Is the Management of Rectal Cancer Using a Watch and Wait Approach Feasible, Safe and Effective in a Publicly Funded General Hospital?

AIMS: Although there is emerging evidence to suggest equivalent oncological outcomes using a watch and wait approach compared with primary total mesorectal excision surgery, there is a paucity of evidence about the safety and efficacy of this approach in routine clinical practice. Here we report the long-term outcomes and quality of life from patients managed with watch and wait following a clinical complete response (cCR) to neoadjuvant therapy. MATERIALS AND METHODS: Patients with adenocarcinoma of the rectum with cCR following neoadjuvant therapy managed using watch and wait were retrospectively identified. Demographic data, performance status, pretreatment staging information, oncological and surgical outcomes were obtained from routinely collected clinical data. Quality of life was measured by trained clinicians during telephone interviews. RESULTS: Over a 7-year period, 506 patients were treated for rectal cancer, 276 had neoadjuvant therapy and 72 had a cCR (26.1%). Sixty-three were managed with watch and wait. Thirteen patients had mucosal regrowth. There was no significant difference in the incidence of metastatic disease between the surgical and watch and wait cohorts (P = 0.38). The 13 patients with mucosal regrowth underwent salvage surgery. Eleven of the patients who underwent surgical resection had R0 resections. There was also a statistically and clinically significant improvement in the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) trial outcome index (P = 0.022). CONCLUSION: This study shows that watch and wait is safe and effective outside of tertiary referral centres. It suggests that an opportunistic cCR is durable and when mucosal regrowth occurs it can be salvaged. Finally, we have shown that quality of life is probably improved if a watch and wait approach is adopted.

Identifying predictors of ventral hernia recurrence: systematic review and meta-analysis.

BACKGROUND: Ventra hernias are increasing in prevalence and many recur despite attempted repair. To date, much of the literature is underpowered and divergent. As a result there is limited high quality evidence to inform surgeons succinctly which perioperative variables influence postoperative recurrence. This systematic review aimed to identify predictors of ventral hernia recurrence. METHODS: PubMed was searched for studies reporting prognostic data of ventral hernia recurrence between 1 January 1995 and 1 January 2018. Extracted data described hernia type (primary/incisional), definitions of recurrence, methods used to detect recurrence, duration of follow-up, and co-morbidity. Data were extracted for all potential predictors, estimates and thresholds described. Random-effects meta-analysis was used. Bias was assessed with a modified PROBAST (Prediction model Risk Of Bias ASsessment Tool). RESULTS: Screening of 18 214 abstracts yielded 274 individual studies for inclusion. Hernia recurrence was defined in 66 studies (24.1 per cent), using 41 different unstandardized definitions. Three patient variables (female sex, age 65 years or less, and BMI greater than 25, 30, 35 or 40 kg/m2), five patient co-morbidities (smoking, diabetes, chronic obstructive pulmonary disease, ASA grade III-IV, steroid use), two hernia-related variables (incisional/primary, recurrent/primary), six intraoperative variables (biological mesh, bridged repair, open versus laparoscopic surgery, suture versus mesh repair, onlay/retrorectus, intraperitoneal/retrorectus), and six postoperative variables (any complication, surgical-site occurrence, wound infection, seroma, haematoma, wound dehiscence) were identified as significant prognostic factors for hernia recurrence. CONCLUSION: This study summarized the current evidence base for predicting ventral hernia recurrence. Results should inform best practice and future research.

Radiofrequency ablation for the treatment of haemorrhoidal disease: a minimally invasive and effective treatment modality.

