ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Partial Ribosomal Nontranscribed Spacer Sequences Distinguish Rhagoletis zephyria (Diptera: Tephritidae) From the Apple Maggot, R. pomonella.

The apple maggot, Rhagoletis pomonella (Walsh), was introduced into the apple-growing regions of the Pacific Northwest in the U.S.A. during the past 60-100 yr. Apple maggot (larvae, puparia, and adults) is difficult to distinguish from its morphologically similar sister species, Rhagoletis zephyria Snow, which is native and abundant in the Pacific Northwest. While morphological identifications are common practice, a simple, inexpensive assay based on genetic differences would be very useful when morphological traits are unclear. Here we report nucleotide substitution and insertion-deletion mutations in the nontranscribed spacer (NTS) of the ribosomal RNA gene cistron of R. pomonella and R. zephyria that appear to be diagnostic for these two fly species. Insertion-deletion variation is substantial and results in a 49 base-pair difference in PCR amplicon size between R. zephyria and R. pomonella that can be scored using agarose gel electrophoresis. PCR amplification and DNA sequencing of 766 bp of the NTS region from 38 R. pomonella individuals and 35 R. zephyria individuals from across their geographic ranges led to the expected PCR fragments of approx. 840 bp and 790 bp, respectively, as did amplification and sequencing of a smaller set of 26 R. pomonella and 16 R. zephyria flies from a sympatric site in Washington State. Conversely, 633 bp mitochondrial COI barcode sequences from this set of flies were polyphyletic with respect to R. pomonella and R. zephyria. Thus, differences in NTS PCR products on agarose gels potentially provide a simple way to distinguish between R. pomonella and R. zephyria.

Postoperative chemotherapy improves survival in patients with resected high-risk Stage II colorectal cancer: results of a systematic review and meta-analysis.

AIM: The aim was to assess the benefit of adjuvant chemotherapy in high-risk Stage II colorectal cancer. METHOD: A systematic literature review and meta-analysis was performed comparing survival in patients with resected Stage II colorectal cancer and high-risk features having postoperative chemotherapy vs no chemotherapy. RESULTS: Of 1031 articles screened, 29 were included, reporting on 183 749 participants. Adjuvant chemotherapy significantly improved overall survival [hazard ratio (HR) 0.61, P < 0.0001], disease-specific survival (HR = 0.73, P = 0.05) and disease-free survival (HR = 0.59, P < 0.0001) compared to no chemotherapy. Adjuvant chemotherapy significantly increased 5-year overall survival (OR = 0.53, P = 0.0008) and 5-year disease-free survival (OR = 0.50, P = 0.001). Overall survival and disease-free survival remained significantly prolonged during subgroup analysis of studies published from 2015 onwards (HR = 0.60, P < 0.0001; HR = 0.65, P = 0.0001; respectively), in patients with two or more high-risk features (HR = 0.59, P = 0.0001; HR = 0.70, P = 0.03; respectively) and in colon cancer (HR = 0.61, P < 0.0001; HR = 0.51, P = 0.0001; respectively). Overall survival, disease-specific survival and disease-free survival during subgroup analysis of individual high-risk features were T4 tumour (HR = 0.58, P < 0.0001; HR = 0.50, P = 0.003; HR = 0.75, P = 0.05), < 12 lymph nodes harvested (HR = 0.67, P = 0.0002; HR = 0.80, P = 0.17; HR = 0.72, P = 0.02), poor differentiation (HR = 0.84, P = 0.35; HR = 0.85, P = 0.23; HR = 0.61, P = 0.41), lymphovascular or perineural invasion (HR = 0.55, P = 0.05; HR = 0.59, P = 0.11; HR = 0.76, P = 0.05) and emergency surgery (HR = 0.60, P = 0.02; HR = 0.68, P = 0.19). CONCLUSION: Adjuvant chemotherapy in high-risk Stage II colorectal cancer results in a modest survival improvement and should be considered on an individual patient basis. Due to potential heterogeneity and selection bias of the included studies, and lack of separate rectal cancer data, further large randomized trials with predefined inclusion criteria and standardized chemotherapy regimens are required.

Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Effectiveness of a multidisciplinary patient care bundle for reducing surgical-site infections.

