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ObjectiveHigh-quality colonoscopy (adequate bowel preparation, whole-colon visualisation and removal of all neoplastic polyps) is a prerequisite to start polyp surveillance, and is ideally achieved in one colonoscopy. In a large multinational polyp surveillance trial, we aimed to investigate clinical practice variation in number of colonoscopies needed to enrol patients with low-risk and high-risk adenomas in polyp surveillance.DesignWe retrieved data of all patients with low-risk adenomas (one or two tubular adenomas ResultsThe study comprised 15 581 patients from 38 endoscopy centres in five European countries; 6794 patients had low-risk and 8787 had high-risk adenomas. 961 patients (6.2%, 95% CI 5.8% to 6.6%) underwent two or more colonoscopies before surveillance began; 101 (1.5%, 95% CI 1.2% to 1.8%) in the low-risk group and 860 (9.8%, 95% CI 9.2% to 10.4%) in the high-risk group. Main reasons were poor bowel preparation (21.3%) or incomplete colonoscopy/polypectomy (14.4%) or planned second procedure (27.8%). Need of repeat colonoscopy varied between study centres ranging from 0% to 11.8% in low-risk adenoma patients and from 0% to 63.9% in high-risk adenoma patients. On the second colonoscopy, the two most common reasons for a repeat (third) colonoscopy were piecemeal resection (26.5%) and unspecified reason (23.9%).ConclusionThere is considerable practice variation in the number of colonoscopies performed to achieve complete polyp removal, indicating need for targeted quality improvement to reduce patient burden.Trial registration numberNCT02319928.

Supplementary Figure 1 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 4 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 6 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Table 1, Methods and Materials, Figure Legends 1-6 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 5 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors. [Cancer Res 2009;69(10):4235–43]

Supplementary Figure 2 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Supplementary Figure 3 from Proteasome Inhibition Potentiates Antitumor Effects of Photodynamic Therapy in Mice through Induction of Endoplasmic Reticulum Stress and Unfolded Protein Response

Background Endoscopic screening with polypectomy reduces the incidence of colorectal cancer (CRC). Incomplete polyp removal may attenuate the effect of screening. This randomized trial compared cold snare polypectomy (CSP) with hot snare polypectomy (HSP) in terms of complete polyp resection. Methods We included patients ≥ 40 years of age at eight hospitals in four countries who had at least one non-pedunculated polyp of 4–9 mm detected at colonoscopy. Patients were randomized 1:1 to CSP or HSP. Biopsies from the resection margins were obtained systematically after polypectomy in both groups. We hypothesized that CSP would be non-inferior to HSP, with a non-inferiority margin of 5 %. Logistic regression models were fitted to identify the factors explaining incomplete resection. Results 425 patients, with 601 polyps, randomized to either CSP or HSP were included in the analysis. Of 318 polyps removed by CSP and 283 polyps removed by HSP, 34 (10.7 %) and 21 (7.4 %) were incompletely resected, respectively, with an adjusted risk difference of 3.2 % (95 %CI −1.4 % to 7.8 %). There was no difference between the groups in terms of post-polypectomy bleeding, perforation, or abdominal pain. Independent risk factors for incomplete removal were serrated histology (odds ratio [OR] 3.96; 95 %CI 1.63 to 9.66) and hyperplastic histology (OR 2.52; 95 %CI 1.30 to 4.86) in adjusted analyses. Conclusion In this randomized trial, non-inferiority for CSP could not be demonstrated. Polyps with serrated histology are more prone to incomplete resection compared with adenomas. CSP can be used safely for small polyps in routine colonoscopy practice.

Background: Although colonoscopy is widely used as a screening test to detect colorectal cancer, its effect on the risks of colorectal cancer and related death is unclear. Methods: We performed a pragmatic, randomized trial involving presumptively healthy men and women 55 to 64 years of age drawn from population registries in Poland, Norway, Sweden, and the Netherlands between 2009 and 2014. The participants were randomly assigned in a 1:2 ratio to either receive an invitation to undergo a single screening colonoscopy (the invited group) or to receive no invitation or screening (the usual-care group). The primary end points were the risks of colorectal cancer and related death, and the secondary end point was death from any cause. Results: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden - 28,220 in the invited group, 11,843 of whom (42.0%) underwent screening, and 56,365 in the usual-care group. A total of 15 participants had major bleeding after polyp removal. No perforations or screening-related deaths occurred within 30 days after colonoscopy. During a median follow-up of 10 years, 259 cases of colorectal cancer were diagnosed in the invited group as compared with 622 cases in the usual-care group. In intention-to-screen analyses, the risk of colorectal cancer at 10 years was 0.98% in the invited group and 1.20% in the usual-care group, a risk reduction of 18% (risk ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual-care group (risk ratio, 0.90; 95% CI, 0.64 to 1.16). The number needed to invite to undergo screening to prevent one case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual-care group (risk ratio, 0.99; 95% CI, 0.96 to 1.04). Conclusions: In this randomized trial, the risk of colorectal cancer at 10 years was lower among participants who were invited to undergo screening colonoscopy than among those who were assigned to no screening. (Funded by the Research Council of Norway and others; NordICC ClinicalTrials.gov number, NCT00883792.).

The European Society of Gastrointestinal Endoscopy (ESGE) presents a short list of performance measures for colonoscopy in inflammatory bowel disease (IBD) patients. Current performance measures for colonoscopy mainly focus on detecting (pre)malignant lesions. However, these performance measures are not relevant for all colonoscopy indications in IBD patients. Therefore, our aim was to provide endoscopy services across Europe and other interested countries with a tool for quality monitoring and improvement in IBD colonoscopy. Eight key performance measures and one minor performance measure were recommended for measurement and evaluation in daily endoscopy practice.

