Leptomeningeal disease as a presenting feature of gestational trophoblastic neoplasia: A review and recommendations for management.

OBJECTIVES: Gestational Trophoblastic Neoplasia (GTN) is a rare group of malignant placental-related tumours requiring systemic anti-cancer treatment. Leptomeningeal disease (LMD) related to GTN is not well reported with no consensus in optimal treatment. We offer recommendations for management of these patients. METHODS: We discuss five patients with GTN who presented with features of LMD and were diagnosed with gadolinium-enhanced MRI brain, all of whom received low dose induction etoposide-cisplatin (EP) followed by either EP-etoposide, methotrexate (CNS) and actinomycin-D (EMA) or EMA(CNS)-cyclophosphamide and vincristine (CO). RESULTS: Four out of the five patients additionally received intrathecal methotrexate. Four patients had complete hCG response to first line multi-agent chemotherapy, one patient required second line paclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE), where paclitaxel was substituted with nab-paclitaxel due to anaphylaxis, followed by hysterectomy. One of the four initial complete hCG responders relapsed in the lung requiring further systemic treatment with subsequent lobectomy. Patient reported outcomes indicate persistent neurological symptoms are mild and do not affect functionality and quality of life. CONCLUSION: With a follow-up range of 2-6 years, all five patients remain cured demonstrating excellent survival outcomes with the avoidance of whole-brain radiotherapy in all cases.

Hemostasis biomarkers and incident cognitive impairment: the REGARDS study.

Essentials Cognitive disorders are increasing and vascular risk factors play a role in this. We performed a nested case control study of hemostasis biomarkers and cognitive impairment (CI). Higher baseline fibrinogen, factor VIII and D-dimer were related to incident CI over 3.5 years. Adjusted for other risk factors, 2+ abnormal markers (but not single ones) led to higher risk. SUMMARY: Background Vascular risk factors are associated with cognitive impairment, a condition that imposes a substantial public health burden. We hypothesized that hemostasis biomarkers related to vascular disease would be associated with the risk of incident cognitive impairment. Methods We performed a nested case-control study including 1082 participants with 3.5 years of follow-up in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of 30 239 black and white Americans aged ≥ 45 years. Participants were free of stroke or cognitive impairment at baseline. Baseline D-dimer, fibrinogen, factor VIII and protein C levels were measured in 495 cases who developed cognitive impairment during follow-up (based on abnormal scores on two or more of three cognitive tests) and 587 controls. Results Unadjusted odds ratios (ORs) for incident cognitive impairment were 1.32 (95% confidence interval [CI] 1.02-1.70) for D-dimer > 0.50 µg mL-1 , 1.83 (95% CI 1.24-2.71) for fibrinogen > 90th percentile, 1.63 (95% CI 1.11-2.38) for FVIII > 90th percentile, and 1.10 (95% CI 0.73-1.65) for protein C < 10th percentile. There were no differences in associations by race or region. Adjustment for demographic, vascular and health behavior risk factors attenuated these associations. However, having at least two elevated biomarkers was associated with incident cognitive impairment, with an adjusted OR of 1.73 (95% CI 1.10-2.69). Conclusion Elevated D-dimer, fibrinogen and FVIII levels were not associated with the occurrence of cognitive impairment after multivariable adjustment; however, having at least two abnormal biomarkers was associated with the occurrence of cognitive impairment, suggesting that the burden of these biomarkers is relevant.

