Significant Difference In CSS Research Articles

Clinical outcomes of colistin methanesulfonate sodium in correlation with pharmacokinetic parameters in critically ill patients with multi-drug resistant bacteria-mediated infection: A systematic review and meta-analysis

BackgroundColistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). MethodsA systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (Css,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). ResultsTotal of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 – 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of Css,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) −0.25; 95% CI −0.69 – 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI −0.27–1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 – 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. ConclusionThe mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in Css,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection.

Prognosis of carcinoembryonic antigen (CEA) in stage I colorectal adenocarcinoma and development of a prediction model: a retrospective study based on the SEER database.

To investigate the prognostic significance of preoperative carcinoembryonic antigen (CEA) status in stage I colorectal classical adenocarcinoma (CCA) and mucinous adenocarcinoma (MUC), and to construct a nomogram model of stage I CCA. The SEER database was used to collect 14,226 patients diagnosed with stage I colorectal adenocarcinoma (CA) from 2010 to 2015. The prognostic significance of preoperative CEA status in stage I CA and MUC was examined by propensity-matching score (PSM). We analyzed the factors affecting the prognosis of patients with stage I CCA, and constructed and verified the prognostic model. After PSM, the cancer-specific survival rate (CCS) of CEA-positive patients in stage T1 and T2 CCA was significantly lower than that of CEA-negative patients in stage T1 and T2 [HR = 0.37 (0.29-0.48), P < 0.001], [HR = 0.52 (0.41-0.65), P < 0.001]. However, there was no significant difference in CSS between CEA-positive and CEA-negative patients in T1 and T2 MUC [HR = 0.58 (0.43-0.79), P = 0.096], [HR = 0.76 (0.36-1.62), P = 0.477]. A nomogram was constructed based on the results of the multivariate COX regression model. Based on the AUC of ROC analysis, calibration plot and decision curve analysis (DCA), we concluded that the risk and prognosis model of CCA showed excellent performance. Elevated CEA is a risk factor for stage I CCA, but not for MUC. And the nomogram is accurate enough to predict the risk and prognostic factors of CCA.

Impact of radiation dose to the immune system on disease progression and survival for early-stage non-small cell lung cancer treated with stereotactic body radiation therapy

ObjectivesAlthough the effects of estimated dose of radiation to immune cells (EDRIC) in stage III NSCLC, LA-NSCLC, LS-SCLC and esophageal cancer on clinical outcomes have been studied, its impact in early-stage non-small cell lung cancer (ES-NSCLC) is unknown. In this study, we evaluated the role of EDRIC and identified the factors influencing EDRIC in this population. Methods and materialsWe retrospectively analyzed 211 pathologically confirmed ES-NSCLC patients who were treated with SBRT between 2007 and 2020. EDRIC was calculated based on the model developed by Jin et al. and improved by Ladbury et al. Kaplan–Meier method and Cox proportional hazards regression were adopted to estimate CSS, PFS, LPFS, and DMFS. Pearson correlation was used to assess the correlation between variables. We further validated our findings in an independent cohort of 119 patients with ES-NSCLC. ResultsA total of 211 patients were included with median follow-up of 48 months in the training cohort. The median EDRIC was 2.178 Gy (range: 0.426–6.015). GTV showed a positive correlation with EDRIC (r = 0.707, P = 0.000). In multivariate analysis, higher EDRIC was significantly associated with worse CSS (HR = 1.468, P = 0.009) and DMFS (HR = 1.491, P = 0.016). Considering each EDRIC quartile, there was a significant difference in CSS between 1st and 4th and 1st and 3rd quartile (P = 0.000, P = 0.004, respectively); and DMFS between 1st and 4th,1st and 3rd, and 1st and 2nd quartile (P = 0.000, P = 0.000, P = 0.008, respectively). In the subgroup and validation cohort, EDRIC was also the important prognostic predictor of CSS and DMFS using multivariate analysis. ConclusionEDRIC was an independent predictor of CSS and DMFS in ES-NSCLC, and it was affected by GTV and tumor location. Though EDRIC is a critical determinant of treatment outcomes, it is quantifiable and potentially modifiable. Additional researches exploring the feasibility of achieving lower EDRIC while maintaining adequate tumor coverage during radiotherapy are warranted.

