Ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic esophagogastric adenocarcinoma, after treatment failure on a ramucirumab-based therapy.

Based on results of prior trials (TAGS, REGARD, RAINBOW), the combination of ramucirumab beyond progression with TAS-102 (trifluridine/tipiracil) seems to be promising in advanced esophagogastric adenocarcinoma (EGA). In this multicenter, non-randomized, open-label, investigator-initiated pilot trial, ramucirumab-pretreated patients with metastatic EGA received a maximum of 4 cycles of ramucirumab (8 mg/kg i.v. on day 1 and 15, Q2W) plus TAS-102 (35 mg/m2 p.o. bid on day 1-5 and day 8-12; Q2W). Primary endpoint was tolerability and toxicity, defining a positive trial if the SAE rate according to CTCAE 5.0 will increase <30% (up to 55%) compared to historical results from TAGS trial (SAE rate 43%). Secondary endpoints were further evaluation of safety and assessment of efficacy according to tumor response and overall and progression-free survival (OS/PFS). Twenty patients, 20% gastric and 80% GEJ cancers and 55% with ECOG 0 were enrolled. In total, nine SAEs were reported in 25% [95% CI: 8.7-49.1] of the patients, all without relationship to the systemic therapy. The median OS and PFS were 9.1 months [5.4-10.1] and 2.9 months [1.7-4.8], respectively. In addition, a disease control rate of 45% was obtained. The trial showed a favorable safety profile with a numerically lower incidence of SAEs for the combination of ramucirumab with TAS-102 compared to historical TAGS trial. Furthermore, the combination demonstrated efficacy in the beyond progression setting and therefore warrants further evaluation in a randomized trial compared to TAS-102 alone.

Ramucirumab plus irinotecan / leucovorin / 5-FU versus ramucirumab plus paclitaxel in patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction, who failed one prior line of palliative chemotherapy: the phase II/III RAMIRIS study (AIO-STO-0415).

BACKGROUND: Paclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%-70%, making second-line taxane-containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA. METHODS: The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m2 over 46 h i.v., irinotecan 180 mg/m2 i.v.; 5-FU 400 mg/m2 bolus; leucovorin 400 mg/m2 i.v.; on day 1 and 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m2 (days 1, 8, 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm B). The primary endpoints are overall survival (OS) and objective overall response rate (ORR). Secondary endpoints are progression-free survival (PFS), disease control rate and safety and quality of life as assessed by EORTC-QLQ-C30 questionnaire. DISCUSSION: The already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. TRIAL REGISTRATION: NCT03081143 Date of registration: 13.11.2015.

Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).

The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2 ) on day 1, 8 and 15 plus everolimus (10 mg daily, arm B) d1-d28 or placebo (arm A), repeated every 28 days. Primary end point was overall survival (OS). Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01248403. Between October 2011 and September 2015, 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (arm A, 150, arm B, 150). In the intention to treat population, there was no significant difference in progression-free survival (PFS; everolimus, 2.2 vs placebo, 2.07 months, HR 0.88, P = .3) or OS (everolimus, 6.1 vs placebo, 5.0 months, HR 0.93, P = .54). For patients with prior taxane use, everolimus improved PFS (everolimus, 2.7 vs placebo 1.8 months, HR 0.69, P = .03) and OS (everolimus, 5.8 vs placebo 3.9 months, HR 0.73, P = .07). Combination of paclitaxel and everolimus was associated with significantly more grade 3-5 mucositis (13.3% vs 0.7%; P < .001). The addition of everolimus to paclitaxel did not improve outcomes in pretreated metastatic gastric/gastroesophageal junction (GEJ) cancer. Activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit.

KEYNOTE-585: Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer.