BACKGROUND: Haemorrhoidal disease (HD) is a common colorectal condition that often requires surgical treatment. Less invasive procedures are usually more acceptable to patients. The aim of this study was to report the outcome of a novel and minimally invasive technique employing a radiofrequency ablation (RFA) energy (Rafaelo®) to treat HD. METHODS: A total number of 27 patients who had RFA for the treatment of HD were recruited to this study. The procedure was performed under deep sedation and local anaesthesia. Patients' demographics; haemorrhoid severity score (HSS); quality of life; pain and satisfaction scores; and recurrence rate were recorded. RESULTS: The mean age of the patients was 46 (SD 14) years, 18 (67%) males and 9 (33%) females. The mean body mass index was 25 (SD 4) kg/m2. The predominant symptom of all patients was per-rectal bleeding. HSS improved from 7.2 (SD 1.9) before the procedure to 1.6 (SD 1) after the procedure (p < 0.0001). Postoperative pain scores on a scale of 0-10 were 0, 2 (SD 2), 1 (SD 2), and 0 on immediate, day-1, day-3, and 2-month follow-up questionnaire. The mean satisfacion score was 9 (SD 1.5) out of 10 on 2-month follow-up. Mean time until patients returned to normal daily activity was 3 (SD 1) days following the procedure. Quality-of-life assessments including: visual analogue scale scores (before: mean 70, SD 23; after: mean 82, SD 16; p < 0.001) and EQ-5D-5L (before: mean 0.84, SD 0.15; after: mean 0.94, SD 0.13; p < 0.05) were significantly improved. The mean length of follow-up for recurrence of symptoms was 20 months (range 12-32 months). One patient (4%) reported the recurrence of rectal bleeding 12 months after the procedure. CONCLUSIONS: RFA for the treatment of HD is safe and effective in achieving symptomatic relief. It is associated with minimal postoperative pain and low incidence of recurrence.

A systematic methodological review of non-randomised interventional studies of elective ventral hernia repair: clear definitions and a standardised minimum dataset are needed.

BACKGROUND: Ventral hernias (VHs) often recur after surgical repair and subsequent attempts at repair are especially challenging. Rigorous research to reduce recurrence is required but such studies must be well-designed and report representative and comprehensive outcomes. OBJECTIVE: We aimed to assesses methodological quality of non-randomised interventional studies of VH repair by systematic review. METHODS: We searched the indexed literature for non-randomised studies of interventions for VH repair, January 1995 to December 2017 inclusive. Each prospective study was coupled with a corresponding retrospective study using pre-specified criteria to provide matched, comparable groups. We applied a bespoke methodological tool for hernia trials by combining relevant items from existing published tools. Study introduction and rationale, design, participant inclusion criteria, reported outcomes, and statistical methods were assessed. RESULTS: Fifty studies (17,608 patients) were identified: 25 prospective and 25 retrospective. Overall, prospective studies scored marginally higher than retrospective studies for methodological quality, median score 17 (IQR: 14-18) versus 15 (IQR 12-18), respectively. For the sub-categories investigated, prospective studies achieved higher median scores for their, 'introduction', 'study design' and 'participants'. Surprisingly, no study stated that a protocol had been written in advance. Only 18 (36%) studies defined a primary outcome, and only 2 studies (4%) described a power calculation. No study referenced a standardised definition for VH recurrence and detection methods for recurrence varied widely. Methodological quality did not improve with publication year or increasing journal impact factor. CONCLUSION: Currently, non-randomised interventional studies of VH repair are methodologically poor. Clear outcome definitions and a standardised minimum dataset are needed.

A systematic methodological review of reported perioperative variables, postoperative outcomes and hernia recurrence from randomised controlled trials of elective ventral hernia repair: clear definitions and standardised datasets are needed.

BACKGROUND: This systematic review assesses the perioperative variables and post-operative outcomes reported by randomised controlled trials (RCTs) of VH repair. This review focuses particularly on definitions of hernia recurrence and techniques used for detection. OBJECTIVE: Our aim is to identify and quantify the inconsistencies in perioperative variable and postoperative outcome reporting, so as to justify future development of clear definitions of hernia recurrence and a standardised dataset of such variables. METHODS: The PubMed database was searched for elective VH repair RCTs reported January 1995 to March 2016 inclusive. Three independent reviewers performed article screening, and two reviewers independently extracted data. Hernia recurrence, recurrence rate, timing and definitions of recurrence, and techniques used to detect recurrence were extracted. We also assessed reported post-operative complications, standardised operative outcomes, patient reported outcomes, pre-operative CT scan hernia dimensions, intra-operative variables, patient co-morbidity, and hernia morphology. RESULTS: 31 RCTs (3367 patients) were identified. Only 6 (19.3%) defined hernia recurrence and methods to detect recurrence were inconsistent. Sixty-four different clinical outcomes were reported across the RCTs, with wound infection (30 trials, 96.7%), hernia recurrence (30, 96.7%), seroma (29, 93.5%), length of hospital stay (22, 71%) and haematoma (21, 67.7%) reported most frequently. Fourteen (45%), 11 (35%) and 0 trials reported CT measurements of hernia defect area, width and loss of domain, respectively. No trial graded hernias using generally accepted scales. CONCLUSION: VH RCTs report peri- and post-operative variables inconsistently, and with poor definitions. A standardised minimum dataset, including definitions of recurrence, is required.

