Quantifying the reduction of respiratory motion by mechanical ventilation with MRI for radiotherapy.

BACKGROUND: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions. METHODS: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds. RESULTS: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity. CONCLUSIONS: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible. TRIAL REGISTRATION: Medical Ethics Committee protocol NL.64693.018.18.

Clinically oriented three-step strategy for assessment of adnexal pathology.

OBJECTIVE: To determine the diagnostic performance of ultrasound-based simple rules, risk of malignancy index (RMI), two logistic regression models (LR1 and LR2) and real-time subjective assessment by experienced ultrasound examiners following the exclusion of masses likely to be judged as easy and 'instant' to diagnose by an ultrasound examiner, and to develop a new strategy for the assessment of adnexal pathology based on this. METHODS: 3511 patients with at least one persistent adnexal mass preoperatively underwent transvaginal ultrasonography to assess tumor morphology and vascularity. They were included in two consecutive prospective studies by the International Ovarian Tumor Analysis (IOTA) group: Phase 1 (1999-2005), development of the simple rules and logistic regression models LR1 and LR2, and Phase 2, a validation study (2005-2007). RESULTS: Almost half of the cases (43%) were identified as 'instant' to diagnose on the basis of descriptors applied to the database. To assess diagnostic performance in the more difficult 'non-instant' masses, we used only Phase 2 data (n = 1036). The sensitivity of LR2 was 88%, of RMI it was 41% and of subjective assessment it was 87%. The specificity of LR2 was 67%, of RMI it was 90% and of subjective assessment it was 86%. The simple rules yielded a conclusive result in almost 2/3 of the masses, where they resulted in sensitivity and specificity similar to those of real-time subjective assessment by experienced ultrasound examiners: sensitivity 89 vs 89% (P = 0.76), specificity 91 vs 91% (P = 0.65). When a three-step strategy was applied with easy 'instant' diagnoses as Step 1, simple rules where conclusive as Step 2 and subjective assessment by an experienced ultrasound examiner in the remaining masses as Step 3, we obtained a sensitivity of 92% and specificity of 92% compared with sensitivity 90% (P = 0.03) and specificity 93% (P = 0.44) when using real-time subjective assessment by experts in all tumors. CONCLUSION: A diagnostic strategy using simple descriptors and ultrasound rules when applied to the variables contained in the IOTA database obtains results that are at least as good as those obtained by subjective assessment of a mass by an expert.

[Laparoscopic approach in the pelvic floor surgery]. / Technika laparoskopického prístupu v pánevní chirurgii.

Laparoscopy offers great exposure and surgical detail, reduces blood loss and the need for excessive abdominal packing and bowel manipulation making it an excellent modality to perform pelvic floor surgery. Laparoscopic repair of level I or apical vaginal prolapse may be challenging, due to the need for extensive dissection and advanced suturing skills. However it offers the efficacy of open abdominal sacrocolpopexy, such as lower recurrence rates and less dyspareunia than sacrospinous fixation, as well as the reduced morbidity of a laparoscopic approach.

Laparoscopic sacrocolpopexy.

Laparoscopy offers great exposure and surgical detail, reduces blood loss and the need for excessive abdominal packing-- and bowel manipulation making it an excellent modality to perform pelvic floor surgery. Laparoscopic repair of level I or apical vaginal prolapse may be challenging, due to the need for extensive dissection and advanced suturing skills. However, it offers the efficacy of open abdominal sacrocolpopexy, such as lower recurrence rates and less dyspareunia-- than sacrospinous fixation, as well as the reduced morbidity of a laparoscopic approach.

Imaging in gynaecology: How good are we in identifying endometriomas?

