Prognostic role of chemotherapy-induced nausea and vomiting in recurrent ovarian cancer patients: results of an individual participant data meta-analysis in 1213.

BACKGROUND: The aim of this study was to analyze the potential impact of chemotherapy-induced nausea and vomiting (CINV) on dose reductions, discontinuation of chemotherapy, and survival. PATIENTS AND METHODS: This study was designed as individual participant data meta-analysis with the original study data of three phase II/III trials that were conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) including 1213 patients with recurrent ovarian cancer. Logistic and Cox regression analyses were used to estimate odds and hazard ratios after adjusting for age, ECOG, amount of delivered cycles, amount of recurrences, and amount of comedications and study. RESULTS: The majority of patients developed nausea (58.1%) and almost one third experienced vomiting (31.0%). CINV was not associated with FIGO stage, grading, histology, and number of recurrences. The necessity of dose reduction and discontinuation of chemotherapy did not correlate to nausea and vomiting (p = 0.88, p = 0.39 and p = 0.25, p = 0.54 respectively). Progression-free survival was shorter in patients with grade III/IV nausea and vomiting (p = 0.02; hazard ratio (HR) for grade III/IV nausea 1.58, 95% CI 1.14-2.20, and p = 0.02; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CINV grade III/IV was also associated with poorer overall survival (p < 0.001; HR for grade III/IV nausea 2.35, 95% CI 1.64-3.37, and p < 0.001; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CONCLUSION: CINV is significantly associated with poorer prognosis in recurrent ovarian cancer patients while there was no correlation found with the necessity of dose reduction and prior discontinuation of treatment. This study underlines the importance of prevention and treatment of CINV as part of early best supportive care.

Survival and prognostic factors in patients with recurrent low-grade epithelial ovarian cancer: An analysis of five prospective phase II/III trials of NOGGO metadata base.

OBJECTIVE: Low-grade epithelial ovarian cancers (EOC), constitute the minority among all epithelial cancers. Our study objective was to focus on low-grade recurrent EOC and compare the survival with high-grade disease, as well as in regard to "platinum-sensitive" and "-resistant" recurrences according to platinum-free interval. METHODS: This is an exploratory analysis within the North-Eastern German Society of Gynecological Oncology (NOGGO) database including five randomized phase II/III trials comparing different chemotherapy regimens in recurrent EOC. We conducted survival analyses and cox-proportional regression models. RESULTS: Out of 1050 patients having the first recurrence, 42 (4%) patients had low-grade and 1008 (96%) patients had high-grade disease. In the subgroup of platinum-sensitive recurrences, progression-free survival (PFS) (8.7 m vs 9.7 m, p = 0.7) and overall survival (OS) (23.9 m vs 24.8 m, p = 0.9) did not differ between low-grade and high-grade diseases. In platinum-resistant recurrences, patients with low-grade ovarian cancer had significantly better PFS (7.6 m vs 3.6 m, p = 0.03) and OS (41.9 m vs 9.5 m p = 0.002) in comparison to those with high-grade cancer. At low-grade EOC, there were no significant PFS (p = 0.91) and OS (p = 0.25) differences between platinum-sensitive and -resistant recurrences. Patients with low-grade non-serous histology had lower PFS with compared to those with low-grade serous histology (p = 0.004). At cox regression analysis presence of ascites and residual disease after secondary cytoreductive surgery were independently associated with poor PFS within low-grade recurrent EOC. CONCLUSION: Our study indicates, platinum-free interval does not have any prognostic significance at recurrent low-grade EOC and non-serous histology is associated with poorer outcome in recurrence. Secondary surgical cytoreduction to no-gross residual disease and ascites are independently associated with disease progression.

Independent psychometric validation of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24).

The endometrial cancer (EC)-specific Quality of Life module of the European Organization for Research and Treatment of Cancer (EORTC QLQ-EN24), was developed and validated in one study. We independently validated and assessed the psychometric properties of the instrument. Two hundred and eight women with EC before surgery, during adjuvant treatment and follow-up; in three different cancer centres completed the EORTC QLQ-C30 and the EN24. The questionnaire's completion rate was 100%, except sexuality items, that were answered by 35% of patients. All item-scale correlations for the multi-item scales exceeded the .4 criterion and correlated well with their own scale, while correlations with the other scales were low. The internal consistency of all multi-item scales were satisfactory (Cronbach's alpha coefficients ranging from .77 to .97). Discriminance for single-item scales was low. The QLQ-EN24 module discriminated well between clinically different patients, and there were no differences in quality of life questionnaire scales between patients with body mass index ≤30 when compared to those with >30. This validation study supports the reliability, as well as convergent and divergent validity of the EORTC QLQ-EN24. The module is a useful instrument for the assessment of QOL in patients with EC. However, data concerning sexuality should be interpreted with caution.

