (COPD). The study aimed to quantify blood dendritic cell antigen 2-positive pDCs in lungs of subjects with or without COPD by immunohistochemistry and flow cytometry, combined with the investigation of the influence of cigarette smoke extract (CSE) on the function of pDCs in vitro. pDCs were mainly located in lymphoid follicles, a finding compatible with their expression of lymphoid homing chemokine receptors CXCR3 and CXCR4. pDC accumulated in the lymphoid follicles and in lung digests of patients with mild to moderate COPD, compared with smokers without airflow limitation and patients with COPD Global Initiative for Chronic Obstructive Lung disease (GOLD) stage III-IV. Exposing maturing pDC of healthy subjects to CSE in vitro revealed an attenuation of the expression of co-stimulatory molecules and impaired interferon-α production. Maturing pDC from patients with COPD produced higher levels of tumour necrosis factor (TNF)-α and interleukin (IL)-8 compared to pDC from healthy subjects. CSE significantly impairs the antiviral function of pDCs. In COPD, a GOLD stage dependent accumulation of pDC in lymphoid follicles is present, combined with an enhanced production of TNF-α and IL-8 by maturing pDCs.

Interactions between epithelial cells and dendritic cells in airway immune responses: lessons from allergic airway disease.

Micro-organisms constantly invade the human body and may form a threat to our health. Traditionally, concepts of defence mechanisms have included a protective outer layer of epithelia and a vigilant immune system searching for areas where the integrity of the outer layer may be compromised. Instead of considering these elements as two independent mechanisms, we should be treating them as a single integrated system. This review will present and discuss the role of local immune-competent cells and local epithelia in the recognition of potential pathogens and how the interaction between the two components may affect the initiation of the airway immune response. A concept emerges where airway mucosal dendritic cells act as integrators of both immunostimulatory and immunosuppressive signals that act within actively-involved mucosal tissue.

Presentation of two cases of nasal type NK/T-cell lymphoma.

Nasal type NK/T-cell lymphoma is a rare type of predominantly extranodal non-Hodgkin lymphoma. Early and correct diagnosis with prompt treatment of NK/T-cell lymphoma is important in view of its potentially aggressive behavior and poor response to treatment with additional sites of tumor developing sometimes weeks or months after initial diagnosis. Unfortunately diagnosis of NK/T-cell lymphomas often proves difficult. The diagnosis is essentially based on the clinical presentation of extranodal ulcerative lesions in the upper aero-digestive tract and histopathologic analysis of biopsies using immunohistochemistry. Here we present two cases with nasal-type NK/T-cell lymphoma that illustrate that definitive diagnosis is often delayed due to the atypical initial presentation. We will discuss the pitfalls in diagnosing this rare type of neoplasm and review the treatment options.

The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of the AGO-OVAR.

BACKGROUND: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc). PATIENTS AND METHODS: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response. RESULTS: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFNgamma-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups. CONCLUSIONS: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.

Current approaches in ovarian cancer vaccines.

Much of the current approaches in the treatment of advanced ovarian cancer are directed towards prolongation of duration between primary treatment and remission. Immunotherapy is regarded as one attractive option for consolidation of initial therapeutic responses. In fact, immune reactivity against ovarian carcinoma can be induced by various immunotherapeutical approaches including antibodies, peptides or dendritic cell vaccines. This review provides an overview of recent clinical trials using various concepts of immunotherapy for the treatment of ovarian cancer. Possible reasons for limited clinical success as well as further progress to improve efficacy of current immune intervention strategies, e.g. by vaccines targeting a broader range of tumor-derived antigenic structures or activating diverse host immune functions, will be discussed.

Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. See The biology behind: K. A. Foon and M. Bhattacharya-Chatterjee, Are solid tumor anti-idiotype vaccines ready for prime time? Clin. Cancer Res., 7:1112-1115, 2001.

The aim of the present study was to assess whether the induction of specific immune responses by vaccination with the murine monoclonal anti-idiotypic antibody ACA125, which imitates the tumor-associated antigen CA125, has a positive influence on the survival of patients with recurrent ovarian carcinoma. Forty-two patients with platinum-pretreated recurrences were included in a clinical Phase I/II trial of consolidation in third-line therapy. Patients initially received four immunizations with 2 mg of alum-precipitated anti-idiotype ACA125 every 2 weeks and then monthly applications. No serious allergic reactions could be detected within a maximal control period of 56 months. Hyperimmune sera of 27 of 42 patients (64.2%) showed increased concentrations of human antimouse antibodies. Specific anti-anti-idiotypic antibodies as a marker for induced immunity were detected in 28 of 42 patients (66.7%). The survival of the whole ACA125-treated collective of patients after a mean of 12.6 antibody applications was 14.9 +/- 12.9 months. The survival of patients with a positive immune response was 19.9 +/- 13.1 months in contrast with 5.3 +/- 4.3 months in those patients without detectable anti-CA125 immunity (P < 0.0001). According to these results, vaccination with a suitable anti-idiotypic antibody offers an effective way to induce specific immunity against a primarily nonimmunogenic tumor antigen such as CA125 and is associated with a positive impact on the survival of patients with recurrent ovarian cancer with few side effects, which warrants a Phase III trial for ovarian cancer patients after primary therapy.

Immunological properties of a single-chain fragment of the anti-idiotypic antibody ACA125.