Nausea and vomiting can be either a symptom, or an adverse reaction to treatment. Metoclopramide is an effective agent that can be used to treat nausea and vomiting due to inhibition effect on dopamine D2 receptor and histamine 5-HT3 receptor, causing accelerated gastric emptying, as well as increased gut motility. It is effective in treatment of nausea and vomiting regardless of cause. Some conditions with evidence (based on randomized clinical trials) of metoclopramide effectiveness include migraine, diabetic gastroparesis, patients after chemo- or radiotherapy, after surgery. Even though there is a risk of serious adverse events (including extra-pyramidal syndrome), metoclopramide can be regarded as safe, assuming appropriate patient selection. It can be used also during pregnancy, as well as in pediatric setting, where long-lasting adverse outcomes are observed extremely rarely.

Current guidelines recommend a 10-year interval between screening colonoscopies, but evidence is limited.To assess the long-term risk for colorectal cancer (CRC) and death from CRC after a high- and low-quality single negative screening colonoscopy.Observational study.Polish Colonoscopy Screening Program.Average-risk individuals aged 50 to 66 years who had a single negative colonoscopy (no neoplastic findings).Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) of CRC after high- and low-quality single negative screening colonoscopy. High-quality colonoscopy included a complete examination, with adequate bowel preparation, performed by endoscopists with an adenoma detection rate of 20% or greater.Among 165 887 individuals followed for up to 17.4 years, CRC incidence (0.28 [95% CI, 0.25 to 0.30]) and mortality (0.19 [CI, 0.16 to 0.21]) were 72% and 81% lower, respectively, than in the general population. High-quality examination resulted in 2-fold lower CRC incidence (SIR, 0.16 [CI, 0.13 to 0.20]) and mortality (SMR, 0.10 [CI, 0.06 to 0.14]) than low-quality examination (SIR, 0.32 [CI, 0.29 to 0.35]; SMR, 0.22 [CI, 0.18 to 0.25]). In multivariable analysis, the hazard ratios for CRC incidence after high-quality versus low-quality colonoscopy were 0.55 (CI, 0.35 to 0.86) for 0 to 5 years, 0.54 (CI, 0.38 to 0.77) for 5.1 to 10 years, and 0.46 (CI, 0.25 to 0.86) for 10 to 17.4 years. Only after high-quality colonoscopy did the SIR and SMR for 10.1 to 17.4 years of follow-up not differ compared with earlier observation periods.The general population was used as the comparison group.A single negative screening colonoscopy was associated with reduced CRC incidence and mortality for up to 17.4 years. Only high-quality colonoscopy yielded profound and stable reductions in CRC incidence and mortality throughout the entire follow-up.Polish Ministry of Health.

The proportion of colonoscopies with at least one adenoma (adenoma detection rate [ADR]) is inversely associated with colorectal cancer (CRC) risk and death. The aim of this study was to examine whether such associations exist for colonoscopy quality measures other than ADR.We used data from the Polish Colorectal Cancer Screening Program collected in 2000-2011. For all endoscopists who performed ≥100 colonoscopies we calculated detection rates of adenomas (ADR), polyps (PDR), and advanced adenomas (≥10 mm/villous component/high-grade dysplasia [AADR]); and number of adenomas per colonoscopy (APC) and per colonoscopy with ≥1 adenoma (APPC). We followed patients until CRC diagnosed before recommended surveillance, death, or December 31, 2019. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional-hazard models. We used Harrell's C statistic to compare the predictive power of the quality measures.Data on 173,287 patients (median age, 56 years; 37.8% male) and 262 endoscopists were used. During a median follow-up of 10 years and 1,490,683 person-years, we identified 395 CRCs. All quality measures were significantly associated with CRC risk and death. The relative reductions in CRC risk were as follows: for ADR ≥24.9% (reference12.1%; HR, 0.41; 95% CI, 0.25-0.66), PDR ≥42.7% (reference19.9%; HR, 0.35; 95% CI, 0.24-0.51), AADR ≥9.1% (reference4.1%; HR, 0.69; 95% CI, 0.49-0.96), APC ≥0.37 (reference0.15; HR, 0.35; 95% CI, 0.21-0.58), and APPC ≥1.54 (reference1.19; HR, 0.54; 95% CI, 0.35-0.83). AADR was the only quality measure with significantly lower predictive power than ADR (Harrell's C, 59.7 vs 63.4; P = .001). Similar relative reductions were observed for CRC death.This large observational study confirmed the inverse association between ADR and CRC risk and death. The PDR and APC quality measures appear to be comparable with ADR.

Decision on drug usage during pregnancy is always a balancing between benefits and risks for pregnancy and for the fetus. Proton pump inhibitors are widely used for treatment of gastroesophageal reflux disease, which is also quite prevalent in pregnant women, especially during first trimester. Proton pump inhibitor safety during pregnancy is widely discussed for many years. Article published in “New England Journal of Medicine” in 2010 is considered as one of the most important research papers in this topic. The risk of birth defects in children of women using proton pump inhibitors during pregnancy was analysed basing on national medical registries. Authors show that there is no risk increase in comparison to general population, however in the commentary methodological considerations are discussed, allowing for informed results interpretation.

