Anthony Antoniou

Severe bile salt export pump deficiency : 82 different ABCB11 mutations in 109 families

BACKGROUND & AIMS Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

Extended lymphadenectomy versus conventional surgery for rectal cancer: a meta-analysis

BACKGROUND Lateral pelvic lymph-node metastases occur in 10-25% of patients with rectal cancer, and are associated with higher local recurrence and reduced survival rates. A meta-analysis was undertaken to assess the value of extended lateral pelvic lymphadenectomy in the operative management of rectal cancer. METHODS We searched Medline, Embase, Ovid, Cochrane Library, and Google Scholar for studies published between 1965 and 2009 that compared extended lymphadenectomy (EL) with standard rectal resection. 20 studies, which included 5502 patients from one randomised, three prospective non-randomised, and 14 retrospective case-control studies published between 1984 and 2009, met our search criteria and were assessed. 2577 patients underwent EL and 2925 underwent non-EL for rectal cancer. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. End-points evaluated included peri-operative outcomes, 5-year survival and recurrence rates. FINDINGS Operating time was significantly longer in the EL group by 76.7 min (95% CI 18.77-134.68; p=0.0096). Intra-operative blood loss was greater in the EL group by 536.5 mL (95% CI 353.7-719.2; p<0.0001). Peri-operative mortality (OR 0.81, 95% CI 0.34-1.93; p=0.63) and morbidity (OR 1.45, 95% CI 0.89-2.35; p=0.13) were similar between the two groups. Data from individual studies showed that male sexual dysfunction and urinary dysfunction (three studies: OR 3.70, 95% CI 1.66-8.23; p=0.0012) were more prevalent in the EL group. There were no significant differences in 5-year survival (hazard ratio [HR] 1.09, 95% CI 0.78-1.50; p=0.62), 5-year disease-free survival (HR 1.23, 95% CI 0.75-2.03, p=0.41), and local (OR 0.83, 95% CI 0.61-1.13; p=0.23) or distant recurrence (OR 0.93, 95% CI 0.72-1.21; p=0.60). INTERPRETATION Extended lymphadenectomy does not seem to confer a significant overall cancer-specific advantage, but does seem to be associated with increased urinary and sexual dysfunction.

A National Perspective on the Decline of Abdominoperineal Resection for Rectal Cancer

Objective:To assess rates of abdominoperineal excision of the rectum (APER) for rectal cancer between centers and over time, and to evaluate the influence of patient characteristics, including social deprivation, on APER rate. Methods:Data on patients undergoing APER or anterior resection (AR) in England were extracted from a national administrative database for the years 1996 to 2004. The primary outcome was the proportion of patients presenting with rectal cancer undergoing APER. Hierarchical logistic regression was used to identify independent factors associated with a nonrestorative resection. Results:Data on 52,643 patients were analyzed, 13,109(24.9%) of whom underwent APER. The APER rate significantly reduced over the study period from 29.4% to 21.2% (P < 0.001). Operative mortality following AR decreased significantly during the period of study (5.1% to 4.2%, P = 0.002), while that following APER did not (P = 0.075). Male patients were more likely to undergo APER (P < 0.001), whereas those with an emergency presentation more commonly underwent AR (P < 0.001). Independent predictors of increased APER rate were male gender (odds ratio [OR] = 1.239, P < 0.001) and social deprivation (most vs. least deprived; OR = 1.589, P < 0.001), whereas increasing patient age (OR = 0.977, P = 0.027 per 10-year increase), year of study (2003/4 vs. 1996/7; OR = 0.646, P < 0.001) and initial presentation as an emergency (OR = 0.713, P < 0.001) were associated with lower APER rates. After accounting for case-mix, there was significant between-center variability in APER rates. Conclusion:Socially deprived patients were more likely to undergo abdominoperineal resection. Significant improvements in rates of nonrestorative resection were seen over time but although short-term outcomes following AR have improved, those following APER have not. Permanent stoma rates following rectal cancer surgery may be considered a surrogate marker of surgical quality.

Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes.

The management of primary rectal cancer beyond total mesorectal excision planes (PRC‐bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority.