Risk adapted single-agent dactinomycin or carboplatin for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the outcome of patients treated with second-line chemotherapy for methotrexate-resistant low-risk GTN at the Sheffield Centre, UK between 2001 and 2015, including the novel use of single-agent carboplatin as a strategy to reduce exposure to combination chemotherapy. METHODS: 392 low-risk GTN patients were treated with first-line methotrexate. The selection of chemotherapy regimen following methotrexate-resistance depended on the volume of residual disease as indicated by the serum hCG value at the time, with patients switching to either single-agent dactinomycin at an hCG level<150IU/L from 2001-2010 and <300IU/L since 2010, or to combination treatment with etoposide/dactinomycin (EA) above these thresholds. In order to reduce exposure to more toxic combination chemotherapy regimens, our treatment policy was revised in 2011, with the recommendation of single-agent carboplatin as an alternative to EA at hCG levels >300IU/L. RESULTS: 136 (35%) of 392 received second-line chemotherapy following methotrexate-resistance. 59 patients received single-agent dactinomycin with 53 (90%) patients achieving complete hCG response, 3 patients requiring combination chemotherapy or surgery, and 3 patients subsequently spontaneously resolving. 56 patients received EA chemotherapy with hCG complete response in 50 (89%) patients, and the remaining 6 patients were cured with further multi-agent chemotherapy or surgery. With carboplatin, 17/21 (81%) achieved an overall complete hCG response rate, with 4 patients requiring third-line EA. Carboplatin was well tolerated with no significant alopecia; myelosuppression was the most significant toxicity. Overall survival for all patients was 100%. CONCLUSION: These data show the continued excellent outcomes for methotrexate-resistant low-risk patients treated with single-agent dactinomycin or EA. Our experience with carboplatin is promising and provides an alternative regimen for methotrexate-resistant low-risk disease that avoids alopecia and in-patient treatment.

Readability of out-patient letters copied to patients: can patients understand what is written about them?

UNLABELLED: The National Health Service Plan of 2000 proposed that patients should receive a copy of all correspondence regarding their care. There is concern that the readability of patients' letters may not be appropriate for many patients. MATERIALS AND METHODS: This study determined readability scores for sequential letters written to general practitioners and copied to patients, following ENT consultations at the Royal United Hospital in Bath. Intervention involved educating clinicians in techniques to improve readability. RESULTS AND ANALYSIS: A total of 295 letters from eight clinicians were assessed in the pre-intervention phase. The mean Flesch reading ease score was 61.8 (standard deviation 8.7) and the mean Flesch-Kincaid reading grade was 9.0 (standard deviation 1.7). Re-audit analysed a further 301 letters. There was no significant change in the readability of the letters post-intervention. DISCUSSION: It may not be feasible to present medical information intended for general practitioners in a way that is readable to most of the UK adult population.

Psychometric validity of the 22-item Sinonasal Outcome Test.

OBJECTIVES: We set out to determine the psychometric validation of a disease-specific health related quality of life instrument for use in chronic rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of a pre-existing instrument, the SNOT-20. DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study collecting data on 3128 adult patients undergoing sinonasal surgery in 87 NHS hospitals in England and Wales. Data were collected preoperatively and at 3 months after surgery, and analysed to determine validity of the SNOT-22. Test-retest reliability was assessed in a separate cohort of patients in a single centre. MAIN OUTCOME MEASURES: The SNOT-22, a derivative of the SNOT-20 was the main outcome measure. Patients were also asked to report whether they felt better, the same or worse following surgery. To evaluate the SNOT-22, the internal consistency, responsiveness, known group differences and validity were analysed. RESULTS: Preoperative SNOT-22 scores were completed by 2803 patients. 3-month postoperative SNOT-22 scores were available for 2284 patients of all patients who completed a preoperative form (81.5% response rate). The Cronbach's alpha scores for the SNOT-22 were 0.91 indicating high internal consistency. The test-retest reliability coefficient was 0.93, indicating high reliability of repeated measures. The SNOT-22 was able to discriminate between patients known to suffer with chronic rhinosinusitis and a group of healthy controls (P < 0.0001, t = 85.3). It was also able to identify statistically significant differences in sub-groups of patients with chronic rhinosinusitis. There was a statistically significant (P < 0.0001, t = 39.94) decrease in patient reported SNOT-22 scores at 3 months. At 3 months the overall effect size in all patients was 0.81, which is considered large. We found the minimally important difference that is the smallest change in SNOT-22 score that can be detected by a patient, to be 8.9 points. CONCLUSIONS: We have found the SNOT-22 to be valid and easy to use. It can be used to facilitate routine clinical practice to highlight the impact of chronic rhinosinusitis on the patient's quality of life, and may also be used to measure the outcome of surgical intervention. The minimally important difference allows us to interpret scores in a clinical context, and may help to improve patient selection for surgery.