BACKGROUND: Surgical resection is the only curative treatment option for gastric cancer. Despite widespread adoption of multimodality perioperative treatment strategies, 5-year overall survival rates remain low. In patients with advanced gastric or gastroesophageal junction adenocarcinoma, pembrolizumab has demonstrated promising efficacy and manageable safety as monotherapy in previously treated patients and as first-line therapy in combination with cisplatin and 5-fluorouracil. Combining chemotherapy with pembrolizumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable disease. AIM: To describe the design and rationale for the global, multicenter, randomized, double-blind, Phase III KEYNOTE-585 study to evaluate the efficacy and safety of pembrolizumab plus chemotherapy compared with placebo plus chemotherapy as neoadjuvant/adjuvant treatment for localized gastric or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov : NCT03221426.

Prognosis of incidental gallbladder carcinoma is not influenced by the primary access technique: analysis of 837 incidental gallbladder carcinomas in the German Registry.

BACKGROUND: The use of the laparoscopic approach (LC) for gallbladder carcinoma and incidental gallbladder carcinomas (IGBC) remains controversial. However, recent studies suggest that LC has no adverse effects relative to the open approach. A definitive conclusion regarding the safety of LC that is based on data from a large patient cohort is needed. METHODS: To draw a definite conclusion about the safety of LC in IGBC, data from the 837 patients with IGBC [registered in the German Registry (GR)] were analyzed. RESULTS: Of the 837 patients, 492 underwent LC, 200 underwent open surgery (OC), and 142 initially underwent LC, but the approach was converted to OC. The 5-year survival rates of the three groups indicated that LC was associated with significantly better survival. LC was not associated with a poorer prognosis in patients with T1, T2, or T3 stage disease or in patients who underwent immediate radical re-resection (IRR; n = 330). LC was associated with a significant survival benefit in the 490 patients who did not undergo IRR. LC was comparable with OC in terms of overall recurrence rates and the rate of accidental intraoperative perforation. CONCLUSIONS: The GR data, which relate to a large homogenous patient cohort, showed that when other potential influencing factors, e.g., IRR were eliminated, the primary access technique had no effect on prognosis. Stage-adjusted therapy should always be performed irrespective of the primary access technique.

Dissecting the genetic heterogeneity of gastric cancer.

BACKGROUND: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. METHODS: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. FINDINGS: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. INTERPRETATION: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. FUNDING: German Research Foundation (DFG).

The prognostic impact of positive lymph nodes in stages T1 to T3 incidental gallbladder carcinoma: results of the German Registry.

BACKGROUND: In the literature, the 5 year survival rates for incidental gallbladder carcinoma (IGBC) show large variations in the different T-stages because the lymph node status often is not addressed. Most early-stage carcinomas are identified by laparoscopy as IGBC, and radical re-resection is needed. Staging is impossible without lymph node dissection, so comparison between various survival rates is impossible. This study aimed to determine the influence of lymph node status on the survival of patients with stages T1 to T3 IGBC. METHODS: For data analysis, the German Registry was used. RESULTS: In this study, 709 patients with IGBC were analyzed. The re-resected nodal-negative patients had a significant survival advantage over the re-resected nodal-positive patients. The 5 year survival rate for the patients with nodal-negative re-resected T1 carcinomas was 75%. The re-resected T2 and T3 nodal-negative patients had significantly better survival than the corresponding nodal-positive patients. The influence that the radicalness of the different liver resection techniques had on these results was excluded. 53 patients without radical resection had a known nodal-positive status. Nodal-positive patients with radical re-resection always show a better survival rate than nodal-positive patients without radical re-resection, stage for stage. CONCLUSIONS: Nodal-positive status is a significant negative prognostic factor in T1 to T3 IGBC. Patients with radical re-resection show a better survival rate than those without it. Lymph node dissection is to be highly recommended up to stage T1b. In the case of T2 carcinomas, lymph node dissection of the hepatoduodenal ligament seems to be the minimum volume of lymph node dissection required, but more radical procedures could be beneficial for tumors infiltrating the serosa or beyond.

Perspectives on the Management of Oligometastatic Disease in Esophago-Gastric Cancer.