Background and Aims Inflammatory bowel disease is associated with an increased risk of colorectal cancer, with estimates ranging 2–18%, depending on the duration of colitis. The management of neoplasia in colitis remains controversial. Current guidelines recommend endoscopic resection if the lesion is clearly visible with distinct margins. Colectomy is recommended if complete endoscopic resection is not guaranteed. We aimed to assess the outcomes of all neoplastic endoscopic resections in inflammatory bowel disease. Methods This was a multicentre retrospective cohort study of 119 lesions of visible dysplasia in 93 patients, resected endoscopically in inflammatory bowel disease. Results A total of 6/65 [9.2%] lesions 20 mm in size were treated by EMR vs 35/51 [68.6%] by ESD. Almost all patients [97%] without fibrosis were treated by EMR, and patients with fibrosis were treated by ESD [87%], p < 0.001. In all, 49/78 [63%] lesions treated by EMR were resected en-bloc and 27/41 [65.9%] of the ESD/KAR [knife-assisted resection] cases were resected en-bloc, compared with 15/41 [36.6%] resected piecemeal. Seven recurrences occurred in the cohort. Seven complications occurred in the cohort; six were managed endoscopically and one patient with a delayed perforation underwent surgery. Conclusions Larger lesions with fibrosis are best treated by ESD, whereas smaller lesions without fibrosis are best managed by EMR. Both EMR and ESD are feasible in the management of endoscopic resections in colitis.

Background and study aims European guidelines (ESGE) recommend measuring patient experience and 30-day complication rate after colonoscopy. We compared digital and paper-based feedback on patients’ experience and 30-day complications after screening colonoscopy. Patients and methods Screenees attending for primary screening colonoscopies in two centers from September 2015 to December 2016 were randomized (1:1) to an intervention arm (choice of feedback method) or control arm (routine paper-based feedback). Participants in the intervention arm could choose preferred feedback method (paper-based, automated telephone or online survey) and were contacted by automated telephone 30 days after colonoscopy to assess complications. Control group participants self-reported complications. Primary and secondary endpoints were response rates to feedback and complications questionnaire, respectively. Results There were 1,281 and 1,260 participants in the intervention and control arms, respectively. There was no significant difference in response rate between study groups (64.8 % vs 61.5 %; P = 0.08). Free choice of feedback improved response for participants identified as poor responders: younger than 60 years (60.8 % vs 54.7 %; P = 0.031), male (64.0 % vs 58.6 %; P = 0.045) and in small non-public center (56.2 % vs 42.5 %; P = 0.043).In the intervention arm, 1,168 participants (91.2 %) answered the phone call concerning complications. A total of 79 participants (6.2 %) reported complications, of which two (0.2 %) were verified by telephone as clinically relevant. No complications were self-reported in the control group. Conclusion The overall response rate was not significantly improved with digital feedback, yet the technology yielded significant improvement in participants defined as poor responders. Our study demonstrated feasibility and efficacy of digital patient feedback about complications after colonoscopy.

Primary colonoscopy and fecal immunochemical testing (FIT) are considered first-tier tests for colorectal cancer (CRC) screening. Although colonoscopy is considered the most efficacious test, FIT might achieve higher participation rates. It is uncertain what the best strategy is for offering population-wide CRC screening.This was a multicenter randomized health services study performed within the framework of the Polish Colonoscopy Screening Program between January 2019 and March 2020 on screening-naïve individuals. Eligible candidates were randomly assigned in a 1:1:1 ratio to participate in 1 of 3 competing invitation strategies: control (invitation to screening colonoscopy only); sequential (invitation to primary colonoscopy and invitation for FIT for initial nonresponders); or choice (invitation offering a choice of colonoscopy or FIT). The primary outcome was participation in CRC screening within 18 weeks after enrollment into the study. The secondary outcome was diagnostic yield for advanced neoplasia.Overall, 12,485 individuals were randomized into the 3 study groups. The participation rate in the control group (17.5%) was significantly lower compared with the sequential (25.8%) and choice strategy (26.5%) groups (P.001 for both comparisons). The colonoscopy rates for participants with positive FITs were 70.0% for the sequential group and 73.3% for the choice group, despite active call-recall efforts. In the intention-to-screen analysis, advanced neoplasia detection rates were comparable among the control (1.1%), sequential (1.0%), and choice groups (1.1%).Offering a combination of FIT and colonoscopy as a sequential or active choice strategy increases participation in CRC screening. Increased participation in strategies with FIT do not translate into higher detection of advanced neoplasia. ClinicalTrials.gov, Number NCT03790475.

Colonoscopy surveillance after adenoma removal is an increasing burden in many countries. Surveillance recommendations consider characteristics of removed adenomas, but not colonoscopist performance. We investigated the impact of colonoscopist performance on colorectal cancer risk after adenoma removal.We compared colorectal cancer risk after removal of high-risk adenomas, low-risk adenomas, and after negative colonoscopy for all colonoscopies performed by colonoscopists with low vs high performance quality (adenoma detection rate20% vs ≥20%) in the Polish screening program between 2000 and 2011, with follow-up until 2017. Findings were validated in the Austrian colonoscopy screening program.A total of 173,288 Polish colonoscopies were included in the study. Of 262 colonoscopists, 160 (61.1%) were low performers, and 102 (38.9%) were high performers; 11.1% of individuals had low-risk and 6.6% had high-risk adenomas removed at screening; 82.2% had no adenomas. During 10 years of follow-up, 443 colorectal cancers were diagnosed. For low-risk adenoma individuals, colorectal cancer incidence was 0.55% (95% confidence interval [CI] 0.40-0.75) with low-performing colonoscopists vs 0.22% (95% CI 0.14-0.34) with high-performing colonoscopists (hazard ratio [HR] 2.35; 95% CI 1.31-4.21; P = .004). For individuals with high-risk adenomas, colorectal cancer incidence was 1.14% (95% CI 0.87-1.48) with low-performing colonoscopists vs 0.43% (95% CI 0.27-0.69) with high-performing colonoscopists (HR 2.69; 95% CI 1.62-4.47; P.001). After negative colonoscopy, colorectal cancer incidence was 0.30% (95% CI 0.27-0.34) for individuals examined by low-performing colonoscopists, vs 0.15% (95% CI 0.11-0.20) for high-performing (HR 2.10; 95% CI 1.52-2.91; P.001). The observed trends were reproduced in the Austrian validation cohort.Our results suggest that endoscopist performance may be an important contributor in addition to polyp characteristics in determining colorectal cancer risk after colonoscopy screening.

