CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Registry-derived stage (RD-Stage) for capturing cancer stage at diagnosis for endometrial cancer.

BACKGROUND: Capture of cancer stage at diagnosis is important yet poorly reported by health services to population-based cancer registries. In this paper we describe current completeness of stage information for endometrial cancer available in Australian cancer registries; and develop and validate a set of rules to enable cancer registry medical coders to calculate stage using data available to them (registry-derived stage or 'RD-Stage'). METHODOLOGY: Rules for deriving RD-stage (Endometrial carcinoma) were developed using the American Joint Commission on Cancer (AJCC) TNM (tumour, nodes, metastasis) Staging System (8th Edition). An expert working group comprising cancer specialists responsible for delivering cancer care, epidemiologists and medical coders reviewed and endorsed the rules. Baseline completeness of data fields required to calculate RD-Stage, and calculation of the proportion of cases for whom an RD stage could be assigned, was assessed across each Australian jurisdiction. RD-Stage (Endometrial cancer) was calculated by Victorian Cancer Registry (VCR) medical coders and compared with clinical stage recorded by the patient's treating clinician and captured in the National Gynae-Oncology Registry (NGOR). RESULTS: The necessary data completeness level for calculating RD-Stage (Endometrial carcinoma) across various Australian jurisdictions varied from 0 to 89%. Three jurisdictions captured degree of spread of cancer, rendering RD-Stage unable to be calculated. RD-Stage (Endometrial carcinoma) could not be derived for 64/485 (13%) cases and was not captured for 44/485 (9%) cases in NGOR. At stage category level (I, II, III, IV), there was concordance between RD-Stage and NGOR captured stage in 393/410 (96%) of cases (95.8%, Kendall's coefficient = 0.95). CONCLUSION: A lack of consistency in data captured by, and data sources reporting to, population-based cancer registries meant that it was not possible to provide national endometrial carcinoma stage data at diagnosis. In a sample of Victorian cases, where surgical pathology was available, there was very good concordance between RD-Stage (Endometrial carcinoma) and clinician-recorded stage data available from NGOR. RD-Stage offers promise in capturing endometrial cancer stage at diagnosis for population epidemiological purposes when it is not provided by health services, but requires more extensive validation.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Safety of emergency, elective and day case operating during the winter period at East Suffolk and North Essex NHS Foundation Trust: lessons from the outcomes of 4,254 surgical patients from the first COVID-19 wave.

BACKGROUND: There is limited evidence on perioperative outcomes of surgical patients during the COVID-19 pandemic to inform continued operating into the winter period. METHODS: We retrospectively analysed the rate of 30-day COVID-19 transmission and mortality of all surgical patients in the three hospitals in our trust in the East of England during the first lockdown in March 2020. All patients who underwent a swab were swabbed on or 24 hours prior to admission. RESULTS: There were 4,254 patients and an overall 30-day mortality of 0.99%. The excess surgical mortality in our region was 0.29%. There were 39 patients who were COVID-19 positive within 30 days of admission, 12 of whom died. All 12 were emergency admissions with a length of stay longer than 24 hours. There were three deaths among those who underwent day case surgery, one of whom was COVID-19 negative, and the other two were not swabbed but not suspected to have COVID-19. There were two COVID-19 positive elective cases and none in day case elective or emergency surgery. There were no COVID-19 positive deaths in elective or day case surgery. CONCLUSIONS: There was a low rate of COVID-19 transmission and mortality in elective and day case operations. Our data have allowed us to guide patients in the consent process and provided the evidence base to restart elective and day case operating with precautions and regular review. A number of regions will be similarly affected and should perform a review of their data for the winter period and beyond.

Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.

Real-world Outcomes and Factors Predicting Survival and Completion of Radium 223 in Metastatic Castrate-resistant Prostate Cancer.

