Outcomes of totally robotic Roux-en-Y gastric bypass in patients with BMI ≥ 50 kg/m2: can the robot level out "traditional" risk factors?

Roux-en-Y gastric bypass (RYGB) in patients with body mass index (BMI) ≥ 50 kg/m2 is a challenging procedure and BMI ≥ 50 kg/m2 has been identified as independent risk factor for postoperative complications and increased morbidity in previous studies. The objective of the present study was to assess whether a BMI ≥ 50 kg/m2 and various established risk factors maintain their significance in patients undergoing fully robotic RYGB (rRYGB). A single-center analysis of prospectively collected data of 113 consecutive patients undergoing standardized rRYGB with robotic stapling technique and hand-sewn gastrojejunostomy using the daVinci Xi system. Surgical outcomes were analyzed considering a number of individual perioperative risk factors including BMI ≥ 50 kg/m2. The mean BMI of the total cohort was 50.6 ± 5.5 kg/m2 and 63.7% of patients had a BMI ≥ 50 kg/m2. There were no major surgical and perioperative complications in patients with BMI ≥ 50 kg/m2 as well as in those with BMI < 50 kg/m2 after rRYGB. We identified female sex and surgeon experience but neither body weight, BMI, metabolic disorders, ASA nor EOSS scores as independent factors for shorter operation times (OT) in multivariate analyses. Complication rates and length of hospital stay (LOS) did not significantly differ between patients with potential risk factors and those without. rRYGB is a safe procedure in both, patients with BMI ≥ 50 kg/m2 and with BMI < 50 kg/m2. Higher body weight and BMI did affect neither OT nor LOS. A fully robotic approach for RYGB might help to overcome "traditional" risk factors identified in conventional laparoscopic bariatric surgery. However, larger and prospective studies are necessary to confirm these results.

Hepatic arterial infusion with nanoliposomal irinotecan leads to significant regression of tumor size of colorectal liver metastases in a CC531 rat model.

Long-term therapy for unresectable colorectal liver metastases remains challenging. Intraarterial treatments aim to avoid systemic adverse effects of chemotherapy. Nanoliposomal cytotoxic drugs manage to increase the drug concentration within the tumor while reducing toxicity in healthy tissue.  In this study we analyzed the effect of hepatic arterial infusion (HAI) with nanoliposomal irinotecan with or without the combination of embolization particles in a rat model for colorectal liver metastases. For the study 32 WAG/Rij rats received subcapsular tumor implantation with CC531 rat colonic adenocarcinoma cells. After ten days tumor size was assessed via ultrasound and animals underwent HAI. One group served as control receiving NaCl 0.9 % (Sham), the three treatment groups received either nanoliposomal irinotecan (HAI nal iri), Embocept® S (HAI Embo) or Embocept® S and nanoliposomal irinotecan (HAI Embo+nal iri). Three days after treatment animals were sacrificed after assessment of tumor size. As a result all treatment groups showed a significant reduction in tumor growth compared to Sham (p<0.05). Expression of the apoptosis marker caspase-3 was enhanced in HAI nal iri and HAI Embo+nal iri compared to Sham and HAI Embo and  even significantly enhanced after HAI Embo+nal iri in comparison to Sham (p<0.05). We were able to show that HAI with Embocept® S led to significantly reduced tumor growth while HAI with nanoliposomal irinotecan alone or in combination with Embocept® S even led to a reduction of tumor size. Thus, we demonstrate that intraarterial treatment with nanoliposomal irinotecan effectively inhibits tumor growth in a rat model of colorectal liver metastases and demands further investigation.

Establishing robotic bariatric surgery at an academic tertiary hospital: a learning curve analysis for totally robotic Roux-en-Y gastric bypass.