The European Society of Gastrointestinal Endoscopy and United European Gastroenterology present a short list of key performance measures for lower gastrointestinal endoscopy. We recommend that endoscopy services across Europe adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level: 1 Rate of adequate bowel preparation (minimum standard 90 %); 2 Cecal intubation rate (minimum standard 90%); 3 Adenoma de-tection rate (minimum standard 25%); 4 Appropriate polypectomy technique (minimum standard 80%); 5 Complication rate (minimum standard not set); 6 Patient experience (minimum standard not set); 7 Appropriate post-polypectomy surveillance recommendations (minimum standard not set). Other identified performance measures have been listed as less relevant based on an assessment of their importance, scientific acceptability, feasibility, usability, and comparison to competing measures.

Background The European Society of Gastrointestinal Endoscopy (ESGE) has published guidelines on key performance measures for colonoscopy. We analyzed whether those standards were met in the Polish Colonoscopy Screening Program (PCSP) and whether the monitoring was feasible. Methods We analyzed database records for 43 277 PCSP participants (25 PCSP centers) for the years 2014 – 2015. We used the guideline definitions to calculate values for all key performance measures and compared these with the proposed standards at individual, center, and program level. All data were acquired from the PCSP database, apart from complication data which was assessed from external registries. Results At the program level, four of five minimum standards and one of two target standards (no set minimum standard) were met. Adequate bowel preparation rate was 91.3 % for the whole program (range among individual centers 79.2 % – 99.2 %). Cecal intubation rate was 97.4 % (93.4 % – 99.4 %). Adenoma detection rate was 29.8 % (19.1 % – 39.1 %). An appropriate polypectomy technique was applied in 62.7 % of cases (0.4 % – 97.8 %). Regarding complications, 7-day hospitalization rate after screening colonoscopy was 0.3 % (n = 127), and 30-day all-cause mortality was 0.02 % (n = 9). Patient feedback was assessed in 66.2 % of colonoscopies (7.6 % – 81.8 %). Appropriate post-polypectomy surveillance was proposed in 95.4 % of cases (range 84.9 % – -99.7 %). It was easy to monitor 6 of 7 key performance measures within the PCSP database, but monitoring complications required the additional effort of data extraction from external registries. Conclusions The PCSP meets most proposed minimum standards at program level. Some centers need additional interventions to meet the complete set of quality standards. Use of ESGE performance measures for monitoring colonoscopy is generally feasible in the setting of the colonoscopy screening program.

It is difficult to quantify adverse events related to screening colonoscopy due to lack of valid and adequately powered comparison groups. We compared mortality and rate of unplanned hospitalizations among subjects who underwent screening colonoscopies within the Polish Colonoscopy Screening Program (PCSP) vs unscreened matched controls in Poland.Persons 55-64 years old living in the area covered by the PCSP from 2012 through 2015 were assigned in a (1:1) to a group invited for screening colonoscopy (n = 338,477) or a matched group that would be invited 5 years later (controls, n = 338,557). All subjects in the screening group were assigned proposed screening colonoscopy dates (actual dates when invitees confirmed or rescheduled colonoscopy) and those in the control group were assigned virtual dates corresponding to the matched individuals from the screening group. In the screening group, 55,390 subjects (16.4%) underwent screening colonoscopy. Mortality and hospitalization data were obtained from National Registries. We compared mortality and rate of hospitalization between the groups for defined intervals before and after colonoscopy date. Hospitalizations were divided into related and unrelated to colonoscopy based on ICD codes by 3 specialists. Our primary aim was to compare mortality and hospitalization 6 weeks before and 30 days following the actual or virtual date of colonoscopy in the screening or control group.In the intent to treat analysis, overall there were no significant differences in mortality between the colonoscopy group and control group (0.22% vs 0.22%; risk difference less than .01%; 95% CI, decrease of 0.02% to 0.02%; P = .913). The overall rate of unplanned hospitalization was significantly higher for the colonoscopy group (2.39% vs 2.31% for the control group; risk difference, 0.08%; 95% CI, 0.01%-0.15%; P=.026) for the entire observation period. This was due to the higher rate of hospitalizations after screening (1.10% vs 1.01% for the control group; risk difference, 0.09%; 95% CI, 0.04%-0.14%; P.001) including higher proportion of hospitalizations that were assessed as related to colonoscopy (0.24% vs 0.22% for the control group; risk difference, 0.02%; 95% CI, 0.00%-0.05%; P = .046). In the per-protocol analysis, the overall rate of hospitalizations did not differ significantly between control and screening colonoscopy groups (1.87% vs 1.90%; P=.709). However, screening colonoscopy did increase rates of related hospitalizations after the date of screening (from 0.14% to 0.31%; P.001).In an analysis of data from the PCSP, we found high-quality evidence that colonoscopy as a screening intervention does not increase mortality before or after colonoscopy. However, it may be associated with a small but significant increase in unplanned hospitalizations, especially after the colonoscopy is completed.

