Sheldon C. Cooper

Patients with prostate cancer are less likely to develop oesophageal adenocarcinoma: could androgens have a role in the aetiology of oesophageal adenocarcinoma?

Oesophageal adenocarcinoma (OAC) is more common in men. Androgens may therefore contribute to the pathogenesis of OAC. Prostate cancer (PC), an androgen sensitive tumor with a long natural history, may allow insights into this putative association. West Midlands Cancer Intelligence Unit data from 1977 to 2004 were examined to identify patients with a first malignant primary of PC. Patients were followed until diagnosis of a second primary cancer, death or end of the time period. Age- and period-adjusted standardized incidence ratios (SIR) were calculated as an estimate of the relative risk of a second malignant primary of the oesophagus. Between 1977 and 2004, 44,819 men within the West Midlands developed PC as a first primary malignancy. After exclusion for lack of follow-up, 38,627 men were eligible, providing 143,526 person years at risk for analysis. 86 second primary oesophageal cancers were observed, compared with 110 expected, resulting in an SIR of 0.78 (95% CI 0.62–0.96). There was a reduced risk of OAC 0.7 (0.5–0.95) but not of oesophageal squamous cell carcinoma (OSCC) 1.03 (0.69–1.47). The risk of developing OAC, but not OSCC, is lower than expected in patients with PC. A diagnosis of PC may be associated with aetiological factors that are negatively associated with OAC, or anti-androgen therapy may influence the development of OAC.

The influence of deprivation and ethnicity on the incidence of esophageal cancer in England

The incidence of esophageal cancer (EC), particularly esophageal adenocarcinoma (EAC), has been rising dramatically. In the USA, esophageal squamous cell carcinoma (ESCC) is associated with deprivation and black ethnicity, while EAC is more common among whites. The influence of social deprivation and ethnicity has not been studied in England. West Midlands Cancer Intelligence Unit data were used to study the incidence of ESCC and EAC, and the influence of age, sex, socioeconomic status (Townsend quintiles by postcode) and ethnicity (to individual patients from Hospital Episode Statistics). From 1977 to 2004, a total of 15,138 EC were identified. Five-year directly age standardized incidence rates per 100,000 (95% CI) for men increased from 8.6 (8.0–9.1) in 1977–1981 to 13.7 (13.1–14.3) in 2000–2004 and for women from 5.0 (4.7–5.4) to 6.3 (5.9–6.6). ESCC incidence did not alter, but EAC incidence rose rapidly in males [2.1 (1.9–2.4) to 8.5 (8.1–9.0)] and in females [0.5 (0.4–0.6) to 1.7 (1.5–1.9)]. ESCC was strongly associated with the most socially deprived quintile. EAC was not associated with differences in socioeconomic status. EAC was significantly more common in white men 7.3 (6.9–7.7) and women 1.5 (1.3–1.6) when compared with black and Asian populations. In England the incidence of EAC has rapidly risen, particularly in men over the last three decades. ESCC was strongly associated with social deprivation. EAC was more common in white populations, but no association with the socioeconomic status was found.

Risk factors for the development of oesophageal adenocarcinoma in Barrett's oesophagus: a UK primary care retrospective nested case-control study

Background Oesophageal adenocarcinoma (OAC) incidence is rising rapidly and prognosis remains poor. Endoscopic surveillance of Barrett’s oesophagus (BO) remains controversial. Objective A nested case–control study was undertaken to evaluate risk factors for progression of BO to OAC, potentially guiding surveillance efforts. Methods The Health Improvement Network database includes general practitioner consultations from 5 million UK subjects. BO subjects with 1-year minimum of follow up were followed until development of OAC or end of time on database. Demographic variables (age, gender, smoking, body mass index) and data on medication considered negatively (aspirin/nonsteroidal anti-inflammatory drugs/proton pump inhibitors) or positively associated (lower oesophageal sphincter-relaxing and asthma drugs) with OAC development were studied. Cox regression analysis-derived hazard ratios with 95% confidence intervals estimated the relative risk for OAC progression. Results A total of 3749 BO subjects were studied: 55 developed OAC during 17,743 patient years of follow up, a progression rate of 0.3% per annum. There was 96.7% of the cohort who took proton-pump inhibitors, with no association observed. Increasing age (1.03, 95% CI 1.01–1.05, p = 0.005), male gender (3.06, 95% CI 1.50–6.24, p = 0.002), and having ever smoked (2.36, 95% CI 1.13–4.93, p = 0.023) were associated with progression to OAC, (although smoking lost association on multivariate analysis). Increasing number of drugs used for asthma (2.91, 95% CI 1.10–7.68, p= 0.0314) was also associated. Conclusion In this nested case–control study of BO, male gender, increasing age, and increasing use of asthma drugs were associated with progression to OAC.