AIM: To evaluate the performance of subjective evaluation of ultrasound findings (pattern recognition) to discriminate endometriomas from other types of adnexal masses and to compare the demographic and ultrasound characteristics of the true positive cases with those cases that were presumed to be an endometrioma but proved to have a different -histology (false positive cases) and the endometriomas missed by pattern recognition (false negative cases). METHODS: All patients in the International Ovarian Tumor Analysis (IOTA ) studies were included for analysis. In the IOTA studies, patients with an adnexal mass that were preoperatively examined by expert sonologists following the same standardized ultrasound protocol were prospectively included in 21 international centres. Sensitivity and specificity to discriminate endometriomas from other types of adnexal masses using pattern recognition were calculated. Ultrasound and some demographic variables of the masses presumed to be an endometrioma were analysed (true -positives and false positives) and compared with the variables of the endometriomas missed by pattern recognition (false negatives) as well as the true negatives. RESULTS: IOTA phase 1, 1b and 2 included 3511 patients of which 2560 were benign (73%) and 951 malignant (27%). The dataset included 713 endometriomas. Sensitivity and specificity for pattern recognition were 81% (577/713) and 97% (2723/2798). The true positives were more often unilocular with ground glass echogenicity than the masses in any other category. Among the 75 false positive cases, 66 were benign but 9 were malignant (5 borderline tumours, 1 rare primary invasive tumour and 3 endometrioid adenocarcinomas). The presumed diagnosis suggested by the sonologist in case of a missed endometrioma was mostly functional cyst or cystadenoma. CONCLUSION: Expert sonologists can quite accurately discriminate endometriomas from other types of adnexal masses, but in this dataset 1% of the masses that were classified as endometrioma by pattern recognition proved to be malignancies.

Fluoride therapy for cochlear otosclerosis? an audiometric and computerized tomography evaluation.

The progress of sensorineural hearing loss (SNHL) in patients with cochlear otosclerosis was compared for 19 patients treated with fluoride for 1-5 years and 22 untreated controls. CT scans of eight patients before and after fluoride treatment were evaluated visually. Fluoride therapy arrested the progression of SNHL in the low (250, 500 and 1,000 Hz) (p < 0.001) and high (2 and 4 kHz) (p = 0.008) frequencies. It seemed to be more effective for the higher frequencies in cases with an initial SNHL of < 50 dB. Fluoride administration for 4 years did not seem to be superior to a shorter treatment period (1-2 years). For six patients followed up after discontinuing fluoride therapy there was minimal deterioration in SNHL. There was no clear relationship between the size and site of otospongiotic lesions on CT and the severity of SNHL. Follow-up with CT evaluation did not provide reliable information as to the efficacy of fluoride therapy.

['Surgery by the red-haired barbarians'; Dutch physicians in Japan, 1600-1870]. / 'Chirurgie van de roodharige barbaren'; Hollandse medici in Japan, 1600-1870.

Approximately 400 years ago, Dutch physicians laid the foundations for Western medicine in Japan. Around 1860, Dutch naval surgeons, trainees of the College of Army Surgeons in Utrecht, were to become the founders of the Medical Faculties at the Universities of Nagasaki, Tokyo and Osaka. The earlier Deshima-settlement surgeons Engelbert Kaempfer and Philipp Franz von Siebold played a highly important role in our knowledge of Japan during the 18th and 19th centuries.

Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea.

Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of factors. Many parameters, such as dose, mode of administration, dosage schedule and concomitant administration of protective additives, vary among the published studies. Therefore, we performed a basic dose-effect study on cisplatin ototoxicity in the guinea pig. Albino guinea pigs were treated with cisplatin at daily doses of either 0.7, 1.0, 1.25, 1.5 or 2.0 mg/kg for 8 consecutive days. Electrocochleography was performed on day 10 after which the cochleas were removed and processed for histological examination. The electrophysiological results showed a marked transition from almost no ototoxic effect to a large effect between a daily dose of 1.25 and 1.5 mg/kg (Stengs et al., 1998). Outer hair cell (OHC) counts corresponded well with the electrophysiological results. At daily doses of 0.7, 1.0 and 1.25 mg/kg no statistically significant OHC loss was observed, whereas OHC loss averaged 60% and 65% in the basal turns at daily doses of 1. 5 and 2.0 mg/kg, respectively. Morphological changes in the stria vascularis were present only in cochleas from animals treated with cisplatin doses of 1.0, 1.25 and 1.5 mg/kg/day. Cochleas from animals treated with a daily cisplatin dose of 2.0 mg/kg for 8 consecutive days showed an endolymphatic hydrops. The present study shows that cisplatin, administered at a daily dose of 1.5 mg/kg for 8 consecutive days, provides a degree of OHC loss that is well suited to study the effects of putative protective agents and possible hair cell recovery.