The use of robotic systems in bariatric surgery has constantly increased over the last years. However, beside its technical advantages in morbidly obese patients the conclusive role of robotics in bariatric and metabolic surgery is still under controversial debate. This is an analysis of prospectively collected data of consecutive patients undergoing fully robotic Roux-en-Y gastric bypasses (TR-RYGB) during the first year after implementation of a robotic bariatric program at a tertiary university hospital. All patients were operated by a previously untrained robotic but experienced laparoscopic bariatric surgeon using the daVinci Xi system (Intuitive Surgical, Sarl). Data recording included patient characteristics, operative and functional outcomes, complications and learning curves for surgeon and assistants. In total, 80 patients underwent primary or revisional robotic bariatric surgery. Seventy-two patients (90%) received a TR-RYGB. There were no major complications, re-interventions or readmissions. The overall complication rate was 2.5% (Clavien-Dindo grade I and II). The overall operation time was 140.7 ± 24.6 min and decreased significantly from the first to the last decade of procedures (procedure 1-10: 171.2 ± 26.3 min versus procedure 63-72: 116.0 ± 10.9 min, p < 0.0001). A stabilization of the learning curve was observed after 30 procedures for the surgeon and after five procedures for the bedside assistant. With immediate effect, TR-RYGB is a safe procedure with low complication rates for an experienced laparoscopic bariatric surgeon without prior robotic skills. Learning curves are steep and operation times can be effectively decreased by increasing the experience of the surgeon.

The long-term influence of hospital and surgeon volume on local control and survival in the randomized German Rectal Cancer Trial CAO/ARO/AIO-94.

BACKGROUND: The association of treatment volume and oncological outcome of rectal cancer patients undergoing multidisciplinary treatment is subject of an ongoing debate. Prospective data on long-term local control and overall survival (OS) are not available so far. This study investigated the long-term influence of hospital and surgeon volume on local recurrence (LR) and OS in patients with locally advanced rectal cancers. METHODS: In a post-hoc analysis of the randomized phase III CAO/ARO/AIO-94 trial after a follow-up of more than 10 years, 799 patients with stage II/III rectal cancers were evaluated. LR-rates and OS were stratified by hospital recruitment volume (≤20 vs. 21-90 vs. >90 patients) and by surgeon volume (≤10 vs. 11-50 vs. >50 procedures). RESULTS: Patients treated in high-volume hospitals had a longer OS than those treated in hospitals with medium or low treatment volume (p = 0.03). The surgeon volume was adversely associated with LR (p = 0.01) but had no influence on overall survival. The positive effect of neoadjuvant chemoradiation (CRT) on local control was the strongest in patients being operated by medium-volume surgeons, less in patients being operated by high-volume surgeons and missing in those being operated by low-volume surgeons. CONCLUSIONS: Patients with locally advanced rectal cancers might benefit from treatment in specialized high-volume hospitals. In particular, the surgeon volume had significant influence on long-term local tumour control. The effect of neoadjuvant CRT on local tumour control may likewise depend on the surgeon volume.

Hiatal hernias in patients with GERD-like symptoms: evaluation of dynamic real-time MRI vs endoscopy.