MUC1 Tissue Expression and Its Soluble Form CA15-3 Identify a Clear Cell Renal Cell Carcinoma with Distinct Metabolic Profile and Poor Clinical Outcome.

An altered metabolism is involved in the development of clear cell renal carcinoma (ccRCC). MUC1 overexpression has been found to be associated with advanced disease and poor prognosis. In this study, we evaluated the metabolomic profile of human ccRCC, according to MUC1 expression, and integrated it with transcriptomic data. Moreover, we analyzed the role of MUC1 in sustaining ccRCC aggressiveness and the prognostic value of its soluble form CA15-3. Integrated metabolomic and transcriptomic analysis showed that MUC1-expressing ccRCC was characterized by metabolic reprogramming involving the glucose and lipid metabolism pathway. In addition, primary renal cancer cells treated with a small interfering RNA targeting MUC1 (siMUC1) migrated and proliferated at a slower rate than untreated cancer cells. After cisplatin treatment, the death rate of cancer cells treated with siMUC1 was significantly greater than that of untreated cells. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low levels of CA15-3. In a multivariate analysis, CA15-3 was an independent adverse prognostic factor for cancer-specific and progression-free survival. In conclusion, MUC1 expressing ccRCC is characterized by a particular metabolic reprogramming. The inhibition of MUC1 expression decreases cell motility and viability and improves cisplatin susceptibility, suggesting that this pathway can regulate de novo chemotherapy resistance in ccRCC.

Efficacy and safety of surgery in renal carcinoma patients 75 years and older: a retrospective analysis

ObjectiveTo investigate the efficacy and complications of surgical treatment in patients with renal cell carcinoma aged ≥ 75 years.MethodsFrom January 2009 to May 2019, we assessed 166 patients aged 75 years and older, who either had radical nephrectomy (RN) or partial nephrectomy (PN) as treatments for diagnosed renal cell carcinoma. Patients were divided into one group of patients aged 75–79 years and the second group of patients ≥ 80 years. The complications and survival were compared between the two groups.ResultsAll 166 patients were successfully operated on. Differences between the two groups were statistically significant in intraoperative and postoperative complications and Clavien–Dindo score of ≥ 1 (P = 0.02, P < 0.001, P = 0.001). Univariate analysis revealed no significant correlation between a Clavien–Dindo score ≥ 1 versus gender, body mass index (BMI), lack of symptoms, KPS, baseline GFR, postoperative GFR, tumor size, tumor location, surgical method, and transfusion or no transfusion (ALL P > 0.05). Multifactor analysis showed that age ≥ 80 years, partial nephrectomy, and operation time were independent predictors of a Clavien–Dindo score ≥ 1. No significant difference was found in OS between the two groups, (P < 0.0001), and no significant difference in CSS (P = 0.056). There was no significant difference in OS and CSS between the RN and PN groups (P = 0.143, P = 0.281, respectively).ConclusionsAccording to our findings, the overall safety of surgical therapy for elderly patients with renal cell carcinoma is adequate. PN should be carefully examined, especially over the age of 80. To select suitable patients based on an assessment of the tumor's complexity and patients' physical condition, such as age, underlying diseases and other conditions, technical feasibility, balance of benefits and a case-by-case.

Significance of postoperative adjuvant chemotherapy with an oxaliplatin-based regimen after simultaneous curative resection for colorectal cancer and synchronous colorectal liver metastasis: a propensity score matching analysis