Gastric adenocarcinoma and esophageal cancer are the fifth and seventh most common cancer types worldwide. At the time of initial diagnosis, up to 50% of esophagogastric cancers present with distant metastatic lesions and are candidates for chemotherapy. Curative surgery in this stage is still an experimental approach. Only a small number of these metastatic patients show an oligometastatic disease with no uniform definition of what oligometastatic means in gastric cancer. Nevertheless, the question remains unanswered as to whether these patients are still candidates for curative concepts. Some studies have attempted to answer this question but have not been adequately designed to address the role of a curative-intended multimodal therapy in this setting. The current FLOT-5 is designed to potentially provide a definitive answer to the question of whether curatively intended surgery plays a role or is a disadvantage in this setting.

Dynamic Responsive Inguinal Scaffold Activates Myogenic Growth Factors Finalizing the Regeneration of the Herniated Groin.

BACKGROUND: Postoperative chronic pain caused by fixation and/or fibrotic incorporation of hernia meshes are the main concerns in inguinal herniorrhaphy. As inguinal hernia is a degenerative disease, logically the treatment should aim at stopping degeneration and activating regeneration. Unfortunately, in conventional prosthetic herniorrhaphy no relationship exists between pathogenesis and treatment. To overcome these incongruences, a 3D dynamic responsive multilamellar scaffold has been developed for fixation-free inguinal hernia repair. Made of polypropylene like conventional flat meshes, the dynamic behavior of the scaffold allows for the regeneration of all typical inguinal components: connective tissue, vessels, nerves, and myocytes. This investigation aims to demonstrate that, moving in tune with the groin, the 3D scaffold attracts myogenic growth factors activating the development of mature myocytes and, thus, re-establishing the herniated inguinal barrier. METHODS: Biopsy samples excised from the 3D scaffold at different postoperative stages were stained with H&E and Azan-Mallory; immunohistochemistry for NGF and NGFR p75 was performed to verify the degree of involvement of muscular growth factors in the neomyogenesis. RESULTS: Histological evidence of progressive muscle development and immunohistochemical proof of NFG and NFGRp75 contribution in neomyogenesis within the 3D scaffold was documented and statistically validated. CONCLUSION: The investigation appears to confirm that a 3D polypropylene scaffold designed to confer dynamic responsivity, unlike the fibrotic scar plate of static meshes, attracts myogenic growth factors turning the biological response into tissue regeneration. Newly developed muscles allow the scaffold to restore the integrity of the inguinal barrier.

Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach-A Real World Data Analysis.

After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.

Adequate extent in radical re-resection of incidental gallbladder carcinoma: analysis of the German Registry.

BACKGROUND: Complete surgical resection is the only potentially curative treatment of gallbladder cancer. Gallbladder carcinoma is suspected preoperatively in 30% of patients, and 70% are incidentally discovered by the pathologist (incidental gallbladder carcinoma, IGBC). If IGBC is detected postoperatively, a re-resection, including liver resection and lymph node dissection, in T2 tumor cases and more advanced stages is recommended. It remains unclear whether the prognosis of wedge resection (2-3-cm margin) of the gallbladder bed is the same as that of resection of segments IVb/V. METHODS: The German Registry, founded in 1997, aims to prospectively record all IGBC cases in Germany. In this study patients with a radical re-resection were treated according to the S3 Guidelines in Germany. The aim of this study was to clarify whether different techniques of liver re-resection show comparable results or if they differ depending on the tumor stage in IGBC patients (n = 624). RESULTS: A significant survival advantage in patients who have an early re-resection was observed. There was a trend of better survival in T1 tumor stage patients who undergo the less radical re-resection, especially the wedge-resection technique of 3 cm in the gallbladder bed. In T2 tumor stage patients there is a tendency for better survival with the IVb/V-resection technique compared to the 3-cm wedge resection in the gallbladder bed, and a significant survival benefit for these two techniques compared to less radical resection was evident. T3 tumor cases showed better survival with the more radical resection techniques. CONCLUSIONS: The wedge-resection technique combined with lymph node dissection may be the surgical strategy of choice in T1 tumor cases. For T2 tumors, IVb/V resection combined with lymph node dissection of the hepatoduodenal ligament appears to be the minimum volume of resection required. More radical procedures are needed for tumors infiltrating the serosa or beyond.

