High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer.

BACKGROUND: Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking. METHODS: More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results. RESULTS: At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p < 0.0001). The number of intratumoral CD8+ lymphocytes was strikingly higher in PD-L1 positive (939.5 ± 118.2) than in PD-L1 negative cancers (310.5 ± 24.8). A higher number of intratumoral CD8+ lymphocytes was found in dMMR CRC (PD-L1 positive: 1999.7 ± 322.0; PD-L1 negative: 398.6 ± 128.0; p < 0.0001) compared to pMMR CRC (PD-L1 positive: 793.2 ± 124.8; PD-L1 negative: 297.2 ± 24.2; p < 0.0001). In dMMR and pMMR CRC, PD-L1 expression in tumor cells was unrelated to tumor stage, lymph node status or lymphatic/venous invasion. PD-L1 positivity in tumor associated immune cells was seen in 47.5% of cases and was significantly linked to high numbers of tumor infiltrating CD8+, low tumor stage, and absence of lymph node metastasis and lymphatic/venous invasion (p < 0.0001 each). CONCLUSION: The data support the previously suggested fact that PD-L1 expression in tumor cells is driven by extensive cytotoxic T-cell infiltration in highly immunogenic dMMR and pMMR CRC. Frequent and intense PD-L1 expression in tumor cells of dMMR CRC may contribute to the high response rates of dMMR CRC to immune checkpoint-inhibitors.

Elevated MUC5AC expression is associated with mismatch repair deficiency and proximal tumor location but not with cancer progression in colon cancer.

Mucin 5AC (MUC5AC) is a secreted gel-forming mucin expressed by several epithelia. In the colon, MUC5AC is expressed in scattered normal epithelial cells but can be abundant in colorectal cancers. To clarify the relationship of MUC5AC expression with parameters of tumor aggressiveness and mismatch repair deficiency (dMMR) in colorectal cancer, a tissue microarray containing 1812 colorectal cancers was analyzed by immunohistochemistry. MUC5AC expression was found in 261 (15.7%) of 1,667 analyzable colorectal cancers. MUC5AC expression strongly depended on the tumor location and gradually decreased from proximal (27.4% of cecum cancers) to distal (10.6% of rectal cancers; p < 0.0001). MUC5AC expression was also strongly linked to dMMR. dMMR was found in 21.3% of 169 cancers with MUC5AC positivity but in only 4.6% of 1051 cancers without detectable MUC5AC expression (p < 0.0001). A multivariate analysis showed that dMMR status and tumor localization predicted MUC5AC expression independently (p < 0.0001 each). MUC5AC expression was unrelated to pT and pN status. This also applied to the subgroups of 1136 proficient MMR (pMMR) and of 84 dMMR cancers. The results of our study show a strong association of MUC5AC expression with proximal and dMMR colorectal cancers. However, MUC5AC expression is unrelated to colon cancer aggressiveness.

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes.

BACKGROUND: Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking. METHODS: To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. RESULTS: In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p < 0.0001), suggesting a role of MSI for immune response. CONCLUSIONS: Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.

Anorectal angle at rest predicting successful sacral nerve stimulation in idiopathic fecal incontinence-a cohort analysis.

PURPOSE: Sacral nerve stimulation is an effective treatment for patients suffering from fecal incontinence. However, less is known about predictors of success before stimulation. The purpose of this study was to identify predictors of successful sacral nerve stimulation in patients with idiopathic fecal incontinence. METHODS: Consecutive female patients, receiving peripheral nerve evaluation and sacral nerve stimulation between September 2008 and October 2014, suffering from idiopathic fecal incontinence were included in this study. Preoperative patient's characteristics, anal manometry, and defecography results were collected prospectively and investigated by retrospective analysis. Main outcome measures were independent predictors of treatment success after sacral nerve stimulation. RESULTS: From, all in all, 54 patients suffering from idiopathic fecal incontinence receiving peripheral nerve evaluation, favorable outcome was achieved in 23 of 30 patients after sacral nerve stimulation (per protocol 76.7%; intention to treat 42.6%). From all analyzed characteristics, wide anorectal angle at rest in preoperative defecography was the only independent predictor of favorable outcome in multivariate analysis (favorable 134.1 ± 13.9° versus unfavorable 118.6 ± 17.1°). CONCLUSIONS: Anorectal angle at rest in preoperative defecography might present a predictor of outcome after sacral nerve stimulation in patients with idiopathic fecal incontinence.

Obstructed defecation-an enteric neuropathy? An exploratory study of patient samples.