BACKGROUND: Surgical-site infection (SSI) is associated with significant healthcare costs. To reduce the high rate of SSI among patients undergoing colorectal surgery at a cancer centre, a comprehensive care bundle was implemented and its efficacy tested. METHODS: A pragmatic study involving three phases (baseline, implementation and sustainability) was conducted on patients treated consecutively between 2013 and 2016. The intervention included 13 components related to: bowel preparation; oral and intravenous antibiotic selection and administration; skin preparation, disinfection and hygiene; maintenance of normothermia during surgery; and use of clean instruments for closure. SSI risk was evaluated by means of a preoperative calculator, and effectiveness was assessed using interrupted time-series regression. RESULTS: In a population with a mean BMI of 30 kg/m2 , diabetes mellitus in 17·5 per cent, and smoking history in 49·3 per cent, SSI rates declined from 11·0 to 4·1 per cent following implementation of the intervention bundle (P = 0·001). The greatest reductions in SSI rates occurred in patients at intermediate or high risk of SSI: from 10·3 to 4·7 per cent (P = 0·006) and from 19 to 2 per cent (P < 0·001) respectively. Wound care modifications were very different in the implementation phase (43·2 versus 24·9 per cent baseline), including use of an overlying surface vacuum dressing (17·2 from 1·4 per cent baseline) or leaving wounds partially open (13·2 from 6·7 per cent baseline). As a result, the biggest difference was in wound-related rather than organ-space SSI. The median length of hospital stay decreased from 7 (i.q.r. 5-10) to 6 (5-9) days (P = 0·002). The greatest reduction in hospital stay was seen in patients at high risk of SSI: from 8 to 6 days (P < 0·001). SSI rates remained low (4·5 per cent) in the sustainability phase. CONCLUSION: Meaningful reductions in SSI can be achieved by implementing a multidisciplinary care bundle at a hospital-wide level.

Lymph node yield in right colectomy for cancer: a comparison of open, laparoscopic and robotic approaches.

AIM: Studies have demonstrated a relationship between lymph node (LN) yield and survival after colectomy for cancer. The impact of surgical technique on LN yield has not been well explored. METHOD: This is a retrospective study of right colectomy (RC) for cancer at a single institution from 2012 to 2014. Exclusion criteria were previous colectomy and emergent and palliative operations. All data were collected by chart review. Primary outcomes were LN yield and the LN to length of surgical specimen (LN-LSS) ratio. Multivariable mixed models were created with surgeon and pathologist as random effects. Sensitivity analyses were performed to exclude Stage IV cancers and to analyse groups on an 'as-treated' basis. RESULTS: We identified 181 open (O-RC), 163 laparoscopic (L-RC) and 119 robotic (R-RC) right colectomies. O-RC was more commonly performed in women with metastatic disease. The mean LN yield was 28, 29 and 34 in O-RC, L-RC and R-RC, respectively; the respective mean LN-LSS ratios were 0.83, 0.91 and 1.0. The R-RC approach produced a higher LN yield than the other approaches (P < 0.01), and a higher LN-LSS ratio than O-RC (P < 0.01). These findings were unchanged in sensitivity analyses. CONCLUSION: Robotic right colectomy improves LN yield and the LN-LSS ratio, which may reflect better mesocolic excision. The effect of these findings on survival requires further investigation.

Methodological considerations and impact of school-based interventions on objectively measured physical activity in adolescents: a systematic review and meta-analysis.

OBJECTIVE: The aims of this systematic review and meta-analysis are (i) to determine the impact of school-based interventions on objectively measured physical activity among adolescents and (ii) to examine accelerometer methods and decision rule reporting in previous interventions. METHODS: A systematic search was performed to identify randomized controlled trials targeting adolescents (age: ≥10 years), conducted in the school setting, and reporting objectively measured physical activity. Random effects meta-analyses were conducted to determine the pooled effects of previous interventions on total and moderate-to-vigorous physical activity. Potential moderators of intervention effects were also explored. RESULTS: Thirteen articles met the inclusion criteria, and twelve were included in the meta-analysis. The pooled effects were small and non-significant for both total physical activity (standardized mean difference = 0.02 [95% confidence interval = -0.13 to 0.18]) and moderate-to-vigorous physical activity (standardized mean difference = 0.24 [95% confidence interval = -0.08 to 0.56]). Sample age and accelerometer compliance were significant moderators for total physical activity, with a younger sample and higher compliance associated with larger effects. CONCLUSION: Previous school-based physical activity interventions targeting adolescents have been largely unsuccessful, particularly for older adolescents. There is a need for more high-quality research using objective monitoring in this population. Future interventions should comply with best-practice recommendations regarding physical activity monitoring protocols.