Use of retrieval bags in incidental gallbladder cancer cases.

INTRODUCTION: Accidental intraoperative gallbladder perforation is a problem in laparoscopic surgery, especially in cases with incidental gallbladder carcinoma (IGBC). The question is whether intraoperative gallbladder perforation has a prognostic disadvantage or a retrieval bag provides protection against tumor dissemination. METHODS: A standardized questionnaire was sent to all German surgical clinics based on the central register of "incidental gallbladder carcinoma" of the German Society of Surgery founded in 1997. RESULTS: In 592 IGBC-registered cases, there were 330 laparoscopies, 154 open surgeries, and intraoperative conversion was performed in 106 cases. Of laparoscopic surgeries (n = 330), the recurrence rate was 30%. The recurrence rate for cases with (174/330) and without (156/330) the use of retrieval bag was 32.2% and 27%, respectively. In laparoscopies with intraoperative gallbladder perforation (73/330 cases), the recurrence rate was 38.4%. Of these cases the recurrence rate with (51/73) and without (22/73) the use of retrieval bags was 39.2% and 36.4%, respectively. In 257 cases without intraoperative perforation, tumor recurrence rate was 27.2%, and it was 29.3% or 25.4% with (123/257) and without (134/257) the use of retrieval bags. CONCLUSIONS: According to the registry data, the intraoperative gallbladder perforation results in significant (P = 0.047) prognostic disadvantage and in these cases retrieval bags were used more often (P = 0.001). However, in IGBC cases if intraoperative gallbladder perforation has already happened, the use of retrieval bags had no protective effects.

Multimodal Treatment Strategies in Esophagogastric Junction Cancer: a Western Perspective.

Esophagogastric junction (EGJ) cancer is a solid tumor entity with rapidly increasing incidence in the Western countries. Given the high proportion of advanced cancers in the West, treatment strategies routinely employed include surgery and chemotherapy perioperatively, and chemoradiation in neoadjuvant settings. Neoadjuvant chemoradiation and perioperative chemotherapy are mostly performed in esophageal cancer that extends to the EGJ and gastric as well as EGJ cancers, respectively. Recent trials have tried to combine both strategies in a perioperative context, which might have beneficial outcomes, especially in patients with EGJ cancer. However, it is difficult to recruit patients for trials, exclusively for EGJ cancers; therefore, the results have to be carefully reviewed before establishing a standard protocol. Trastuzumab was the first drug for targeted therapy that was positively evaluated for this tumor entity, and there are several ongoing trials investigating more targeted drugs in order to customize effective therapies based on tissue characteristics. The current study reviews the multimodal treatment concept for EGJ cancers in the West and summarizes the latest reports.

Locally advanced gastro-oesophageal cancer: Recent therapeutic advances and research directions.

Gastric (GC) and gastro-oesophageal (GOJC) adenocarcinomas are often considered as a single entity, even though differences exist in epidemiology, clinical presentation, molecular biology and treatment options. Locally advanced, resectable disease represents a particularly challenging scenario, as many critical issues need to be addressed. In both GC and GOJC among Western countries, systemic chemotherapy demonstrated the greatest benefit when administered before and after surgery and perioperative chemotherapy has been set as a standard in this setting. Nonetheless, multiple chemotherapy regimens have been tested and direct comparisons have been only recently presented. Adjuvant chemoradiotherapy is an option as well, but several trials have questioned its role when more effective combination regimens are used. With regards to GOJC, preoperative chemoradiotherapy is an alternative to perioperative chemotherapy, as it is associated with higher pathologic responses and a different toxicity profile: however, a definitive comparison with chemotherapy is ongoing. Herein, we review the current options for the treatment of resectable GC and GOJC and the main open questions in the management of these patients, trying to depict an update of the available algorithms for everyday practice. Moreover, we summarize the design and preliminary results of the randomized trials in progress that will hopefully give definitive answers to the most debated issues in the field.

