Parameters predicting postoperative pain and quality of life after hemorrhoidectomy: follow-up results from a prospective multicenter randomized trial.

PURPOSE: Pain and reduced quality of life (QoL) are major subjects of interest after surgery for hemorrhoids. The aim of this study was to find predictive parameters for postoperative pain and QoL after hemorrhoidectomy. METHODS: This is a follow-up analysis of data derived from a multicenter randomized controlled trial including 770 patients, which examines the usefulness of tamponade after hemorrhoidectomy. Different pre-, intra-, and postoperative parameters were correlated with pain level assessed by NRS and QoL by the EuroQuol. RESULTS: At univariate analysis, relevant (NRS > 5/10 pts.) early pain within 48 h after surgery was associated with young age (≤ 40 years, p = 0.0072), use of a tamponade (p < 0.0001), relevant preoperative pain (p = 0.0017), pudendal block (p < 0.0001), and duration of surgery (p = 0.0149). At multivariate analysis, not using a pudendal block (OR 2.64), younger age (OR 1.55), use of a tamponade (OR 1.70), and relevant preoperative pain (OR 1.56) were significantly associated with relevant early postoperative pain. Relevant pain on day 7 was significantly associated only with relevant early pain (OR 3.13, p < 0.001). QoL overall remained at the same level. However, n = 229 (33%) patients presented an improvement of QoL and n = 245 (36%) an aggravation. Improvement was associated with a reduction of pain levels after surgery (p < 0.0001) and analgesia with opioids (p < 0.0001). CONCLUSION: Early relevant pain affects younger patients but can be prevented by avoiding tamponades and using a pudendal block. Relevant pain after 1 week is associated only with early pain. Relief in preexisting pain and opioids improve QoL. TRIAL REGISTRATION: DRKS00011590 12 April 2017.

Advancement Flap for Treatment of Complex Cryptoglandular Anal Fistula: Prediction of Therapy Success or Failure Using Anamnestic and Clinical Parameters.

BACKGROUND: Multiple new procedures for treatment of complex anal fistula have been described in the past decades, but an ideal single technique has yet not been identified. Factors that predict the outcome are required to identify the best procedure for each individual patient. The aim of this study was to find those predictors for advancement flap at midterm follow-up. METHODS: From 2012 to 2015 in a tertiary university clinic, all patients who underwent advancement flap for treatment of complex cryptoglandular fistula were prospectively enrolled. Pre- and postoperatively standardized anamnestic and clinical examinations were performed. Predictive factors for therapy failure were identified using univariate and multivariate analysis. RESULTS: Out of 65 patients, 61 (93%) completed all examinations and were included in the study. Therapy failure after a mean follow-up period of 25 months occurred in total n = 11 patients (18%). There was no significant disturbance of continence among the entire study cohort as shown by the incontinence score (preop 0.34 ± 0.91 pts., postop 0.37 ± 0.97 pts.; p = 0.59). Univariate analysis for risk factors for therapy failure revealed age (p = 0.004), history of surgical abscess drainage (p = 0.04), BMI (p = 0.002), suprasphincteric fistula (p = 0.019) and horseshoe abscess (p = 0.036) as independent parameters for therapy failure. During multivariate analysis, only history of surgical abscess drainage (OR = 8.09, p = 0.048, 95% CI 0.98-64.96), suprasphincteric fistula (OR = 6.83, p = 0.032, 95% CI 1.17-6.83) and BMI (OR = 1.23, p = 0.017, 95% CI 1.03-1.46) were independent parameters for therapy failure. CONCLUSION: Advancement flap for treatment of complex fistula is effective and has low risk of disturbed continence. BMI, suprasphincteric fistula and history of surgical abscess drainage are predictors for therapy failure.

Quality of life after laparoscopic resection rectopexy.