A pilot study of the SNOT 22 score in adults with no sinonasal disease.

OBJECTIVE: To determine the SNOT 22 score in a normal population. STUDY DESIGN: Analysis of SNOT 22 scores participants with no sinonasal disease. SETTING: Bath, UK. PARTICIPANTS: 116 participants from a local hospital and tennis club. RESULTS: Results were obtained from 54 men and 62 women with a mean age of 40 (range 19-75). SNOT score ranged from 0-50 with a mean score of 9.3 (95% confidence interval range of 7.5-11.1). The modal score was 0 and the median score 7 (95% confidence interval range of 5-8). CONCLUSION: Due to the scewed nature of the data, the median score (7) is taken as the normal SNOT 22 score. We recommend that in an clincial situation a SNOT 22 score of 7 be used a a guide for "normal", and that care should be taken when suggesting treatment on patients with a score below this level.

Efficacy of Gyrus diego microdissector at varying oscillation speeds.

OBJECTIVE: To determine the efficacy of the Gyrus diego microdissector at increasing oscillation speeds, using an in vitro tissue model. BACKGROUND: It had not previously been established whether microdissectors were more efficient at higher or lower speeds. METHODS: We investigated the effect of varying microdissector oscillation speeds on the weight of material aspirated in a given time. A 4 mm straight blade was used with constant suction strength. Jelly and liver were used to simulate polyps and muscle plus connective tissue, respectively. Water was used as a control. Repeat readings were taken at speeds of 1000, 2000, 3000, 4000 and 5000 rpm. Data were analysed using linear bivariate regression. RESULTS: The results showed significant linear trends in the cases of liver and jelly, with faster cutter speeds being associated with higher aspiration rates. CONCLUSION: These results suggest that microdissector efficacy increases with speed, up to 5000 rpm.

Timing of co-phenylcaine administration before rigid nasendoscopy: a randomized, controlled trial.

Rigid nasendoscopy is a commonly used method of examining the nasal cavity and postnasal space. Co-phenylcaine is useful for its vasoconstrictive and anaesthetic properties, but the length of time allowed for it to take effect is variable. We performed a single-blind, randomized, controlled trial to determine whether it was better to allow one or 10 minutes for co-phenylcaine to take effect. Fifty patients were randomized into two groups, 25 in each. Patients in the 10 minute group experienced less discomfort (p=0.02) and less pain (p=0.018) than those in the one minute group. Ease of examination was also greater in the 10 minute group, as was the quality of the image obtained (p<0.001).

A comparison of endoscopic and microscopic removal of wax: a randomised clinical trial.

OBJECTIVES: Using a microscope to achieve a view of the canal during dewaxing is the most commonly performed method of dewaxing in secondary care, but an endoscope can also be used. We set out to compare endoscopic and microscopic dewaxing. DESIGN: Randomised clinical trial. SETTING: Otolaryngology Outpatient Department. PARTICIPANTS: One hundred participants selected sequentially from patients requiring dewaxing of their ears to allow examination of the tympanic membrane. Patients with external or middle ear pathology were excluded. METHODS: Patients were randomly assigned to have dewaxing performed using microinstruments aided by vision with a microscope or an endoscope. All participants who were entered the study completed the study. MAIN OUTCOME MEASURES: Levels of pain and discomfort experienced by the participants were assessed by a visual analogue scale (VAS). Difficulty of performing the dewaxing indicated by the endoscopist using a VAS. The length of time taken to perform the dewaxing was also recorded. RESULTS: Endoscopic dewaxing was less uncomfortable than microscopic dewaxing for patients (VAS median values 5 and 25 respectively; P < 0.002) as well as less painful (VAS median values 3.5 and 10 respectively; P < 0.075). Endoscopic dewaxing was easier to perform than microscopic dewaxing (VAS median values for difficulty were 9 and 20 respectively; P < 0.005) and took less time (mean time for endoscopic dewaxing was 1.8 min versus 3.3 min for microscopic dewaxing (P < 0.001). Ninety-one per cent of ears could be dewaxed with a Jobson-Horne probe or wax hook. CONCLUSIONS: The cost of an operating microscope suitable for use with dewaxing is approximately 10 times that of a suitable endoscope, dewaxing is a cheaper alternative to microscopic dewaxing that has benefits for the patient and clinician.