Background & Aims With advances in endoscopic imaging, it is possible to differentiate adenomatous from hyperplastic diminutive (1–5 mm) polyps during endoscopy. With the optical Resect-and-Discard strategy, these polyps are then removed and discarded without histopathology assessment. However, failure to recognize adenomas (vs hyperplastic polyps), or discarding a polyp with advanced histologic features, could result in a patient being considered at low risk for metachronous advanced neoplasia, resulting in an inappropriately long surveillance interval. We collected data from international cohorts of patients undergoing colonoscopy to determine what proportion of patients are high risk because of diminutive polyps advanced histologic features and their risk for metachronous advanced neoplasia. Methods We collected data from 12 cohorts (in the United States or Europe) of patients undergoing colonoscopy after a positive result from a fecal immunochemical test (FIT cohort, n = 34,221) or undergoing colonoscopies for screening, surveillance, or evaluation of symptoms (colonoscopy cohort, n = 30,123). Patients at high risk for metachronous advanced neoplasia were defined as patients with polyps that had advanced histologic features (cancer, high-grade dysplasia, ≥25% villous features), 3 or more diminutive or small (6–9 mm) nonadvanced adenomas, or an adenoma or sessile serrated lesion ≥10 mm. Using an inverse variance random effects model, we calculated the proportion of diminutive polyps with advanced histologic features; the proportion of patients classified as high risk because their diminutive polyps had advanced histologic features; and the risk of these patients for metachronous advanced neoplasia. Results In 51,510 diminutive polyps, advanced histologic features were observed in 7.1% of polyps from the FIT cohort and 1.5% polyps from the colonoscopy cohort (P = .044); however, this difference in prevalence did not produce a significant difference in the proportions of patients assigned to high-risk status (0.8% of patients in the FIT cohort and 0.4% of patients in the colonoscopy cohort) (P = .25). The proportions of high-risk patients because of diminutive polyps with advanced histologic features who were found to have metachronous advanced neoplasia (17.6%) did not differ significantly from the proportion of low-risk patients with metachronous advanced neoplasia (14.6%) (relative risk for high-risk categorization, 1.13; 95% confidence interval 0.79–1.61). Conclusion In a pooled analysis of data from 12 international cohorts of patients undergoing colonoscopy for screening, surveillance, or evaluation of symptoms, we found that diminutive polyps with advanced histologic features do not increase risk for metachronous advanced neoplasia.

ObjectiveTo estimate overdiagnosis of colorectal cancer (CRC) for screening with sigmoidoscopy and faecal occult blood testing (FOBT).DesignSimulation study using data from randomised trials.SettingPrimary screening, UK, NorwayParticipants152 850 individuals from the Nottingham trial and 98 678 individuals from the Norwegian Colorectal Cancer Prevention (NORCCAP) trial.InterventionCRC screening.Outcome measureWe estimated overdiagnosis using long-term data from two randomised trials: the Nottingham trial comparing FOBT screening every other year to no-screening, and the NORCCAP trial comparing once-only sigmoidoscopy screening to no-screening. To estimate the natural growth of adenomas to CRC, we used the following microsimulation models: (i) the Microsimulation Screening Analysis; (ii) the CRC Simulated Population model for Incidence and Natural history; (iii) the Simulation Model of Colorectal Cancer; (iv) a model derived by the German Cancer Research Center. We defined overdiagnosed cancers as the difference between the observed number of CRCs in the no-screening arm and the expected number of cancers in screening arm (sum of observed and prevented by adenoma removal). The amount of overdiagnosis is defined as the number of overdiagnosed cancers over the number of cancers observed in the no-screening arm.ResultsOverdiagnosis estimates were highly dependent on model assumptions. For FOBT screening with 2354 cancers observed in control arm, four out of five models predicted overdiagnosis, range 2.0% (2400 cancers expected in screening) to 7.6% (2533 cancers expected in screening). For sigmoidoscopy screening with 452 cancers observed in control arm, all models predicted overdiagnosis, range 25.2% (566 cancers expected in screening) to 128.1% (1031 cancers expected in screening).ConclusionsThe amount of overdiagnosis estimated based on the microsimulation models varied substantially. Microsimulation models may not give reliable estimates of the preventive effect of adenoma removal, and should be used with caution to inform guidelines.

ispartof: UNITED EUROPEAN GASTROENTEROLOGY JOURNAL vol:6 issue:7 pages:1108-1108 ispartof: location:England status: published

Introduction Cumulative colon cancer risk is estimated at 2%–18% depending on duration of colitis. Management of flat neoplasia in colitis remains controversial. BSG guidelines recommend colectomy if complete endoscopic resection isn’t guaranteed. Aim of this study was to assess need for surgery in the management of flat neoplasia in colitis. Methods A multicentre cohort study of all flat neoplasia endoscopically resected in colitis in 5 tertiary European centres from 2008–2017. Results 101 flat neoplasia were resected in 85 patients at 5 European centres. Mean age 61 years (range 28–82). Mean size of lesions 34 mm (range 8–120 mm). 40% of the lesions were treated by KAR. There was no difference in lesion location between EMR and KAR. Lesions >20 mm in size were removed more by KAR than EMR. More lesions removed by KAR (26) had fibrosis compared to EMR (15). 7 complications occurred in the cohort; 3 cases of bleeding and 4 perforations. Bleeding was controlled endoscopically. 3 perforations were managed endoscopically and 1 required surgery. 7/86 (8.1%) lesions with follow up data had recurrence. Multi-variate regression analysis concluded; 33. EMR leads to higher recurrence rates, irrespective of size, location and fibrosis (p–value of 0.048) 34. KAR leads to higher complication rates in the colon as compared to rectum (p–value of 0.045) 35. KAR shows a trend towards better en–bloc resection (p–value 0.063). 5 lesions underwent surgery; 3 due to cancer; 1 due to perforation; 1 due to failure of endoscopic resection. Histology; 88 adenoma (low-grade dysplasia), 6 adenoma (high-grade dysplasia), 3 cancers and 4 sessile serrated polyps. Conclusions This is the largest reported cohort of endoscopic resection of flat neoplasia in colitis. We demonstrate that both KAR and EMR are feasible in colitis with only 5% of patients requiring surgery. Fibrosis is very common in colitis. Recurrence is higher with EMR and complications higher with KAR. Our data shows that lesions with fibrosis are best treated by KAR, and those with fibrosis and