PURPOSE: This study evaluated continence, constipation, and quality of life (QoL) after laparoscopic resection rectopexy (LRR) for full-thickness rectal prolapse. Results were compared with existing data after perineal rectosigmoidectomy (PRS). METHODS: From May 2003 to February 2008, consecutive patients suffering from full-thickness rectal prolapse undergoing LRR were retrospectively studied. A standardized questionnaire including the Cleveland Clinic Constipation and Incontinence Scores (CCCS and CCIS) as well as general and constipation-related QoL scores (EQ-5D and PAC-QOL) was administered. Results were compared with those after PRS. For statistic analysis, the Wilcoxon test (EQ-5D and EQ-VAS) and two-sample Student's t test (CCCS, CCIS, and PAC-QOL) were used for LRR, for the comparison of both procedures Mann-Whitney test (EQ-5D) and two-sample Student's t test (EQ-VAS, CCCS, CCIS, and PAC-QOL). RESULTS: Eighteen patients, 15 female, aged 58.1 (±20.2) years underwent LRR. Eleven patients completed follow-up. Postoperatively, neither functional outcome nor QoL improved. Two recurrences occurred, morbidity was n = 2, and mortality n = 1. In comparison, patients after PRS benefit from improved constipation, general QoL measures, status of health, and all dimensions of constipation-related QoL. CONCLUSIONS: Patients after LRR do not benefit from improved general nor constipation-related QoL nor improved functional results compared to PRS.

Risk factors for therapy failure after surgery for perianal abscess in children.

Purpose: The role of surgery in managing perianal abscesses in the pediatric population is debatable, and data on recurrence risk is rare. This study aimed to evaluate the efficiency of surgery for a perianal abscess in children and identify parameters that predict recurrence. Methods: We performed a retrospective review of all children younger than age 14 requiring surgery for a perianal abscess from 2000 to 2018. Results: Out of 103 enrolled patients, 27 (26%) had recurrent perianal disease. Recurrences appeared after a median of 5 months (range: 1-18 months), in 12 cases as perianal abscess and 15 cases as fistula in ano. Anal fistula probing was performed in 33% of all patients, of which 16 (15%) underwent fistulotomy. In univariate analysis, older age (p = 0.034), fistula probing (p = 0.006) and fistulotomy (p = 0.009) was associated with treatment success. History of perianal abscess, multilocal occurrence, and the presence of enteric flora in wound swabs was associated with treatment failure (p = 0.002, OR = 0.032). In multivariate analysis, anal fistula probing was independently associated with treatment success (p = 0.019, OR = 22.08), while the history of perianal abscess was associated with treatment failure (p = 0.002, OR = 0.032). Conclusion: Our study identified probing for fistula as a predictor of therapy success, while the history of perianal abscess was identified as a predictor of treatment failure. Therefore, in all children with perianal abscess, fistula probing and if present, fistulotomy should be performed.

What happens in stapled transanal rectum resection?

INTRODUCTION: Stapled transanal rectum resection is becoming increasingly popular as a surgical option for the treatment of obstructive defecation syndrome. However, details about the anatomical changes produced by stapled transanal rectum resection and its correlation with success or failure is poorly understood. The aim of this study was to correlate the defecographical and clinical patterns in patients treated with stapled transanal rectum resection. PATIENTS AND METHODS: Based on a multi-institutional stapled transanal rectum resection registry composed of a total of 182 patients, correlation analysis of clinical and radiological parameters was prospectively obtained from 51 patients with a completed 12-month follow-up. RESULTS: Postoperative defecography shows significant changes in the following parameters: intussusception (89%-19%; P < .0001), enterocele (38%-18%; P = .038), rectocele (mean ± SD: 27.1 ± 7.4 mm to 16.5 ± 9.7 mm; P < .0001), rectal lumen (mean ± SD: 46 ± 11.4 mm to 35 ± 9.9 mm; P < .0001), anorectal angle (mean ± SD: 146.4 ± 10.6° to 132.4 ± 11.1°; P = .002), pelvic floor descent (mean ± SD: 59 ± 18 mm to 47 ± 1.3 mm; P = .0001), and, as a dynamic parameter, dynamic pelvic floor descent (mean ± SD: 30 ± 0.8 mm to 17 ± 0.4 mm; P < .0001). Of these parameters, reduction of intussusception (r = 0.433, 95% CI 0.15-0.61; P = .003), rectocele (r = 0.507, 95% CI 0.26-0.67; P = .001), and dynamic pelvic floor descent (r = 0.427, 95% CI 0.31-0.64; P = .001) correlated with a significant improvement in constipation. Reduction of intussusception positively affected postoperative continence (r = 0.524, 95% CI 0.29-0.70; P = .001), whereas reduced rectal lumen size correlated with incontinence and fecal urgency (r = -0.557, 95% CI -0.69 to -0.28; P = .001). CONCLUSIONS: Improved constipation after stapled transanal rectum resection is associated with improvement of intussusception, rectocele, and dynamic pelvic floor descent. Postoperative continence is determined by 2 parameters, reduction of intussusception and rectal lumen size, which have opposing effects. Reduction of rectal lumen size may be responsible for new-onset fecal urgency, which is occasionally seen after stapled transanal rectum resection.

