The effects of frequent follow-up on compliance in patients receiving PAP therapy due to OSA.

OBJECTIVE: We planned to investigate the effect of close monitoring on compliance and the factors affecting compliance among patients receiving positive airway pressure (PAP) treatment due to obstructive sleep apnea (OSA). PATIENTS AND METHODS: This study was a single-center, prospective, randomized, controlled study. Between January 2022 and May 2022, 192 patients who were 18 years of age or older, had been newly diagnosed with OSA, and underwent PAP titration at our sleep laboratory were included in the study. RESULTS: One hundred twenty-eight patients were randomized as group 1 (study group) and group 2 (control group). There was no correlation between good continuous positive airway pressure (CPAP) compliance and diabetes mellitus, hypertension, hyperthyroidism, or allergic rhinitis. However, there was a statistically significant correlation between good CPAP compliance and chronic obstructive pulmonary disease (COPD) or asthma. CONCLUSIONS: Sleeping with such a device will be very difficult and uncomfortable. As observed from previous studies, adherence to CPAP is a critical problem worldwide regardless of geography, education, age, and sex. Telemedicine monitoring may be a good follow-up tool. Nevertheless, the essential tool is interpersonal communication by phone calls, face-to-face computer communication, or frequent visits.

The European Medicines Agency review of sacituzumab govitecan for the treatment of triple-negative breast cancer.

Sacituzumab govitecan (SG) is an antineoplastic agent which combines a humanized monoclonal antibody binding to trophoblast cell surface antigen-2 (Trop-2)-expressing cancer cells, linked with cytotoxic moiety SN-38 (govitecan) with topoisomerase I inhibitor action. On 22 November 2021, a marketing authorization valid through the European Union (EU) was issued under the European Medicines Agency (EMA)'s accelerated assessment program for SG as monotherapy for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, including at least one of them for advanced disease. The assessment was based on results from an open-label, randomized, phase III trial to evaluate the safety, tolerability, pharmacokinetics and efficacy of SG versus treatment of physician's choice (TPC) in patients with mTNBC who received at least two prior treatments including at least one of them for advanced disease. The efficacy results in the overall population, based on mature data, showed a statistically significant improvement of SG over TPC in progression-free survival (PFS) and overall survival (OS). The median PFS was 4.8 months versus 1.7 months [hazard ratio (HR) = 0.43, n = 529; 95% CI 0.35-0.54; P < 0.0001] and the median OS was 11.8 months versus 6.9 months (HR = 0.51, n = 529; 95% CI 0.41-0.62; P < 0.0001). The most common (>30%) side effects of SG were diarrhea, neutropenia, nausea, fatigue, alopecia, anemia, constipation and vomiting. The aim of this manuscript is to summarize the scientific review of the application leading to regulatory approval in the EU.

The EMA review of trastuzumab emtansine (T-DM1) for the adjuvant treatment of adult patients with HER2-positive early breast cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab [a monoclonal antibody against human epidermal growth factor receptor 2 (HER2)] and DM1 (an inhibitor of tubulin polymerisation). It was initially approved in the European Union for the treatment of adult patients with HER2-positive unresectable locally advanced or metastatic breast cancer (BC) who had previously received trastuzumab and taxanes. On 18 December 2019, a variation of the marketing authorisation was approved extending this use to the adjuvant therapy of adult patients with HER2-positive early BC who have residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted therapy. A phase III randomised, multicentre, open-label trial compared T-DM1 with trastuzumab as adjuvant therapy in patients with HER2-positive early BC who had received preoperative chemotherapy and HER2-targeted therapy followed by surgery, with a finding of invasive residual disease in the breast and/or axillary lymph nodes. The study met its primary endpoint by showing an increased 3-year invasive disease-free survival rate in the T-DM1 arm (88.3%) compared with the trastuzumab arm (77.0%), with an unstratified hazard ratio of 0.50 (95% confidence interval: 0.39-0.64). There was a higher incidence of hepatotoxicity (37.3% versus 10.6%), thrombocytopenia (28.5% versus 2.4%), peripheral neuropathy (32.3% versus 16.9%), haemorrhage (29.2% versus 9.6%) and pulmonary toxicity (2.8% versus 0.8%) in the T-DM1 arm compared with the control arm. The aim of this manuscript was to summarise the scientific review of the application leading to regulatory approval of this additional indication in the European Union.