PURPOSE: Although various strategies exist for chronic constipation therapy, the pathogenesis of chronic constipation is still not completely understood. The aim of this exploratory experimental study is to elucidate alterations of the autonomous enteric nervous system at the molecular level in patients with obstructed defecation, who represent one of the most predominant groups of constipated patients. METHODS: Full-thickness rectal wall samples of patients with obstructed defecation were analyzed and compared with controls. Differential gene expression analyses by RNA-Seq transcriptome profiling were performed and gene expression profiles were assigned to gene ontology pathways by application of different biological libraries. RESULTS: Analysis of the transcriptome showed that genes associated with the enteric nervous system functions were significantly downregulated in patients with obstructed defecation. These affected functions included developmental processes and synaptic transmission. CONCLUSIONS: Our results therefore indicate that obstructed defecation may represent an enteric neuropathy, comparable to Hirschsprung disease and slow-transit constipation.

Sphincter-sparing intersphincteric rectal resection as an alternative to proctectomy in long-standing fistulizing and stenotic Crohn's proctitis?

PURPOSE: Long-standing fistulizing and stenotic proctitis (LFSP) in Crohn's disease (CD) indicates the end stage of the disease. Definitive diversion such as proctectomy is considered to be the only surgical option. The impact of intersphincteric sphincter-sparing anterior rectal resection (IAR) as an alternative to proctectomy is unclear. The aim of this study was to evaluate feasibility, morbidity, outcome, and quality of life (QL) in patients with LFSP undergoing intended IAR. PATIENTS AND METHODS: Out of a single institution database, 15 patients with LFSP intended for surgery from 856 patients with CD were selected for follow-up analyses. RESULTS: In 12/15 cases, IAR was carried out while 3/15 patients underwent primary proctectomy due to malignancy (n = 2) or due to patient's wish (n = 1). In one case, IAR revealed unexpected malignancy, which led to secondary proctectomy. In patients with IAR, complete healing of fistulas and stenosis was observed in 46% (n = 5) while 36% (n = 4) of patients showed relapse of fistula and 18% (n = 2) developed restenosis. Ileostomy closure was performed in seven patients from which six patients remained stoma free. QL and fecal incontinence measured by standardized scoring systems were unchanged while stool frequency was reduced after IAR in patients with ileostomy closure. The rate of malignancy in this cohort was 20% (n = 3). CONCLUSION: LFSP in CD was associated with 20% of malignant transformation. Although IAR fails to improve QL, it is a suitable procedure for the treatment of fistulas and stenosis associated with acceptable healing rates and can avoid a permanent stoma.

Neurostimulated levator augmentation--a new approach in restoring continence.

PURPOSE: Restoration of continence remains a major challenge in patients after abdominoperineal rectal excision (APE) or with end-stage fecal incontinence. A new surgical technique, the neurostimulated levator augmentation, was introduced for pelvic floor augmentation using dynamic graciloplasty in order to restore anorectal angulation. The aim of this study was to assess feasibility and efficiency. METHODS: From November 2009 to March 2014, n = 17 patients underwent neurostimulated levator augmentation (n = 10 after APE, n = 5 intractable idiopathic fecal incontinence, n = 2 traumatic anal amputation). Gracilis muscle was transposed through the obturator foramen into the pelvic cavity, positioned in a U-shaped sling behind the rectum, fixed to the contralateral os pubis to restore anorectal angulation, and then conditioned by neurostimulation. Questionnaires analyzing function and quality of life were administered. RESULTS: For neurostimulated levator augmentation, four patients suffered from complications that needed operative intervention (n = 3 wound infection, n = 1 colon perforation); three pharmacological treatment and two complications needed no further invasive intervention. One patient died due to causes unrelated to the operation, and no complication required intensive care management. Fecal incontinence in patients with idiopathic incontinence improved significantly after surgery as well as incontinence episodes, urgency, and disease-specific quality of life through all dimensions. Generic quality of life was significantly better after surgery in all patients. After median follow-up of 17 months (2-45), all but one patient would undergo the procedure again. CONCLUSIONS: Neurostimulated levator augmentation was feasible in all patients with acceptable morbidity. It may represent a new therapeutic option in selected patients with intractable fecal incontinence.

Multimodal therapy in treatment of rectal cancer is associated with improved survival and reduced local recurrence - a retrospective analysis over two decades.