The concurrence of histologically positive resection margins and sessile morphology is an important risk factor for lymph node metastasis after complete endoscopic removal of malignant colorectal polyps.

INTRODUCTION: The optimal procedure to be followed after colonoscopic polypectomy of malignant colorectal polyps with nontumour-free resection margins at histology is a matter of controversy. While some authors recommend merely local or segmental follow-up resection, others favour an oncological resection. PATIENTS AND METHODS: One hundred five patients, each with a single malignant polyp, were investigated. Patients with a macroscopically evident malignant polyp and those in whom the endoscopist reported incomplete polypectomy were excluded from the study. RESULTS: Postpolypectomy morbidity was 4%, and postoperative was 14%. In only 39 cases were the resection margins adjudged to be tumour-free. Histology following subsequent surgery or the follow-up examinations revealed a local recurrence or residual carcinoma at the polypectomy site in only three (2.8%) cases and lymph node metastasis in eight (7.6%) cases. Five patients had remnant adenoma at the polypectomy site. Of the high-risk factors, histological incomplete removal (n = 66, p = 0.04, odds ratio (OR) 10.2) and lymph vessel infiltration (n = 7, p = 0.02, OR 9.2) revealed a significant correlation with lymph node metastasis, but not with remnant tumour. In the case of sessile polyp, the assessment of histological incomplete removal was highly significantly correlated with lymph node metastasis (n = 55, p = 0.007, OR 18.1). CONCLUSIONS: Polypectomy artefacts appear to be responsible for the discrepancy between histology and the tumour remnants actually present. On the other hand, histologically incompletely removed sessile malignant polyps represent an appreciably higher risk for lymph node metastasis. Such cases should, therefore, be submitted to further oncological resection.

Efficacy of conservative treatment of perianal abscesses in children and predictors for therapeutic failure.

BACKGROUND: The optimal management of perianal abscess in children is controversial. PURPOSE: To evaluate the efficiency of conservative treatment of perianal abscess in children and identify parameters that predict therapy failure. METHODS: All cases of children younger than 14 years of age with perianal abscesses between 2001-2016 were evaluated. RESULTS: Of the 113 enrolled patients, 64 underwent subsequent surgery for advanced disease (primary surgery group). Conservative treatment was initiated in 49 patients (primary conservative group) but was stopped because of inefficiency in 25 patients, who were referred for surgery after a median 7.03 days (range, 2 to 16 days). The other 24 patients (48%) initially achieved complete remission after conservative treatment, but 10 were readmitted after a median 34 months (range, 3 to 145 months) with recurrent disease. There were no significant differences in permanent success after conservative treatment between infants (10 of 29, 34%) and older children (4 of 20 [20%], P=0.122). Overall, conservative treatment alone was effective in only 14 of 113 patients. Recurrence after surgery occurred in 16 patients (25%) in the primary surgery group and 11 patients (22%) in the primary conservative group (P=0.75). Univariate analysis of predictors for conservative treatment failure revealed inflammatory values (C-reactive protein and white blood count, P=0.017) and abscess size (P=0.001) as significant parameters, whereas multivariate analysis demonstrated that only abscess size (odds ratio, 3.37; P=0.023) was significant. CONCLUSION: Conservative treatment of perianal abscess is permanently efficient in only a minority of children but is not associated with a higher recurrence rate after subsequent surgery. Abscess size is a predictor for therapy failure.