Proposal for a national triage system for the management of ventral hernias.

Ventral hernia disease is becoming increasingly prevalent and complex. Subspecialisation for patients with challenging conditions requiring surgery has been shown to improve postoperative outcomes. Worldwide, there is an emergence of specialist hernia centres using new and innovative techniques to repair large and complicated ventral hernias. After a national meeting of hernia experts, we present an algorithm to be used as a national triage system for patients with ventral hernias, with the aim of ensuring that patients are operated on by the most appropriate surgeon. Evidence-based clinical risk factors and ventral hernia parameters are used for risk stratification and patient triage. We hope that this algorithm will guide future ventral hernia management in the UK.

Barrel maturation, oak alternatives and micro-oxygenation: influence on red wine aging and quality.

The impact of micro-oxygenation (MOX) in conjunction with a variety of oak alternatives on phenolic composition and red wine aging was investigated and compared with traditional barrel aging. Although several studies concluded that MOX give similar results to barrel aging, few have compared them directly and none directly compared MOX with and without wood alternatives and barrel aging. Results confirmed that MOX had a positive effect on colour density, even after 5 months of bottle aging. This is supported by an increase in polymeric phenol and pigment content not only with aging but in the MOX compared to barrel matured wine treatments. Descriptive analysis showed that MOX in combination with wood alternatives such as oak chips and staves could mimic short term (six months) barrel aging in new American and French oak barrels in regards to sensory characteristics.

Intervertebral discitis caused by nontypeable Haemophilus influenzae in an adult: Case report.

INTRODUCTION: Haemophilus influenzae is a common cause of bacterial meningitis in children and can cause upper respiratory tract infections in adults, but has yet to be reported solely involving intervertebral discitis. PRESENTATION OF CASE: A 67-year-old builder presenting with fever, myalgia and back pain is found to have intervertebral discitis (confirmed on MRI) caused by H. influenzae (identified on blood cultures). DISCUSSION: A nontypeable form of H. influenzae has not been reported causing discitis. We describe a case in a relatively fit individual who was treated successfully with antimicrobial treatment. A preceding upper respiratory tract infection is the presumed source of infection, predisposed by long-term low-dose steroid therapy. CONCLUSION: H. influenzae is a rare, but treatable cause of discitis.

Visual evoked potentials in infants exposed to methadone in utero.

We investigated the effects of maternal drug misuse on neonatal visual evoked potentials (VEPs). Flash VEPs were recorded within 4 days of birth from 21 term infants of mothers misusing drugs and prescribed substitute methadone and 20 controls. Waveforms were classified as typical, atypical, immature or non-detectable, and amplitude and latencies were measured. VEPs from drug-exposed infants were less likely to be of typical waveform and more likely to be immature or non-detectable (p<0.01) than those of control infants. They were also smaller in amplitude (median 10.8 vs 24.4 microV, p<0.001). VEPs of drug-exposed infants had matured after 1 week but remained of lower amplitude than VEPs of newborn controls (p<0.01) and were non-detectable in 15%. Flash VEPs differ between maternal drug-exposed and non-drug-exposed newborns. Future research should address the specific effects of maternal methadone and/or other illicit drug misuse on infant VEPs, and associations between neonatal VEPs and subsequent visual development.

Atypical development of Sertoli cells and impairment of spermatogenesis in the hypogonadal (hpg) mouse.