BACKGROUND: The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival. METHODS: Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010. RESULTS: The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6% vs. 60%) and adjuvant chemotherapy (37.9% vs. 58.4%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60% to 79%. CONCLUSION: In our study population, the implementation of treatment changes over the last decade improved the patient's outcome significantly. Improvements were most evident for UICC stage III rectal cancer.

Complete pathological remission of locally advanced, unresectable pancreatic cancer (LAPC) after intensified neoadjuvant chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) has an extremely poor prognosis. Results of neoadjuvant (radio-)chemotherapy approaches aiming at achieving resectability are currently not satisfactory. CASE REPORT: We report the case of a 67-year-old woman with histologically confirmed pancreas carcinoma that was not resectable on first surgical exploration who achieved a well-documented complete pathological remission (pCR). The carcinoma became resectable after consecutive neoadjuvant treatment with nanoparticle albumin-bound (nab)-paclitaxel/gemcitabine and FOLFIRINOX chemotherapy regimens. CONCLUSION: This is the first reported LAPC case in which neoadjuvant chemotherapy alone has been shown to lead to demonstrated pCR. CA19-9 levels, but not imaging criteria, were useful for response prediction and timing of the Whipple's procedure. The findings in this case suggest possible conceptual changes in the treatment approach for LAPC, and indicate that the new effective chemotherapy regimens should be integrated into clinical trials for LAPC.

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.

Central perforated VRAM flap and neurostimulated levator augmentation for functional and aesthetical reconstruction after abdominoperineal excision in cancer.

BACKGROUND: Preservation of quality of life regarding fecal continence after abdominoperineal excision (APE) in cancer is challenging. Simultaneous soft tissue coverage and restoration of continence mechanism can be provided through an interdisciplinary collaboration of colorectal and plastic reconstructive surgery. OBJECTIVE: Evaluation of surgical procedure and outcome combining soft tissue reconstruction using a central perforated vertical rectus abdominis myocutaneous flap (VRAM), implementing a perineostoma and restoring anorectal angle augmenting the levator ani by neurostimulated graciloplasty. METHODS: 14 Patients underwent APE due to cancer. In all patients coverage was achieved by pedicled VRAM and simultaneous pull-through descendostomy (perineostoma). 10 of those patients received a levator augmentation additionally. Postoperative complications, functional measures of continence as well as quality of life were obtained. RESULTS: Perineal minor complication rate was 43% without need of surgical intervention. All but one VRAM survived. Continence measures and disease specific life quality showed a good preservation of continence in most patients. CONCLUSION: The results present a complex therapy option accomplished by a collaboration of two highly specialized partners (visceral and plastic surgery) after total loss of the sphincter function and consecutive fecal insufficiency after APE.

DOG1 overexpression is associated with mismatch repair deficiency and BRAF mutations but unrelated to cancer progression in colorectal cancer.

INTRODUCTION: The transmembrane channel protein DOG1 (Discovered on GIST1) is normally expressed in the gastrointestinal interstitial cells of Cajal and also in gastrointestinal stroma tumors arising from these cells. However, there is also evidence for a relevant role of DOG1 expression in colorectal cancers. This study was undertaken to search for associations between DOG1 expression and colon cancer phenotype and key molecular alterations. METHODS: A tissue microarray containing samples from more than 1,800 colorectal cancer patients was analyzed by immunohistochemistry. RESULTS: DOG1 immunostaining was detected in 503 (30.2%) of 1,666 analyzable colorectal cancers and considered weak in 360 (21.6%), moderate in 78 (4.7%), and strong in 65 (3.9%). Strong DOG1 immunostaining was associated with advanced pT stage (p=0.0367) and nodal metastases (p=0.0145) but these associations were not retained in subgroups of 1,135 mismatch repair proficient and 86 mismatch repair deficient tumors. DOG1 positivity was significantly linked to several molecular tumor features including mismatch repair deficiency (p=0.0034), BRAF mutations (p<0.0001), nuclear p53 accumulation (p=0.0157), and PD-L1 expression (p=0.0199) but unrelated to KRAS mutations and the density of tumor infiltrating CD8 positive lymphocytes. CONCLUSION: Elevated DOG1 expression is frequent in colorectal cancer and significantly linked to important molecular alterations. However, DOG1 overexpression is largely unrelated to histopathological parameters of cancer aggressiveness and may thus not serve as a prognostic parameter for this tumor entity.

Mucin 5AC expression is common but unrelated to tumor progression in pancreatic adenocarcinoma.