A multivariate analysis of the factors predicting hearing outcome after surgery for cholesteatoma in children.

OBJECTIVE: To explore factors influencing hearing outcomes in children treated by canal wall up (CWU) and canal wall down (CWD) mastoid surgery. METHODS: Retrospective cohort study including three units in Bristol and Bath, UK. Ninety consecutive children underwent cholesteatoma mastoid surgery, with the first procedure between 1998 and 2001; minimum follow up was three disease-free years. RESULTS: The CWU and CWD cohorts significantly differed in pre-operative stage and hearing. After disease eradication, air conduction (AC) thresholds changed by +4.0 dB (95 per cent confidence intervals (95% CI) -2.0, 10.1) in the CWD group and -5.3 dB (95% CI -9.3, 1.3) in the CWU group (p=0.029). Using multiple linear regression to account for cohort differences, AC thresholds were increased by: pre-operative AC threshold (p<0.0001), initial ossicular stage (p=0.013), and CWD-surgery (p=0.005). CONCLUSION: Disease-free hearing was better with CWU-surgery, less initial ossicular damage, and better pre-operative hearing. Worse initial disease increased the likelihood of CWD surgery. Wider use of ossiculoplasty in the CWU cohort (51 per cent vs 5 per cent) may partially explain the superior results.

Mergers. Turn of the screw.

Managing the process of a merger with staff support and job counselling reduces stress. But the experience is not pain-free. The expectation that senior staff would be found other jobs in the NHS proved unrealistic. From a total staff of 6,000 there were 38 redundancies, of which 13 were voluntary. Early retirement and redundancy costs were higher than expected. Staff still show signs of distress a year after the merger took place.

High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

Streptococcus iniae, a human and animal pathogen: specific identification by the chaperonin 60 gene identification method.

It was recently reported that Streptococcus iniae, a bacterial pathogen of aquatic animals, can cause serious disease in humans. Using the chaperonin 60 (Cpn60) gene identification method with reverse checkerboard hybridization and chemiluminescent detection, we identified correctly each of 12 S. iniae samples among 34 aerobic gram-positive isolates from animal and clinical human sources.

Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.

Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.

A study of respiratory infections in a healthy adult population during the 1987 Australian winter.

During the 1987 Australian winter, respiratory illness patterns were studied in a population of 454 healthy adults, aged 18-59, over a period of 45 days. These patterns were matched with data obtained from laboratory diagnoses for respiratory viruses, Mycoplasma pneumoniae and bacteria. Influenza B/1/86 was by far the most prevalent pathogen but other viruses including influenza A, paramyxoviruses, respiratory syncytial virus and coronavirus OC-43 were also present, either alone or in combination during the sampling period. Overall, 92 males and 101 females experienced one episode, 12 males and 22 females experienced two episodes and four females experienced three episodes. However, there were only 52 instances of viral or M. pneumoniae infections, of which 37 had a defined aetiology, while the remainder were clinically silent. No bacterial pathogens could be detected from throat swabs taken from 15 of 37 volunteers in whom a viral infection was detected, or from 43 of 70 volunteers who did not experience such infections. The study indicates that major deficiencies in our understanding of the aetiology of respiratory viral illness are probably due to methodological problems in obtaining laboratory diagnoses for many respiratory viruses, and that great difficulties exist in establishing an aetiology for respiratory infections based upon clinical symptoms alone.

Long-stay older patients in acute hospitals: are they bed blockers?

This analysis of the use of acute hospitals by older people identifies the extent of long stays by elderly patients and the eventual outcomes of these stays in terms of separations to residential care or the community. The effect of casemix on length of stay and differences associated with location of hospital are also discussed. Less than 0.5% of all acute hospital inpatients are older people who could be considered nursing home type patients. These patients use some 9% of all acute bed days and, in most cases, these beds would otherwise be unoccupied. It is unlikely therefore that they are 'blocking' beds that could be used to relieve waiting lists.