Efficient dose-dependent and time-dependent protein transduction of pancreatic carcinoma cells in vitro and in vivo using purified VP22-EGFP fusion protein.

We constructed a prokaryotic vector expressing a truncated VP22-EGFP gene and purified this fusion protein from Escherichia coli cultures using nickel resin. Application of purified VP22-EGFP protein to human pancreatic carcinoma cells showed a highly efficient time-dependent and dose-dependent uptake and resulted in green fluorescence predominantly located in the nuclei of treated cells. Purified VP22-EGFP efficiently translocated into deeper layers of pancreatic tumor cell spheroids. Homogeneous uptake into the whole tumor was observed after peritumoral injection in human pancreatic tumors in SCID mice. We conclude that the direct application of purified VP22 fusion proteins offers a new, peptide-mediated and potentially systemic therapy for pancreatic cancer. This opens the possibility of achieving specific antitumor effects induced by fused apoptosis-enhancing proteins.

Ganciclovir prodrug therapy is effective in a murine xenotransplant model of human lung cancer.

BACKGROUND: Therapy failures have been reported for retroviral gene transfer of herpes simplex virus thymidine kinase (HSV-TK) gene followed by systemic ganciclovir application in human lung cancer. Use of the HSV-TK mutant TK30 in combination with a VSV-G pseudotyped retroviral vector was found to enhance the efficacy of prodrug therapy. The present study evaluated this therapeutic strategy in human non-small cell lung cancer cell lines in a preclinical murine xenotransplant model. METHODS: Intrathoracally induced by HSV-TK30 transduced non-small cell lung cancer cell lines Colo 699 (adenocarcinoma) and KNS 62 (squamous cell carcinoma) were monitored for local tumor growth, survival, and metastases. So-called bystander effects were investigated in tumors consisting of as little as 25% TK30 transfected cells and by analysis of gap junctional protein connexin-43 expression. RESULTS: Survival was significantly prolonged, and tumor growth and pleural metastases were reduced in HSV-TK30-positive tumors of both cell lines. A significant therapeutic effect in bystander experiments was observed in squamous cell carcinoma. This was correlated with higher expression of connexin-43. CONCLUSIONS: Delivery of HSV-TK30 in a VSV-G pseudotyped retroviral vector and subsequent ganciclovir application provided therapeutic efficacy. Despite of low transduction rates achievable in gene transfer in situ, prodrug therapy appears to be feasible in tumor cells with efficient bystander effects.

Resistance developing after long-term ganciclovir prodrug treatment in a preclinical model of NSCLC.

BACKGROUND: We recently demonstrated a 100% increase in the survival period with ganciclovir (GCV) therapy in mice hearing orthotopic HSV-TK-positive non-small cell lung cancer (NSCLC) tumors. However, long-term survival was not achieved. The aim of the present study was to evaluate tumor growth during extended GCV therapy and to monitor the herpes simplex virus thymidine kinase (HSV-TK) gene and protein in tumors at different time points. MATERIALS AND METHODS: The human NSCLC cell line KNS 62 was retrovirally transduced with the HSV-TK30 gene. Cell suspensions in which 100% or 25% of the cells were TK30-positive were inoculated subcutaneously in SCID bg mice. Tumor growth was evaluated during GCV therapy and HSV-TK DNA, RNA and protein were analyzed at different time points using PCR, RT-PCR and immunoblotting. RESULTS: HSV-TK DNA, RNA and TK30 protein were demonstrated in the tumors 21 days after subcutaneous tumor inoculation. TK-positive tumors regressed during GCV therapy and tumors in which 25% of the cells were TK-positive grew significantly more slowly than control tumors did. After 4 weeks of GCV therapy, HSV-TK DNA, RNA and TK protein were not detectable in the remaining tumors, which were therefore resistant to further GCV therapy. CONCLUSION: Prodrug therapy of the NSCLC cell line KNS 62, including bystander effects, is sufficient. Nevertheless, GCV-resistant tumors develop after functional loss of the TK gene. In the clinical context, further studies will need to evaluate immunological bystander effects or combinations with other drugs.