BackgroundExpansion of the indication for liver resection and new regimens for systemic chemotherapy have improved postoperative outcomes for synchronous colorectal liver metastases (CRLM). However, such cases can still have a high recurrence rate, even after curative resection. Therefore, there is a need for postoperative adjuvant chemotherapy (POAC) after liver resection in patients with CRLM. There are few studies of the efficacy of POAC with an oxaliplatin-based regimen after simultaneous resection for colorectal cancer and CRLM with curative intent. The goal of the study was to compare POAC with oxaliplatin-based and fluoropyrimidine regimens using propensity score (PS) matching analysis.MethodsThe subjects were 94 patients who received POAC after simultaneous resection for colorectal cancer and synchronous CRLM, and were enrolled retrospectively. The patients were placed in a L-OHP (+) group (POAC with an oxaliplatin-based regimen, n = 47) and a L-OHP (−) group (POAC with a fluoropyrimidine regimen, n = 47). Recurrence-free (RFS), cancer-specific (CSS), unresectable recurrence-free (URRFS), remnant liver recurrence-free (RLRFS), and extrahepatic recurrence-free (EHRFS) survival were analyzed.ResultsBefore PS matching, the L-OHP (+) and (−) groups had no significant differences in RFS, CSS, URRFS, RLRFS, and EHRFS. Univariate analysis indicated significant differences in age, preoperative serum CEA (≤ 30.0 ng/mL/ > 30.0 ng/mL), differentiation of primary tumor (differentiated/undifferentiated), T classification (T1–3/T4), number of hepatic lesions and maximum diameter of the hepatic lesion between the L-OHP (+) and (−) groups. After PS matching using these confounders, RFS was significantly better among patients in the L-OHP (+) group compared with the L-OHP (−) group (HR 0.40, 95% CI 0.17–0.96, p = 0.04). In addition, there was a trend towards better RLRFS among patients in the L-OHP (+) group compared with the L-OHP (−) group (HR 0.42, 95% CI 0.17–1.02, p = 0.055). However, there were no significant differences in CSS, URRFS and EHRFS between the L-OHP (+) and (−) groups.ConclusionsPS matching analysis demonstrated the efficacy of POAC with an oxaliplatin-based regimen in RFS and RLRFS.

MP24-10 NO SURVIVAL DIFFERENCE BETWEEN PATIENTS WITH DE NOVO MUSCLE-INVASIVE BLADDER CANCER COMPARED TO THOSE THAT PROGRESS IN ROUTINE CLINICAL PRACTICE

INTRODUCTION AND OBJECTIVE: Although consensus frequently suggests that patients who progress to muscle-invasive bladder cancer (MIBC) have worse outcomes than those that present de novo, contemporary studies have been equivocal. The concept is important not only with respect to understanding the biology of the disease but also clinical decision making. The primary objective of this study was to determine if there is a difference in cancer-specific (CSS) and overall survival (OS) between radical cystectomy (RC) patients who presented either with de novo MIBC or those patients who progressed to MIBC. METHODS: This retrospective population-based study reports early and late outcomes of all patients treated within Ontario during 2009-2013 based on their presentation of bladder cancer (de novo vs. progression from non-invasive disease). All incident cases that underwent RC were identified using the Ontario Cancer Registry (OCR) and linked to treatment records. Records from the Canadian Institute for Health Information were used to identify those patients treated with RC. As stage of disease was not routinely available, a team of trained data abstractors obtained and reviewed surgical pathology reports for all RC cases. Statistical analysis of the survival data was performed using the Kaplan-Meier method and Cox proportional hazards were used to adjust for known confounders. RESULTS: 1573 patients underwent RC between 2009 and 2013 in the province of Ontario. 893 were diagnosed with de novo MIBC and 79% had clinical T2 or greater disease at the time of TURBT. 680 were identified as progressors, and 49% had clinical T2 or greater disease at the time of TURBT. Further, neoadjuvant chemotherapy was received by 17% and 13% of de novo patients and progressors respectively. Several process indicators and early outcomes spread to be equivalent between the cohorts including 30 day mortality with a hazard ratio of 1.69 (95% CI 0.90-3.19). There was improved CSS and OS for progressors compared to de novo MIBC patients with hazard ratios of 0.85 (95% CI 0.74-0.98) and 0.90 (95% CI 0.79-1.03) respectively in unadjusted analysis for the whole cohort. However, when controlled for patients with only clinical T2 or greater disease, there was no difference in either CSS or OS between groups in adjusted analysis. CONCLUSIONS: This study shows, when controlled for clinical stage, no significant difference in CSS or OS between patients with de novo MIBC and progressors of MIBC in routine clinical practice. Source of Funding: none

Long-term outcomes of colorectal cancer surgery for elderly patients: a propensity score-matched analysis.