Myeloid translocation genes differentially regulate colorectal cancer programs.

Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1-/- mice have progressive depletion of all intestinal secretory cells, and Mtg16-/- mice have a decrease in goblet cells. Furthermore, both Mtgr1-/- and Mtg16-/- mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc1638/+-dependent intestinal tumorigenesis. Mtgr1-/- mice, but not Mtg16-/- mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of chromatin immunoprecipitation sequencing data sets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1-/- tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context-dependent effect on intestinal tumorigenesis.

A Medium-Throughput Single Cell CRISPR-Cas9 Assay to Assess Gene Essentiality.

BACKGROUND: Target selection for oncology is a crucial step in the successful development of therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of specific loci offers an alternative method to RNA interference and small molecule inhibitors for determining whether a cell line is dependent on a specific gene product for proliferation or survival. In our initial studies using CRISPR-Cas9 to verify the dependence on EZH2 activity for proliferation of a SMARCB1/SNF5/INI1 mutant malignant rhabdoid tumor (MRT) cell line, we noted that the initial reduction in proliferation was lost over time. We hypothesized that in the few cells that retain proliferative capacity, at least one allele of EZH2 remains functional. To verify this, we developed an assay to analyze 10s-100s of clonal cell populations for target gene disruption using restriction digest and fluorescent fragment length analyses. RESULTS: Our results clearly show that in cell lines in which EZH2 is essential for proliferation, at least one potentially functional allele of EZH2 is retained in the clones that survive. CONCLUSION: This assay clearly indicates whether or not a specific gene is essential for survival and/or proliferation in a given cell line. Such data can aid the development of more robust therapeutics by increasing confidence in target selection.

Risk stratification by the Appendicitis Inflammatory Response score to guide decision-making in patients with suspected appendicitis.

BACKGROUND: Current management of suspected appendicitis is hampered by the overadmission of patients with non-specific abdominal pain and a significant negative exploration rate. The potential benefits of risk stratification by the Appendicitis Inflammatory Response (AIR) score to guide clinical decision-making were assessed. METHODS: During this 50-week prospective observational study at one institution, the AIR score was calculated for all patients admitted with suspected appendicitis. Appendicitis was diagnosed by histological examination, and patients were classified as having non-appendicitis pain if histological findings were negative or surgery was not performed. The diagnostic performance of the AIR score and the potential for risk stratification to reduce admissions, optimize imaging and prevent unnecessary explorations were quantified. RESULTS: A total of 464 patients were included, of whom 210 (63·3 per cent) with non-appendicitis pain were correctly classified as low risk. However, 13 low-risk patients had appendicitis. Low-risk patients accounted for 48·1 per cent of admissions (223 of 464), 57 per cent of negative explorations (48 of 84) and 50·7 per cent of imaging requests (149 of 294). An AIR score of 5 or more (intermediate and high risk) had high sensitivity for all severities of appendicitis (90 per cent) and also for advanced appendicitis (98 per cent). An AIR score of 9 or more (high risk) was very specific (97 per cent) for appendicitis, and the majority of patients with appendicitis in the high-risk group (21 of 30, 70 per cent) had perforation or gangrene. Ultrasound imaging could not exclude appendicitis in low-risk patients (negative likelihood ratio (LR) 1·0) but could rule-in the diagnosis in intermediate-risk patients (positive LR 10·2). CT could exclude appendicitis in low-risk patients (negative LR 0·0) and rule-in appendicitis in the intermediate group (positive LR 10·9). CONCLUSION: Risk stratification of patients with suspected appendicitis by the AIR score could guide decision-making to reduce admissions, optimize utility of diagnostic imaging and prevent negative explorations.

Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis.

In normal colon, claudin-7 is one of the highly expressed claudin proteins and its knockdown in mice results in altered epithelial cell homeostasis and neonatal death. Notably, dysregulation of the epithelial homeostasis potentiates oncogenic transformation and growth. However, the role of claudin-7 in the regulation of colon tumorigenesis remains poorly understood. Using a large colorectal cancer (CRC) patient database and mouse models of colon cancer, we found claudin-7 expression to be significantly downregulated in cancer samples. Most notably, forced claudin-7 expression in poorly differentiated and highly metastatic SW620 colon cancer cells induced epithelial characteristics and inhibited their growth in soft agar and tumor growth in vivo. By contrast, knockdown of claudin-7 in HT-29 or DLD-1 cells induced epithelial-to-mesenchymal transition (EMT), colony formation, xenograft-tumor growth in athymic mice and invasion. Importantly, a claudin-7 signature gene profile generated by overlapping the DEGs (differentially expressed genes in a high-throughput transcriptome analysis using claudin-7-manipulated cells) with human claudin-7 signature genes identified high-risk CRC patients. Furthermore, Rab25, a colon cancer suppressor and regulator of the polarized cell trafficking constituted one of the highly upregulated DEGs in claudin-7 overexpressing cells. Notably, silencing of Rab25 expression counteracted the effects of claudin-7 expression and not only increased proliferation and cell invasion but also increased the expression of p-Src and mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 that were suppressed upon claudin-7 overexpression. Of interest, CRC cell lines, which exhibited decreased claudin-7 expression, also exhibited promoter DNA hypermethylation, a modification associated with transcriptional silencing. Taken together, our data demonstrate a previously undescribed role of claudin-7 as a colon cancer suppressor and suggest that loss of claudin-7 potentiates EMT to promote colon cancer, in a manner dependent on Rab25.

Hepatic uterus-like mass misdiagnosed as hepatic abscess.

BACKGROUND: Hepatic endometriosis/uterus-like mass is rare and may be overlooked during hepatic cyst workups. We report a case of uterus-like mass, misdiagnosed as hepatic abscess. CASE REPORT: A 47-year-old woman developed abdominal pain and vomiting. Infectious colitis with hepatic abscess was diagnosed, and remained antibiotic-refractory. Fine-needle aspiration and core biopsies showed benign contents. The patient presented to our institution with symptoms and normal blood work. Laparoscopic excision demonstrated a 1.4-cm cyst composed of endometrial glands (estrogen receptor+ and progesterone receptor+) and stroma (CD10+) with smooth muscle actin (SMA+), arranged in an organoid fashion. The patient, status-post hysterectomy, had no history or symptoms of endometriosis. CONCLUSION: This rare case illustrates the merit of considering uterus-like mass/endometriosis in the differential diagnosis of antibiotic-refractory hepatic cysts. Cyst heterogeneity may confound needle biopsy. We report the first instance of a hepatic uterus-like mass, with a review of related entities, postulated histogenesis, and important clinical associations.

Experts reviews of the multidisciplinary consensus conference colon and rectal cancer 2012: science, opinions and experiences from the experts of surgery.

The first multidisciplinary consensus conference on colon and rectal cancer was held in December 2012, achieving a majority of consensus for diagnostic and treatment decisions using the Delphi Method. This article will give a critical appraisal of the topics discussed during the meeting and in the consensus document by well-known leaders in surgery that were involved in this multidisciplinary consensus process. Scientific evidence, experience and opinions are collected to support multidisciplinary teams (MDT) with arguments for medical decision-making in diagnosis, staging and treatment strategies for patients with colon or rectal cancer. Surgery is the cornerstone of curative treatment for colon and rectal cancer. Standardizing treatment is an effective instrument to improve outcome of multidisciplinary cancer care for patients with colon and rectal cancer. In this article, a review of the following focuses; Perioperative care, age and colorectal surgery, obstructive colorectal cancer, stenting, surgical anatomical considerations, total mesorectal excision (TME) surgery and training, surgical considerations for locally advanced rectal cancer (LARC) and local recurrent rectal cancer (LRRC), surgery in stage IV colorectal cancer, definitions of quality of surgery, transanal endoscopic microsurgery (TEM), laparoscopic colon and rectal surgery, preoperative radiotherapy and chemoradiotherapy, and how about functional outcome after surgery?