Traditional and laparoscopic appendectomy in adults: outcomes in English NHS hospitals between 1996 and 2006.

Objective:This study investigated length of stay, readmission rates, and postoperative mortality in adult patients undergoing traditional and laparoscopic appendectomy in England between April 1, 1996, and March 31, 2006. Methods:All procedures coded to the “H01—Emergency Excision of Appendix” procedure code in the Hospital Episode Statistics database were included. Multivariate analyses were used to identify independent predictors of length of hospital stay, 30-day and 365-day mortality. Results:A total of 259,735 procedures were assigned to the H01-Emergency excision of appendix OPCS-4 3-digit code procedure between 1996 and 2006. A laparoscopic technique was employed in 16,315 (6.3%). A greater proportion of deaths occurred in hospital within 30 days of “open” appendectomy surgery (0.25%) compared with procedures utilizing a laparoscopic technique (0.09%, P < 0.001). One-year mortality rates, measured over a 5-year period, were also higher after open surgery (0.64% vs. 0.29%, P < 0.001). Multiple logistic regressions demonstrated that an open operative technique, older age, male gender, and increasing comorbidity were strong independent determinants of early and 1-year postoperative mortality after emergency appendectomy. The duration of stay for patients undergoing open emergency appendectomy exceeded that for patients undergoing the laparoscopic technique (P < 0.001). Patients undergoing a laparoscopic technique were, however, more likely to be readmitted within 28 days of surgery (7.10% vs. 4.95%, P < 0.001). Conclusions:Laparoscopic appendectomy is safe and associated with lower postoperative mortality rates than open procedures. The cost implications are uncertain as this technique is associated with shorter hospital stay but higher subsequent readmission rates.

Chemoradiotherapy for anal cancer in HIV patients causes prolonged CD4 cell count suppression

BACKGROUND Despite the advent of highly active antiretroviral therapy, anal cancer remains a significant health problem in human immunodeficiency virus (HIV) patients. We present the clinical features and treatment outcomes of anal cancer in 60 HIV-positive patients over a 20-year period. PATIENTS AND METHODS A prospective database of all HIV-positive individuals managed in a specialist unit since 1986 includes 11 112 patients (71 687 person-years of follow-up). Sixty patients with anal cancer were identified. Their clinicopathological and treatment details were analysed. RESULTS At anal cancer diagnosis, the mean age was 44 years (range: 28-75 years) and the median CD4 cell count was 305 mm-3 (range: 16-1252 mm-3). Fifty (83%) had chemoradiotherapy (CRT). Forty-six (92%) responded, of whom 10 (22%) subsequently relapsed with locoregional (70%), metastatic disease (10%) or both (20%). The overall 5-year survival is 65% (95% confidence interval 51% to 78%). The median CD4 count fell from 289 mm-3 before CRT to 132 mm-3 after 3 months and to 189 mm-3 after 1 year (P < 0.05). Six patients in remission of anal cancer died of acquired immunodeficiency syndrome defining illnesses. CONCLUSIONS The management of anal cancer with CRT achieves similar outcomes as the general population. CRT is associated with significant prolonged CD4 suppression that may contribute to late deaths of patients in remission.BACKGROUND Despite the advent of highly active antiretroviral therapy, anal cancer remains a significant health problem in human immunodeficiency virus (HIV) patients. We present the clinical features and treatment outcomes of anal cancer in 60 HIV-positive patients over a 20-year period. PATIENTS AND METHODS A prospective database of all HIV-positive individuals managed in a specialist unit since 1986 includes 11 112 patients (71 687 person-years of follow-up). Sixty patients with anal cancer were identified. Their clinicopathological and treatment details were analysed. RESULTS At anal cancer diagnosis, the mean age was 44 years (range: 28-75 years) and the median CD4 cell count was 305 mm(-3) (range: 16-1252 mm(-3)). Fifty (83%) had chemoradiotherapy (CRT). Forty-six (92%) responded, of whom 10 (22%) subsequently relapsed with locoregional (70%), metastatic disease (10%) or both (20%). The overall 5-year survival is 65% (95% confidence interval 51% to 78%). The median CD4 count fell from 289 mm(-3) before CRT to 132 mm(-3) after 3 months and to 189 mm(-3) after 1 year (P<0.05). Six patients in remission of anal cancer died of acquired immunodeficiency syndrome defining illnesses. CONCLUSIONS The management of anal cancer with CRT achieves similar outcomes as the general population. CRT is associated with significant prolonged CD4 suppression that may contribute to late deaths of patients in remission.