To investigate the effect of old age on the perioperative, short-term, and long-term surgical outcomes of elderly patients undergoing curative surgery for colorectal cancer (CRC). The subjects of this retrospective study were 526 patients who underwent curative resections for stage I-III CRC between March 2005 and March 2016. We divided the patients into a young group (< 75years old, n = 361) and an elderly group (≥ 75years old, n = 165) and compared the clinicopathological factors and prognoses of the two groups. We performed a propensity score-matched (PSM) analysis with inverse probability of treatment weighting (IPTW) to avoid confounding bias. The elderly group had more right-sided tumors and more comorbidities than the young group. After PSM, there were 148 patients in each group. Although the elderly group had significantly shorter overall survival than the young group, the two groups did not differ significantly in cancer-specific survival (CSS; P = 0.136) or recurrence rate (RR; P = 0.317). Multivariate analysis with IPTW also revealed no significant difference in CSS (P = 0.171) or RR (P = 0.284) between the young and elderly groups. Our findings were limited by the study's retrospective single-institute conditions, and the inclusion of only patients who underwent radical resections. Primary tumor resection is appropriate for elderly patients with CRC.

Impact of histologic variants on the oncological outcomes of patients with upper urinary tract cancers treated with radical surgery: a multi-institutional retrospective study

No definitive evidence exists regarding the clinical significance of histologic variants (HV) in upper urinary tract cancer. We investigated the impact of HV on prognosis in patients with upper urinary tract cancer following radical surgery. We retrospectively analyzed 451 patients with upper urinary tract cancer who underwent radical nephroureterectomy at six affiliated hospitals from 1990 to 2015. Patients with distant metastatic disease prior to surgery and those who received neoadjuvant chemotherapy were excluded, leaving 441 eligible patients. Patients were classified into two groups: pure urothelial carcinoma (UC) and HV. The clinicopathological variables of each group were examined using Kaplan-Meier plots and proportional Cox hazard ratios (HR) to compare the oncological outcomes between the two groups. HV included 37 patients (8%). Compared with the pure UC patients, HV patients had significantly worse recurrence-free survival (RFS) and cancer-specific survival (CSS; RFS p = 0.0002, CSS p = 0.0001). Multivariate analysis for RFS revealed HV were independent predictors (HR 1.92; p = 0.026), but the association did not remain significant for CSS. There was no significant difference in CSS between the adjuvant chemotherapy (AC) group and the non-AC group for all HV patients, except in patients with ≥ pT3 tumor or positive lymph node status where the AC group had significantly favorable CSS. HV in upper urinary tract cancer are independent predictors for RFS, but not for CSS. AC improved CSS for HV patients with ≥ pT3 tumor or positive lymph node status.

Adjuvant radiotherapy following pancreaticoduodenectomy for ampullary adenocarcinoma improves survival in node-positive patients: a propensity score analysis.

This study aimed to evaluate the impact of adjuvant radiotherapy in patients undergoing pancreaticoduodenectomy (PD) for ampullary adenocarcinoma. Using the Surveillance, Epidemiology, and End Results, patients with non-metastatic ampullary adenocarcinoma between 2004 and 2013 were identified. Cancer-specific survival and overall survival were estimated using Kaplan-Meier and Cox regression to obtain adjusted hazard ratio of survival. In this study, 1106 patients with ampullary adenocarcinoma were identified, of which 27% received adjuvant radiotherapy and the remaining 73% (803/1106) patients did not receive any adjuvant radiotherapy. In the matched cohort, there were still no significant difference in CSS (median 41 vs 35, p=0.28) and OS (median 32 vs 30, p=0.26) between patients receiving adjuvant radiotherapy and those under observation alone. However, in patients with N2 (Fig.4) disease, both CSS (median 27 vs 19months, p=0.0044) and OS (median 23 vs 17months, p=0.0091) were significantly longer for patients receiving adjuvant radiotherapy. In summary, adjuvant radiotherapy following PD for ampullary adenocarcinoma significantly improves survival in patients with N2 disease. Future studies defining "high-risk" groups using larger cohorts will enable reliable appraisal on the benefit of adjuvant radiotherapy to allow for a more personalized approach in treating patients.