Surgery for recurrent ovarian cancer: Options and limits.

Cytoreductive surgery is the backbone of the multimodal therapy in primary ovarian cancer patients. Despite the effect of various tumor biological factors such as grading and histological subtype, the surgical outcome is the most important prognostic factor for both progression free- and overall survival. In contrast, the management of recurrent situation has long remained a subject of an emotional international discussion. To date, only few prospective studies have focused on the effect of surgery in relapsed ovarian cancer. The available retrospective data associate complete cytoreduction with prognosis improvement. However, the selection of patients eligible for surgery in recurrent situation is the essential issue. The establishment of predictive factors for complete tumor resection and defining the patient group with recurrent disease who might profit from this approach are crucial. The available predictors of complete resection depend on the results of primary surgery and the current patient's situation. Women who underwent primary complete cytoreduction are in good performance status, and those who have only minimal ascites volume (less than 500 ml) in the recurrent situation have 76% likelihood of undergoing complete resection and survival prolongation. Moreover, the complete cytoreduction in the tertiary cytoreductive approach has been evaluated and showed a potential positive influence on patients' survival. This review concentrates on the recent data and highlights the need of further randomized trials to develop and incorporate operative standards in recurrent ovarian cancer.

Influence of body weight changes on survival in patients undergoing chemotherapy for epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer is a highly fatal gynecologic malignancy with a poor prognosis. Therefore, identification of new modifiable prognostic factors is important. Due to the fact that the effect of body weight changes during chemotherapy for EOC is still not very well known we aimed to describe, considering evidence, role of body weight changes in relation to survival. MATERIALS AND METHODS: Between October 2014 and August 2015 we systematically searched the following databases: Medline, Scopus, Web of Science and EMBASE to identify the studies describing the influence of body weight changes on survival in patients undergoing chemotherapy for EOC. RESULTS: We identified 601 potentially relevant publications, however finally only one article was included for data extraction and analysis. The overall survival in the selected paper was significantly associated with body weight changes during the first-line chemotherapy. Nevertheless, no influence on progression free survival was found. CONCLUSIONS: The analyzed data provides initial evidence, showing poorer overall survival  associated with body weight loss and improved overall survival associated with body weight gain during primary chemotherapy for epithelial ovarian cancer. Prospective and retrospective trials are an urgent calling to confirm this conclusion.

Bupropion and naltrexone for smoking cessation: A double-blind randomized placebo-controlled clinical trial.

Combination of non-nicotine pharmacotherapies has been underexamined for cigarette smoking cessation. A randomized, double-blind, parallel-group double-dummy study evaluated two medications, bupropion (BUP) and naltrexone (NTX), in treatment-seeking cigarette smokers (N = 121) over a 7-week treatment intervention with 6-month follow-up. Smokers were randomized to either BUP (300 mg/day) + placebo (PBO) or BUP (300 mg/day) + NTX (50 mg/day). The primary outcome was biochemically verified (saliva cotinine, carbon monoxide) 7-day, point-prevalence abstinence. BUP + NTX was associated with significantly higher point-prevalence abstinence rates after 7-weeks of treatment (BUP + NTX, 54.1%; BUP + PBO, 33.3%), P = 0.0210, but not at 6-month follow-up (BUP + NTX, 27.9%; BUP + PBO, 15.0%), P = 0.09. Continuous abstinence rates did not differ, P = 0.0740 (BUP + NTX, 26.2%; BUP + PBO, 13.3%). Those receiving BUP + NTX reported reduced nicotine withdrawal, P = 0.0364. The BUP + NTX combination was associated with elevated rates of some side effects, but with no significant difference in retention between the groups.

Carcinoma of the recto-vaginal septum. Comprehensive literature review.