Introduction: Mucin 5AC (MUC5AC) belongs to the family of secreted gel-forming mucins. It is physiologically expressed in some normal mucin producing epithelial cells but also in pancreatic, ovarian, and colon cancer cells. The role of MUC5AC expression in cancer is not fully understood. This study was designed to explore the role of MUC5AC for pancreatic cancer progression, its association to microsatellite instability, and its diagnostic utility. Methods: Mucin 5AC expression was studied immunohistochemically in a tissue microarray (TMA) from 532 pancreatic cancers, 61 cancers of the ampulla Vateri, six acinar cell carcinomas and 12 large sections of pancreatitis. Results: Mucin 5AC staining was interpretable in 476 of 599 (79%) arrayed cancers. Staining was completely absent in normal pancreas and pancreatitis, but frequent in pancreatic cancer. Membranous and cytoplasmic MUC5AC expression was most common in pancreatic adenocarcinomas (71% of 423), followed by carcinomas of the ampulla Vateri (43% of 47), and absent in six acinar cell carcinomas. Mucin 5AC expression was unrelated to tumor phenotype (tumor stage, tumor grade, lymph node, and distant metastasis), and microsatellite instability in ductal adenocarcinomas and carcinomas of the ampulla Vateri. Conclusion: Our study indicates that MUC5AC is an excellent biomarker for pancreatic cancer diagnosis, especially to support the sometimes-difficult diagnosis on small biopsies. Mucin 5AC expression is unrelated to pancreatic cancer aggressiveness.

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.

How complicated is complicated diverticulitis?--phlegmonous diverticulitis revisited.

PURPOSE: The purpose of this study is to elucidate the accuracy of a clinical classification system for acute diverticulitis with special regard to "phlegmonous diverticulitis". METHODS: A consecutive patient series (n = 318; General Hospital Nuremberg, 1/2004-12/2006) was classified preoperatively (imaging with 4/16-slice spiral CT scanner) according to the Hansen and Stock (H&S) classification which is commonly used in Germany and evaluated based on histopathology. RESULTS: Pre-treatment classification grouped 30 patients (9.4%) as uncomplicated diverticulitis (type I according to H&S), for whom treatment was merely conservative. One hundred twelve patients (35.2%) were classified as phlegmonous diverticulitis (type IIA), 84 (26.4%) as "covered perforations" (type IIB) and 27 (8.5%) as "free perforations" (type IIC), and 54 (17.0%) as chronically recurrent diverticulitis (type III, 17.0%). The remaining 11 patients (3.5%) were not staged preoperatively. Accuracy of staging of complicated diverticulitis differed significantly between type IIC (100.0%), type IIB (91.0%), and type IIA (36.1%). The latter group was frequently understaged as it concealed a substantial number of patients (n = 44; 53.0%) with IIB disease. Neither laboratory tests (CRP/WBC) nor clinical parameters allowed distinction of correctly and falsely staged patients with type IIA disease. CONCLUSIONS: Patients with phlegmonous diverticulitis (type IIA) represent the most challenging group among patients with acute diverticulitis as they are frequently understaged and conceal cases with covered perforations (type IIB). This may support the view to subsume phlegmonous diverticulitis (type IIA) under complicated diverticulitis.

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.

Curative in situ ablation of colorectal liver metastases-experimental and clinical implementation.

INTRODUCTION: In situ ablation of colorectal liver metastases is frequently assessed for palliative treatment only. The establishment of clinically relevant lesion size and a lack of long-term survival data were regarded as main limitations to using them with curative intention. In contrast to surgical liver resection, whose oncological findings seem to have remained unchanged over the years, the in situ ablation methods have considerably changed technically and clinically in the last few years. OBJECTIVE: The aim of the paper was to point out experimental and clinical data underlining the impact of in situ ablation for potentially curative treatment of colorectal liver metastases. DISCUSSION: On the basis of experimental data, the aim of complete local tumor control (R0 ablation) can only be obtained if additional energy is applied after reaching the tumor-adapted maximal coagulation volume. Analogous to the oncological safety margin in surgical resection, we defined this decisive energy difference as the "energy safety margin" for in situ ablation. The energy safety margin is the energy that must be additionally applied after reaching the plateau in the energy/volume curve to achieve complete tumor coagulation. In addition to that, in situ ablation should be combined with temporary interruption of hepatic perfusion whenever possible to prevent intralesional recurrences. In this way, the thermoprotective mechanism of hepatic perfusion can be effectively eliminated. With restrictions, the survival data after ablation in specialized centers is comparable to surgical resection with concomitantly lower morbidity and mortality. Based on recent findings and with the corresponding expertise in the field of ablation and state-of-the-art equipment, ablation is, thus, an alternative to surgical resection. The combined application of surgical resection and ablation is also a suitable method for increasing the R0 rate and thus helps improve the prognosis of treated patients. In summary, it can be said that in situ ablation is a useful expansion of the therapeutic spectrum of liver metastases and can be applied as an alternative to or in combination with surgical resection.