A comparative study of colorectal surgical outcome in a national audit separated by 15 years.

AIM: The Wales-Trent Bowel Cancer Audit (WTBA) was carried out in 1993, and since 2001 Welsh Bowel Cancer Audits (WBCA) have taken place annually. Screening for bowel cancer in Wales was introduced in 2008. This study compared patient variables, the role of surgery and operative mortality rates over the 15-year interval between the WTBA and the last WBCA before the introduction of population screening. METHOD: Data from the WTBA in 1993 were compared with those of the WBCA including patients diagnosed between April 2007 and March 2008. RESULTS: In 1993, 1536 patients were diagnosed with colorectal cancer (CRC) compared with 1793 in 2007-2008. Patient demographics and American Society of Anesthesiology (ASA) score did not change during these periods. Surgical treatment for CRC decreased (93% in 1993 vs 80% in 2007-2008; P < 0.001) particularly in the use of resectional surgery (84% in 1993 vs 71% in 2007-2008; P < 0.001). The 30-day postoperative mortality rate fell from 7.4% in 1993 to 5.9% in 2007-2008 (P = 0.097). Advanced disease at operation was more prevalent in the WTBA (25% of all operated patients were Stage IV in 1993 vs 13% in 2007-2008; P < 0.001). The use of surgery in patients with metastatic disease also declined over this period. CONCLUSION: Surgery is used less frequently in the management of CRC compared with 15 years previously, and is a factor in the reduction of the interpreted 30-day operative mortality.

Comparing cytosolic expression to peroxisomal targeting of the chimeric L1/L2 (ChiΔH-L2) gene from human papillomavirus type 16 in the methylotrophic yeasts Pichia pastoris and Hansenula polymorpha.

The chimeric ChiΔH-L2 gene from human papillomavirus type 16, consisting of structural proteins L1 and L2, was successfully expressed in the cytosol of both Pichia pastoris and Hansenula polymorpha during methanol induction. In addition, a novel approach was employed whereby ChiΔH-L2 was targeted to the peroxisome using peroxisomal targeting sequence 1 (PTS1) to compare ChiΔH-L2 yields in the peroxisome vs the cytosol. The ChiΔH-L2 gene was yeast-optimized and cloned into plasmids aimed at genomic integration. Levels of intracellular ChiΔH-L2 accumulation in the cytosol were highest in P. pastoris KM71 strain KMChiΔH-L2 (1.43 mg/l), compared to the maximum production level of 0.72 mg/l obtained with H. polymorpha. ChiΔH-L2 targeting to the peroxisome was successful; however, it appeared to negatively affect ChiΔH-L2 production in both P. pastoris and H. polymorpha.

Development of a social morbidity score in patients with chronic ulcerative colitis as a potential guide to treatment.

AIM: Present quality of life instruments for inflammatory bowel disease do not evaluate many social aspects of patients' lives that are potentially important in clinical decision making. We have developed a new Social Impact of Chronic Conditions - Inflammatory Bowel Disease (SICC-IBD) questionnaire to assess these areas. METHOD: A 34-item questionnaire was piloted to determine quality of life relating to education, personal relationships, employment, independence and finance. It was compared with the Short Form 36-Item version 2 (SF-36v2) and the Inflammatory Bowel Disease Questionnaire (IBDQ) in 150 patients with chronic ulcerative colitis on an endoscopic surveillance register who had never had surgery. RESULTS: Reliability and validity testing enabled the questionnaire to be shortened to only eight items. There was a high level of reliability (Cronbach's α=0.72). The questionnaire correlated well with the social functioning domain of the SF-36 (rs=0.56) and was able to distinguish clinical severity of disease. CONCLUSION: The SICC-IBD is a new tool for assessment of patients with ulcerative colitis, which has identified new aspects of social disability for further study and for potential use as an additional tool in therapy decisions.

The EURECCA project: Data items scored by European colorectal cancer audit registries.