Carcinoma of the recto-vaginal septum is an extremely rare entity. We performed a MEDLINE-based search on recto-vaginal septum carcinoma, focussing on its management, in order to clarify which are the best treatment options for this disease. In addition an unpublished case report has been added to the review. 34 case reports were included in our review. Surgery and adjuvant chemoradiation therapy seem to be the most common treatment option. However, since primary surgical treatment leads to mutilation by removing a large portion of the vagina and the anal sphincter with a permanent terminal colostomy, primary platinum-based chemoradiation therapy could be considered. In case of extragastrointestinal stromal tumours primary surgical treatment seems to be the best option. Due to the rarity of this entity only limited data is available. Therefore further investigation is necessary.

Current management of ovarian cancer.

Cytoreductive surgery remains an accepted standard treatment of primary ovarian cancer. In advanced stages adjuvant platin/taxane chemotherapy with addition of anti-angiogenic agent, i.e., bevacizumab is recommended. The management of recurrent ovarian cancer remains a field of controversies. Surgery and/or systemic treatment are currently investigated in prospective trials. Retrospective data show prognosis improvement in patients who underwent complete cytoreduction. Thus, the selection of patients eligible for surgery in recurrent situation is the essential issue. The available predictors of complete resection depend on results of primary surgery and current patients situation. Women who fulfill these criteria have 76% likelihood of undergoing complete resection and survival prolongation. On the other hand there is a large group of patients in whom surgery might be too dangerous and demand an effective systemic treatment. Currently in a second-line several options are available, again including anti-angiogenic agents. The management of further recurrences is a subject of several clinical trials, nevertheless standards are still missing. Due to histological subtype and/or BRCA mutation status, the therapy in ovarian cancer might undergo revision in a near future.

The expression of BRCA1, P53, KAI1, and Nm23 in ovaries of BRCA1 mutation carriers after prophylactic adnexectomy.

INTRODUCTION: High mortality rate, absence of reliable methods for early diagnosis and poor prognosis of advanced ovarian cancer prompted to investigate the role of prophylactic oophorectomy in BRCA1 mutation carriers as well as evaluate the expression of BRCA1, p53, Nm23, and KAI1 proteins in ovarian tissue from these patients. MATERIALS AND METHODS: Ovaries from BRCA1 mutation carriers underwent prophylactic adnexectomy and control group of patients were operated from other than cancer reasons. The expression of selected proteins was studied using immunohistochemical staining. The intensity of immunostaining and the number of tumor cells showing the reaction for selected proteins were analyzed. RESULTS: We have analyzed ovarian tissues from 18 BRCA1 mutation carriers and 11 women included in control group. Positive expression of BRCA1 protein was presented in 83.3 % cases in BRCA1 mutation carriers and in 72.7 % in the control group (p > 0.05). Positive expression of p53 protein was observed, respectively, in 27.8 vs. 36.4 % (p > 0.05), Nm23 protein 77.7 vs. 90.9 % (p > 0.05), and KAI1 in 72.2 vs. 72.7 % (p > 0.05). Mean percent of tumor cells that showed the reaction for selected proteins as well as the intensity of immunostaining for all analyzed proteins seems to be lower in BRCA1 mutation carriers. CONCLUSIONS: However, any significant differences between study group and control group have not been found; there were similar trends showing reduced expression of studied proteins in BRCA1 mutation carriers.

The need for accredited training in gynaecological oncology: a report from the European Network of Young Gynaecological Oncologists (ENYGO).

BACKGROUND: Primary data on training experiences of European gynaecological oncology trainees are lacking. This study aims to evaluate trainee profile, satisfaction and factors affecting the training experience in gynaecological oncology in Europe. PATIENTS AND METHODS: A web-based anonymous survey sent to ENYGO members/trainees in July 2011. It included sociodemographic information and a 22-item (1-5 Likert scale) questionnaire evaluating training experience in gynaecological oncology. Chi-square tests were used for evaluating the independence of categorical variables and t-test (parametric)/Mann-Whitney (non-parametric) tests for differences between two independent groups on continuous data. Cluster analysis was used to identify groupings in multivariate data and Cronbach's-alpha for questionnaire reliability. A multivariable linear regression model was used to assess the effect of variables on training satisfaction. RESULTS: One hundred and nineteen gynaecological-oncology trainees from 31 countries responded. The mean age was 37.4 (S.D, 5.3) years and 55.5% were in accredited training posts. Two clusters identified in the cohort (Calinski-Harabasz, CH = 47.35) differed mainly by accredited training (P = 0.003). The training-satisfaction score (TSS) had high reliability (Cronbach's alpha, 0.951) and was significantly associated with accredited posts (P < 0.0005), years of training (P = 0.001) and salary (P = 0.002). The TSS was independent of age (P = 0.360), working hours (P = 0.620), overtime-pay (P = 0.318), annual leave (P = 0.933), gender (P = 0.545) and marital status (P = 0.731). Accredited programme trainees scored significantly higher than others in 17 of 22 aspects of training. The areas of greater need included advanced laparoscopic/urological/colorectal surgery, radiation oncology, palliative-care, cancer genetics and research opportunities. CONCLUSIONS: Our data demonstrate the importance of accredited training and the need for harmonisation of gynaecological oncology training within Europe.