The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

The effect of cochlear implant bed preparation and fixation technique on the revision cochlear implantation rate.

OBJECTIVE: This study aimed to determine the effect of the subperiosteal tight pocket technique versus the bone recess with suture fixation technique on the revision cochlear implantation rate and complications. METHODS: This retrospective study included 1514 patients who underwent cochlear implantation by 2 senior surgeons between October 2002 and January 2016. Revision cases were identified and analysed. RESULTS: In all, 52 patients (3.34 per cent) underwent revision cochlear implantation. The revision rate was 7.18 per cent in the subperiosteal tight pocket group versus 2.37 per cent in the bone recess with suture fixation group (p < 0.001). Device failure was the most common reason for revision surgery in both groups. There was a significant difference in the device failure rate between the bone recess with suture fixation group (2.11 per cent) and subperiosteal tight pocket group (6.88 per cent) (p < 0.001). CONCLUSION: Accurate fixation of the cochlear implant receiver/stimulator is crucial for successful cochlear implantation. As the bone recess with suture fixation technique is associated with a lower revision rate and a similar complication rate as the subperiosteal tight pocket technique, it should be the preferred fixation technique for cochlear implantation.

Evaluation of the possible protective role of naringenin on gentamicin-induced ototoxicity: A preliminary study.

OBJECTIVES: The purpose of this study is to evaluate the possible protective role of naringenin in gentamicin-induced ototoxicity through an audiological, biochemical and histopathological evaluation. METHODS: This study was conducted on 32 adult male rats that were randomized into 4 groups(control, gentamicin, naringenin + gentamicin, and naringenin). Naringenin was given to the rats via oral gavage in a dose of 50 mg/kg/day during the 14 day study period. Gentamicin was given by the intraperitoneal route in a dose of 120 mg/kg/day. Audiological assessment was performed by the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) measurements, applied to all rats at the beginning of the study, and also on day 14. Biochemical parameters were calculated on day 14 to evaluate the oxidative and antioxidative status. Their cochleae were removed and examined histopathologically, also on day 14. The cochlea of animals were evaluated with the terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick end labeling (TUNEL) method for apoptosis. RESULTS: On days 14, DPOAE values and ABR thresholds were preserved in group 3(naringenin + gentamicin) when compared with group 2(gentamicin)(p < 0.008). The total oxidant status values and oxidative stress index values were significantly higher in group 2(gentamicin) than in other groups (p < 0.008). The total antioxidant status value was significantly higher in group 3(naringenin + gentamicin) and group 4(naringenin) than in group 2(gentamicin)(p < 0.008). The number of TUNEL positive cells in both the organ of Corti and the stria vascularis were found to be statistically lower in group 3(naringenin + gentamicin) than in group 2(gentamicin)(p < 0.05). CONCLUSION: Our study has demonstrated that the ototoxic effect generated by gentamicin could be ameliorated with the concurrent use of naringenin.

Incomplete endochondral ossification of the otic capsule, a variation in children: evaluation of its prevalence and extent in children with and without sensorineural hearing loss.

BACKGROUND AND PURPOSE: Endochondral ossification of the otic capsule is a process that continues postnatally; hence, incomplete endochondral ossification is seen as pericochlear hypoattenuation on temporal bone CT scans of children. We determined the prevalence and extent of this entity in a large series and assessed its relation to age and underlying sensorineural hearing loss. MATERIALS AND METHODS: Initially, temporal bone CTs of 40 children with sensorineural hearing loss were retrospectively assessed and compared with those of a control group scanned for non-sensorineural hearing loss reasons to assess any difference in the prevalence or extent of incomplete endochondral ossification. Then the CT scans of 510 children (age range, 17 days to 17 years) were retrospectively reviewed, and any observed endochondral ossification areas were classified as mild, moderate, or extensive, according to their extent. RESULTS: Neither the presence nor degree of incomplete endochondral ossification had any significant correlation with the presence of sensorineural hearing loss (P = .08 and P = .1, respectively). Incomplete endochondral ossification was more frequently seen (62% of cases) than complete ossification. There was no statistically significant correlation between incomplete endochondral ossification and sex (P = .8), but an inverse correlation was found between the presence of incomplete endochondral ossification and increasing age (P < .001). Overall, mild incomplete endochondral ossification was the most frequent involvement pattern (44.4%). CONCLUSIONS: The pericochlear hypoattenuation in the otic capsule representing incomplete endochondral ossification is a normal finding in children and can be seen as a marked curvilinear hypoattenuation at younger ages in the absence of any clinical disorder.

