Double-blind, randomised controlled trial on the efficacy of saline nasal irrigation with sodium hyaluronate after endoscopic sinus surgery.

OBJECTIVE: There is a growing interest in sodium hyaluronate for the clinical management of patients who undergo functional endoscopic sinus surgery for chronic rhinosinusitis, because of the mucosal regenerative properties of this macromolecule. However, its role in post-operative care is still debated. This study aimed to evaluate the effect of sodium hyaluronate administered via nasal irrigation with saline, in the post-operative period, after functional endoscopic sinus surgery. METHODS: A multicentric, prospective, randomised, double-blind, parallel group study was conducted on 56 consecutive patients who underwent functional endoscopic sinus surgery for chronic rhinosinusitis without polyps. Group 1 received the standard therapy of normal saline; group 2 received saline plus sodium hyaluronate. RESULTS: Both objective and subjective measurements, in terms of endoscopic appearance and patient-reported satisfaction, were significantly better in group 2 compared to group 1. CONCLUSION: Sodium hyaluronate may be a useful adjunct to nasal saline irrigation in the early post-operative period following functional endoscopic sinus surgery.

Use of balloon catheter dilation and steroid-eluting stent in light and severe rhinosinusitis of frontal sinus: a multicenter retrospective randomized study.

OBJECTIVE: Frontal sinus surgery has an increased rate of re-stenosis, if compared to other sinuses. It depends mainly on recurrent inflammation and abnormal scarring at the frontal recess and its reduction represents one of the keys to therapeutic success. Balloon catheter dilation (BCD) and implantable sinus stents/spacers represent strategies to improve sinus ventilation respecting the integrity of mucosa and reducing abnormal post-surgical scarring. The purpose of this study was to evaluate the effectiveness, safety and correct indication about the use of BCD and a non-absorbable stent (Relieva Stratus™ MicroFlow spacer) in the management of chronic rhinosinusitis (CRS) of the frontal sinus. PATIENTS AND METHODS: In this multicentric retrospective study we included a population of 76 frontal sinuses with non-polypoid CRS. 41 frontal sinuses were treated with BCD alone and 35 frontal sinuses with BCD + Spacer. We analyzed both radiological (Lund-McKay CT scoring modified by Zinreich) and symptomatological results (SNOT-20 questionnaire) before surgery and after 12 months, dividing our population in two main groups: group "L" (light/mild frontal CRS) and group "S" (moderate/severe frontal CRS). RESULTS: Our results confirm a good safety and effectiveness of BCD in the management of frontal CRS and show a good safety but a not significative effectiveness of Relieva Stratus™ MicroFlow spacer when added to BCD in the management of light and severe frontal chronic rhinosinusitis. CONCLUSIONS: BCD is an acclared option in the management of frontal CRS and in the near future, utilization of stents/spacers could become a new and effective weapon in the management of rhinosinusitis, both like an adjunct to standard therapies, and in patient populations where the use of systemic drugs is contraindicated.

Horizontal lateral lamella as a risk factor for iatrogenic cerebrospinal fluid leak. Clinical retrospective evaluation of 24 cases.

BACKGROUND: Several authors highlighted the limitations of the Keros classification system in predicting intracranial entry risk. Recently, our group proposed a new classification system based on the angle formed between the lateral lamella of the cribriform plate (LLCP) and the continuation of an horizontal plane passing through the cribriform plate (Gera classification). The aim of this study was to analyze whether the risk of iatrogenic cerebrospinal fluid leak (CSF-L) was better predicted by Keros or Gera classification. METHODOLOGY: The pre-operative CT scans of 24 patients (CSF-L group) who suffered from iatrogenic CSF-L during endoscopic sinus surgery (ESS) were compared to those obtained from a group of 100 patients who underwent uneventful ESS (control group). The skull base measurements as well as the distribution of Keros and Gera classes in the 2 groups were analyzed. RESULTS: No difference in the distribution of Keros classes or in the depth of the cribriform plate between CSF-L and control group were demonstrated. On the contrary, significant differences in the distribution of Gera classes and in the degree of the angle formed by the LLCP and the continuation of the horizontal plane passing through the cribriform plate were found. In particular, according to Gera classification system, 19 out of 24 patients in the CSF-L group were considered at risk for iatrogenic CSF-L. CONCLUSIONS: Gera classification system might be more sensitive to anatomical variations associated with CSF-L than the Keros one, further suggesting the application of the former during the preoperative CT scan evaluation.

Use of balloon catheter dilation vs. traditional endoscopic sinus surgery in management of light and severe chronic rhinosinusitis of the frontal sinus: a multicenter prospective randomized study.

