Standardization of the Definition and Surgical Management of Splenic Flexure Carcinoma by an International Expert Consensus Using the Delphi Technique: Room for Improvement?

BACKGROUND: Surgical management of splenic flexure carcinoma remains controversial. OBJECTIVE: This study aimed to establish an expert international consensus on splenic flexure carcinoma management. DESIGN: A 3-round online-based Delphi study was conducted between September 2020 and April 2021. SETTING: The first round included 18 experts from 12 different countries. For the second and third rounds, each expert in the first round was asked to invite 2 more colorectal surgeons (n = 47). Out of 47 invited experts, 89% (n = 42) participated in the second and third rounds of the consensus. INTERVENTIONS: A total of 35 questions were created and sent via the online questionnaire tool. MAIN OUTCOME MEASURES: Levels of recommendation based on voting concordance were graded as follows: more than 75% agreement was defined as strong, between 50% and 75% as moderate, and below 50% as weak. RESULTS: There was moderate consensus on the definition of splenic flexure (55%) as 10 cm from either side where the distal transverse colon turns into the proximal descending colon. Also, experts recommended an abdominopelvic CT scan plus intraoperative exploration (moderate consensus, 72%) for tumor localization and cancer registry. Segmental colectomy was the preferred technique for the management of splenic flexure carcinoma in the elective setting (72%). Moderate consensus was achieved on the technique of complete mesocolic excision and central vascular ligation principles for splenic flexure carcinoma (74%). Only strong consensus was achieved on the surgical approach for minimally invasive surgery (88%). LIMITATIONS: Subjective decisions are based on individual expert clinical experience and not evidence based. CONCLUSIONS: This is the first internationally conducted Delphi consensus study regarding splenic flexure carcinoma. The definition of splenic flexure remains ambiguous. To more effectively compare oncologic outcomes among different cancer registries, guidelines need to be developed to standardize each domain and avoid arbitrary definitions. See Video Abstract at http://links.lww.com/DCR/C143 . ESTANDARIZACIN DE LA DEFINICIN Y MANEJO QUIRRGICO DEL CARCINOMA DE NGULO ESPLNICO ESTABLECIDO POR UN CONSENSO INTERNACIONAL DE EXPERTOS UTILIZANDO LA TCNICA DELPHI ESPACIO PARA MEJORAR: ANTECEDENTES:El tratamiento quirúrgico del cáncer de ángulo esplénico sigue siendo controvertido.OBJETIVO:Establecer un consenso internacional de expertos sobre el manejo del cáncer del ángulo esplénico.DISEÑO:Se condujo un estudio Delphi en línea de 3 rondas entre septiembre de 2020 y febrero de 2021.ESCENARIO:La primera ronda incluyó a 18 expertos de 12 países distintos. Para la segunda y tercera rondas, a cada experto de la primera ronda se le pidió que invitara a 2 cirujanos colorrectales más de su región (n = 47). De los 47 expertos invitados, el 89% (n = 42) participó en la segunda y tercera ronda del consenso.INTERVENCIONES:Se crearon y enviaron un total de 35 preguntas a través de la herramienta de cuestionario en línea.PRINCIPALES MEDIDAS DE RESULTADO:Los niveles de recomendación basados en la concordancia de votos fueron jerarquizados de la siguiente manera: más del 75% de acuerdo se definió como fuerte, entre 50 y 75% como moderado y por debajo del 50% como débil.RESULTADOS:Hubo un consenso moderado sobre la definición de ángulo esplénico (55%) como 10 cm desde cualquier lado donde el colon transverso distal se convierte en el colon descendente proximal. Así también, los expertos recomendaron la tomografía computarizada abdominopélvica más la exploración intraoperatoria (consenso moderado, 72%) para la localización del tumor y el registro del ángulo esplénico. La colectomía segmentaria fue la técnica preferida para el tratamiento del cáncer de ángulo esplénico en el caso de ser electivo (72%). Se logró un consenso moderado sobre la técnica de escisión completa del mesocolon y los principios de ligadura vascular a nivel central para el cáncer de ángulo esplénico (74%). Solo se logró un fuerte consenso sobre el abordaje quirúrgico para la cirugía mínimamente invasiva (88%).LIMITACIONES:Decisiones subjetivas basadas en la experiencia clínica de expertos individuales y no basadas en evidencia.CONCLUSIONES:Este es el primer estudio internacional de consenso Delphi realizado sobre el cáncer de ángulo esplénico. Si bien encontramos un consenso moderado sobre las modalidades de diagnóstico preoperatorio y el manejo quirúrgico, la definición de ángulo esplénico sigue siendo ambigua. Para comparar de manera más efectiva los resultados oncológicos entre diferentes registros de cáncer, se deben desarrollar pautas para estandarizar cada dominio y evitar definiciones arbitrarias. Consulte Video Resumen en http://links.lww.com/DCR/C143 . (Traducción-Dr. Osvaldo Gauto ).