Testes of hypogonadal (hpg) mice show arrested postnatal development due to congenital deficiencies of gonadotrophin-releasing hormone (GnRH) and gonadotrophin synthesis and secretion. Follicle-stimulating hormone (FSH), androgen or oestrogen treatment restore qualitatively normal spermatogenesis in hpg testes. Understanding the cellular and molecular changes accompanying hormone-induced spermatogenesis in hpg mice requires detailed morphological analyses of the germ cells and Sertoli cells in the untreated hpg testis. We compared seminiferous epithelial cytology in adult hpg, immature and adult wild-type mice using unbiased optical disector-based stereology, immunolocalization of Sertoli cell microtubules (MT), espin (a component of the blood-testis barrier), markers of Sertoli cell maturity (p27(kip1) and WT-1), and electron microscopy. Hpg testes had marked reductions in weight, seminiferous cord volume and length, and severe spermatogenic impairment with germ cells per testis < 1% of adult wild-type testes. Sertoli cell nuclei expressed WT-1 in hpg testes, but often were centrally located, similar to 9-14-day-old wild-type testes, and they expressed p27(kip1), indicating that hpg Sertoli cells were post-mitotic. Hpg testes had significantly (P < 0.05) reduced Sertoli cells per testis (0.56 million) compared with 10-day wild-type (1.15 million) and adult wild-type testes (2.06 million). Immunofluorescence labelling of normal adult Sertoli cells showed supranuclear MT columns and basally located espin, but these features were absent in 10-day-old and hpg Sertoli cells. Hpg Sertoli cells showed pleomorphic nuclear ultrastructure with mature-type nucleoli, similar to normal adult-type Sertoli cells, but hpg Sertoli cells exhibited incomplete tight junctions that lacked ectoplasmic specializations. We conclude that in hpg mice, chronic gonadotrophin insufficiency restrains Sertoli cell proliferation and maturation, forming pseudo-adult-type Sertoli cells that are incapable of supporting germ cell proliferation and maturation.

Human transforming growth factor alpha (TGF-alpha) is digested to a smaller (1-43), less biologically active, form in acidic gastric juice.

BACKGROUND: Transforming growth factor alpha (TGF-alpha) is a 50 amino acid peptide with potent proliferative and cytoprotective activity present in gastric mucosa and juice. AIMS: To determine the forms and biological activity of natural and recombinant TGF-alpha following incubation with acid pepsin. PATIENTS: Human gastric juice was obtained under basal conditions from patients taking acid suppressants and from volunteers undergoing intragastric neutralisation. METHODS: Samples were analysed using mass spectroscopy and/or high pressure liquid chromatography with radioimmunoassay. Biological activity was determined using thymidine incorporation into rat hepatocytes and an indomethacin/restraint induced gastric damage rat model. RESULTS: TGF-alpha(1-50) is cleaved to TGF-alpha(1-43) by acid pepsin and this is the predominant form in normal gastric juice. However, intragastric neutralisation or taking acid suppressants caused the predominant form to be TGF-alpha(1-50). TGF-alpha(1-43) had only half of the ability to maximally stimulate [(3)H]thymidine incorporation into primary rat hepatocytes (28 177 (1130) DPM/well for 2.16 nM TGF-alpha(1-43) v 63 184 (3536) DPM/well for TGF-alpha(1-50); p<0.001). A similar reduced potency was seen when used in an indomethacin induced rat gastric damage model (0.18 micro mol/kg/h of TGF-alpha(1-43) reduced ulcer area by 19% whereas TGF-alpha(1-50) reduced area by 62%; p<0.001). CONCLUSIONS: TGF-alpha(1-50) is cleaved to the TGF-alpha(1-43) form by acid pepsin, causing 2-5-fold loss of biological activity. Such changes may have relevance to the actions of acid suppressants and the importance of this peptide in both normal and abnormal growth.

Patterns of alcohol consumption after liver transplantation.