OBJECTIVE: Chronic rhinosinusitis (CRS) of the frontal sinus is a complex pathological condition and many surgical techniques were described to treat this area endoscopically, like traditional endoscopic sinus surgery (ESS) and balloon catheter dilation (BCD). PATIENTS AND METHODS: We designed a multicenter prospective randomized study to assess the validity and safety of BCD vs. ESS in symptomatological chronic rhinosinusitis of the frontal sinus enrolling a population of 102 adult patients (64 men and 38 women; overall 148 frontal sinuses studied) with non-polypoid CRS. For a better evaluation of the disease, in our study we decided to analyze both radiological (Lund-McKay CT scoring modified by Zinreich) and symptomatological results (SNOT-20 questionnaire). We divided the population affected in two groups, one with light/mild frontal CRS and the other with moderate/severe frontal CRS, basing on radiological findings at Lund-MacKay modified by Zinreich score. Every group was divided in two subgroups, in one we used BCD and in the other we used traditional ESS. RESULTS: The current literature does not support the suggestion that indications for BCD and ESS are identical, and additional research is needed to determine the role for BCD in specific patient populations. The results showed a not statistically significative difference between BCD and conventional ESS of the frontal sinus in patients with light/mild CRS and in patients with moderate/severe CRS at Lund-Mackay modified by Zinreich score. The same not statistically significative difference was observed comparing the results of SNOT-20 questionnaire in the group of light/mild frontal chronic rhinosinusitis. However, we noticed a statistically significant better outcome of SNOT-20 score in patients with moderate/severe chronic rhinosinusitis that underwent BCD of frontal sinus compared to ESS. CONCLUSIONS: BCD and ESS are two alternative weapons in the baggage of every endoscopic surgeon, even because they present similar outcomes, safeness and effectiveness both in light/mild and moderate/severe chronic rhinosinusitis of the frontal sinus. An interesting result of our study was the statistically significant better outcome of SNOT-20 score in patients that underwent BCD of frontal sinus for a moderate/severe CRS, compared to those that underwent a traditional ESS.

Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma. Feasibility and tolerability in elderly and chemotherapy-ineligible patients.

INTRODUCTION: Cetuximab plus radiotherapy (RT) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma (LASCCHN) patients. We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy (VMAT) with the RapidArc technique in a simultaneous integrated boost (SIB) regime. The primary end point was the assessment of acute toxicity and the feasibility of the combined approach. MATERIALS AND METHODS: Between December 2008 and March 2010, 22 patients were submitted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN. None of the patients was suitable for chemotherapy because of important comorbidities (the majority suffered of heart chronic diseases). All patients underwent planning CT (additional image modalities were acquired for contouring purposes in the same treatment position: MRI in 12 and FDG-PET in 4 out of 22 patients). VMAT, by means of RapidArc, and SIB with two dose levels of 54.45 Gy and 69.96 Gy in 33 fractions were adopted. All patients included in the analysis were concomitantly treated with cetuximab: administration of the drug was initiated 1 week before RT at a loading dose of 400 mg/m(2) body surface area over a period of 120 min, follow by a weekly 60 min infusion of 250 mg/m(2) for the duration of RT. Patients were assessed for toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: All but 2 patients completed treatment and achieved the minimum follow-up of 12 months after the end of the treatment. Of the 22 patients, 18% (4 patients) showed grade 1, 36% (8 patients) grade 2, and 36% (8 patients) showed grade 3 dermatitis, while 9% (2 patients) had grade 1, 36% (8 patients) grade 2, and 45% (10 patients) had grade 3 mucositis/stomatitis. No grade 4 toxicities were recorded. Considering blood parameters, 3 cases of grade 1 anemia and 1 case of grade 2 thrombocytopenia were observed. Nobody required feeding tube placement during treatment. CONCLUSION: The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques, when cetuximab is concomitantly administered.

Sinonasal inverted papilloma: 84 patients treated by endoscopy and proposal for a new classification.

AIM: To suggest a new classification system for sinonasal papilloma based on a critical analysis of surgical indications and results obtained. METHODS: We analysed surgical data from 84 cases of sinonasal papilloma treated endoscopically. RESULTS: In 58 males and 26 females, between 25 and 85 years, the ethmoid sinus (63 cases), the maxillary sinus (43), and the nasal fossa (22) were mostly involved. No case of endocranial extension or carcinoma was reported. Complications were reported in 15.4% of patients, as well as 5 recurrences (5.9%). Median follow up was 39,5 months. To categorise the tumour for the most appropriate surgical treatment, we propose a classification based on 6 main categories that depend on the location, origin and extension of the tumour. CONCLUSION: The classification that we propose presents advantages for prognosis and surgical indication in comparison with other classifications.

Effect of short-term restricted food intake on canine pseudopregnancy.