Balance after stapedotomy: analysis of balance with computerized dynamic posturography.

OBJECTIVES: The aim of this study was to investigate vestibular symptoms and their effect on the balance in otosclerosis patients undergoing stapedotomy operations. DESIGN & SETTING: Prospective study at an academic tertiary referral centre. PARTICIPANTS: Thirty-three patients undergoing stapedotomy were included in the study. MAIN OUTCOME MEASURES: Sensory organisation test (SOT) protocol of computerized dynamic posturography was used to analyse the balance in patients preoperatively, in the first postoperative week and the first postoperative month. Postoperative vestibular symptoms were analysed with a grading system. Audiograms were obtained preoperatively and 1 month after the operation. RESULTS: Preoperatively, all patients were asymptomatic when considering the vestibular system; however, eight of them got low SOT scores on vestibular examination. Postoperatively 82% of the patients had vestibular complaints in variable severity. In the first week, all but one patient become asymptomatic. This patient recovered by the end of postoperative second week. However, a significant drop in SOT scores was encountered at the first week testing (Student's T-test, P = 0.001). One month after the operation, all patients were asymptomatic and SOT scores recovered at least to preoperative level. Neither patient characteristics, nor audiological findings were found to be correlated with vestibular changes. CONCLUSION: Stapedotomy causes a temporary balance loss in a high percentage of patients which then recover to their former levels in the first postoperative month.

A high peritoneal large pore fluid flux causes hypoalbuminaemia and is a risk factor for death in peritoneal dialysis patients.

BACKGROUND: Hypoalbuminaemia is common in peritoneal dialysis (PD) patients and has an associated high mortality. An excess morbidity and mortality has previously been found in patients with high peritoneal transport. A high peritoneal large pore fluid flux (Jv(L)) results in increased peritoneal loss of protein that possibly contributes to patient morbidity. Alternatively, hypoalbuminaemia and high transport status could be just a marker of capillary pathology associated with atherosclerotic comorbidity. METHODS: Peritoneal dialysis capacity computer modelling of peritoneal transport, based on Rippe's three-pore model, was performed to measure Jv(L) in 155 incident PD patients 2-4 weeks after PD initiation. Patient clinical and biochemical status was determined -6, -3, -1, 1 and 6 months after PD initiation, and every 6 months thereafter. Jv(L) was redetermined in prevalent patients 2 and 4 years after PD initiation. RESULTS: Jv(L) was 0.106+/-0.056 ml/min/1.73 m(2) (median 0.094, interquartile range 0.068-0.128). It was correlated to age*** (*P<0.05; **P<0.01; ***P<0.001) (20-30 years 0.079+/-0.04; 70 years 0.121+/-0.071), but not to gender. No correlation to diabetic or preexisting renal replacement therapy was seen, but patients with atherosclerosis had higher Jv(L) (0.123+/-0.06 vs 0.100+/-0.056*) as had patients with other systemic disease (0.121+/-0.68 vs 0.100+/-0.051*). Jv(L) was positively correlated to area parameter (r = 0.41***), and negatively correlated to plasma albumin (-0.36***). Patients were divided into three equal groups: group 1, Jv(L) <0.075 ml/min/1.73 m(2); group 2, 0.075-0.11; group 3: >0.11. There was no difference between the groups in p-albumin prior to PD. Immediately after PD start, differences between the three groups appeared (1 month p-albumin: (micromol/l) group 1, 548+/-83; group 2, 533+/-86; group 3, 497+/-78**), and persisted for up to 6 years. No significant change in Jv(L) was seen at 2 and 4 years. Patients with significant albuminuria also had hypoalbuminaemia (<1 g/day: 546+/-81 mumol/l; >2 g/day: 503+/-54 micromol/l). Intermittent PD ameliorated the effect of Jv(L) on albumin losses and clearance. Mortality was increased significantly with raised Jv(L), independently of age (2 year mortality: group 1, 10%, group 3, 32%*). There was no overall effect on technique survival, but hypoalbuminaemic group 3 patients had a higher failure rate. CONCLUSION: Jv(L) is related to hypoalbuminaemia and mortality after PD initiation. A high Jv(L) seems to be a marker of preexisting vascular pathology, and to cause hypoalbuminaemia after PD initiation. It is suggested that peritoneal albumin loss can have an identical pathogenic effect as urinary albumin loss, by causing an iatrogenic "nephrotic" syndrome.