AIMS: To analyse outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with radium 223 (Ra-223) across the Yorkshire and Humber Cancer Network. MATERIALS AND METHODS: A regional, multicentre, retrospective cohort study of 189 men undergoing Ra-223 for mCRPC between March 2014 and April 2017 was undertaken. Factors predicting overall survival and completion of planned treatment were assessed. RESULTS: The median overall survival for the entire cohort was 10.5 months. Those completing five to six cycles of Ra-223 had a higher overall survival of 18.6 months. On multivariable analysis, four factors remained independent significant predictors of overall survival: age (P = 0.005, hazard ratio 1.07 [1.02-1.12]); number of cycles of Ra-223: 5-6 versus 1-4 (P ≤ 0.001, hazard ratio 0.10 [0.005-0.20]); baseline alkaline phosphatase (P = 0.044, hazard ratio 1.06 [1.002-1.12]); neutrophil-to-lymphocyte ratio (P = 0.033, hazard ratio 1.19 [1.01-1.40]). Baseline performance status 0 versus 2 (P = 0.026, odds ratio 0.080 [0.001-0.74]) and higher baseline haemoglobin (P = 0.028, odds ratio 1.04 [1.004-1.074]) were independent predictors of the completion of five to six cycles of Ra-223. CONCLUSIONS: Younger age, completion of five to six cycles of Ra-223, lower alkaline phosphatase and neutrophil-to-lymphocyte ratio are predictors of overall survival. This is the first study to report neutrophil-to-lymphocyte ratio as an independent predictor of overall survival in a Ra-223 cohort. Good performance status and higher baseline haemoglobin predict the completion of five to six cycles of Ra-223.

A cadaveric study showing the anatomical variations in the branches of the dorsalis pedis artery at the level of the ankle joint and its clinical implication in ankle arthroscopy.

Introduction Pseudoaneurysm formation following ankle arthroscopy is a rare but potentially catastrophic complication. The placement of anterior ankle portals carries inherent risk to the superficial and deep peroneal nerves, as well as to the dorsalis pedis artery. Anatomical variations in the dorsalis pedis and the presence of branches at the joint line may increase the risk of vascular injury and pseudoaneurysm formation during arthroscopy. There is limited anatomical evidence available regarding the branches of the dorsalis pedis artery, which occur at the point at which they cross the ankle joint. Objectives The objective of the study was to describe the frequency and direction of branches of the dorsalis pedis crossing the ankle joint. Materials and Methods Nineteen cadaveric feet were carefully dissected to explore the course of the dorsalis pedis artery, noting in particular the branching pattern at the joint line. Results Eleven of the nineteen feet had a branch of the dorsalis pedis artery that crossed the level of the ankle joint. Out of these, six were lateral, four medial and one bilateral. Eight of the eleven specimens had one branch at, or just before, the level of the joint. Two specimens had two branches and one had three branches crossing the ankle, which were all in the same direction, crossing laterally to the main trunk of the dorsalis pedis. Conclusions Our study demonstrated high rates of branching of the dorsalis pedis artery at the level of the ankle joint. The role of these branches in pseudoaneurysm formation during anterior hindfoot surgery remains unclear.

Surgical outcomes and sleep endoscopy for children with sleep-disordered breathing and hypotonia.

OBJECTIVE: To study the efficacy of surgical management for obstructive sleep apnea (OSA) syndrome in children with hypotonia, and to identify common anatomic sites of airway obstruction. METHODS: Retrospective chart review of polysomnographic parameters and quality of life instrument scores for seventy eight children with hypotonia who underwent surgical intervention for sleep-disordered breathing at two tertiary children's hospitals, and analysis of drug-induced sleep endoscopy data using a previously validated scoring system. RESULTS: Children undergoing surgical intervention had baseline severe OSA with a statistically significant improvement in apnea-hypopnea index from 23.6 to 11.1 after surgery, but persistent severe OSA. OSA-18 sleep-related quality of life measurement and overall quality of life score showed statistically and clinically significant improvements, from 72.0 to 43.4 and from 5.3 to 7.6 respectively. Sleep endoscopy showed an average obstructive score of 7.2/15 (n = 39), with multi-level obstruction in 49% of children. Greater than 50% obstruction was observed at the tongue base in 64% of patients, velum in 46%, lateral pharyngeal wall in 38%, supraglottis in 38%, and adenoid in 23%. CONCLUSION: OSA syndrome is challenging to treat in hypotonic children. Severe residual OSA is common after surgical intervention, but improvement in quality of life is clinically and statistically significant. The tongue base is the most common site of persistent airway obstruction. Drug-induced sleep endoscopy can identify sites of airway obstruction and may aid in surgical planning for high-risk patients.

Clinical Characteristics and prognostic analysis of Triple-negative Breast Cancer: Single institute experience.