Cisplatin-induced ototoxicity: morphological evidence of spontaneous outer hair cell recovery in albino guinea pigs?

Cisplatin is frequently used in the treatment of various forms of malignancies. Its therapeutic efficacy, however, is limited by the occurrence of sensorineural hearing loss. Little is known about the course of hearing loss over longer time intervals after cessation of cisplatin administration. Infrequently, recovery of hearing has been described in animals and humans. Stengs et al. (1997) treated guinea pigs with cisplatin at a daily dose of 1.5 mg/kg for 8 consecutive days and subsequently studied cochlear function after survival times varying from 1 day to 16 weeks. Spontaneous improvement of the hair cell-related potentials (cochlear microphonics and summating potentials) was observed starting 2 weeks after cessation of treatment. In the present study we examined light microscopically the cochleas used in the study of Stengs et al. (1997). One day after cessation of cisplatin administration outer hair cell (OHC) loss in the basal cochlear turn averaged 66%. In the 1-week survival group, OHC counts were similar to those of the 1-day survival group. In the 4-week survival group, however, a relatively small loss of OHCs was found in the basal cochlear turn; OHC loss averaged only 15%. A similar loss was found after 8 weeks. In the 16-week survival group, OHC loss in the basal turn increased to 48%, but this was not statistically significant. Our histological observations are in line with the electrophysiological data from the same animals. Our findings suggest that OHCs recover from cisplatin-induced damage 1-4 weeks after treatment. However, the results do not allow a conclusion as to whether the observed recovery is due to the formation of new OHCs or to (self-)repair of damaged OHCs.

Histological effects of co-administration of an ACTH((4-9)) analogue, ORG 2766, on cisplatin ototoxicity in the albino guinea pig.

Cisplatin is one of the most potent antineoplastic drugs presently known, but its therapeutic efficacy is seriously limited by several side effects such as ototoxicity. Several compounds that are known for their nephroprotective effects also seem to reduce the incidence and severity of cisplatin-induced ototoxicity. Hamers et al. (1994) and De Groot et al. (1997) investigated the possibly protective effect of concomitant administration of the ACTH((4-9)) analogue ORG 2766 upon cisplatin ototoxicity in guinea pigs. Animals were treated with cisplatin at a daily dose of 2.0 mg/kg for 8 consecutive days and ORG 2766 at a daily dose of 75 mcg/kg for 9 days. Concomitant administration of cisplatin plus ORG 2766 resulted in a bimodal distribution of the electrophysiological data (compound action potential and cochlear microphonics amplitudes) and the histological data (outer hair cell (OHC) counts). It was surmised that this dichotomy might occur at a certain cisplatin dose. We investigated whether this protective effect of ORG 2766 could be enhanced by reducing the daily dose of cisplatin while maintaining the same dose of ORG 2766. Thirty-six animals were treated with daily i.p. injections of cisplatin at a dose of 1.0 mg/kg (n=18) or 1.5 mg/kg (n=18) for 8 consecutive days. When comparing the mean OHC counts of the different experimental groups, treatment with cisplatin at a daily dose of 1.5 mg/kg for 8 consecutive days resulted in a considerable loss of OHCs, which was significantly reduced after co-administration of ORG 2766. Co-treatment with ORG 2766 did not result in a change in the volume of the scala media. The present results are in agreement with the electrophysiological results published earlier (Stengs et al., 1998b).

Experimental autoimmune inner ear disease: an electrocochleographic and histophysiologic study.