PURPOSE: To assess the diagnostic potential of real-time MRI for assessment of hiatal hernias in patients with GERD-like symptoms compared to endoscopy. MATERIAL AND METHODS: One hundred eight patients with GERD-like symptoms were included in this observational cohort study between 2015 and 2017. Real-time MRI was performed at 3.0 Tesla with temporal resolution of 40 ms, dynamically visualizing the esophageal transport of a pineapple juice bolus, its passage through the gastroesophageal junction, and functional responses during Valsalva maneuver. Hernia detection on MRI and endoscopy was calculated using contingency tables with diagnosis of hernia on either modality as reference. RESULTS: Of 108 patients, 107 underwent successful MRI without adverse events; 1 examination was aborted to inability to swallow pineapple juice in supine position. No perforation or acute bleeding occurred during endoscopy. Median examination time was 15 min. Eighty-five patients (79.4%) were diagnosed with hiatal hernia on either real-time MRI or endoscopy. Forty-six hernias were visible on both modalities. Seventeen hernias were evident exclusively on MRI, and 22 exclusively on endoscopy. Sixteen of the 63 MRI-detected hernias (25.4%) were detectable only during Valsalva maneuver, which were smaller compared to hernias at rest (median - 13.5 vs - 33.0 mm, p < 0.001). Diagnostic accuracy for hernia detection was comparable for MRI and endoscopy (sensitivity 74% vs 80%, p = 0.4223; specificity 100% vs 100%, p > 0.99). CONCLUSION: Real-time MRI is a fast and safe modality for assessment of the gastroesophageal junction, without radiation exposure or administration of gadolinium-based contrast media. Although MRI and endoscopy yield comparable diagnostic accuracy, dynamic MRI sequences are able to visualize hiatal hernias that were occult on static MRI sequences or endoscopy in a relevant number of cases. KEY POINTS: • Real-time MRI is a safe and fast imaging modality for examination of the gastroesophageal junction, combining anatomical and functional information for enhanced detection of hiatal hernias. • Real-time MRI and endoscopy yield comparably high diagnostic accuracy: real-time MRI visualizes hiatal hernias that were occult on endoscopy in a relevant number of patients; however, several hiatal hernias detected on endoscopy were occult on real-time MRI. • There is clinical potential of real-time MR imaging in patients with GERD-like symptoms and equivocal findings on endoscopy or pH-metry, for anatomical visualization in patients planned for surgical intervention, or those with suspected fundoplication failures.

Real-time MRI for the dynamic assessment of fundoplication failure in patients with gastroesophageal reflux disease.

PURPOSE: To assess the diagnostic potential of dynamic real-time MRI for fundoplication failure in patients with persistent or recurrent GERD-like (gastroesophageal reflux disease) complaints. MATERIAL AND METHODS: Twenty-two consecutive patients (male n = 11; female n = 11; median age 59 years) with recurrent or persistent GERD-like symptom after fundoplication were enrolled between 2015 and 2017. Median duration of GERD-like symptoms was 21 months. Real-time MRI (3 Tesla) was performed at 40 ms temporal resolution using undersampled radial fast low-angle shot acquisitions with nonlinear inverse image reconstruction. MRI movies dynamically visualized bolus transit of pineapple juice through the gastroesophageal junction, position of the fundoplication wrap and recurring hernia or reflux during Valsalva maneuver. MRI results were compared to endoscopic findings. RESULTS: Real-time MRI was successfully completed in all patients without adverse events (average examination time 15 min). Morphological correlates for GERD-like symptoms were evident in 20 patients (90.1%) with gastric reflux in 19 cases. Nine patients (40.1%) had wrap disruption and recurrent gastric hernia. Wrap migration or telescoping hernia was detected in nine patients (40.1%). One patient presented with continued reflux despite intact fundoplication wrap. Esophageal dysmotility with delayed bolus passage was observed in one case. On endoscopy, gastric hernia or wrap disruption was diagnosed in seven cases, and esophagitis or Barret's metaplasia in nine cases. CONCLUSION: Real-time MRI is a fast and safe modality for dynamic imaging after fundoplication, without radiation exposure or administration of gadolinium-based contrast media. In a relevant number of cases, real-time MRI reveals correlates for GERD-like symptoms. KEY POINTS: • Real-time MRI reliably visualizes the gastroesophageal junction after fundoplication surgery. • Patients with recurring GERD-like symptoms have a high rate of morphological failure patterns that can be identified by real-time MRI. • Dynamic assessment of gastroesophageal junction by real-time MRI is a perspective diagnostic tool for detection of fundoplication failure.

Hepatic arterial infusion of irinotecan and EmboCept® S results in high tumor concentration of SN-38 in a rat model of colorectal liver metastases.

