Benjamin Garlipp

Left‐liver hypertrophy after therapeutic right‐liver radioembolization is substantial but less than after portal vein embolization

In patients with liver malignancies potentially amenable to curative extended right hepatectomy but insufficient size of the future liver remnant (FLR), portal vein embolization (PVE) of the tumor‐bearing liver is used to induce contralateral liver hypertrophy but leaves the tumor untreated. Radioembolization (RE) treats the tumor in the embolized lobe along with contralateral hypertrophy induction. We performed a matched‐pair analysis to compare the capacity for hypertrophy induction of these two modalities. Patients with right‐hepatic secondary liver malignancies with no or negligible left‐hepatic tumor involvement who were treated by right‐lobar PVE (n = 141) or RE (n = 35) at two centers were matched for criteria known to influence liver regeneration following PVE: 1) baseline FLR/Total liver volume ratio (<25 versus ≥25%); 2) prior platinum‐containing systemic chemotherapy; 3) embolization of segments 5‐8 versus 4‐8; and 4) baseline platelet count (<200 versus ≥200 Gpt/L).The primary endpoint was relative change in FLR volume from baseline to follow‐up. Twenty‐six matched pairs were identified. FLR volume increase from baseline to follow‐up (median 33 [24‐56] days after PVE or 46 [27‐79] days after RE) was significant in both groups but PVE produced significantly more FLR hypertrophy than RE (61.5 versus 29%, P < 0.001). Time between treatment and follow‐up was not correlated with the degree of contralateral hypertrophy achieved in both groups. Although group differences in patient history and treatment setting were present and some bias cannot be excluded, this was minimized by the matched‐pair design, as remaining group differences after matching were found to have no significant influence on contralateral hypertrophy development. Conclusion: PVE induces significantly more contralateral hypertrophy than RE with therapeutic (nonlobectomy) doses. However, contralateral hypertrophy induced by RE is substantial and RE minimizes the risk of tumor progression in the treated lobe, possibly making it a suitable modality for selected patients. (Hepatology 2014;59:1864–1873)

Neoadjuvant chemoradiotherapy for rectal carcinoma: effects on anastomotic leak rate and postoperative bladder dysfunction after non-emergency sphincter-preserving anterior rectal resection

IntroductionRandomized trials have demonstrated a reduction in local recurrence rate in rectal cancer patients treated with preoperative chemoradiotherapy and total mesorectal excision (TME) compared to patients undergoing TME alone. Accordingly, preoperative chemoradiotherapy in all UICC stages II and III rectal cancers has been recommended in the German treatment guidelines as of 2004. However, this policy has been questioned in recent years, partly due to concern regarding an increase in postoperative complications through preoperative therapy. Studies on this issue are sparse; most have been conducted in specialized centers, included relatively few patients, and yielded partly contradicting results. It was the aim of our analysis to investigate the influence of preoperative chemoradiotherapy on anastomotic leak rate and postoperative bladder dysfunction in rectal cancer patients using a representative data set from the Quality Assurance in Rectal Cancer Surgery multicenter observational trial.MethodThis is a retrospective analysis of data from the Quality Assurance in Rectal Cancer Surgery prospective multicenter observational trial. Data of all patients undergoing curatively intended sphincter-preserving resection for UICC stage I through III rectal carcinoma between 01 Jan 2005 and 31 Dec 2007 with or without preoperative chemoradiotherapy (groups A and B, respectively) were included. Multivariate statistical analysis using propensity score analysis was carried out regarding outcome parameters total anastomotic leak rate, rate of anastomotic leaks requiring reoperation, and postoperative bladder dysfunction.ResultsA total of 2,085 patients were included (group A, n = 676, group B, n = 1,409). Significant differences were present between groups regarding age, sex, distance of the tumor from the anal verge, pT-stage, UICC stage, hepatic risk factors, and use of protective enterostomy by univariate analysis. Multivariate logistic regression including these parameters was used to calculate the propensity score (likelihood to be assigned to group A or B as a consequence of the individual profile of these factors) for each patient. When outcome parameters were compared between groups A and B after stratification for propensity score, no significant differences regarding postoperative bladder dysfunction (p = 0.12), total anastomotic leak rate (p = 0.56), and anastomotic leaks requiring reoperation (p = 0.56) could be demonstrated.ConclusionNeoadjuvant chemoradiotherapy for rectal carcinoma does not increase the risk for anastomotic leakage or postoperative bladder dysfunction after curatively intended sphincter-preserving rectal resection.