BACKGROUND: Triple-negative breast cancer (TNBC) is a poor prognostic subset of breast cancer that lacks the benefit of specific targeted therapy. MATERIALS AND METHODS: A prospective study of the clinical profile of triple negative breast cancer cases at a tertiary referral centre. The duration of the study period was 26 months and the median follow up period was ten months. A total of 111 invasive breast cancer patients were evaluated from 1st August 2009 to 31st October 2011. We examined TNBC patients with respect to clinicopathological parameters, adjuvant chemotherapy regimens and relapse free survival. RESULTS: In our study, patients were young (median age at presentation, 47yrs), premenopausal (54%), tumour size was discordant with lymph node positivity, the histology was predominantly intraductal carcinoma (90%), histological grade higher than two (90%). Relapses were early and preferential visceral (32%) and CNS metastasises (11.7%). 91% of patients were eligible for adjuvant therapy but only 80% of the patients could complete full course of adjuvant chemotherapy. Anthracycline-based regimens (43%), sequential anthracycline and taxane-based regimen (24%) and other regimes like CMF (13%) were used as adjuvant chemotherapy in eligible TNBC patients. Median relapse free survival in patients following adjuvant chemotherapy was around 10 months at last follow-up. CONCLUSIONS: Patients with TNBC have aggressive clinicopathological characteristics with early and higher rate of disease relapse and therefore derive inadequate benefit from current adjuvant chemotherapy. So, new treatment strategies in adjuvant chemotherapy for TNBC are needed.

Dapagliflozin in type 2 diabetes: effectiveness across the spectrum of disease and over time.

BACKGROUND: Despite many available therapies, patients with type 2 diabetes mellitus (T2DM) frequently do not achieve/maintain glycaemic control. Furthermore, side effects such as hypoglycaemia and weight gain may limit therapy choices. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces hyperglycaemia by increasing glucosuria independently of insulin, representing a novel approach in T2DM. Dapagliflozin efficacy, safety and tolerability were evaluated across a wide range of clinical trials. METHODS: Dapagliflozin 10-mg efficacy data from (i) two short-term, active-comparator studies (vs. metformin-XR over 24 weeks and vs. glipizide over 52 weeks), (ii) pooled 24-week analyses of five placebo-controlled trials (as monotherapy or add-on therapy), and (iii) long-term studies over 2 years; dapagliflozin 5- and 10-mg pooled safety data from 12 placebo-controlled trials; and cardiovascular safety and malignancy data from 19 dapagliflozin studies were evaluated. RESULTS: In treatment-naïve patients (baseline HbA1c 9%), dapagliflozin reduced HbA1c (-1.45%) similarly to metformin-XR (-1.44%). In metformin-treated patients (baseline HbA1c 7.7%), dapagliflozin achieved a clinically significant reduction (-0.52%) similar to glipizide (-0.52%). In pooled 24-week analyses, dapagliflozin vs. placebo differences in HbA1c, weight and systolic blood pressure (SBP) were -0.60%, -1.61 kg and -3.6 mmHg, respectively. At 2 years, dapagliflozin vs. placebo differences in HbA1c and weight were -0.44 to -0.80% and -2.41 to -3.19 kg, respectively, and vs. glipizide, differences in HbA1c, weight, and SBP were -0.18%, -5.06 kg, and -3.89 mmHg, respectively. Major hypoglycaemia with dapagliflozin was rare (< 0.1%). Urinary tract and genital infections were more common with dapagliflozin, but responded to standard care and rarely led to study discontinuation. Events of renal failure/impairment and malignancies were rare and balanced across treatment groups. Pooled analyses did not indicate that dapagliflozin increased cardiovascular event risk. CONCLUSIONS: Dapagliflozin improved glycaemic control, decreased body weight, and lowered blood pressure across the spectrum of T2DM disease, with maintenance of these benefits over time.

Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: risk factors and response to treatment.

High fevers and/or rashes prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥ 12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥ 13.2 Gy)-based myeloablative conditioning. Tacrolimus (n=35) or CYA (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥ 38.5 °C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% confidence interval) of PES was 77% (66-88%). The incidence of PES was significantly higher in patients who received CYA as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact OS or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of CYA for GVHD prophylaxis increases the risk of PES following dual UCB transplantation.

A double blind randomised trial of IIb or not IIb neck dissections on electromyography, clinical examination, and questionnaire-based outcomes: a feasibility study.