Intraarterial chemotherapy for colorectal liver metastases (CRLM) can be applied alone or together with embolization particles. It remains unclear whether different types of embolization particles lead to higher intratumoral drug concentration. Herein, we quantified the concentrations of CPT-11 and its active metabolite SN-38 in plasma, liver and tumor tissue after hepatic arterial infusion (HAI) of irinotecan, with or without further application of embolization particles, in a rat model of CRLM. Animals underwent either systemic application of irinotecan, or HAI with or without the embolization particles Embocept® S and Tandem™. Four hours after treatment concentrations of CPT-11 and SN-38 were analyzed in plasma, tumor and liver samples by high-performance liquid chromatography. Additionally, DNA-damage and apoptosis were analyzed immunohistochemically. Tumor tissue concentrations of SN-38 were significantly increased after HAI with irinotecan and EmboCept® S compared to the other groups. The number of apoptotic cells was significantly higher after both HAI with irinotecan and EmboCept® S or Tandem™ loaded with irinotecan compared to the control group. HAI with irinotecan and EmboCept® S resulted in an increased SN-38 tumor concentration. Both HAI with irinotecan and EmboCept® S or Tandem™ loaded with irinotecan were highly effective with regard to apoptosis.

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.

The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up. The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up. High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

Stage-Dependent Frequency of Lymph Node Metastases in Patients With Rectal Carcinoma After Preoperative Chemoradiation: Results from the CAO/ARO/AIO-94 Trial and From a Comparative Prospective Evaluation With Extensive Pathological Workup.

BACKGROUND: For patients with ycT1/2 rectal carcinomas after neoadjuvant chemoradiotherapy, local excision instead of radical surgery has increasingly been discussed as a way to avoid postoperative morbidity associated with radical surgery. OBJECTIVE: The purpose of this study was to determine the incidence of lymph node metastases in total mesorectal excision specimens with ypT0, ypT1/2, and ypT3/4 rectal cancers. DESIGN: This is a prospective and retrospective cohort study. SETTINGS: This study was conducted in tertiary referral hospitals that are part of the German Rectal Cancer Study Group. PATIENTS: A total of 479 patients with stage II and III rectal cancers treated within phase III trials of the German Rectal Cancer Study Group were evaluated. Specimens from 81 patients treated in the Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society (CAO/ARO/AIO-04) trial were prospectively studied with extensive microscopic screening of the entire mesorectum. The frequency and localization of nodal metastases were specified and compared with those of 398 patients having received neoadjuvant chemoradiation within the CAO/ARO/AIO-94 trial. MAIN OUTCOME MEASURES: Frequency and localization of mesorectal lymph node metastases in patients with ypT0, ypT1/2, or ypT3/4 cancer were measured. RESULTS: A mean number of 28.0 ± 13.7 nodes were detected per specimen within the prospective group. A total of 25% of patients in the ypT1/2 group had nodal metastases compared with 40% in the ypT3/4 group. Patients with node-positive ypT1/2 had a mean number of 2.2 metastases, and 55% of these metastases were located far from the primary lesion in the proximal mesorectum. Within the CAO/ARO/AIO-94 cohort (n = 398), 19% of patients with ypT1/2 (ypT1 = 22%; ypT2 = 18%) had ypN+ status compared with 43% with ypT3/4 cancers (ypT3 = 40%; ypT4 = 73%). LIMITATIONS: Low numbers of patients with ypT0 limited the evaluation of nodal metastases in pathologic complete responders. CONCLUSIONS: Even in good responders (ypT1/2), >20% of rectal carcinomas still harbored residual lymph node metastases. Local excision for patients with ycT1/2 rectal cancers would, thus, miss metastases in a considerable percentage and might involve the risk of significant undertreatment in a number of patients.

HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer.