BACKGROUND: Screening flexible sigmoidoscopy (FSG) reduces incidence and mortality of colorectal cancer (CRC). Previously reported results from the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial had a median follow-up of 12 years. Whether the benefit is sustained over the long-term, and remains so in both sexes and all age groupings is uncertain. We report on long-term results after an additional 5 years of follow-up. METHODS: Participants in the PLCO (NCT00002540) were recruited from the general population in the catchment areas of 10 screening centers across the US, without previous diagnosis of a PLCO cancer or current cancer treatment. From 1993-2001, the PLCO randomized men and women aged 55-74 years within blocks stratified by center, age and sex to usual care or FSG at baseline and again at 3 or 5 years. The primary endpoint was cause-specific mortality and secondary endpoints included incidence and tumor staging; cause of death was determined without knowledge of study arm. Using an intent-to-treat analysis, we assessed incidence and mortality rates overall, by time-period, and by combinations of sex, age (55-64; 65-74), location (distal/proximal), and stage. FINDINGS: After a median follow-up of 15·8 years for incidence (25(th) 13·2 / 75(th) 18·0) and 16.8 years (14·4 / 18·9) for mortality, the incidence of CRC was significantly lower in the intervention arm (1461 cases; 12·55 per 10000 person-years (PY)) compared to usual care (1761 cases; 15.33 per 10000 PY; relative risk(RR)=0·82; 95% confidence interval (95%CI) 0·76–0·88). Similarly, mortality was lower in the intervention arm (417 deaths; 3·37 per 10000 PY) than the usual care arm (549; 4·48 per 10000 PY RR=0·75; 95%CI 0·66–0·85). The reduction in mortality was limited to the distal colon, with no significant effect in the proximal colon. Reductions in incidence were significantly larger in men than women (p(interaction)=0·04) and reductions in mortality were significantly larger in the older age group (65-74 vs. 55-64 at enrollment; p(interaction)=0·01). INTERPRETATION: Reduction in CRC incidence and mortality from FSG screening is sustained over the long-term. The benefit is limited to the distal colon, and the benefits are greater in men and in older people. Differences by sex and age should be examined in other ongoing trials of CRC screening to help clarify if different screening strategies would achieve greater risk reduction.

INTRODUCTION In Poland, anti-tumor necrosis factor (TNF) therapy for Crohn disease (CD) is reimbursed in inflammatory disease (CD activity index [CDAI]300 points) or perianal disease, in cases where conventional treatment has failed. OBJECTIVES We assessed patients receiving TNF inhibitors to establish how limited access to the therapy influences the selection of the population for treatment. PATIENTS AND METHODS Consecutive adult patients with CD starting infliximab or adalimumab in the years 2014 to 2015 were included in the study. Age at symptom onset and diagnosis of CD, disease location and behavior, previous treatment, CDAI, and body mass index (BMI) were evaluated. Subsequently, the age and sex of all patients with CD on anti‑TNF therapy reimbursed by the Polish National Health Fund were analyzed. RESULTS Among 256 patients, there were 113 women (44.1%) and 143 men (55.9%). The median time from diagnosis to enrollment was longer in women than in men (9 years vs 5.5 years; P = 0.02), and the proportion of women receiving TNF inhibitors for 5 years or less since diagnosis was lower than that of men (42.5% vs 57.7%; P = 0.017). Disease locations, behavior, and CDAI were similar between the groups, while the median BMI was lower in women than in men (20.6 kg/m2 vs 22.6 kg/m2; P = 0.01). In Poland in general, in the years 2010 to 2015, TNF inhibitors for CD were taken by fewer women than men (2208 vs 4789; 46%; 95% confidence interval, 45-48). The median age of treated women was 29 years and that of men-27 years (P0.001). CONCLUSIONS Compared with their male counterparts, women with CD receive TNF inhibitors less frequently, at an older age, and following a longer disease duration. It is unknown whether this is a regional or more widespread phenomenon.

INTRODUCTION In Poland, anti-tumor necrosis factor (TNF) therapy for Crohn disease (CD) is reimbursed in inflammatory disease (CD activity index [CDAI] >300 points) or perianal disease, in cases where conventional treatment has failed. OBJECTIVES We assessed patients receiving TNF inhibitors to establish how limited access to the therapy influences the selection of the population for treatment. PATIENTS AND METHODS Consecutive adult patients with CD starting infliximab or adalimumab in the years 2014 to 2015 were included in the study. Age at symptom onset and diagnosis of CD, disease location and behavior, previous treatment, CDAI, and body mass index (BMI) were evaluated. Subsequently, the age and sex of all patients with CD on anti‑TNF therapy reimbursed by the Polish National Health Fund were analyzed. RESULTS Among 256 patients, there were 113 women (44.1%) and 143 men (55.9%). The median time from diagnosis to enrollment was longer in women than in men (9 years vs 5.5 years; P = 0.02), and the proportion of women receiving TNF inhibitors for 5 years or less since diagnosis was lower than that of men (42.5% vs 57.7%; P = 0.017). Disease locations, behavior, and CDAI were similar between the groups, while the median BMI was lower in women than in men (20.6 kg/m2 vs 22.6 kg/m2; P = 0.01). In Poland in general, in the years 2010 to 2015, TNF inhibitors for CD were taken by fewer women than men (2208 vs 4789; 46%; 95% confidence interval, 45-48). The median age of treated women was 29 years and that of men-27 years (P