Re-operation outcome in patients referred to a gynecologic oncology center with presumed ovarian cancer FIGO I-IIIA after sub-standard initial surgery.

BACKGROUND: Surgery is the mainstay of treatment for early ovarian cancer both as therapeutic and comprehensive staging. Only the latter allows appropriate tailoring of systemic treatment. However, the compliance with guidelines for comprehensive staging has been reported to be only moderate and, therefore, re-staging procedures are commonly indicated to avoid undertreatment. The purpose of our study was to evaluate re-operation in a tertiary gynecologic oncology unit after primary operation for presumably ovarian cancer FIGO I-IIIA in general gynecology departments. MATERIAL AND METHODS: Forty consecutive patients after primary surgery in the outside institutions for presumed early ovarian cancer with assumed tumor spread limited to the pelvis (FIGO I-IIIA) admitted to our department between 1999 and 2007 were included. In 35 cases re-staging surgery in our unit was indicated. The intra- and post-operative results were compared with initial diagnosis and sites of undetected disease were evaluated. Reasons for re-staging and referral pattern were studied. RESULTS: 40 patients were enrolled of whom 53% came by self-referral. Only 18% were referred by the primary surgeon and the remaining patients were referred by their home gynecologist. Only 5 patients (13%) were classified as having had a comprehensive staging by surgical records and pathology reports and 35 patients underwent comprehensive re-staging laparotomy after which 20 patients (50%) experienced an upstaging including 13 patients with final diagnosis of FIGO stage IIIC. Most frequent sites of primarily undetected tumor were peritoneum (pelvic 34%, diaphragm 13%, paracolic 8%), lymph nodes (para aortic 32%, pelvic 11%), intestines 24%, and residual omental tissue 18%. The indication for post-operative chemotherapy was modified in 53% of patients. CONCLUSION: Comprehensive staging of presumed early ovarian cancer has been described as major problem especially outside gynecologic oncology units. Re-staging results in our department confirmed this deficiency by showing a considerable proportion of upstaging associated with alterations of recommendations for systemic treatment. However, series like this may even underestimate the problem, because incomplete staging is unfortunately accompanied by non-systematic referral practices not reflecting staging quality.

Prognostic impact of additional extended surgical procedures in advanced-stage primary ovarian cancer.

BACKGROUND: Treatment of advanced-stage ovarian carcinoma includes radical cytoreductive surgery, which aims at removing all visible tumor tissue followed by platinum and paclitaxel chemotherapy. Complete tumor resection may require extended surgical procedures. This paper reports on the prognostic impact of extensive surgery and surgical morbidity in patients with advanced-stage ovarian carcinoma. METHODS: Patients with ovarian carcinoma [Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIIB-IV] undergoing primary surgery in our tertiary gynecologic oncology unit between 1997 and 2007 were eligible for this study. The impact of established prognostic factors and the interaction with extent of surgical procedures on survival were assessed. RESULTS: A total of 267 patients aged between 29 and 88 years (median 64 years) were eligible for this study. Overall survival time was improved in patients who underwent complete tumor resection [hazard ratio (HR) 3.61 (1.91-6.61), P < 0.001]. No significant survival difference was observed between completely operated patients in whom extended or standard surgical procedures were applied [HR 1.37 (0.70-2.69), P = 0.358], and severe surgical complications were found to be equally distributed between the two patient groups. CONCLUSIONS: Our results may encourage the application of extended surgical procedures in patients who would otherwise be rendered incompletely debulked after primary cytoreduction. We could demonstrate an impact of complete tumor resection on patient prognosis and this was not traded off for extensive additional surgical morbidity.

Early life insult from cigarette smoke may be predictive of chronic diseases later in life.