OBJECTIVE: In this study, we evaluate the frequency of HER-2 and HER-3 expression in liver metastases from patients with colorectal cancer (CRLM). We analyzed the potential of HER-2 and HER-3 as therapeutic targets and evaluated their prognostic value. PATIENTS AND METHODS: Overall 208 patients with CRLM were enrolled. HER-2 and HER-3 expression were determined in metastatic tissue of diagnostic punch biopsies (n = 29) or resection specimens (n = 179). The results of immunohistochemistry (IHC) scoring and In-situ-hybridization (ISH)-amplification were correlated with clinical parameters and for the 179 resected patients with cancer-specific (CSS) and overall survival (OS). The mean follow-up time was 56.7 months. RESULTS: Positivity of HER-2 status (IHC score 2+/ISH+ and IHC 3+) was found in 8.2% of CRLM. High expression of HER-3 (IHC score 2+ and IHC 3+) was detected in 75.0% of liver metastases. CSS after liver surgery was determined and was independent from the HER-2 status (p = 0.963); however HER-3 was prognostic with a favorable course for patients showing an overexpression of HER-3 (p = 0.037). CONCLUSIONS: HER-2 overexpression occurs in only 8% of patients with CRLM but with 75% of cases HER-3 is frequently overexpressed in CRLM. Therefore, HER-2 and particularly HER-3 could serve as novel targets to be addressed within multimodal treatment approaches.

Comprehensive lymph node morphometry in rectal cancer using acetone compression.

AIMS: Acetone compression (AC) is an elution compression technique for the comprehensive pathological examination of fatty tissue. Here AC is combined with digital morphometry to evaluate the impact of preoperative (neoadjuvant) chemoradiotherapy (neoCRT) on lymph node (LN) numbers and morphology in locally advanced rectal cancer. AC is compared with complete embedding of the mesorectal fat (whole mesorectal embedding (WME)) to exclude artificial alterations and to the standard technique, manual dissectioning (MD). METHODS: 320 rectal cancer specimens were subjected to LN morphometry. Neoadjuvant CRT was applied in 204 specimens. LNs were prepared either with AC (n=138), WME (n=51) or MD (n=131). 8523 LNs were assessed including 530 nodes with metastases. RESULTS: LN prepared by AC and WME showed similar morphologies. AC revealed reduced LN sizes in neoCRT specimens compared with primary resection (2.2; 2.4 mm, p=0.049) while the LN number was comparable (27; 30/specimen). AC yielded 28 LN/specimen on average, MD yielded 22 LN (p<0.001). In neoCRT specimens, MD yielded less LN compared with primary resection (19; 25). MD detected less small LN (<2 mm; MD: 25%; AC: 56%) while 24 of the 135 LN metastases found by AC were ≤2 mm in diameter. CONCLUSIONS: AC does not alter LN morphology and is especially suited to retrieve small LN after neoadjuvant CRT of rectal cancer. Neoadjuvant multimodality treatment caused reduced LN sizes while the LN numbers were not affected. When compared with MD, AC proved more reliable in the retrieval of LN from rectal cancer specimens after neoCRT.

Preoperative chemoradiation therapy with capecitabine/oxaliplatin and cetuximab in rectal cancer: long-term results of a prospective phase 1/2 study.