A study of appendiceal crypt cell adenocarcinoma (so-called goblet cell carcinoid and its related adenocarcinoma)

Goblet cell carcinoids (GCCs) of the appendix are rare tumors, characterized by a carcinoid-like organoid growth pattern. Despite the term carcinoid, neuroendocrine features are inconspicuous, and its behavior is distinct from carcinoid. Its high-grade counterpart is designated as adenocarcinoma ex GCC. We conducted a retrospective study of 105 tumors to find prognostic values of a variety of clinicopathologic features. The tumors were subclassified as low grade, equivalent to classic type, and high grade, defined as loss of organoid pattern, and a proportion (%) of low and high grades were documented in each tumor. Correlations between survival and various clinicopathologic parameters were investigated. One-third were pure low grade, while the remainder contained variable high-grade component ranging from 5% to 95%. Neuroendocrine cell component ranged from 0% to 90% (median, 5), while mucus cell component ranged from 5% to 100% (median, 70). By univariate analysis, size, stage, high-grade component, nuclear grade, surgery, and chemotherapy correlated with cancer-related survival (CSS), and by multivariate analysis, stage (P=.001), high-grade component (P=.008), and tumor size (P=.005) correlated with CSS. There was significant difference in CSS when the cases were grouped by high-grade component: <40%, 40% to 90%, and ≤90% (P<.001). Our results indicate that staging and proportion of high-grade histology may provide important prognostic information. Neuroendocrine component was insignificant in both low- and high-grade areas. In light of our findings, this tumor type is best regarded as a variant of adenocarcinoma, and the term crypt cell adenocarcinoma more appropriately reflects the nature and origin of this tumor group.

Increased Expression of the Autocrine Motility Factor is Associated With Poor Prognosis in Patients With Clear Cell-Renal Cell Carcinoma.

Glucose-6-phosphate isomerase (GPI), also known as phosphoglucose isomerase, was initially identified as the second glycolytic enzyme that catalyzes the interconversion of glucose-6-phosphate to fructose-6-phosphate. Later studies demonstrated that GPI was the same as the autocrine motility factor (AMF), and that it mediates its biological effects through the interaction with its surface receptor (AMFR/gp78). In this study, we assessed the role of GPI/AMF as a prognostic factor for clear cell renal cell carcinoma (ccRCC) cancer-specific (CSS) and progression-free survival (PFS). In addition, we evaluated the expression and localization of GPI/AMF and AMFR, using tissue microarray-based immunohistochemistry (TMA-IHC), indirect immunofluorescence (IF), and confocal microscopy analysis.Primary renal tumor and nonneoplastic tissues were collected from 180 patients who underwent nephrectomy for ccRCC. TMA-IHC and IF staining showed an increased signal for both GPI and AMFR in cancer cells, and their colocalization on plasma membrane. Kaplan–Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low GPI expression. In particular, patients with high tissue levels of GPI had a 5-year survival rate of 58.8%, as compared to 92.1% for subjects with low levels (P < 0.0001). Similar findings were observed for PFS (56.8% vs 93.3% at 5 years). At multivariate analysis, GPI was an independent adverse prognostic factor for CSS (HR = 1.26; P = 0.001), and PFS (HR = 1.16; P = 0.01).In conclusion, our data suggest that GPI could serve as a marker of ccRCC aggressiveness and a prognostic factor for CSS and PFS.

Surgical management for upper urinary tract transitional cell carcinoma (UUT‐TCC): a systematic review

Surgical management of upper urinary tract transitional cell carcinoma (UUT-TCC) has significantly changed over the past two decades. Data for several new surgical techniques, including nephron-sparing surgery (NSS), is emerging. The study systematically reviewed the literature comparing (randomised and observational studies) surgical and oncological outcomes for various surgical techniques MEDLINE, EMBASE, Cochrane Library, CINAHL, British Nursing Index, AMED, LILACS, Web of Science, Scopus, Biosis, TRIP, Biomed Central, Dissertation Abstracts, ISI proceedings, and PubMed were searched to identify suitable studies. Data were extracted from each identified paper independently by two reviewers (B.R. and B.S.) and cross checked by a senior member of the team. The data analysis was performed using the Cochrane software Review manager version 5. Comparable data from each study was combined in a meta-analysis where possible. For dichotomous data, odds ratios with 95% confidence intervals (CIs) were estimated based on the fixed-effects model and according to an intention-to-treat analysis. If the data available were deemed not suitable for a meta-analysis it was described in a narrative fashion. One randomised control trial (RCT) and 19 observational studies comparing open nephroureterectomy (ONU) and laparoscopic NU (LNU) were identified. The RCT reported the LNU group to have statistically significantly less blood loss (104 vs 430 mL, P < 0.001) and mean time to discharge (2.30 vs 3.65 days, P < 0.001) than the ONU group. At a median follow-up of 44 months, the overall 5-year cancer-specific survival (CSS; 89.9 vs 79.8%) and 5-year metastasis-free survival rates (77.4 vs 72.5%) for the ONU were better than for LNU, respectively, although not statistically significant. A meta-analysis of the observational studies favoured LNU group for lower urinary recurrence (P < 0.001) and distant metastasis. The meta-analyses for local recurrence for the two groups were comparable. One retrospective study comparing ONU with a percutaneous approach for grade 2 disease reported no significant differences in CSS rates (53.8 vs 53.3 months). Three retrospective studies compared NSS and radical NU, and reported no significant differences in overall CSS and recurrence-free survival between the two approaches. Five retrospective studies compared various techniques of en bloc excision of the lower ureter. No technique was reported to be better (operative and oncological) than any other. This review concludes that there is a paucity of good quality evidence for the various surgical approaches for UUT-TCC. The techniques have been assessed and reported in many retrospective single-centre studies favouring LNU for better perioperative outcomes and comparable oncological safety. The reported observational studies data is further supported by one RCT.