Systemic immunization with swine inner ear antigens in complete Freund's adjuvant induces functional disturbances in the cochlea. Morphometric data indicate that an endolymphatic hydrops develops within 2 weeks. It diminishes 6 weeks after immunization. A progressive decrease in the compound action potential amplitude is observed from 2 to 6 weeks after immunization. Enhancement of the amplitude of the summating potential is present without a clear overall correlation to the presence of endolymphatic hydrops. The amplitude of the cochlear microphonics shows no significant changes after immunization. Western blot analysis of the sera performed 2 and 6 weeks after immunization shows enhanced reactivity at 68, 50, 45, and 27 kd molecular weights, as compared to controls. The same spectrum of cross-reacting antibodies is believed to be instrumental in immune-mediated sensorineural hearing loss in patients. Apparently, cross-reacting antibodies and released mediators disturb cochlear homeostasis, resulting in the observed changes in the electrophysiological responses. However, these changes are not clearly related to structural changes at the light and electron microscopic levels.

Immune-mediated sensorineural hearing loss.

A review is given on the way our knowledge of pathways of immune responses inside and in the immediate vicinity of the inner ear has gradually developed over the past two decades. Immune reactivity plays a more important role in the etiopathogenesis and natural course of various inner ear disorders than was thought originally. They comprise certain forms of fluctuating or rapidly progressive sensorineural hearing loss (SNHL) with or without endolymphatic hydrops. Patients may present themselves clinically with symptoms resembling Ménière's disease or even with sudden deafness. Immune-mediated audio-vestibular dysfunctioning is either a separate disease entity or part of a more generalized (auto-) immune process. The various attempts which have been made to develop methods or tests to confirm the diagnosis of immune-mediated SNHL are critically reviewed, including the treatment responses to immunosuppressive therapy. Various animal models are furthermore presented.

Revision surgery for chronic otitis media: a learning experience. Report on 389 cases with a long-term follow-up.

The objective of this study was to evaluate, during a long-term follow-up period, the results of revision surgery for chronic otitis media with or without cholesteatoma. Intact canal wall and canal wall down procedures were performed. The surgical history of every patient was assessed before the operation. A dry, relatively safe, and disease-free ear was created in 90% of the reoperated ears (N = 389). The recurrence rate of cholesteatoma was 5% for the total group. Reperforations of the tympanic membrane occurred in 10%, and persistent or recurrent otorrhea was present in 10% of cases. The functional hearing results were quite satisfactory. A residual air-bone gap of < or =30 dB was reached in 70.3% of the cases after revision tympanoplasty only (N = 41). Revision mastoidectomy with revision tympanoplasty as a one-stage procedure led subsequently, in 76% of intact canal wall procedures (N = 113) and 55% of canal wall down procedures (N = 98), to a residual air-bone gap of < or =30 dB.

Induction of endolymphatic hydrops in the guinea pig by perisaccular deposition of sepharose beads carrying and not carrying immune complexes.

We tried to induce endolymphatic hydrops in guinea pig cochleas by unilateral, perisaccular deposition of sepharose beads carrying immune complexes. Controls consisted of the deposition of sepharose beads without immune complexes and the contralateral, untreated ear. The effects of the treatment were studied by light microscopy and electrophysiological recordings of the gross cochlear potentials 1, 2, and 6 weeks after treatment. Each condition included six animals. Analysis of variance of the morphometric data concerning the ears treated with deposition of the beads showed a statistically significant difference (P = 0.04) between the degree of hydrops found for the beads with immune complexes and for those without. The difference between the treated ears and the contralateral untreated ears was significant (P = 0.01) for the beads with immune complexes and not significant (P = 0.8) for those without immune complexes while there was no significant effect of post-treatment time interval. Analysis of variance of the electrophysiological data, collected in response to tone bursts at the apex of the cochlea, showed no significant differences between the results for the beads with and without immune complexes. Therefore these results were pooled. One week after treatment the pooled results for the compound action potential showed a small decrease in amplitude, just significant at 2 kHz, but not at 4 and 8 kHz. This decrease disappeared completely after 6 weeks. The pooled results for the negative summating potential (SP) showed a significant increase in magnitude at all frequencies decreasing with post-treatment interval. The cochlear microphonics did not demonstrate any change in amplitude after treatment. The results indicate that deposition of sepharose beads with immune complexes induces endolymphatic hydrops. Also, deposition of the sepharose beads itself may have induced hydrops together with enhancement of the SP. SP enhancement may be related to the development of endolymphatic hydrops rather than to the presence of hydrops as such. This may be based on pressure build-up while hydrops develops.