Conversion in Laparoscopic Colorectal Cancer Surgery: Impact on Short- and Long-Term Outcome

INTRODUCTION Despite the well-documented safety and effectiveness of laparoscopic colorectal surgery in curative intention, the role of conversion and its impact on short- and long-term outcome after resection of a carcinoma are unclear and continue to give rise to controversial discussion. METHODS Within the framework of a prospective, multicenter observational study (Laparoscopic Colorectal Surgery Study Group), into which a total of 5,863 patients from 69 hospitals were recruited over a period of 10 years, a subgroup of all patients who had undergone curative resection was analyzed with regard to the effects of conversion. RESULTS Of the 1409 patients who had undergone curative resection for colorectal carcinoma, conversion had to be performed in 80 (5.7%) cases for the most diverse reasons. The duration of surgery (median: 183 vs. 241 minutes; P<.001) was significantly longer in the conversion group. Perioperatively, significant disadvantages were noted in converted patients in terms of intraoperative blood loss (median: 243 vs. 573 mL, P<.001), need for perioperative blood transfusion (10.8% vs. 33.8%; P<.001), and resumption of bowel movement (median: after 3 vs. 4 days; P<.001). With regard to postoperative morbidity, significant disadvantages were observed in converted patients, in particular in terms of specific surgical complications, including a higher rate of anastomotic insufficiency (5.0% vs. 13.8%; P=.003) and a higher reoperation rate (4.9% vs. 15.0%; P=.001). In the long term, conversion was associated with lower overall survival, but not with poorer disease-free survival. CONCLUSION Significantly higher postoperative morbidity was observed in patients after conversion, in particular in terms of specific surgical complications. In addition, conversion is associated with overall lower survival but not with poorer disease-free survival.

Factors influencing the quality of total mesorectal excision

Total mesorectal excision (TME) has become the standard of care for rectal cancer. Incomplete TME may lead to local recurrence.

Epidemiology, surgical management and early postoperative outcome in a cohort of gastric cancer patients of a tertiary referral center in relation to multi-center quality assurance studies.

UNLABELLED The aim of the study was to analyze epidemiologic parameters, treatment-related data and prognostic factors in the management of gastric cancer patients of a university surgical center under conditions of routine clinical care before the onset of the era of multimodal therapies. By analyzing our data in relation with multi-center quality assurance trials [German Gastric Cancer Study - GGCS (1992) and East German Gastric Cancer Study - EGGCS (2004)] we aimed at providing an instrument of internal quality control at our institution as well as a base for comparison with future analyses taking into account the implementation of evolving (multimodal) therapies and their influence on treatment results. MATERIAL AND METHODS Retrospective analysis of prospectively gathered data of gastric cancer patients treated at a single institution during a defined 10-year time period with multivariate analysis of risk factors for early postoperative outcome. RESULTS From 04/01/1993 through 03/31/2003, a total of 328 gastric cancer patients were treated. In comparison with the EGGCS cohort there was a larger proportion of patients with locally advanced and proximally located tumors. 272 patients (82.9%) underwent surgery with curative intent; in 88.4% of these an R0 resection was achieved (EGGCS/GGCS: 82.5%/71.5%). 68.2% of patients underwent preoperative endoluminal ultrasound (EUS) (EGGCS: 27.4%); the proportion of patients undergoing EUS increased over the study period. Diagnostic accuracy of EUS for T stage was 50.6% (EGGCS: 42.6%). 77.2% of operated patients with curative intent underwent gastrectomy (EGGCS/GGCS: 79.8%/71.1%). Anastomotic leaks at the esophagojejunostomy occurred slightly more frequently (8.8%) than in the EGGCS (5.9%) and GGCS (7.2%); however, postoperative morbidity (36.1%) and early postoperative mortality (5.3%) were not increased compared to the multi-center quality assurance study results (EGGCS morbidity, 45%); EGGCS/GGCS mortality, 8%/8.9%). D2 lymphadenectomy was performed in 72.6% of cases (EGGCS: 70.9%). Multivariate analysis revealed splenectomy as an independent risk factor for postoperative morbidity and ASA status 3 or 4 as an independent risk factor for early postoperative mortality. The rate of splenectomies performed during gastric cancer surgery decreased substantially during the study period. CONCLUSIONS Preoperative diagnostics were able to accurately predict resectability in almost 90% of patients which is substantially more than the corresponding results of both the EGGCS and the GGCS. In the future, more wide-spread use of EUS will play an increasing role as stage-dependent differentiation of therapeutic concepts gains acceptance. However, diagnostic accuracy of EUS needs to be improved. Our early postoperative outcome data demonstrate that the quality standard of gastric cancer care established by the EGGCS is being fulfilled at our institution in spite of distinct characteristics placing our patients at higher surgical risk. Besides being a valuable instrument of internal quality control, our study provides a good base for comparison with ongoing analyses on future developments in gastric cancer therapy.