The aim of this double-blind randomised controlled trial was to evaluate the feasibility of a study to compare differences using electromyographic (EMG) or nerve conduction studies (NCS), questionnaires completed by patients, and range of movement, after selective supraomohyoid neck dissection in patients with and without level IIb for node-negative oral cancer. Between January 2006 and July 2008 we recruited 57 previously untreated consecutive patients with node-negative T1 or T2 squamous cell carcinomas (SCC) of the anterior two-thirds of the tongue and floor of the mouth. Thirty-eight patients were randomised (32 unilateral and 6 bilateral dissections) into two groups. Preoperatively and at 6 weeks postoperatively we collected EMG or NCS data on trapezius muscle activity (primary outcome), the University of Washington quality of life scale (UWQoLv4), the neck dissection impairment index (NDII), and range of movement. At 6 months data on range of movement and data from the questionnaires were obtained. There was a greater mean fall in trapezius M-response amplitude for those who had IIb dissected, which suggested that inclusion of this level caused additional morbidity. However, it was not significant for patients who had unilateral dissections or for all necks combined. Changes in M-amplitude from baseline to 6 weeks, and from baseline to 6 months were strongly associated with changes in the shoulder domain of the UWQoL and the NDII, but were less strong for change in range of movement. This feasibility study has shown that a randomised controlled trial (RCT) is achievable. The combination of EMG or NCS with questionnaire data preoperatively and to 6 weeks would suffice and would simplify a new study design.

Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa.

Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3 were 0.155 and 0.003, respectively. No evidence was seen for influence of CYP2C8 genotype on AQ efficacy or toxicity, but sample size limited these assessments. The variant most common in Africans, CYP2C8(*)2, showed defective metabolism of AQ (threefold higher K(m) and sixfold lower intrinsic clearance), and CYP2C8(*)3 had markedly decreased activity. Considering drugs likely to be coadministered with AQ, the antiretroviral drugs efavirenz, saquinavir, lopinavir, and tipranavir were potent CYP2C8 inhibitors at clinically relevant concentrations. Variable CYP2C8 activity owing to genetic variation and drug interactions may have important clinical implications for the efficacy and toxicity of AQ.

Re-activation of a dormant tumor suppressor gene maspin by designed transcription factors.

The controlled and specific re-activation of endogenous tumor suppressors in cancer cells represents an important therapeutic strategy to block tumor growth and subsequent progression. Other than ectopic delivery of tumor suppressor-encoded cDNA, there are no therapeutic tools able to specifically re-activate tumor suppressor genes that are silenced in tumor cells. Herein, we describe a novel approach to specifically regulate dormant tumor suppressors in aggressive cancer cells. We have targeted the Mammary Serine Protease Inhibitor (maspin) (SERPINB5) tumor suppressor, which is silenced by transcriptional and aberrant promoter methylation in aggressive epithelial tumors. Maspin is a multifaceted protein, regulating tumor cell homeostasis through inhibition of cell growth, motility and invasion. We have constructed artificial transcription factors (ATFs) made of six zinc-finger (ZF) domains targeted against 18-base pair (bp) unique sequences in the maspin promoter. The ZFs were linked to the activator domain VP64 and delivered in breast tumor cells. We found that the designed ATFs specifically interact with their cognate targets in vitro with high affinity and selectivity. One ATF was able to re-activate maspin in cell lines that comprise a maspin promoter silenced by epigenetic mechanisms. Consistently, we found that this ATF was a powerful inducer of apoptosis and was able to knock down tumor cell invasion in vitro. Moreover, this ATF was able to suppress MDA-MB-231 growth in a xenograft breast cancer model in nude mice. Our work suggests that ATFs could be used in cancer therapeutics as novel molecular switches to re-activate dormant tumor suppressors.

Effects of nicotine and a cannabinoid receptor agonist on negative contrast: distinction between anxiety and disappointment?