Evidence is rapidly accumulating that links cigarette smoke (CS) exposure in utero with the development of a variety of disease pathologies in the older offspring including, type 2 diabetes, obesity, certain childhood cancers and respiratory disorders. The role that the fetal environment plays in these late-onset outcomes and the underlying cellular/molecular mechanisms by which these CS-induced effects may occur are currently unknown. Although we are becoming more aware of the fact that prenatal insult can underlie childhood/adult diseases, critical knowledge gaps still exist including gene-environment interactions, and how a CS-induced imbalance in immune dynamics (i.e. TH1/TH2) might affect asthma development and/or exacerbation later in life. In this mini-review we introduce the concept of sexual dimorphism in CS-induced late-onset disease outcomes, as well as explore the mechanisms by which CS exposure in utero can lead to cardiovascular, cancer and respiratory abnormalities in the exposed offspring. By addressing such questions using animal models, appropriate intervention strategies can be developed that will help to protect children's health and their long-term quality of life.

Radiation treatment planning in brain tumours: potential impact of 3-O-methyl-6-[(18)F]fluoro-L-DOPA and PET.

AIM: Amino acid PET has become an important diagnostic tool for brain tumour imaging. In this data analysis, the potential impact of amino acid PET with 3-O-methyl-6-[(18)F]fluoro-L-DOPA ([(18)F]OMFD) on radiation treatment planning is addressed by the following questions: 1. Was tumour tissue identified with OMFD-PET which was not covered by the conventionally derived planning target volume (PTV)? 2. Would the PTV have been changed incorporating OMFD-PET? PATIENTS, METHODS: OMFD-PET of 25 patients after subtotal resection of malignant glioma was evaluated. The region of elevated tracer uptake of PET and of contrast enhancing masses on MRI were outlined as separate gross tumour volumes (GTV(MRI) and GTV(OMFD)) and reconstructed in the planning CT for comparison with the conventionally drawn GTV(conv). A PTV(new) based on GTV(conv+MRI) was calculated. Pairwise differential volumes were calculated to estimate overlap and differential volumes delineation by each image modality and the PTV(conv) and PTV(new) respectively. RESULTS: Differential volume analysis showed > 10 cm(3) of GTV(OMFD) outside GTV(conv) and GTV(MRI) in 5/25 patients respectively. From GTV(MRI) > 10 cm(3) were found outside GTV(OMFD) in 8/25 patients. Although all tumour areas indicated by [(18)F]OMFD were covered by the conventionally derived PTV, based on a GTV(OMFD+MRI), the PTV(new) would have been enlarged >20% in seven patients. In seven patients the PTV(new) would have been reduced. CONCLUSION: OMFD-PET indicated tumour tissue outside the tumour region identified with MRI, adding valuable information for the delineation of the GTV in radiation treatment planning. OMFD-PET contains the potential to tailor the high dose radiation to the appropriate tumour volume, especially if dose escalation is desired.

Coexpression of human chorionic gonadotropin beta subunit and its receptor in nontrophoblastic gynecological cancer.

A considerable number of biochemical and physiologic studies evaluate the roles of gonadotropins in carcinogenesis. Latest reports show that human chorionic gonadotropin (hCG), and especially its beta subunit, are secreted by a variety of malignant tumors of different origin. However, the mechanism of hCG action and its role in tumor development is not known yet. This study, with the help of reverse transcription-polymerase chain reaction and immunohistochemistry, is an attempt to document the molecular presence of the hCGbeta and luteinizing hormone/hCG receptor (LH/hCGR) in the ovarian, endometrial, and uterine cervix cancer tissues. The LH/hCGR, coexpressed with hCGbeta, may act as a potential mediator of hCG action in nontrophoblastic gynecological cancers.

Significance of hypoxia in uterine cervical cancer. Multicentre study.