Bcl-2 and LMP1 expression in nasopharyngeal carcinomas.

In vitro studies of B-cells immortalized by Epstein-Barr Virus (EBV) have shown that B-cell leukemia/lymphoma-2 (bcl-2) protein expression is upregulated by the EBV-latency-associated antigen, latent membrane protein 1 (LMP1). The same phenomenon has also been observed in epithelial cells in vitro. However, such correlation between these 2 markers has not been shown in nasopharyngeal carcinoma (NPC), in which EBV infection is a well-known etiologic factor. This retrospective study examined 35 cases of undifferentiated NPC to answer the question of whether LMP1 and/or bcl-2 presence can be used as biomarkers at treatment response, as well as to see the relationship between bcl-2 and LMP in NPC. Of the 35 patients, 26 (74.3%) were bcl-2, and 10 (28.6%) were LMP1-positive. Although a significant correlation was observed between bcl-2 and LMP1 staining (P =.003), it appeared that bcl-2 expression could be independent of LMP1. Statistical analysis showed that cervical lymph node metastasis (P =.04) and cranial nerve involvement (P =.03) are the only variables that significantly affect patient survival. At this time, bcl-2 and LMP1 presence are not significant indicators of outcome; however, although they are not directly related to survival, expression of both bcl-2 and LMP1 was strongly correlated with cervical lymph node metastasis, which is a potent predictor of patient survival.

4-aryl-6,6-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones: synthesis, chromatographic resolution and pharmacological activity.

In this study, a series of 4-aryl-6,6-dimethyl-1,2,3,4,5,6,7,8- octahydroquinazoline-2,5-diones were synthesized by condensing urea with 4,4-dimethyl-1,3-cyclohexanedione and appropriate aromatic aldehydes according to the Biginelli reaction. The structures of the compounds were characterized by spectroscopic methods. The racemic compounds were resolved into the enantiomers by HPLC on amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD). The compounds were tested in vitro for their calcium antagonistic activities. BaCl2-induced contractions of rat ileum were inhibited dose-dependently. Compounds 3 and 5 exerted weak calcium antagonistic activity on smooth muscles compared with the standard, nicardipine.

Investigation of the ototoxic effects of interferon alpha2A on the mouse cochlea.

This prospective randomized study investigates the possible toxic effects of interferon (IFN) alpha2A on the mouse cochlea. Thirty-six albino Swiss mice that were randomly assigned to 3 groups underwent baseline auditory brain stem response testing bilaterally to objectively assess baseline hearing levels. The first group received a single dose of 50,000 units, and the second group received 100,000 units of IFN-alpha2A intraperitoneally, whereas the third group was given no medication. Repeat auditory brain stem response testing revealed a significant rise in mean baseline peak equivalent sound pressure level thresholds in the groups that received IFN (P < 0.001). Histologically, the cochleae of mice that received IFN had a decreased number of fibroblasts in the spiral limbus, as well as prominent cytoplasmic vacuolation of these cells, compared with control animals. Loss of hair cells was not observed. It is possible that reversible biochemical and metabolic changes in the cochlea, rather than morphologic abnormalities, manifest IFN ototoxicity.

The value of elective neck dissection in treatment of cancer of the tongue.

PURPOSE: The "adequate" therapy of tongue cancer has not yet been determined. The authors report their experience with 58 N(0) patients to elucidate the role of elective neck dissection in surgical treatment of cancer of the tongue. MATERIALS AND METHODS: The files of 58 N(0) patients with tongue cancer were evaluated retrospectively. In every patient, partial glossectomy continuous with neck dissection was the mainstay of the treatment. TNM staging, intraoperative N staging, pathologically confirmed cervical lymph node metastases and their levels, and clinical outcomes (local and regional recurrences) were recorded. The sensitivity and specificity of intraoperative staging was determined. RESULTS: Fifty-four percent (31/58) of the patients presented as T(1), and 26% (15/58) as T(2). The overall occult metastasis rate was 29.3% (17/58). The occult metastasis rate for T(1) and T(2) lesions was 19.4% (6/31) and 26.7% (4/15), respectively. The sensitivity of intraoperative staging was 76.5%, and the specificity was 51.2%. CONCLUSIONS: The rate of occult metastasis to the neck is too high in all tongue cancer cases to take the risk of regional recurrence, and the surgeon can not solely depend on neck palpation for determination of neck metastasis. Radiologic investigations and fine-needle aspiration decrease, but never reduce to zero the rate of false-negative examination. There is an obvious indication for neck dissection, even in early cases.