Eco-friendly laparoscopic home trainer.

Introduction: Laparoscopic surgery is becoming the main surgical technique in use today. Surgical trainees have to be able to practice these skills in a safe environment. This article describes the design of a novel cheap home laparoscopic trainer using recycled and reusable items. Methods: This novel home laparoscopic trainer is designed using a mobile phone, torch, and shoe box. Fifteen surgical trainees with variable laparoscopic experience used the device and provided feedback by filling in a Likert scale questionnaire. Results: This is a device that is easy to make and reuse with equipment that is easily accessible in most environments. All the trainees who used the device found it easy to use and helpful for practicing hand-eye coordination. Conclusions: This is simple and low-cost device allows trainees to practice laparoscopic skills in a safe environment. It provides a design that is accessible and recyclable, hence useful as a low-technology device in places where finances are limited.

Colorectal cancer in HIV positive individuals: The immunological effects of treatment

BACKGROUND AND OBJECTIVES Since the introduction of highly active antiretroviral therapy (HAART), non-AIDS defining malignancies including colorectal cancer (CRC) have emerged as major health concerns for people living with HIV. METHODS From a prospective database of 11,112 HIV seropositive individuals, we identified 11 patients with CRC. Clinicopathological details on the presentation, treatment and outcomes were collected. RESULTS All were male with a median age of 50 years (range 36-67) and median duration of HIV infection of 7.2 years (range 0-21). Five had metastatic disease at presentation, including 1 patient with a small cell cancer of the rectum. Patients were treated along conventional lines for CRC with concomitant HAART and opportunistic infection prophylaxis. During treatment, median CD4 cell counts fell from 357/mm(3) at CRC diagnosis to 199/mm(3), although no opportunistic infections were recorded. Three patients have died and the 5-year overall survival measured 65% (95% confidence interval 32-98%). CONCLUSIONS Treatment for CRC reduces cellular immunity and potentially puts HIV patients at risk of opportunistic infections; knowledge of HIV status prior to starting treatment is essential. This risk may be reduced by concomitant HAART and prophylaxis. Clinicians managing CRC should consider screening patients for HIV before starting chemotherapy or radiotherapy.

Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More?

Background: Appendiceal neuroendocrine neoplasms (ANEN) are mostly indolent tumours treated effectively with simple appendectomy. However, controversy exists regarding the necessity of oncologic right hemicolectomy (RH) in patients with histologic features suggestive of more aggressive disease. We assess the effects of current guidelines in selecting the surgical strategy (appendectomy or RH) for the management of ANEN. Methods/Aims: This is a retrospective review of all ANEN cases treated over a 14-year period at 3 referral centres and their management according to consensus guidelines of the European and the North American Neuroendocrine Tumor Societies (ENETS and NANETS, respectively). The operation performed, the tumour stage and grade, the extent of residual disease, and the follow-up outcomes were evaluated. Results: Of 14,850 patients who had appendectomies, 215 (1.45%) had histologically confirmed ANEN. Four patients had synchronous non-ANEN malignancies. One hundred and ninety-three patients had index appendectomy. Seventeen patients (7.9%) had lymph node metastases within the mesoappendix. Forty-nine patients underwent RH after appendectomy. The percentages of 30-day morbidity and mortality after RH were 2 and 0%, respectively. Twelve patients (24.5%) receiving completion RH were found to have lymph node metastases. Two patients had liver metastases, both of them synchronous. The median follow-up was 38.5 months (range 1-143). No patient developed disease recurrence. Five- and 10-year overall survival for all patients with ANEN as the only malignancy was both 99.05%. Conclusions: The current guidelines appear effective in identifying ANEN patients at risk of harbouring nodal disease, but they question the oncological relevance of ANEN lymph node metastases. RH might present an overtreatment for a number of patients with ANEN.