PURPOSE: We have previously shown that the addition of cetuximab to chemoradiation therapy failed to improve complete response rates (pCR) in rectal cancer. Here we report the long-term results of the cetuximab added to preoperative radiation therapy with capecitabine and oxaliplatin (CET-CAPOX-RT) phase 1/2 study that evaluated preoperative chemoradiation with cetuximab, capecitabine, and oxaliplatin in patients with rectal cancer. METHODS AND MATERIALS: The median follow-up was 63 months (range, 5-73 months). Sixty patients were enrolled; 3 patients were excluded due to protocol violation, and 4 died before surgery. Total mesorectal excision was performed in 53 patients, in 85% (n=45) with curative intention (M0-status). Secondary end points including overall survival (OS) disease-free survival (DFS) and cancer-specific survival (CSS) were calculated. The prognostic value of KRAS mutation status was also assessed. RESULTS: Histopathological examination confirmed ypUICC stages 0 (n=4; pCR), I (n=17), II (n=10), III (n=14), and IV (n=8). For patients who underwent surgery (n=53), OS at 1, 3, and 5 years was 88.7%, 83%, and 75.5%, respectively, whereas CSS rates were 94.1%, 88.1%, and 78.1%, respectively. In the 45 patients who were treated with curative intent (M0), the OS rates at 1, 3, and 5 years were 91.1%, 88.9%, and 86.7%, respectively; whereas CSS rates were 97.6%, 95.2%, and 90.3%, respectively; and DFS rates were 90.7%, 88.3%, and 88.3%, respectively. We did not find any locoregional failure in patients with M0-status (n=45). Chronic toxicity was rare. KRAS mutations, as detected in 33.3%, showed no correlation with the clinicopathological parameters nor significance for either OS (P=.112), CSS (P=.264), or DFS (P=.565). CONCLUSIONS: Taken together, chemoradiation therapy combined with cetuximab is safe, feasible, and offers excellent survival rates. KRAS mutation status was not a predictive factor. Importantly, lack of improvement in pCR rate did not translate to poor survival in our clinical trial.

Lymph node metastases in rectal cancer after preoperative radiochemotherapy: impact of intramesorectal distribution and residual micrometastatic involvement.

INTRODUCTION: After neoadjuvant chemoradiation (CRT), the pathologic determined lymph node (LN) status is the most important prognostic factor in rectal cancer patients. Here we assessed the prognostic impact of residual LN micrometastases (<0.2 cm) and the intramesorectal distribution of LN metastases. PATIENTS AND METHODS: Surgical specimens from 81 patients with cUICC II/III rectal cancer undergoing neoadjuvant CRT and total mesorectal excision within the German Rectal Cancer Trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was paraffin embedded and screened microscopically. The number and distribution of mesorectal LN macrometastases and micrometastases were correlated with disease-free (DFS) and cancer-specific overall survival (CSS). RESULTS: A total of 2412 LNs were detected (mean 29.8±13.7). Twenty-five patients had residual LN metastases (ypN+). The incidence of metastases in the peritumoral mesorectum was higher (7.7%) than that proximal to the tumor (1.5%), whereas no metastases were identified below the tumor level. Patients with both proximal and peritumoral involvement showed a significantly reduced CSS (hazard ratio=5.4; P<0.05). Fourteen patients with ypN+ status (56%) had micrometastases, 9 patients (36%) had only micrometastatic involvement. Patients with nodal macrometastases had a reduced DFS (P<0.01) and CSS (P<0.005) as compared with ypN0 patients, whereas residual micrometastases had no influence on survival. CONCLUSIONS: Despite the high incidence of residual LN micrometastases they did not seem to have a prognostic impact in this series. Micrometastases might indicate responsive tumors to CRT with a more favorable biology. The intramesorectal distribution of LN metastases had a prognostic impact and should be validated in further studies.

Frequency of HER-2 positivity in rectal cancer and prognosis.