RATIONALE: Animals trained to lick for a sucrose solution of a given incentive value that subsequently encounter an incentive downshift (i.e. 32-4% sucrose) display an exaggerated decrease in the amount consumed, relative to unshifted controls. This change has been classified as a successive negative contrast (SNC) effect. The emotional component to this robust behavioural change is dynamic and changes from post-shift day (PSD) 1 to 2. Anxiolytics block SNC, but the possible link between anxiety and SNC needs further exploration. Both nicotine and a cannabinoid receptor agonist have been reported to change anxiety and both have actions on the reward process, but their effects on SNC have not been investigated. OBJECTIVES: To determine: (1) whether exposure to SNC evokes an anxiogenic response; (2) whether an anxiolytic dose of nicotine has the same effects on SNC as those of chlordiazepoxide; (3) the effects of a low (anxiolytic) and a high (anxiogenic) dose of the cannabinoid receptor agonist CP 55,940 on SNC. METHODS: Two groups of animals were given access to high (32%) or low (4%) sucrose solutions for 5 min per day for 10 days. On PSD 1 and 2, the shifted group had access to a devalued incentive (from 32 to 4% sucrose) and the unshifted group remained at 4% sucrose. The volumes (ml) of sucrose solution consumed were measured pre-shift and on PSD 1 and 2. In experiment 1, immediately after SNC testing on PSD 1 and 2, the rats were tested in the social interaction and elevated plus-maze tests of anxiety. In experiment 2, the effects of chlordiazepoxide (5 and 7.5 mg/kg) and nicotine (0.1 mg/kg) were examined on PSD 1 and 2. In experiment 3, the effects of CP 55,940 (5 and 40 microg/kg) were examined on PSD 1 and 2. RESULTS: There were no anxiogenic effects of shift in either test of anxiety on either test day. However, on PSD 1, the shifted group had significantly higher locomotor activity and spent a higher percentage of time on the open arms, perhaps reflecting search strategies. Nicotine was without significant effect on SNC on either test day. On PSD 1, chlordiazepoxide (5 mg/kg) and CP 55,940 (5 and 40 microg/kg, IP) blocked SNC. On PSD 2, both doses of chlordiazepoxide and the low, anxiolytic dose of CP 55,940 (5 microg/kg) blocked SNC, the high dose of CP 55,940 was without effect. CONCLUSIONS: The pattern of results allows for the separation between effects on anxiety and SNC. The block of contrast on PSD 1 was independent of changes in anxiety, since both anxiolytic and anxiogenic drug doses were effective. It is suggested that this may provide an animal model of disappointment in which the cannabinoid system plays an important role. An anxiolytic action would seem to be a necessary, but not a sufficient, action to block SNC on PSD 2.

Treatment of hemorrhagic radiation proctitis with 4 percent formalin.

PURPOSE: The purpose of this study was to review our results in patients undergoing treatment with 4 percent formalin for radiation-induced injury to the rectum. METHODS: A retrospective review of office charts was performed, identifying all patients undergoing formalin treatment. Patient gender, initial malignancy, prior treatments, response to treatment with formalin, complications, and length of follow-up were reviewed. All patients had flexible endoscopy to assess for proximal sources of bleeding. The indication for treatment was a symptomatic patient with endoscopic evidence of radiation injury. A cotton pledget was used for direct application of 4 percent formalin to the affected area via a rigid proctoscope or anoscope. The treatment was repeated if blanching did not occur or if bleeding continued. Patients were followed up at three-week to four-week intervals and treatment was repeated based on the above indications. Treatments were continued until cessation of bleeding occurred or, when treatment failed, operative treatment was required. RESULTS: Thirty-six patients were identified. Three were lost to follow-up. Symptoms included bleeding in all but one patient, who presented with an ulcer. There were 33 (26 male) patients. Seventeen (51.5 percent) patients had prior treatment. The number of formalin treatments ranged from 1 to 13, with a mean of 3.4. The follow-up ranged from 1 to 60 months, with a mean of 18 months. Twenty-nine (88 percent) patients had improvement or cessation of symptoms. Four (12 percent) patients failed treatment. Two patients were noted to have full-thickness ulcers and both failed formalin treatment. No complications were noted related to formalin treatment. CONCLUSION: We conclude that formalin therapy is a safe and effective form of treatment that can be performed in the office with minimal discomfort and no complications. It can be performed multiple times until results are achieved. Formalin therapy may be useful as a first-line treatment for chronic radiation proctitis, however, a prospective controlled trial comparing modalities is required to prove this to be true.

Risk-adjusted comparative audit. Is Possum applicable to head and neck surgery?

Possum (the physiological and operative severity score for the enumeration of mortality) is used in many surgical specialities for comparative audit. We investigated its validity in relation to head and neck surgery by retrospectively scoring 301 operative interventions. We also applied the P-Possum (Portsmouth Possum) equation for mortality. We compared our observed with the predicted outcomes. We introduced two new variables, radiotherapy and previous surgery to the operative site, to test their association with outcome. We found that Possum is valid for morbidity but predicts more accurately for high-risk than for low-risk groups. Neither Possum or P-Possum accurately predicts mortality. Radiotherapy and previous surgery were both significant for the development of postoperative complications (P = 0.002, P = 0.007 respectively) and are worthy of inclusion in a Possum score for head and neck surgery.