A non-pharmaceutical, dietary option may be useful to manage clinical pseudopregnancy (PSP). To describe the effect of short-term food restriction on canine PSP, 16 privately owned, overtly pseudopregnant bitches were randomly assigned to one of the following groups: Limit-fed (increasing amounts of a restricted maintenance: 50%, 40%, 30% restriction for 2, 3 and 2 days respectively) during 7 days (n = 8) or Maintenance-fed of the same food and period (n = 8). The bitches were physically examined and blood samples were taken for prolactin and progesterone determinations on days 2, 5 and 8. By day 8, none of the bitches had completely regressed the condition although all (8/8) the animals of the Limit-fed and two (25%) of the Maintenance-fed group improved in condition decreasing mammary size and secretion (p < 0.05). No day or group effects were observed for serum prolactin and progesterone concentrations (>0.05). It is concluded that although an 8-day food restriction did not cure PSP, it seemed to hasten PSP signs involution in these bitches. No endocrine change was related to these clinical findings.

The lysosomal protease cathepsin D is efficiently sorted to and secreted from regulated secretory compartments in the rat basophilic/mast cell line RBL.

Basophils and mast cells contain a peculiar class of inflammatory granules that discharge their content upon antigen-mediated crosslinking of IgE-membrane receptors. The pathways for granule biogenesis and exocytosis in these cells are still largely obscure. In this study we employed the rat basophilic leukemia (RBL)/mast cell line to verify the hypothesis that inflammatory granules share common bioactive molecules and functional properties with lysosomes. We demonstrate that inflammatory granules, as identified by the monoclonal 5G10 antibody (which recognises an integral membrane protein) or by Toluidine Blue staining, have an intralumenal acidic pH, possess lysosomal enzymes and are accessible by fluid-phase and membrane endocytosis markers. In addition, we studied the targeting, subcellular localisation and regulated secretion of the lysosomal aspartic protease cathepsin D (CD) as affected by IgE receptor stimulation in order to obtain information on the pathways for granule biogenesis and exocytosis. Stimulation with DNP-BSA of specific IgE-primed RBL cells led to a prompt release of processed forms of CD, along with other mature lysosomal hydrolases. This release could be prevented by addition of EGTA, indicating that it was dependent on extracellular calcium influx. Antigen stimulation also induced exocytosis of immature CD forms accumulated by ammonium chloride, suggesting the existence of an intermediate station in the pathway for granule biogenesis still sensitive to regulated exocytosis. The targeting of molecules to secretory granules may occur via either a mannose-6-phosphate-dependent or mannose-6-phosphate-independent pathway. We conclude that endosomes and lysosomes in basophils/mast cells can act as regulated secretory granules or actually identify with them.

Regulation of protein sorting at the TGN by plasma membrane receptor activation.

We show that in the rat basophilic leukemia cell line RBL, the physiological stimulation of the IgE receptor or direct activation of PKC leads to the missorting of proteins to the plasma membrane, diverting them from their normal intracellular destination. This is demonstrated for two classes of proteins that are normally targeted to the secretory lysosomes via completely different mechanisms, i.e. proteoglycans and the aspartic protease cathepsin D. In the latter case, normal processing of the enzyme is also affected, leading to secretion of the immature form of cathepsin. The present study shows how completely different sorting mechanisms, such as those for delivering proteoglycans and cathepsin D to secretory lysosomes, might share common regulatory signals and are similarly affected when the levels of these signals are perturbed. Finally, protein kinase C appears to be a major player in the signal transduction pathways, leading to proteoglycan and cathepsin D missorting.

Transformation by oncogenic ras-p21 alters the processing and subcellular localization of the lysosomal protease cathepsin D.

The expression, processing, and intracellular localization of cathepsin D (CD), an endosomal-lysosomal protease involved in malignancy, were studied in rat embryo fibroblasts transformed with an active mutant of c-Ha-ras oncogene. The pattern of the processed molecular forms of CD, comprising two single-chain mature forms of 45 and 43 kDa and two double-chain mature forms of 34 + 9 kDa and 30 + 14 kDa, expressed by the parental cell line was similar to that found in normal rat liver cells. By contrast, in the ras-transfected counterpart this pattern was profoundly altered in that the 45 kDa species was much less represented and the 30 + 14 kDa species virtually absent. In both untransformed and ras-transformed cells the conversion of proCD into mature forms was not inhibited by ammonium chloride, which is known to increase the intravacuolar pH of post-Golgi compartments. Yet, this drug induced the accumulation of the 43 and 45 kDa molecular forms of mature CD in ras-transformed cells and of the 34 kDa molecule in untransformed cells. As compared to controls, in ras-transformed fibroblasts vacuolar compartments containing CD were reduced in number and mostly located toward the periphery of the cell. This contrasted with the perinuclear distribution of CD-positive granules in untransformed cells. Serum deprivation did not affect the growth, nor the intra- and extracellular accumulation of CD activity in ras-transformed cultures, while it blocked the growth and strongly stimulated the accumulation of CD in the medium in cultures of control fibroblasts. Altogether these data are indicative for a crucial role of ras GTPase in the regulation of the transport between post-Golgi organelles.