CabaGast: multicentre, Phase II study with cabazitaxel in previously treated patients with advanced or metastatic adenocarcinoma of the esophagogastric junction and stomach.

INTRODUCTION: This is a single-arm study (NCT01956149) to determine the prolonged (≥ 4 months) disease control rate with cabazitaxel administered in second-(or later) setting for patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (EGJ) and stomach. METHODS: 65 patients with advanced EGJ and stomach cancer were treated with 20 mg/m2 cabazitaxel every 3 weeks for a maximum of six cycles. The main objective of the study is a prolonged disease control rate (pDCR: CR, PR or SD lasting at least 4 months). Secondary outcome measures were overall survival, progression-free survival, response rate by subgroup (with vs without previous treatment with a taxane) and toxicity. Patients were assessed for tumor response every 6 weeks during therapy and during the follow-up (up to 12 months). RESULTS: 65 patients (median age: 63, range 31-86 years) were assigned to treatment. Median no. of prior therapies that had received prior taxane therapy was 2. 80%. Patients received a median of two cycles of cabazitaxel. Efficacy results are for the ITT population. The mDCR in n = 65 patients was 10.8% (95% CI 4.4-20.9%). There was a control of disease (CR + PR + SD) in n = 26 patients of n = 65, corresponding to a DCR of 40.0% (95% CI 28.0-52.9%). In patients without prior taxane use, it was 46.2% (95% CI 25.1-80.8%) and in patients with only one prior therapy, DCR was 50.0% (95% CI 31.3-68.7%). The median overall survival was 4.6 months (95% CI 3.16, 5.59) in the whole ITT population. In patients with only one prior therapy, median OS was 5.4 months (95% CI 2.60, 7.43) and in patients without taxane pretreatment, it was 6.4 months (95% CI 1.38, 14.17). The median progression-free survival time was 1.5 months (95% CI 1.32, 2.27) in the whole ITT population, 2.9 months (95% CI 0.72, 4.67) without prior taxane therapy and was 1.7 (95% CI 1.28, 3.35) months in patients with only one prior therapy median. CONCLUSIONS: Cabazitaxel is active in heavily pretreated patients with metastatic and advanced esophagogastric junction and gastric adenocarcinoma. Efficacy results in a classic second-line population are comparable to other second-line studies, therefore, under the limitations of this trial, (single arm, Phase II design) cabazitaxel might be an option especially in patients without prior taxane therapy, in second line and even further line therapy of metastatic and advanced esophagogastric junction and gastric adenocarcinoma.

Gallbladder carcinoma: Prognostic factors and therapeutic options.