BACKGROUND: Uncertainty exists about the extent and consequences of a return to alcohol consumption after liver transplantation for alcoholic liver disease (ALD). AIMS: To determine the prevalence and consequences of alcohol consumption in patients transplanted for ALD. METHODS: A retrospective case controlled study of all patients transplanted for ALD at the Queen Elizabeth Hospital, Birmingham, between 1987 and 1996. RESULTS: Seventy patients with ALD were transplanted, of which 59 survived more than three months; 56 were interviewed. Twenty eight had consumed some alcohol after transplantation; for the nine "heavy drinkers" (HD), the median time to resumption of alcohol intake was six months and for the 19 "moderate drinkers" (MD) it was eight months. There was no significant difference in episodes of acute rejection or compliance with medication between those who were abstinent, MD, or HD. Histological evidence of liver injury was common in ALD patients who had returned to drink. Mild fatty change was found in 1/11 biopsy specimens from abstinent patients but moderate to severe fatty change and ballooned hepatocytes were seen in 3/5 MD and 2/5 HD specimens. Two HD patients had early fibrosis. One HD patient had died of alcohol related complications. CONCLUSIONS: Moderate to heavy alcohol consumption occurs in patients transplanted for ALD. Patient recall of abstinence advice is unreliable, and patients return to alcohol mainly within the first year after liver transplantation. Return to alcohol consumption after liver transplantation is associated with rapid development of histological liver injury including fibrosis.

Alterations in classical cadherins associated with progression in ulcerative and Crohn's colitis.

Human colitis is a condition associated with a spectrum of altered morphologic changes and cellular adhesion. The role of cadherins, which are powerful morphoregulatory cell adhesion molecules, in colitis is provocative and as yet unknown. Herein, we present results that suggest a strong correlation between the deregulation of two cadherin molecules, E- and P-cadherins, and the progression of human colitis. We examined the expression and structural integrity of E- and P-cadherins in inflamed, dysplastic, or neoplastic human ulcerative colitis (UC) (n=58), human Crohn's colitis (n = 30), and normal tissue (n = 20) to assess cadherin function in normal and abnormal epithelium. E-cadherin is strongly expressed in normal colorectal epithelium, whereas in left-sided UC it is either down-regulated or has a single-base pair mutation in exon 4 resulting in an amino acid alteration (6 of 58 UC cases). By contrast, P-cadherin is dramatically up-regulated in both Crohn's disease and ulcerative colitis and especially in dysplastic ulcerative tissue. In vitro transfected SW-480 colorectal cells containing E-cadherin mutations identical to those in vivo were associated with increased spontaneous disaggregation compared with cells transfected with wild-type E-cadherin. Based on this evidence, we hypothesize that a small subset of colorectal cells expressing mutant E-cadherin are associated with widespread ulceration, whereas those expressing P-cadherin are associated with a rapidly dividing immature phenotype that includes dysplasia. The differential expression of mutated and wild-type cadherins examined herein are associated with a broad spectrum of abnormal epithelial phenotypes, lymphocyte integrin binding, and resistance to denudation, as is seen in the colitis adenocarcinoma sequence.

Augmentation of the early phase of liver regeneration after 70% partial hepatectomy in rats following selective Kupffer cell depletion.

BACKGROUND/AIMS: Kupffer cells are located in the liver sinusoids adjacent to hepatocytes and elaborate a range of growth regulatory molecules involved in regulating hepatocyte proliferation. In vitro observations imply the potential for Kupffer cells to exert both stimulatory and inhibitory influences on hepatocyte DNA synthesis. We aimed to determine the overall effect of Kupffer cell activity during the early regenerative processes after partial hepatectomy. METHODS: We investigated hepatocyte DNA synthesis, induced by partial hepatectomy in rats, following selective elimination of Kupffer cells by liposome encapsulated dichlormethylene bisphosphonate (Cl2MBP). RESULTS: We demonstrate that the early phase of liver regeneration was enhanced following Kupffer depletion, as indicated by a greater proportion of hepatocytes undergoing DNA synthesis, and a higher mitotic index. This was associated with an alteration in the balance of growth factors in the liver; HGF and TGFbeta mRNA were reduced in Kupffer cell-depleted animals, and IL-1beta mRNA was absent. In addition, in the absence of partial hepatectomy, the selective depletion of Kupffer cells leads to an increase in the proliferation of hepatocytes in resting liver undergoing DNA synthesis. CONCLUSION: The overall effect of depleting the liver of Kupffer cells is to enhance the proliferation rate of hepatocytes, both after partial hepatectomy and in the resting state.