Sound localising ability in children with bilateral sequential cochlear implants

ObjectivesTo evaluate the sound localisation ability in children with sequential bilateral cochlear implants and the potential influence of age at the time of the first implantation, years of experience with the first implanted ear and the inter-implant interval (time between the first and the second cochlear implantation). MethodsSixty-three prelingually deaf children (mean age, 11.03; range, 6.5–17 years; SD, 3.09) were tested after 12 and 24 months of using bilateral cochlear implants. Every child was tested with each ear alone and both ears together. Five loudspeakers were placed in a 180° horizontal arch with 45° of separation between each loudspeaker. The child was placed 1.5m from the speakers. For each test run, three stimuli were presented at 65dB (A) from each speaker for a total of 15 stimulus presentations. For each test run, we calculated the mean angular error (MAE) and the proportion of correct speakers identified (CSS: correct speaker score). Performance by chance for the MAE was 72° and for the CSS was 20% (1 of 5 speakers). ResultsAfter 12 months of using bilateral CIs, the added effect of the second CI in the MAE was minor, and there was no significant difference in CSS between listening in the unilateral condition and listening in bilateral condition. After 24 months, however, the added effect of the second CI in the MAE was significant (mean diff=12.2°; 95% CI; 4.5–20.0°, p=0.003). The mean bilateral CSS increased significantly to 38% (diff=7.7%; 95% CI; 1.4–14.0%; p=0.019) while the mean unilateral CSS remained at a similar level (27%). The influence of age at the time of the first implantation on CSS after 24 months was not significant (p=0.96). However, the inter-implant interval showed a significant decrease in score by 1.4% per year between the two implants (p=0.04). ConclusionSound localisation with two versus one CI in children with a sequential bilateral cochlear implantation was significantly improved 24 months (but not 12 months) after the second implantation. A shorter inter-implant interval showed a small but significant beneficial effect on sound localisation.

Steady-state Pharmacokinetics of Clozapine in Refractory Schizophrenic Saudi Arabian Patients

The steady-state pharmacokinetics of the atypical antipsychotic drug clozapine in schizophrenic Saudi Arabian patients was studied and correlated with the clinical outcome. Twenty-six schizophrenic patients were given clozapine over a period of 2–41 months. The daily dose ranged from 100 to 700 mg, and the frequency of administration varied from 1 to 2 times daily. A blood sample was collected from each patient at the midpoint of the dosing interval and was repeated on different days in six randomly selected patients to establish the steady-state condition. The concentration of clozapine in plasma (Css) was measured by HPLC with UV detection at 250 nm using C18 bonded SepPak cartridges for sample preparation. The apparent oral clearance (CLp.o.) was calculated from the equation: CLp.o. = dose/tCss where t is the time between two consecutive doses. The effectiveness of the treatment was evaluated by the standard Positive and Negative Syndrome Scale (PANSS). The mean ± s.d. steady-state concentration (Css) was 491 ± 299 ng mL−1 There were no significant differences in Css or any of the pharmacokinetic parameters studied between the 11 patients who responded positively to the treatment and the 15 patients who responded negatively. These results do not support the hypothesis that there is a positive correlation between higher plasma concentrations and positive response from clozapine in Saudi Arabian patients.