ObjectivePain associated with colonoscopy is a major burden for patients. We investigated modifiable factors associated with patient-reported pain during and after colonoscopy.DesignThis cross-sectional analysis included database records from 23 centres participating in a population-based colonoscopy screening programme in Poland. Colonoscopies were performed under three sedation modalities: none, benzodiazepine-opioid sedation or propofol sedation. We used Gastronet (a validated tool) to assess patients’ pain during and after colonoscopy; pain was scored on a four-point scale (no, little, moderate or severe pain), with moderate to severe defined as painful. We used multivariate logistic regression models to estimate ORs for painful colonoscopy and calculated risk-adjusted ratios of painful colonoscopies per endoscopist and compared it to the mean rate.ResultsOf 35 216 screening colonoscopies in 2014 and 2015 included in our study, 22 725 (64.5%) patients returned valid Gastronet questionnaires. The proportion of examinations described as causing pain during (after) the procedure was 22.5% (14.2%) for unsedated, 19.9% (13.5%) for benzodiazepine-opioid sedation and 2.5% (7.5%) for propofol sedation. Propofol sedation, higher case volume of endoscopists, newest endoscope generation and adequate bowel preparation were significantly associated with lower odds of painful colonoscopy. Pain scores after colonoscopy showed similar associations. Adjusted pain rates during and after colonoscopy varied 11 and over 23-fold, respectively, between endoscopists.ConclusionWe identified several independent, modifiable factors associated with pain during and after colonoscopy, of which individual endoscopist was the most important. Dedicated training should be considered to decrease variability among endoscopists.

Background and Aims Cytomegalovirus (CMV) often reactivates in the course of inflammatory bowel disease, but the significance of this remains disputable. Our aim was to evaluate whether severity of CMV colitis is associated with a colectomy risk in ulcerative colitis (UC) patients. The secondary aim was to evaluate agreement between immunohistochemistry (IHC) and blood CMV polymerase chain reaction (PCR). Methods UC patients with IHC CMV assessment in the colon hospitalized in a referral unit between 2005-2012 were retrospectively identified. The course and severity of the disease were analyzed, with inflammation graded histologically across the range 0-3. The numbers of IHC–positive cells per biopsy section were counted, while results for blood CMV PCR were also retrieved. Data on colectomies were also collected. Results Of 141 patients, 95 were analyzed, with 33 found to be IHC-positive, and 62 negative. The colectomy risk was significantly higher in patients with ≥5 IHC-positive cells, as opposed to those with none or less than 5 (p=0.014) with median follow-up of 1.9 and 3.2 years, respectively. The IHC-positive had lower hemoglobin (median 11.0 g/dl vs 12.0; p=0.028) and albumin (median 29.5 g/l vs 33.1; p=0.038) levels and more intense histologic inflammation (p=0.020) compared with the negative. There was substantial agreement between IHC and blood PCR (Cohen’s kappa coefficient 0.72). Conclusions Five or more CMV IHC-positive cells per biopsy section was indicative of a greater colectomy risk. CMV infection was related to more severe inflammation. Blood CMV PCR is a useful tool in UC.

IMPORTANCE Although some countries have implemented widespread colonoscopy screening, most European countries have not introduced it because of uncertainty regarding participation rates, procedure-related pain and discomfort, endoscopist performance, and effectiveness. To our knowledge, no randomized trials on colonoscopy screening currently exist. OBJECTIVE To investigate participation rate, adenoma yield, performance, and adverse events of population-based colonoscopy screening in several European countries. DESIGN, SETTING, AND POPULATION A population-based randomized clinical trial was conducted among 94959 men and women aged 55 to 64 years of average risk for colon cancer in Poland, Norway, the Netherlands, and Sweden from June 8, 2009, to June 23, 2014. INTERVENTIONS Colonoscopy screening or no screening. MAIN OUTCOMES AND MEASURES Participation in colonoscopy screening, cancer and adenoma yield, and participant experience. Study outcomes were compared by country and endoscopist. RESULTS Of 31 420 eligible participants randomized to the colonoscopy group, 12 574 (40.0%) underwent screening. Participation rates were 60.7% in Norway (5354 of 8816), 39.8% in Sweden (486 of 1222), 33.0% in Poland (6004 of 18 188), and 22.9% in the Netherlands (730 of 3194) (P < .001). The cecum intubation rate was 97.2%(12 217 of 12 574), with 9726 participants (77.4%) not receiving sedation. Of the 12 574 participants undergoing colonoscopy screening, we observed 1 perforation (0.01%), 2 postpolypectomy serosal burns (0.02%), and 18 cases of bleeding owing to polypectomy (0.14%). Sixty-two individuals (0.5%) were diagnosed with colorectal cancer and 3861 (30.7%) had adenomas, of which 1304 (10.4%) were high-risk adenomas. Detection rates were similar in the proximal and distal colon. Performance differed significantly between endoscopists; recommended benchmarks for cecal intubation (95%) and adenoma detection (25%) were not met by 6 (17.1%) and 10 of 35 endoscopists (28.6%), respectively. Moderate or severe abdominal pain after colonoscopy was reported by 601 of 3611 participants (16.7%) examined with standard air insufflation vs 214 of 5144 participants (4.2%) examined with carbon dioxide (CO2) insufflation (P < .001). CONCLUSIONS AND RELEVANCE Colonoscopy screening entails high detection rates in the proximal and distal colon. Participation rates and endoscopist performance vary significantly. Postprocedure abdominal pain is common with standard air insufflation and can be significantly reduced by using CO2.