AIMS: The EURECCA (European Registration of Cancer Care) consortium is currently formed by nine independently founded national colorectal audit registrations, of which most already run for many years. The cumulative experience of EURECCA's participants could be used to identify a 'core dataset' that covers all important aspects needed for high quality auditing and at the same time lacking needless data items that only consumes administrative effort. The aim of this study is to compare the data items used by the nine registries participating in EURECCA to identify a core dataset and explore options for future research. METHODS: All colorectal outcome registrations participating in the EURECCA project were asked to supply a list with all the data items they score. Items were scored 'present' if they appeared literally in a registration or in case they could be calculated using other items in the same registration. The definition of a 'shared data item' was that at least eight of the nine participating registries scored the item. RESULTS: The number of registered data items varied between 254 (Belgium) and 83 (Norway). Among the 45 variables were patient data, data about preoperative staging, surgical treatment, pre- or postoperative radio- and/or chemotherapy, and follow-up. Items about tumour recurrence or quality of life were scored too little to become shared data items. CONCLUSIONS: A total of 45 items were collected by 8 or more of the participating registries and subsequently met the criteria for a shared data item.

Claudin-2 expression increases tumorigenicity of colon cancer cells: role of epidermal growth factor receptor activation.

Claudin-2 is a unique member of the claudin family of transmembrane proteins, as its expression is restricted to the leaky epithelium in vivo and correlates with epithelial leakiness in vitro. However, recent evidence suggests potential functions of claudin-2 that are relevant to neoplastic transformation and growth. In accordance, here we report, on the basis of analysis of mRNA and protein expression using a total of 309 patient samples that claudin-2 expression is significantly increased in colorectal cancer and correlates with cancer progression. We also report similar increases in claudin-2 expression in inflammatory bowel disease-associated colorectal cancer. Most importantly, we demonstrate that the increased claudin-2 expression in colorectal cancer is causally associated with tumor growth as forced claudin-2 expression in colon cancer cells that do not express claudin-2 resulted in significant increases in cell proliferation, anchorage-independent growth and tumor growth in vivo. We further show that the colonic microenvironment regulates claudin-2 expression in a manner dependent on signaling through the EGF receptor (EGFR), a key regulator of colon tumorigenesis. In addition, claudin-2 expression is specifically decreased in the colon of waved-2 mice, naturally deficient in EGFR activation. Furthermore, genetic silencing of claudin-2 expression in Caco-2, a colon cancer cell line, prevents the EGF-induced increase in cell proliferation. Taken together, these results uncover a novel role for claudin-2 in promoting colon cancer, potentially via EGFR transactivation.

The National Bowel Cancer Audit Project: what do trusts think of the National Bowel Cancer Audit and how can it be improved?

PURPOSE: The National Bowel Cancer Audit Project (NBOCAP) collects data from hospitals in the UK and aims to improve surgical outcomes and quality of care for patients. The aims of this study were to understand why trusts were/were not participating in the NBOCAP and how to improve the quality of data collected and feedback. METHODS: This was a prospective e-survey on colorectal surgeons' attitudes towards and opinions of the NBOCAP, within trusts in the UK. A questionnaire was emailed to members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI). RESULTS: Of the 171 trusts contacted by email, 66% of trusts (n = 117) had at least 1 consultant respond. Of the 117 trusts that responded, 60 (51.2%) had submitted data to the NBOCAP. A total of 549 consultants received the questionnaire, and 159 (29.0%) consultants responded. Fifty-one per cent (n = 60) of the trusts had submitted data to the NBOCAP. Reasons for data submission included the following: comparison of a units' data with national data (56.8%), a national audit improves outcomes (45.9%) and generation of information for use at a local level (42.6%). The main reasons for non-submission were as follows: lack of technical support (23.6%), lack of funding (19.6%) and lack of dedicated audit time (18.9%). Ninety-six (60.4%) consultants felt that the audit report should identify individual trust results. Fifty-three per cent of consultants (n = 87) rated their trusts' resources for audit as being very poor or poor. CONCLUSION: Consultant members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) within hospital trusts in the UK feel participation in the National Bowel Cancer Audit improves patients' quality of care and surgical outcomes. Increased awareness of the benefits of the NBOCAP and improved allocation of resources from hospital trusts could improve participation.