PURPOSE: The aim of the study was to evaluate hypoxia markers (VEGF, GLUT-1, and HIF-1alpha) in cervical cancer tissue depending on staging (FIGO) and grading. We also analyzed the adverse effects of radiotherapy according to expression levels of hypoxic markers in the studied tissue. MATERIAL AND METHODS: Expression of hypoxia-inducible factor-1alpha (HIF-1alpha), glucose transporter 1 (GLUT-1) and vascular endothelial growth factor (VEGF, also known as proangiogenic factor) were estimated in biopsy or surgical specimens from 106 patients diagnosed with uterine cervical cancer. Immunohistochemical methods with EbVision+ complex using monoclonal antibodies anti-VEGF and anti-HIF-1alpha and polyclonal antibody anti-GLUT-1 were applied. RESULTS AND CONCLUSIONS: Hypoxia features measured by percentage of cells undergoing reaction with antibodies anti-HIF-1alpha, anti-GLUT-1 and anti-VEGF were similar in all clinical stages; however the biggest hypoxia features were shown in low differentiated cancers G2 and G3. The 5-year survival for FIGO Stage III patients was shorter in cases with a high expression of hypoxic markers. We observed adverse effects in 45.3% of patients, which occurred more often in patients with higher expression of the studied factors. The presence of hypoxic cells is established as one of the most important factors affecting resistance against tumor radiotherapy and patient prognosis.

Tobacco, alcohol and caffeine use in a low-income, pregnant population.

This study examined the relationship between smoking, drinking and heavy caffeine use (> three caffeinated drinks per day) among pregnant women who reported smoking cigarettes and drinking alcohol prior to conception. Demographic predictors of smoking, drinking and caffeine use during pregnancy were also identified. Pregnant women (n = 237) attending a university-based, public clinic were identified during screening for a larger intervention study. Logistic regression analyses revealed a significant relationship between pregnancy smoking and drinking (OR= 8.1), as well as between smoking and harmful caffeine use (OR=3.1). Age predicted smoking and drinking in pregnancy, with older women being more likely to use both substances. Caucasian women were more likely to continue smoking, while African-American women were more likely to continue drinking. Increased attention should be paid to the co-occurrence of multiple health risk behaviours during pregnancy and to the specific needs of subgroups of high-risk women.

The anionic oxy-Cope rearrangement: using chemical reactivity to reveal the facile isomerization of the parent substrates in the gas phase.

The rearrangements of 1,5-hexadiene-3-oxide and 3-methyl-1,5-hexadiene-3-oxide have been studied in the gas phase, using both Fourier transform mass spectrometry (FTMS) and the flowing afterglow (FA) technique. Gas-phase studies of ionic rearrangements can be limited by analysis techniques such as collision-induced dissociation, which have the potential of driving the rearrangement prior to fragmentation. In the studies reported here, we have utilized methanol-O-d, methyl nitrite, and dimethyl disulfide as chemical reactivity probes to discern whether rearrangement of either of the alkoxides to their corresponding enolates occurs. Of the three structural probe reagents, dimethyl disulfide has been found to be most ideal, since it reacts efficiently with both alkoxides and enolates to produce a unique product from each. On the basis of the reactions observed between dimethyl disulfide and anions generated from 1,5-hexadien-3-ol and 3-methyl-1,5-hexadien-3-ol, we have found that the gas-phase Cope rearrangement of both tertiary and secondary alkoxides occurs under both FTMS and FA conditions. Use of dimethyl disulfide in the FTMS and evaluation of ion residence time in the FA lead to the establishment of an upper limit on the Delta H(*) of the rearrangement of both the parent secondary and tertiary substrates as approximately 11 kcal mol(-1) at 298 K. This value is consistent with our B3LYP/6-31+G* prediction. The rearrangement is also faster in the gas phase than in solution, in accord with theoretical predictions.

Physicians' accuracy and interrator reliability for the diagnosis of unstable meniscal tears in patients having osteoarthritis of the knee.

OBJECTIVE: To determine clinicians' accuracy and reliability for the clinical diagnosis of unstable meniscus tears in patients with symptomatic osteoarthritis of the knee. DESIGN: A prospective cohort study. SETTING: A single tertiary care centre. PATIENTS: One hundred and fifty-two patients with symptomatic osteoarthritis of the knee refractory to conservative medical treatment were selected for prospective evaluation of arthroscopic debridement. INTERVENTION: Arthroscopic debridement of the knee, including meniscal tear and chondral flap resection, without abrasion arthroplasty. OUTCOME MEASURES: A standardized assessment protocol was administered to each patient by 2 independent observers. Arthroscopic determination of unstable meniscal tears was recorded by 1 observer who reviewed a video recording and was blinded to preoperative data. Those variables that had the highest interobserver agreement and the strongest association with meniscal tear by univariate methods were entered into logistic regression to model the best prediction of resectable tears. RESULTS: There were 92 meniscal tears (77 medial, 15 lateral). Interobserver agreement between clinical fellows and treating surgeons was poor to fair (kappa < 0.4) for all clinical variables except radiographic measures, which were good. Fellows and surgeons predicted unstable meniscal tear preoperatively with equivalent accuracy of 60%. Logistic regression modelling revealed that a history of swelling and a ballottable effusion were negative predictors. A positive McMurray test was the only positive predictor of unstable meniscal tear. "Mechanical" symptoms were not reliable predictors in this prospective study. The model was 69% accurate for all patients and 76% for those with advanced medial compartment osteoarthritis defined by a joint space height of 2 mm or less. CONCLUSIONS: This study underscored the difficulty in using clinical variables to predict unstable medial meniscal tears in patients with pre-existing osteoarthritis of the knee. The lack of interobserver agreement must be overcome to ensure that the findings can be generalized to other physician observers.