Mycophenolate mofetil therapy in the management of inflammatory bowel disease — A retrospective case series and review

BACKGROUND AND AIMS The role of mycophenolate mofetil (MMF) as an immunomodulatory drug in managing inflammatory bowel disease (IBD) is yet to be fully defined. We reviewed our experience of MMF in treating patients with IBD. METHODS Retrospective analysis was performed on all patients treated with MMF for inflammatory bowel disease between 2003 and 2011. Remission was assessed by reviewing clinical, endoscopic and laboratory indices. RESULTS We identified 36 patients, 23 male (64%), median age 46years (range 19-75). Nineteen patients had Crohns disease, 16 with ulcerative colitis (UC), and one with indeterminate colitis. 33 patients (92%) had previously received azathioprine; 32 of whom discontinued this due to side-effects. 26 patients (72%) were concurrently taking oral corticosteroids. Median length of MMF treatment observed was 21.5months (IQR 9.7-31.6). At 8weeks, 29 patients (81%) had either achieved or maintained remission. After 6months, 19 of 33 patients (58%) were in sustained steroid-free remission. At the end of the observation period, 29 patients (81%) remained on MMF. 13 patients (36% of original treatment group; UC/IBDU 8, Crohns 5) maintained steroid free remission. Median time in remission was 21.4months (IQR 11.0-30.0). Drug side-effects were experienced by 7 patients (19%), managed by dose reduction in 5 patients, with discontinuation in 2 (6%). CONCLUSIONS Mycophenolate mofetil may represent a promising treatment for inducing and maintaining remission in IBD patients intolerant of thiopurines. It may be of more value and relevance in ulcerative colitis, since less alternative proven therapies are available.

The risk of oesophageal cancer is not affected by a diagnosis of breast cancer.

Oesophageal adenocarcinoma (OAC) is less common and develops at a later age in women compared with men. Endogenous oestrogen may therefore protect against OAC development. A cohort of women with breast cancer, a tumour commonly treated with oestrogen antagonists, was examined to identify the subsequent risk of developing OAC. Earlier studies have implicated radiotherapy in increasing oesophageal cancer (OC) risk among women with breast cancer. West Midlands Cancer Intelligence Unit data recording cancer diagnosis and treatment information was examined to identify patients with a first malignant primary breast cancer during 1977–2004. Patients were followed until diagnosis of a second primary cancer, death or end of the time period examined. Age-adjusted and period-adjusted standardized incidence ratios (SIR) were calculated as an estimate of relative risk for a second primary OC. Seventy-three thousand six hundred and thirteen women were eligible for the study, providing 486 679 person years at risk for analysis. One hundred and thirty-two second primary OCs were observed, compared with 121 expected (SIR 1.09; 95% confidence interval: 0.91–1.29). Radiotherapy treatment in 37 888 women did not affect the risk of a second primary OC (SIR 1.07; 95% confidence interval: 0.79–1.41). No difference was identified when examined by OC morphology. There was no association between breast cancer and a second primary OC. Radiotherapy that avoids deep irradiation in the treatment of breast cancer, local nodes or recurrence was not associated with an increased risk of developing a second primary OC.

A Novel Phenotype of Glycogen Storage Disease Presenting as Gastrointestinal Neuromuscular Disease

Introduction Gastric smooth muscle layers are electrically excited by slow waves. In the normal stomach, slow waves propagate longitudinally in ring wavefronts from the upper corpus to the distal antrum. Circumferential propagation does not appear to occur, likely because there is no excitable tissue available circumferentially in these rings. However, rapid circumferential propagation has been observed in isolated gastric tissues and during gastric pacing. In this study, the propagation profiles of slow wave behaviors in diabetic gastroparesis were defined at high resolution (HR). The hypothesis was that circumferential propagation occurs during dysrhythmia, presenting a novel marker of gastric electrical dysfunction. Methods HR (multi-electrode) mapping was performed in 7 patients with diabetic gastroparesis undergoing laparotomy for stimulator implantation. Anterior serosal recordings were taken using flexible PCB arrays (256 electrodes; 4 mm spacing; 36cm2), and activation mapping was performed. Velocity fields were calculated using a finite difference approach incorporating a Gaussian filter smoothing function. Amplitudes were calculated using a peak-trough detection algorithm. Longitudinal and circumferential propagation data from corpus recordings were compared with Students t-test. Means±SEM are reported. Results Atypical or dysrhythmic propagation was observed in 6/7 patients, including incomplete conduction block, complete block with escape, ectopic pacemaking in the corpus and antral tachygastria (freq range: 2.7-4.2 cpm). Circumferential propagation was associated with all of these events (circumferential velocity 6.6 ± 0.9 mm/s vs longitudinal velocity 2.9 ± 0.2 mm/s; p<0.01). Extracellular slow wave amplitudes were also ~2.5x higher during circumferential propagation (411±66 uV vs 170±27 uV; p<0.01). Isochronalmapping demonstrated that circumferential propagation led to the rapid restoration of a normal longitudinal wavefront distal to the source of the dysrhythmia. However, circumferential propagation also promoted organized retrograde propagation in the case of antral tachygastria. Conclusions Propagation abnormalities in diabetic gastroparesis include conduction blocks, escape, and ectopic events, potentially as a consequence of known ICC network degradation. Circumferential propagation emerges in many of these abnormal patterns because excitable tissue becomes available in the circumferential direction. Circumferential conduction is found to be associated with high velocities and high amplitudes, which could therefore serve as useful clinical indicators for abnormal slow wave propagation. Functionally, rapid circumferential propagation serves to restore normal slow wave propagation distal to conduction defects, however it can also promote organized retrograde tachygastria.

Recurrent ascending cholangitis due to small intestinal bacterial overgrowth, gastrointestinal dysmotility and an afferent loop

Summary We report a complex case involving an extremely rare cause of gastrointestinal dysmotility and an afferent loop, which together predisposed to the development of small intestinal bacterial overgrowth. The bacteria subsequently became multi-resistant. As a further consequence of the dysmotility, repeated bile duct reflux occurred despite the afferent loop being unobstructed. This bile duct reflux produced recurrent sepsis through repeated episodes of ascending cholangitis. Ultimately, the patient was referred to a National Small Intestinal Transplant Centre for consideration for enterectomy and subsequent transplantation. We describe the difficulties encountered in managing this unique case and discuss the underlying aetiology.