[More than 10 years of revision-cleaning and revision-reconstructive ear surgery in chronic otitis media; good long-term results]. / Meer dan 10 jaar revisie-sanerende en revisie-reconstructieve oorchirurgie bij chronische otitis media; goede langetermijnresultaten.

OBJECTIVE: To describe the long-term results of revision surgery in patients with chronic otitis media. SETTING: University Hospital, Utrecht, the Netherlands. METHODS: A personal series of 323 revision mastoidectomies and (or) revision tympanoplasties was evaluated. Surgery was performed between 1981-1995 with a follow-up of one (minimal) to 14 years (maximal). Anatomical and functional results of various subgroups were compared. RESULTS: A preoperative incidence of cholesteatoma of 34% (n = 99) dropped after revision surgery to 11% residual/recurrent cholesteatomas (n = 9). A dry, safe and disease-free ear with a closed tympanic membrane was obtained in nearly 90% of the cases. However, in 5% (n = 10) without pre-existent cholesteatoma (n = 199), a cholesteatoma developed de novo after revision surgery. A residual air-bone hearing gap < or = 30 dB resulted in 79% of the patients after revision tympanoplasty only (n = 27). Revision mastoidectomy with revision tympanoplasty in open (n = 91) and closed (n = 92) procedures lead to a residual air-bone gap < or = 30 dB in 56% of the open cases (n = 91) and in 73% of the closed cases (before the operation the figures were 37% and 55% respectively). CONCLUSION: Revision mastoid surgery and (or) revision tympanoplasty can be quite rewarding and successful.

Immune-mediated sensorineural hearing loss with or without endolymphatic hydrops: a clinical and experimental approach.

Since 1979, when McCabe first described a pattern of bilateral sensorineural hearing loss (SNHL) characterized by a rapid progression over days to weeks, the postulated autoimmune basis of this disease remains unknown. Various attempts have been made to develop the best assays that will clinically confirm the diagnosis and will help identify those patients who may respond to immunosuppressive therapy. The Western blot assay has now been widely applied by different research groups. It has been suggested that antibody to the 68-kD protein is most closely associated with this disorder. Recent analyses suggest that the protein of interest is probably a heatshock protein (hsp 70) with this molecular weight. This disease pattern of rapidly progressive bilateral SNHL presents itself clinically as a different disease than endolymphatic hydrops with fluctuating SNHL, and it is most often associated with vertigo and roaring tinnitus. Meniere's disease may be also immune-mediated, but lacks an autoimmune basis. Its etiopathogenesis is different. A critical review of our own Western blot analyses from patients with either idiopathic rapidly progressive SNHL (N = 33), sudden deafness (N = 53), or other SNHL forms (N = 71) is presented. Immuno-suppressive treatment responses were evaluated. A new concept of immune-mediated endolymphatic hydrops was also further developed on the basis of recent experimental data and earlier clinical observations in order to focus on another aspect of this most intriguing inner-ear disease.

Demonstration of intermediate filament proteins in the guinea pig vestibular labyrinth by a new, high-resolution cryotechnique.

In order to establish the more precise localization of IFPs in the vestibular labyrinth we have developed an immunohistochemical method using semithin cryosections from guinea pig inner ear. The vestibular end organs were fixed by intralabyrinthine perfusion with formaldehyde and glutaraldehyde. Microdissection was performed, followed by decalcification in EDTA. After specimen embedding in gelatin, semithin cryosections (1 micron) were prepared. Prior to the immunohistochemical staining, a new antigen-unmasking treatment was performed. Monoclonal antibodies for cytokeratins (Cks), vimentin, neurofilament protein (NF), and glial fibrillary acidic protein (GFAP) were used and visualized with an indirect ABC method. In the guinea pig vestibular labyrinth, Cks8, 18 and 19 were present. Vimentin and NF were stained positively, GFAP negatively. These results are in accordance with our previous results in the human vestibular labyrinth except for Ck7. The high-resolution cryotechnique in combination with a new antigen-unmasking method may yield more, and more detailed information about the localization of IFPs in the vestibular region.