Subchronic toxicity of cyclohexane in rats and mice by inhalation exposure.

Inhalation studies were conducted to determine the potential toxicity and/or potential neurotoxicity of cyclohexane. Groups of rats and mice were exposed to 0, 500, 2000, or 7000 ppm concentrations of cyclohexane vapor 6 hr/day, 5 days/week for 14 weeks. Subgroups of rats and mice were further observed during a 1-month recovery period. Functional observational battery (FOB) and motor activity (MA) behavioral tests were conducted on rats. These tests were conducted prior to the exposure series and during weeks 4, 8, and 13 on non-exposure days. Clinical pathology evaluations were conducted after approximately 7, 13, and 18 weeks. Approximately 14 and 18 weeks after study initiation, tissues from rats and mice were histologically processed and evaluated by light microscopy. During exposure to 2000 or 7000 ppm, rats and mice had a diminished response or an absent response to delivery of a punctate auditory alerting stimulus. Immediately following removal of rats from the inhalation chambers, 7000 ppm males and females and 2000 ppm females displayed a compound-related increase in the incidence of wet and/or stained fur (which occurred in the areas of the mouth, chin, and/or perineum). These signs were transient, were not observed during exposure or prior to exposure the following day, and were not associated with any behavioral or morphological changes. During exposure sessions, mice exposed to 7000 ppm exhibited clinical signs of toxicity which included hyperactivity, circling, jumping/hopping, excessive grooming, kicking of rear legs, standing on front legs, and occasional flipping behavior. Clinical signs of toxicity observed in 7000 ppm mice immediately after exposure included hyperactivity, hyperreactivity, ruffled fur (females only), gait abnormalities, spasms in both rear legs, and excessive grooming (males only). The clinical signs observed in mice during and immediately after exposure were transient, and were not present prior to the subsequent exposure. A few mice exposed to 2000 ppm appeared hyperactive during exposure in the latter portion of the study. There were no compound-related changes in mean body weights, body weight gains, food consumption, food efficiency, or mortality; and there were no ophthalmological abnormalities in rats or mice. In addition, there were no compound-related effects on 37 different behavioral parameters assessed during the FOB or during motor activity tests in rats. Male and female mice exposed to 7000 ppm had slight increases in measures of circulating erythrocyte mass (red blood cells, hemoglobin, hematocrit) and plasma protein concentration (males only). Male rats and male and female mice exposed to 7000 ppm had significantly increased relative liver weights, and 7000 ppm male mice also had significantly increased absolute liver weights at the end of the exposure period. At the end of the 1-month recovery period, absolute and relative liver weights of male and female mice were similar to control. However, relative liver weights of 7000 ppm male rats continued to be significantly higher at the end of the recovery period. Male and female rats exposed to 7000 ppm had a significantly increased incidence of hepatic centrilobular hypertrophy at the end of the exposure period, which was not observed at the conclusion of the 1-month recovery period. No microscopic changes were observed in mice. In rats, the no-observed-effect level (NOEL) for acute, transient effects was 500 ppm based on a diminished/absent response to an auditory alerting stimulus at 2000 ppm and above. The NOEL for subchronic toxicity in rats was 7000 ppm based on the lack of adverse effects on body weight, clinical chemistry, tissue morphology, and neurobehavioral parameters. In mice, the NOEL for acute, transient effects was 500 ppm based on behavioral changes during exposure at 2000 ppm and above. The NOEL for subchronic toxicity in mice is 2000 ppm based on hematological changes at 7000 ppm.