Protocol of the PANCALYZE trial: a multicenter, prospective study investigating the tumor biomarkers CXCR4, SMAD4, SOX9 and IFIT3 in patients with resected pancreatic adenocarcinoma to predict the pattern of recurrence of the disease

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies today with an urgent need for novel therapeutic strategies. Biomarker analysis helps to better understand tumor biology and might emerge as a tool to develop personalized therapies. The aim of the study is to investigate four promising biomarkers to predict the clinical course and particularly the pattern of tumor recurrence after surgical resection.DesignPatients undergoing surgery for PDAC can be enrolled into the PANCALYZE trial. Biomarker expression of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. Immunohistochemistry expression pattern of all four biomarkers will be combined into a single score. Beginning with the hospital stay clinical data from enrolled patients will be collected and followed. Different adjuvant chemotherapy protocols will be used to create subgroups. The combined biomarker expression score will be correlated with the further clinical course of the patients to test the hypothesis if CXCR4 positive, SMAD4 negative, SOX9 positive, IFIT3 positive tumors will predominantly develop metastatic spread.DiscussionPancreatic cancer is associated with different patterns of progression requiring personalized therapeutic strategies. Biomarker expression analysis might be a tool to predict the pattern of tumor recurrence and discriminate patients that develop systemic metastatic disease from those with tumors that rather develop local recurrence over time. This data might lead to personalized adjuvant treatment decisions as patients with tumors that stay localized might benefit from adjuvant local therapies like radiochemotherapy as compared to those with systemic recurrence who would benefit exclusively from chemotherapy.Moreover, the pattern of propagation might be a predefined characteristic of pancreatic cancer determined by the genetic signature of the tumor. In the future, biomarker expression analysis could be performed on tumor biopsies to develop personalized therapeutic pathways right after diagnosis of cancer.Trial registrationGerman Clinical Trials Register, DRKS00006179.

Modified transarterial chemoembolization with locoregional administration of sorafenib for treating hepatocellular carcinoma: feasibility, efficacy, and safety in the VX-2 rabbit liver tumor model.

PURPOSE We aimed to assess the feasibility, efficacy and safety of a local application of sorafenib within a conventional transarterial chemoembolization in the VX-2 tumor-bearing rabbit model. METHODS VX-2 tumors were induced in the left liver lobe of 10 New Zealand White rabbits. After two weeks, growth was verified by contrast-enhanced computed tomography (CT). Five rabbits were treated by transarterial chemoembolization using an emulsion of sorafenib and ethiodized oil (referred to as SORATACE; n=5). Rabbits receiving oral sorafenib for two weeks (n=2) and untreated rabbits (n=3) served as controls. After two weeks, contrast-enhanced CT was performed, followed by animal necropsy. RESULTS The change in tumor diameter between baseline and follow-up was significantly different in the SORATACE group compared with the other groups; tumor shrinkage was observed in the SORATACE group only (P = 0.016). In both control groups, preserved hypervascularity was seen in the follow-up CT in all but one tumor. All tumors in the SORATACE group were devascularized in the follow-up CT. Importantly, substantial parenchymal damage in nontargeted areas of the tumor-bearing liver lobe was seen in rabbits treated with SORATACE. CONCLUSION SORATACE demonstrated high efficacy in the treatment of experimental VX-2 liver tumors but was also associated with substantial liver parenchymal toxicity.