In patients with advanced rectal cancer (cUICC II and III) multimodality therapy resulted in better long-term local tumor control. Ongoing clinical trials are focusing on therapy intensification to improve disease-free (DFS) and cancer-specific survival (CSS), the integration of biomarkers for prediction of individual recurrence risk, and the identification of new targets. In this context, we investigated HER-2, a member of the epidermal growth factor receptor family, whose expression pattern and role was unclear in rectal cancer. A total of 264 patients (192 male, 72 female; median age 64 y) received standardized multidisciplinary treatment according to protocols of phase II/III trials of the German Rectal Cancer Study Group. HER-2 status was determined in pretherapeutic biopsies and resection specimens using immunohistochemistry scoring and detection of silver in situ hybridization amplification. Tumors with an immunohistochemistry score of 3 or silver in situ hybridization ratios of ≥2.0 were classified HER-2 positive; these results were correlated with clinicopathologic parameters [eg, resection (R) status, nodal status ((y)pN)], DFS, and CSS. Positive HER-2 status was found in 12.4% of biopsies and in 26.7% of resected specimens. With a median follow-up of 46.5 months, patients with HER-2 positivity showed in trend a better DFS (P=0.1) and a benefit in CSS (P=0.03). The 5-year survival rate was 96.0% (HER-2 positive) versus 80.0% (HER-2 negative). In univariate and multivariate analyses, HER-2 was an independent predictor for CSS (0.02) along with the (y)pN status (P<0.00001) and R status (P=0.011). HER-2 amplification is detectable in a relevant proportion (26.7%) of rectal cancer patients. For the development of innovative new therapies, HER-2 may represent a promising target and should be further assessed within prospective clinical trials.

Oxaliplatin-Induced Leukocytoclastic Vasculitis under Adjuvant Chemotherapy for Colorectal Cancer: Two Cases of a Rare Adverse Event.

Leukocytoclastic vasculitis is a multicausal systemic inflammatory disease of the small vessels, histologically characterized by inflammation and deposition of both nuclear debris and fibrin in dermal postcapillary venules. The clinical picture typically involves palpable purpura of the lower legs and may be associated with general symptoms such as fatigue, arthralgia and fever. Involvement of the internal organs, most notably the kidneys, the central nervous system or the eyes, is possible and determines the prognosis. Oxaliplatin-induced leukocytoclastic vasculitis is a very rare event that limits treatment options in affected patients. We report 2 patients who developed the condition under chemotherapy for advanced rectal and metastatic colon carcinoma, respectively; a termination of the therapy was therefore necessary. While current therapies for colorectal cancer include the combination of multimodal treatment with new and targeted agents, rare and unusual side effects elicited by established agents also need to be taken into account for the clinical management.

Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival.

BACKGROUND: The transmembrane glycoprotein CD133 (cluster of differentiation 133; also known as Prominin or PROM1) has been described as a potential stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study, CD133 expression was evaluated in pre-RCT tumor biopsies and the corresponding post-RCT surgical specimens from patients with locally advanced rectal adenocarcinoma, and expression levels were correlated with histopathologic features and clinical follow-up. METHODS: One hundred twenty-six patients with International Union Against Cancer (UICC) stage II/III rectal cancer who received preoperative 5-fluorouracil (5-FU)-based RCT within the German Rectal Cancer Trials were investigated. Pre-RCT and post-RCT CD133 expression levels were determined using immunohistochemistry and were correlated with histopathologic parameters, tumor regression grade, cancer recurrence, and patient survival. RESULTS: Compared with pre-RCT biopsies, significantly higher CD133 expression was observed in tumor specimens (P = .01). However, no correlations were observed for either biopsies or tumor specimens between CD133 expression levels, histopathologic characteristics, or survival. In matched analyses of corresponding biopsy/tumor pairs, patients who had an increased fraction of CD133-expressing (CD133+) cells after preoperative RCT had significantly higher residual tumor stages (P = .02) and lower histopathologic tumor regression (P < .01). Moreover, these patients had significantly reduced disease-free survival and cancer-specific overall survival in univariate analysis (P < .001 and P = .004, respectively) and multivariate analysis (P = .003 and P = .024, respectively). CONCLUSIONS: The enrichment of CD133+ cancer cells during preoperative RCT was correlated with minor local tumor response, increased distant cancer recurrence, and decreased survival. The current results indicate that the up-regulation of intratumoral CD133 expression, in contrast to absolute pre-RCT and post-RCT CD133 levels, plays an important role in tumor progression and metastasis in patients with rectal cancer who are receiving neoadjuvant RCT.

Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model.