The outcome of gallbladder carcinoma is poor, and the overall 5-year survival rate is less than 5%. In early-stage disease, a 5-year survival rate up to 75% can be achieved if stage-adjusted therapy is performed. There is wide geographic variability in the frequency of gallbladder carcinoma, which can only be explained by an interaction between genetic factors and their alteration. Gallstones and chronic cholecystitis are important risk factors in the formation of gallbladder malignancies. Factors such as chronic bacterial infection, primary sclerosing cholangitis, an anomalous junction of the pancreaticobiliary duct, and several types of gallbladder polyps are associated with a higher risk of gallbladder cancer. There is also an interesting correlation between risk factors and the histological type of cancer. However, despite theoretical risk factors, only a third of gallbladder carcinomas are recognized preoperatively. In most patients, the tumor is diagnosed by the pathologist after a routine cholecystectomy for a benign disease and is termed ''incidental or occult gallbladder carcinoma'' (IGBC). A cholecystectomy is performed frequently due to the minimal invasiveness of the laparoscopic technique. Therefore, the postoperative diagnosis of potentially curable early-stage disease is more frequent. A second radical re-resection to complete a radical cholecystectomy is required for several IGBCs. However, the literature and guidelines used in different countries differ regarding the radicality or T-stage criteria for performing a radical cholecystectomy. The NCCN guidelines and data from the German registry (GR), which records the largest number of incidental gallbladder carcinomas in Europe, indicate that carcinomas infiltrating the muscularis propria or beyond require radical surgery. According to GR data and current literature, a wedge resection with a combined dissection of the lymph nodes of the hepatoduodenal ligament is adequate for T1b and T2 carcinomas. The reason for a radical cholecystectomy after simple CE in a formally R0 situation is either occult invasion or hepatic spread with unknown lymphogenic dissemination. Unfortunately, there are diverse interpretations and practices regarding stage-adjusted therapy for gallbladder carcinoma. The current data suggest that more radical therapy is warranted.

Influence of high- and low-volume liver surgery in gallbladder carcinoma.

AIM: To clarify whether the performance of liver resections (LR) for incidental gallbladder carcinoma (IGBC)'s depends more on the experience of the hospitals in liver surgery than on complying with the guidelines in Germany. METHODS: For data analysis, we used the Surgical Association of Endoscopy and Ultrasound and Minimally Invasive Surgery Central Registry of "IGBC" of the German Society of Surgery (the German Registry). In 2010, we started a second form by requesting the frequency of LR at the various hospitals in Germany. The indication for LR was irrelevant. The aim was to determine the overall frequency of liver resections at the hospitals. We divided the hospitals according to their experience in liver surgery into high- (HV), mid- (MV), and low-volume (LV) LR hospitals. RESULTS: This study includes 487 IGBC's from 167 centers. There were 36 high-volume, 32 mid-volume, and 99 low-volume centers. In the high-volume centers, the mean (range) number of liver resections was 101 (40-300). In the mid-volume centers, the mean (range) number of liver resections was 26 (20-39). In the low-volume centers, the mean (range) number of liver resections was 6.5 (0-19) (P < 0.001). LV's perform LR for T2-3 gallbladder carcinomas significantly less often than high-volume or mid-volume centers (χ(2) = 13.78, P = 0.001). In HV's and MV's, 61% of the patients with an indication for liver resection underwent LR, but in LV centers, only 41% with an indication for LR underwent LR (P < 0.001). In cases of T1b carcinomas, LR was performed significantly more often in HV's (P = 0.009). CONCLUSION: The central problem is that the performance of the required liver resection in IGBC in Germany depends on the hospital experience in liver surgery and not on the recommendations of the German guidelines.

Benefits of reoperation of T2 and more advanced incidental gallbladder carcinoma: analysis of the German registry.

OBJECTIVE: The aim of this study was to determine which T stages of incidental gallbladder carcinoma (IGBC) actually benefit from an early reresection (ERR). BACKGROUND: The IGBC is a carcinoma first detected by the pathologist. The indication for the cholecystectomy was a benign disease. The indication for an ERR is debated in the literature, and different recommendations are often drawn based on data collected from only small groups. METHODS: A register was founded in 1997 to prospectively record all IGBCs in Germany. All the patients who had a reresection in this study were treated according to the German Guidelines of Surgery and Oncology. This study analyzes 439 cases of IGBC. RESULTS: There was a significant benefit for the 85 of 200 T2 patients who did have an ERR. There was no benefit though for the 32 of 85 T3 patients who did have an ERR. There is a significantly better survival rate for T2 patients with negative lymph nodes, and there is a trend for better survival for T3 patients with negative lymph nodes. CONCLUSION: An ERR should be highly recommended for patients with IGBC in the T2 stage, because it improves their survival positive. Without an ERR, it is almost impossible to definitively determine the nodal status or to obtain exact staging for estimating the prognosis.