Vaccination with anti-idiotypic antibodies has been described as a promising concept for treatment of several malignant diseases. The murine monoclonal anti-idiotypic antibody ACA125 imitates a specific epitope of the tumor-associated antigen CA125 expressed by 80% of ovarian carcinomas. In the first clinical trial it could be shown that mAb ACA125 is able to elicit anti-anti-idiotypic antibodies (Ab3) with anti-CA125 specificity in patients with advanced ovarian cancer. In order to improve the capabilities of anti-idiotype vaccines we generated a genetically engineered single-chain fragment (scFv) ACA125 composed of heavy- and light-chain variable regions connected by a flexible linker. The antigenicity of scFv ACA125 was demonstrated by immunizing rats i.p. with scFv or complete mAb in complete/incomplete Freund's adjuvants (CFA/IFA) or precipitated by aluminium hydroxide. Negative control groups included applications of irrelevant mouse IgG or adjuvants alone. Anti-anti-idiotypic antibodies (Ab3) directed against the mAb ACA125 as well as specific anti-CA125 antibodies (Ab1') could be detected in all animals treated with scFv in CFA/IFA. Nevertheless, antibody titers were lower than when the complete mAb ACA 125 was used. Suprisingly, an increase of specificity could not be observed in scFv-immunized animals, which had been expected because of the lack of heavy- and light-chain constant regions that could raise rather unspecific anti-isotypic and anti-allotypic rat anti-(mouse Ig) antibodies (RAMA). In contrast, the RAMA responses detected in these rats were even stronger than those following immunization with complete mAb ACA125. In conclusion, the anti-idiotypic scFv ACA125 alone cannot improve the immunogenic features of the corresponding mAb, but provides a useful tool for the further development of genetic vaccines.

Evaluation of immunological responses in patients with ovarian cancer treated with the anti-idiotype vaccine ACA125 by determination of intracellular cytokines--a preliminary report.

In a first clinical trial, 45 patients with advanced ovarian carcinoma and recurrences were treated with the murine monoclonal anti-idiotypic antibody (Ab2) designated ACA125 for active immunotherapy. The monoclonal antibody (MAb) ACA125 mimics a specific epitope of the tumor-associated antigen CA125 expressed by most malignant ovarian tumors. Patients with CA125-positive tumors are immunologically tolerant to CA125, which could be overcome by the use of an anti-idiotypic antibody as a surrogate for the tumor antigen CA125. An immunological response to the anti-idiotype ACA125 in these patients was associated with a statistically significant survival prolongation. Humoral immunity to ACA125 was assessed by induction of anti-anti-idiotypic antibodies (Ab3) directed against CA125. Using flow cytometric detection methods we observe alterations of the intracellular cytokines IFN-gamma, IL-2, and IL-4 at the single-cell level during the course of immunization. There was a strong increase of intracellular IFN-gamma and IL-2 characteristic for a Th1 cell type immune response after treatment with ACA125. A delayed induction of Th2 type response, which promotes antibody-mediated immunity by B cells, could also be detected. The understanding of the kinetics of Th1 and Th2 responses could be important to improve treatment schedules for effective immunotherapy with anti-idiotype vaccines.

Production of a single-chain fragment of the murine anti-idiotypic antibody ACA125 as phage-displayed and soluble antibody by recombinant phage antibody technique.

The F(ab')2 fragment of the murine monoclonal anti-idiotypic antibody ACA125 mimicking the tumor-associated antigen CA125 is used as a vaccine for the induction of an anti-tumoral immunity in patients with ovarian carcinoma. We tried to generate a single-chain fragment (ScFv) composed of ACA125 heavy- and light-chain variable domains connected by a polypeptide linker as an alternative to the corresponding F(ab')2 fragment. Heavy- and light-chain genes of antibody-producing mouse hybridoma cell line were amplified separately and assembled into a ScFv gene with linker DNA by the polymerase chain reaction (PCR). The ScFv gene was ligated into the phagemid vector pCANTAB5E, which allows the production of both phage-displayed and soluble ScFv. Transformed Escherichia coli TG1 cells were infected with M13K07 helper phage to yield recombinant phage, which display ScFv fragments as a g3p fusion protein on the surface of the filamentous phage M13. Recombinant phages could be selected by binding to the idiotypic antibody OC125 after one round of panning and directly used to reinfect E. coli TG1 cells. The E. coli nonsuppressor strain HB2151 was infected with an antigen-positive phage clone, previously screened by enzyme-linked immunosorbent assay (ELISA), to express soluble ScFv fragments. Functional soluble ScFv binding to the idiotypic antibody OC125 F(ab')2 could be detected in the bacterial periplasm by Western blot and ELISA. The variable heavy- and light-chain genes of the ACA125 ScFv fragment were further sequenced and compared with known antibody sequences.

Absence of emetic effects of morphine and loperamide in Suncus murinus.

The house musk shrew Suncus murinus recently has been introduced for the study of emesis. We investigated the emetic effects of the opioids morphine (0.1-21.5 mg/kg i.p.) and loperamide (0.01-10 mg/kg i.p.) and found a complete lack of emetogenic potential. Nicotine, however, dose dependently induced vomiting in the Suncus with an ED50 of 8.8 mg/kg s.c. and a 100% incidence at 20 mg/kg. This drug-induced vomiting was reduced by morphine or loperamide: ED50 values obtained were 1.2 mg/kg i.p. for morphine and 0.7 mg/kg i.p. for loperamide. Naloxone (2 mg/kg s.c.) antagonised the inhibitory effect of morphine (2 mg/kg i.p.) or loperamide (10 mg/kg i.p.). Serotonin (20 mg/kg s.c.) had less reliable emetogenic potency than nicotine in the Suncus with incidences between 50 and 100%. However, the serotonin-induced vomiting was abolished by morphine and loperamide and this inhibition was antagonised by naloxone. These results suggest that systemically administered opioids are pure antiemetics in Suncus murinus in contrast to other animal models and man. Naloxone antagonism indicates that this antiemetic effect is mediated by opioid receptors.