Histopathological predictors of occult lymph node metastases in supraglottic squamous cell carcinomas.

Lymph node metastasis appears to be the most important factor determining survival in patients with squamous cell carcinoma of the larynx. Supraglottic laryngeal carcinomas have a known tendency to metastasize to cervical lymph nodes because of the extensive lymphatic network present. This retrospective cohort study was conducted to define possible histopathological parameters affecting cervical lymph node metastasis and then using these parameters to create a scale to predict occult lymph node metastasis in supraglottic squamous cell carcinoma. The pathological slides of 61 operated patients were reevaluated for tumor grade, lymphatic-vascular invasion, invasion pattern of tumor margins, perineural invasion and lymphocytic infiltration. Grade (P < 0.001), lymphatic-vascular invasion (P < 0.001) and tumor margins (P = 0.007) were found to be closely associated with neck metastasis. To define the risk factors for occult metastasis, a grading scale was created by using grade (G), lymphatic-vascular invasion (L) and tumor margin (M) findings of patients. None of the patients with a GLM value of zero developed occult metastasis. On the other hand occult metastasis was found in 58.8% of N0 patients with a GLM value that was more than zero. These findings indicate that patients with high-grade tumors having infiltrating borders and lymphatic-vascular invasion have a high risk for occult metastasis so that elective treatment of the neck either by neck dissection or radiotherapy should be added to therapy. Serial sections of specimens are needed to avoid missing metastatic loci of disease.

Transmaxillary excision of a rare cavernous hemangioma of the infratemporal fossa.

Cavernous hemangiomas that manifest as a primary tumor of the infratemporal fossa are exceedingly rare. We report such a case in a 40-year-old woman. Her lesion was excised via a transantral anterior approach. Although this approach is usually recommended only for biopsy, in selected cases it can be used to excise a lesion without causing any significant complications. We recommend the transantral anterior approach for relatively small, benign lesions that show no evidence of invasion into surrounding tissues because it does not expose the patient to surgical complications such as transient or permanent facial nerve injury or cosmetic deformity.

Enantioseparation of 3,4-dihydroxyphenylalanine and 2-hydrazino-2-methyl-3-(3,4-dihydroxyphenyl)propanoic acid by capillary electrophoresis using cyclodextrins.

The enantiomeric separations of 3,4-dihydroxyphenylalanine (dopa) and 2-hydrazino-2-methyl-3-(3,4-dihydroxyphenyl)propanoic acid (carbidopa) by capillary electrophoresis were studied using several native, neutral and anionic cyclodextrins as chiral additives and uncoated fused-silica capillaries. The effect of the type and concentration of the cyclodextrin added to 20 mM phosphate buffer (pH 2.5) on enantioseparation and migration times was studied. A high resolution value of 15.63 was obtained for dopa enantiomers with a buffer containing 20 mM single isomer, heptakis(2,3-diacetyl-6-sulfato)-beta-cyclodextrin. The enantiomers of carbidopa were separated using 20 mM carboxymethyl-beta-cyclodextrin as a chiral resolving agent. Both methods allowed the determination of 0.1% of the D-enantiomer (second migrating) in the presence of the L-enantiomer (first migrating) of dopa and carbidopa with a good precision. These methods also gave good results in terms of precision for both peak area, migration time, linearity and accuracy.

Melanotic neuroectodermal tumor of infancy: report of two cases and review of literature.

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, distinctive neoplasm containing melanin; it primarily affects the maxilla of the infants during the first year of life. Approximately 150 instances of this tumor are reported in the medical literature. Genesis of the tumor is obscure and the diagnosis is challenging for the pathologist. Two cases operated by the first author are presented, and the diagnostic features and treatment alternatives of MNTI discussed.