BACKGROUND: Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model. METHODS: 100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%. RESULTS: At the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 µm for manual UC and 553.5 ± 326.9 µm for automatic UC versus 149.0 ± 74.3 µm for manual ME and 257.6 ± 119.4 µm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93). CONCLUSIONS: Thermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels.

Optimal lymph node harvest in rectal cancer (UICC stages II and III) after preoperative 5-FU-based radiochemotherapy. Acetone compression is a new and highly efficient method.

INTRODUCTION: Preoperative 5-fluorouracil-based radiochemotherapy (RCT), followed by total mesorectal excision, is accepted as standard therapy in rectal cancers (UICC stages II and III). The accurate evaluation of ypN status after RCT with valuable lymph node (LN) harvest is essential for postoperative risk-adapted treatment decisions. Actual numbers of assessed LNs and validity of ypN status vary extensively depending on the methods used. MATERIAL AND METHODS: This prospective study validates the acetone compression (AC), whole mesorectal compartment embedding (WME), and fat clearance (FC) methods for LN retrieval in n=257 rectal cancer specimens obtained from 2 high-volume surgical centers. For optimal LN retrieval, the AC method (n=161 specimens: 52 cases with RCT, 109 cases without RCT) was compared with the WME (n=64 cases, with RCT) and FC methods (n=32 cases: 17 cases with RCT, 15 cases without RCT). The efficacy of LN retrieval, costs involved, and molecular diagnostics were measured. RESULTS: Using the AC method, 41 LNs (mean; range 14 to 86 LNs) were detectable in total mesorectal excision specimens after RCT and 44 LNs (mean; range 9 to 78 LNs) in cases without RCT. The LN yield after RCT obtained by using the AC method was equivalent to that of the WME method (mean 32 LNs/specimen; range 12 to 81 LNs) but demonstrated a better time and cost-efficacy. In addition, the AC method facilitated assessment of any tumor deposits, including perineural invasion, and did not hamper molecular analyses. The AC method increased LN retrieval 4- to-6-fold as compared with the literature and 2-fold compared with manual dissection after the FC method. DISCUSSION: The AC method is the method of choice for accurate LN staging in locally advanced rectal cancer, especially after preoperative RCT, and is well suited for routine gastrointestinal pathology workup.

Gender-specific acute organ toxicity during intensified preoperative radiochemotherapy for rectal cancer.

Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil-based (5-FU-based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity. All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5-FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade ≥3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone. Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5-FU+oxaliplatin. A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity. These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity.

Thymidylate synthase as a prognostic biomarker for locally advanced rectal cancer after multimodal treatment.

PURPOSE: For years, 5-fluorouracil (5-FU) has been the backbone of radiochemotherapy (RCT) of locally advanced rectal cancer. Its main target, thymidylate synthase (TS), is speculated to be an important biomarker for response prediction and long-term prognosis. In this study, we analyzed TS expression in the rectal cancer tissue of 208 patients to evaluate its predictive/prognostic potential. METHODS: All patients included were diagnosed with locally advanced adenocarcinoma of the rectum (UICC II and III) and were treated within randomized clinical trials of the German Rectal Cancer Study Group. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 167 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. TS levels and further clinicopathological parameters were assessed in univariate and multivariate analyses. Additionally, a TS gene polymorphism was analyzed with respect to the intratumoral protein levels. RESULTS: Low TS expression in pretreatment biopsies correlated with impaired patient survival (p = 0.015). Analysis of a 28-bp repeat revealed a correlation between the *3/*3 genotype and high TS expression in pretherapeutic biopsies. In this study, a correlation of TS expression and grade of RCT-induced tumor regression was not found. Histopathological examination confirmed a complete tumor remission in 16 patients (9.6%). Analyses of the resection specimen indicated an unfavorable prognosis for patients with low intratumoral TS expression in case of detected lymph node metastases (p = 0.04). CONCLUSIONS: TS can serve as a prognostic biomarker indicating an unfavorable prognosis for patients with low TS expression.