Laser-induced thermotherapy (LITT) elevates mRNA expression of connective tissue growth factor (CTGF) associated with reduced tumor growth of liver metastases compared to hepatic resection.

BACKGROUND AND OBJECTIVES: Proliferation and synthesis of hepatocellular tissue after tissue damage are promoted by specific growth factors such as hepatic tissue growth factor (HGF) and connective growth factor (CTGF). Laser-induced thermotherapy (LITT) for the treatment of liver metastases is deemed to be a parenchyma-saving procedure compared to hepatic resection. The aim of this study was to compare the impact of LITT and hepatic resection on intrahepatic residual tumor tissue and expression levels of mRNA HGF/CTGF within liver and tumor tissue. STUDY DESIGN/MATERIALS AND METHODS: Two independent adenocarcinomas (CC531) were implanted into 75 WAG rats, one in the right (untreated tumor) and one in the left liver lobe (treated tumor). The left lobe tumor was treated either by LITT or partial hepatectomy. The control tumor was submitted to in-situ hybridization of HGF and CTGF 24-96 hours and 14 days after intervention. RESULTS: Volumes of the untreated tumors prior to intervention were 38+/-8 mm(3) in group I (laser), 39 +/- 7 mm(3) in group II (resection), and 42 +/- 12 mm(3) in group III (control) and did not differ significantly (P > 0.05). Fourteen days after the intervention the mean tumor+/-SEM volume of untreated tumor in group I (laser) [223 +/- 36] was smaller than in group II (resection) [1233.28 +/- 181.52; P < 0.001], and in group III (control) [978.92 +/- 87.57; P < 0.003]. Forty-eight hours after the intervention intrahepatic mRNA expression level of HGF in group II (resection) was almost twofold higher than in group I (laser) [7.2 +/- 1.0 c/mf vs. 3.9 +/- 0.4 c/mf; P<0.01]. Fourteen days after the intervention intrahepatic mRNA expression level of CTGF in group I (laser) was higher than in group II (resection) [13.89 +/- 0.77 c/mf vs. 9.09 +/- 0.78 c/mf; P < 0.003]. CONCLUSIONS: LITT leads to a decrease of residual tumor growth in comparison to hepatic resection. Accelerated tumor growth after hepatic resection is associated with higher mRNA level of HGF and reduced tumor growth after LITT with higher mRNA level of CTGF. The increased CTGF-mediated regulation of ECM may cause reduced residual tumor growth after LITT.

In-vivo evaluation of a novel bipolar radiofrequency device for interstitial thermotherapy of liver tumors during normal and interrupted hepatic perfusion.

BACKGROUND: Only monopolar systems have thus far been available for radiofrequency ablation of liver tumors, whose application is restricted because of the incalculable energy flow, reduction of electrical tissue conduction, and limited lesion size. The aim of this study was to evaluate a novel internally cooled bipolar radiofrequency application device under in vivo conditions and to compare the effect of this system on lesion size when combined with hepatic arterial microembolization or complete hepatic blood flow occlusion. MATERIALS AND METHODS: In a porcine liver model, RFA (60 W, 12 min) was performed with either normal (n = 12), partially interrupted (arterial microembolization via a hepatic artery catheter n = 12) or completely interrupted hepatic perfusion (Pringle's maneuver, n = 12). RFA parameters (impedance, power output, temperature, applied energy) were determined continuously during therapy. RFA lesions were macroscopically assessed after liver dissection. RESULTS: Bipolar RFA induced clinical relevant ellipsoid thermal lesions without complications. Hepatic inflow occlusion led to a 4.3-fold increase in lesion volume after arterial microembolization and a 5.8-fold increase after complete interruption (7.4 cm(3)versus 31.9 cm(3)versus 42.6 cm(3), P < 0.01). CONCLUSIONS: The novel bipolar RFA device is a safe and effective alternative to monopolar RFA-systems. Interrupting hepatic perfusion significantly increases lesion volumes in bipolar RFA. This beneficial effect can also be achieved in the percutaneous application mode by RFA combined with arterial microembolization via a hepatic artery catheter.