Primary graft non-function (PNF) is a rare, life-threatening complication of liver transplantation. Increasing use of extended criteria donor pools and high-risk recipients seem to influence the incidence of PNF. Primary failure is associated with high patient morbidity and inferior graft survival. The only available treatment for PNF is emergency hepatic retransplantation, which is also correlated with significant morbidity and mortality. Therefore, researchers are working to identify risk factors of diagnostic value to prevent PNF. The current study attempted to explore liver proteomic patterns in patients with PNF. Using two-dimensional gel electrophoresis and liquid chromatography-mass spectrometry (LC-MS), we compared liver protein homogenates from 3 patients with PNF to those obtained from 6 healthy liver samples to identify potential new biomarkers of PNF. Our comparisons revealed 21 proteins with differential expression (13 upregulated and 8 downregulated). Most of these proteins are involved in energy metabolism, lipid metabolism, peptide cleavage, cell differentiation, and apoptosis. Although none of these proteins appeared more than once in separate analyses, this preliminary study shows that two-dimensional gel electrophoresis and LC-MS may allow identification of characteristic proteins to be used as biomarkers of a life-threatening complication of liver transplantation. Larger-scale analyses could improve patient care by finding suitable prognostic and therapeutic options. These data represent the first global proteomic approach to study PNF.

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca(2+) fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.

The aim of this analysis was to retrospectively review video recordings of malignant polyps10 mm in search for suspicious macroscopic features in white light endoscopy.Database entries and recordings of screening colonoscopies from a single tertiary referral center between June 2009 and December 2012 were reviewed. Malignant polyps10 mm were analyzed. The recordings were reviewed by two expert endoscopists in search for suspicious morphological features: irregular contours, central depression, contact bleeding, shape deformity, central depression, chicken skin sign, circumscribed area with abnormal vascular and/or surface pattern. Then, six experienced endoscopists watched the recordings in search of listed features. Next, video recordings of these malignant polyps were mixed with randomly drawn video recordings of 20 non-malignant polyps matched by size and reviewed by 14 blinded endoscopists to assess the sensitivity and specificity for the diagnosis of malignant polyps.Five of the 8651 (0.06%) subjects who underwent screening colonoscopy during the study period were diagnosed with a malignant polyp10 mm. Only one of them was ad hoc identified by performing endoscopist as suspicious. On recordings review performed by the experts, each of the four remaining polyps presented at least one suspicious macroscopic feature. Presence of these features was confirmed by experienced endoscopists. The sensitivity and specificity for the diagnosis of malignant polyp were 73.21% and 85.35%, respectively, if at least two suspicious macroscopic features defined malignant polyp.On careful white light endoscopy examination small malignant colorectal polyps show suspicious macroscopic features, which were frequently unrecognized by examining endoscopists.

Objective Since the initiation of the Liver Transplant Program, 500 liver procedures have been performed. Polycystic liver disease (PLD) and polycystic kidney-liver disease (PKLD) have been rare indications for orthotopic liver transplantation (OLT). Only 7 patients (1.4%) underwent transplantation due to PLD and PKLD. Materials and Methods The group consisted of 4 patients who underwent OLT (0.8%) and 3 patients who received simultaneous liver kidney transplantation (LKT; 0.6%). Our objective was to analyze the indications for either OLT or combined LKT as well as indications for surgical techniques during OLT among patients with PLD or PKLD. Results The main indication for OLT was massive hepatomegaly causing severe physical handicaps, fatigue, and clinically advanced malnutrition. All 3 patients with indications for combined LKT were dialysis-dependent. None of the patients had symptoms of end-stage liver disease and/or hepatic failure. In 4 cases, a portal bypass was applied, and the piggy-back method used in the other 3 cases. The hepatectomy caused no uncommon difficulty. In cases of simultaneous transplantations, the kidney was implanted separately after OLT. All patients are alive following the transplantation; major surgical complications have occurred. Conclusions Patients with PLD can undergo OLT safely with good results. They benefit from the relief of abdominal distension and anorexia. Patients with PKLD who are dialysis-dependent should undergo simultaneous LKT. The surgical technique was solely dependent on the intraoperative conditions determined during the dissection phase.

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors. [Cancer Res 2009;69(10):4235–43]

Background HO-1 participates in the degradation of heme. Its products can exert unique cytoprotective effects. Numerous tumors express high levels of HO-1 indicating that this enzyme might be a potential therapeutic target. In this study we decided to evaluate potential cytostatic/cytotoxic effects of zinc protoporphyrin IX (Zn(II)PPIX), a selective HO-1 inhibitor and to evaluate its antitumor activity in combination with chemotherapeutics. Methods Cytostatic/cytotoxic effects of Zn(II)PPIX were evaluated with crystal violet staining and clonogenic assay. Western blotting was used for the evaluation of protein expression. Flow cytometry was used to evaluate the influence of Zn(II)PPIX on the induction of apoptosis and generation of reactive oxygen species. Knock-down of HO-1 expression was achieved with siRNA. Antitumor effects of Zn(II)PPIX alone or in combination with chemotherapeutics were measured in transplantation tumor models. Results Zn(II)PPIX induced significant accumulation of reactive oxygen species in tumor cells. This effect was partly reversed by administration of exogenous bilirubin. Moreover, Zn(II)PPIX exerted potent cytostatic/cytotoxic effects against human and murine tumor cell lines. Despite a significant time and dose-dependent decrease in cyclin D expression in Zn(II)PPIX-treated cells no accumulation of tumor cells in G1 phase of the cell cycle was observed. However, incubation of C-26 cells with Zn(II)PPIX increased the percentage of cells in sub-G1 phase of the cells cycle. Flow cytometry studies with propidium iodide and annexin V staining as well as detection of cleaved caspase 3 by Western blotting revealed that Zn(II)PPIX can induce apoptosis of tumor cells. B16F10 melanoma cells overexpressing HO-1 and transplanted into syngeneic mice were resistant to either Zn(II)PPIX or antitumor effects of cisplatin. Zn(II)PPIX was unable to potentiate antitumor effects of 5-fluorouracil, cisplatin or doxorubicin in three different tumor models, but significantly potentiated toxicity of 5-FU and cisplatin. Conclusion Inhibition of HO-1 exerts antitumor effects but should not be used to potentiate antitumor effects of cancer chemotherapeutics unless procedures of selective tumor targeting of HO-1 inhibitors are developed.