State of the Art in the Treatment of Gastrointestinal Stromal Tumors.

Background: Gastrointestinal stromal tumors (GISTs) are the most frequently diagnosed mesenchymal neoplasms of the gastrointestinal tract. Despite their biological and clinical heterogeneity, the majority of these tumors are positive for the receptor tyrosine kinase KIT and are driven by KIT- or platelet-derived growth factor receptor alpha (PDGFRA)-activating mutations. There are still uncertainties regarding their clinical and molecular characterization and the optimal treatment regimens, making it difficult to establish a universal treatment algorithm for these tumors. Summary: From a clinical perspective, the main difference between GISTs and other gastrointestinal neoplasms is that the benign or malignant behavior of GISTs cannot be predicted from histopathology, but instead relies on empirically established scoring systems. Clinical data suggest that malignant potential may be an inherent quality of some GISTs rather than a feature acquired by the tumor during disease progression. Thus, some patients may require prolonged anti-tumor treatment even after complete surgical removal of the tumor. Key Message: Although GISTs are the most frequently occurring mesenchymal neoplasms in the gastrointestinal tract, no universal treatment algorithms exist. This paper reviews the current evidence that guides the management of GISTs. Practical Implications: The management of localized GISTs involves the use of surgical resection, with the inclusion of preoperative tyrosine kinase inhibitor treatment for locally advanced, primarily unresectable tumors and for resectable cases requiring extensive surgery. Imatinib is also indicated as adjuvant therapy after complete surgical removal of GISTs with a high estimated risk of recurrence unless specific mutations conferring imatinib resistance are present. The optimal duration of adjuvant treatment is still controversial. For patients with metastatic imatinib-sensitive GISTs, imatinib constitutes the first-line standard treatment. Molecular characterization of the tumor (with respect to the PDGFRA and KIT genes) is mandatory prior to imatinib therapy. Sunitinib and regorafenib are established as alternative treatments for patients demonstrating generalized disease progression on imatinib. New tyrosine kinase inhibitors such as ponatinib and crenolanib as well as drugs targeting alternative pathways are currently under investigation. Surgery and locally ablative treatments may be indicated in some metastatic patients.

Surgical treatment of gastric cancer: Oncologic outcome of neoadjuvant treatment in the German multicenter observational study II.

139 Background: Neoadjuvant chemotherapy is broadly established in European centers when treating locally advanced gastric cancer. However, there still remain questions as to the benefit of this extended form of treatment in regards to tumor location and stage. Methods: Data obtained in the ongoing prospective, multicenter observational study (German Gastric Cancer Study II) on quality assurance in surgical therapy of gastric cancer containing a total of 2897 patients treated from 01/01/2007 through 31/12/2009 in 145 surgical departments to evaluate. Results: Overall, 506 patients (18.4%) received neoadjuvant treatment in regards to all tumor stages. Of the 530 patients with adenocarcinoma of the gastroesophageal junction (GEJ) 34.5% (n=183) received chemotherapy. In detail, 30.1% (n=873) of the patients were found to be in stage I. In regards to the mean time of survival for advanced stages (III/IV 6th editiion) a survival benefit for patients receiving neoadjuvant treatment (n=356) of 12.0 months was de...

The evidence for resection post-selective internal radiation therapy

Selective internal radiation therapy (SIRT) has become a well-established modality for the palliative treatment of primary and metastatic liver tumors. As a consequence of the growing experience with this treatment, research has recently focused on its potential as a component in the management of patients for curative treatment. However, reports on the use of surgical resection, local tumor ablation or liver transplantation in conjunction with SIRT have hitherto been limited to individual case studies and small case series (usually comprising fewer than five patients), making it difficult to define the future role for SIRT in this setting.