Regulation of rat hepatocyte protein kinase C beta isoenzymes by the lipid peroxidation product 4-hydroxy-2,3-nonenal: A signaling pathway to modulate vesicular transport of glycoproteins.

A major aldehydic end product of the peroxidation of arachidonic acid, 4-hydroxy-2,3-nonenal (HNE), has recently been considered for its potential involvement in a variety of cell functions. Here we report on the differential regulation of rat hepatocyte protein kinase C (PKC) isoforms by concentrations of HNE actually detectable in specific biological fluids or tissues. PKC betaI and, to a much greater extent, PKC betaII activities were markedly increased by 0.1 micromol/L HNE (final concentration in cell medium) whereas they were unaffected or even inhibited by 1 to 10 micromol/L HNE. On the contrary, the calcium independent PKC delta activity was inhibited by 0.1 micromol/L and increased by 1 and 10 micromol/L. Further, we show here that HNE-induced stimulation of PKC betaI and betaII activities, both in cytosolic and in membrane fractions, is paralleled by a marked stimulation of the anterograde transport of a lysosomal enzyme within the central vacuolar system. In fact, the treatment with 0.1 micromol/L HNE accelerated the PKC-dependent transport of lysosomal procathepsin D from the trans-Golgi network to the endosomal-lysosomal compartment and, in addition, increased the exocytosis of mature cathepsin D (CD) from these compartments. On the other hand, hepatocyte cotreatment with a selective inhibitor of classic PKCs prevented the aldehyde-induced activation of CD transport. These results support the possible involvement of HNE in the PKC-dependent regulation of the traffic of secretory glycoproteins, and point to remarkable implications of this aldehyde in the pathophysiology of various exocytic processes including hepatocyte lipoprotein secretion.

Differentiation-induced changes in the content, secretion, and subcellular distribution of lysosomal cathepsins in the human colon cancer HT-29 cell line.

Enterocyte-like differentiated HT-29 colon carcinoma cells were shown to contain far higher intracellular levels of activity of lysosomal cathepsins B, D, and L than their undifferentiated counterparts. In the latter, inhibition of lysosomal functions by leupeptin or ammonium chloride led to a marked increase in the cell-associated activity of the three cathepsins. High levels of pro-cathepsins B, D, and L were found in the culture media of both HT-29 cell populations. Ammonium chloride and chloroquine, which are known to impair the mannose-6-phosphate-dependent trafficking of lysosomal-targeted proteins, did not increase the secretion of the three cathepsins in either undifferentiated or differentiated cultures of HT-29 cells. Analyses by cell fractionation revealed heterogeneities with regard to the density and the content of lysosomal cathepsins between the two cell populations. Leupeptin induced the accumulation of mature lysosomal cathepsins B and L in light density organelles in undifferentiated HT-29 cells. Altogether, these data demonstrate that (1) the expression and subcellular distribution of cathepsins B, D, and L in HT-29 cells are influenced by their state of enterocytic differentiation, (2) the segregation of lysosomal cathepsins is largely inefficient in this tumor cell line and does not increase upon differentiation, and (3) the mannose-6-phosphate-receptor-dependent pathway plays a minor role in the sorting of the three cathepsins, both in undifferentiated and enterocytic-differentiated HT-29 cells.

[Percutaneous treatment of symptomatic renal cysts: effects of the combination of sclerotherapy with alcohol and fibrin glue (tissucol)]. / Trattamento percutaneo delle cisti renali sintomatiche: effetti dell'associazione di scleroterapia con alcol e di colla di fibrina (tissucol).

The percutaneous treatment of symptomatic renal cysts has grown in therapeutic importance over the last years. The international literature includes many reports on the sclerotherapy of renal cysts with different sclerosing agents. The authors report their experience with the percutaneous treatment of renal cysts by combining pure alcohol and fibrin glue. The glue serves the purpose to seal the walls of the cyst already damaged by alcohol. The results of the combined treatment show that relief of symptoms was obtained in all patients, with no major or minor complications. Complete cyst ablation was obtained only in 16% of cases, while a partial recurrence was seen in 80% of patients, with an average regrowth < 35% of the initial cyst volume. None of these patients presented further symptoms. At present, the follow-up time ranges 3 to 34 months.