Gene transfer and expression of enhanced green fluorescent protein in variant HT-29c cells.

AIM: To study the expression of enhanced green fluorescent protein (EGFP) gene in retrovirally transduced variant HT-29 cells. METHODS: The retroviral vector prkat EGFP/neo was constructed and transfected into the 293T cell using a standard calcium phosphate precipitation method. HT-29c cells (selected from HT-29 cells) were transduced by a retroviral vector encoding the GEFP gene. The fluorescence intensity of colorectal carcinoma HT-29c cells after transduced with the EGFP bearing retrovirus was visualized using fluorescence microscope and fluorescence activated cell sorter (FACS) analysis. Multiple biological behaviors of transduced cells such as the proliferating potential and the expression of various antigens were comparatively analyzed between untransduced and transduced cells in vitro. EGFP expression of the fresh tumor tissue was assessed in vivo. RESULTS: After transduced, HT-29c cells displayed a stable and long-term EGFP expression under the nonselective conditions in vitro. After cells were successively cultured to passage 50 in vitro, EGFP expression was still at a high level. Their biological behaviors, such as expression of tumor antigens, proliferation rate and aggregation capability were not different compared to untransduced parental cells in vitro. In subcutaneous tumors, EGFP was stable and highly expressed. CONCLUSION: An EGFP expressing retroviral vector was used to transduce HT-29c cells. The transduced cells show a stable and long-term EGFP expression in vitro and in vivo. These cells with EGFP are a valuable tool for in vivo research of tumor metastatic spread.

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo.

BACKGROUND AND AIMS: Recently we demonstrated that phosphatidylinositol 3-kinase (PI3K) is overexpressed in human lung cancer. This study evaluated whether the PI3K inhibiting agent wortmannin affects proliferation of human lung cancer cells in vitro and in vivo. METHODS: Effects of exposure of human non-small-cell lung cancer (NSCLC) cells (KNS-62, Colo-699) to wortmannin were investigated in vitro by proliferation, cytotoxicity, and DNA fragmentation assays. In vivo we examined the effects of blocking PI3K by wortmannin prior to xenotransplantation of human NSCLC cells into SCID-bg mice and the effect of systemic wortmannin administration following intrapulmonary xenotransplantation of human NSCLC. RESULTS: Exposure of KNS-62 and Colo-699 lung cancer cells to wortmannin inhibited proliferation in correlation to concentration in vitro. In vivo the blocking of PI3K by wortmannin prior to xenotransplantation caused a significant delay in the growth of subcutaneously induced tumors. Systemic wortmannin administration increased mean survival after intrapulmonary xenotransplantation of human NSCLC significantly by 38% and 47%. CONCLUSIONS: These data suggest inhibition of PI3K activity as a potential target for treatment of human NSCLC. Systemic toxicity of wortmannin requires development of improved PI3K inhibitors with favorable pharmacological properties.

Retroviral endostatin gene transfer inhibits growth of human lung cancer in a murine orthotopic xenotransplant model.

BACKGROUND AND AIMS: The administration of endostatin, a potent anti-angiogenic agent, will be required for extended periods of time as a cancer treatment. The aim of the present study was to induce endogenous endostatin secretion in a continuous fashion, based on retroviral gene transfer. The tumor response was evaluated in an orthotopic murine tumor model of human lung cancer. MATERIALS AND METHODS: Human non-small-cell lung cancer cells (KNS 62) were retrovirally transduced with the human endostatin gene. An orthotopic murine xenotransplant model was used to investigate tumor growth, metastases and survival. After 4 weeks of subcutaneous growth, endostatin expression was measured by immunoblot analysis in tumor lysates. RESULTS: The growth of the subcutaneous tumors was significantly delayed, and orthotopic tumor growth and pleural metastases were significantly reduced in endostatin-transduced KNS 62 tumors. Prolongation of survival subsequent to orthotopic tumor induction was demonstrated. Strong endostatin expression was found in subcutaneous tumors after 4 weeks. CONCLUSION: Retroviral transduction of the human endostatin gene is capable of achieving long-term endostatin expression. Endostatin transduction provides significant anti-tumor effects with regard to local tumor growth, metastases and survival.