Complete mesocolic excision for right colonic cancer: prospective multicentre study.

BACKGROUND: Complete mesocolic excision (CME) for right colonic cancer is a more complex operation than standard right hemicolectomy but evidence to support its routine use is still limited. This prospective multicentre study evaluated the effect of CME on long-term survival in colorectal cancer centres in Germany (RESECTAT trial). The primary hypothesis was that 5-year disease-free survival would be higher after CME than non-CME surgery. A secondary hypothesis was that there would be improved survival of patients with a mesenteric area greater than 15 000 mm2. METHODS: Centres were asked to continue their current surgical practices. The surgery was classified as CME if the superior mesenteric vein was dissected; otherwise it was assumed that no CME had been performed. All specimens were shipped to one institution for pathological analysis and documentation. Clinical data were recorded in an established registry for quality assurance. The primary endpoint was 5-year overall survival for stages I-III. Multivariable adjustment for group allocation was planned. Using a primary hypothesis of an increase in disease-free survival from 60 to 70 per cent, a sample size of 662 patients was calculated with a 50 per cent anticipated drop-out rate. RESULTS: A total of 1004 patients from 53 centres were recruited for the final analysis (496 CME, 508 no CME). Most operations (88.4 per cent) were done by an open approach. Anastomotic leak occurred in 3.4 per cent in the CME and 1.8 per cent in the non-CME group. There were slightly more lymph nodes found in CME than non-CME specimens (mean 55.6 and 50.4 respectively). Positive central mesenteric nodes were detected more in non-CME than CME specimens (5.9 versus 4.0 per cent). One-fifth of patients had died at the time of study with recorded recurrences (63, 6.3 per cent), too few to calculate disease-free survival (the original primary outcome), so overall survival (not disease-specific) results are presented. Short-term and overall survival were similar in the CME and non-CME groups. Adjusted Cox regression indicated a possible benefit for overall survival with CME in stage III disease (HR 0.52, 95 per cent c.i. 0.31 to 0.85; P = 0.010) but less so for disease-free survival (HR 0.66; P = 0.068). The secondary outcome (15 000 mm2 mesenteric size) did not influence survival at any stage (removal of more mesentery did not alter survival). CONCLUSION: No general benefit of CME could be established. The observation of better overall survival in stage III on unplanned exploratory analysis is of uncertain significance.

The outcome of patients with inflammatory bowel disease-associated colorectal cancer is not worse than that of patients with sporadic colorectal cancer-a matched-pair analysis of survival.

PURPOSE: Patients with inflammatory bowel disease (IBD) have an increased risk for colorectal cancer (CRC). In IBD patients, cancer is often diagnosed in advanced stages and conflicting data on survival compared to sporadic CRC have been reported. The aim of this study was to directly compare clinical characteristics and prognosis of patients with IBD-CRC and sporadic CRC. METHODS: The clinical and pathological data of 63 patients with IBD-CRC and 3710 patients with sporadic CRC treated at the University Hospital of Erlangen between 1995 and 2015 were compared. Forty-seven M0 patients with IBD were matched with sporadic CRC patients after curative resection (R0) according to tumor localization, stage, sex, and year of treatment. Overall and disease-free survival were compared. RESULTS: Sixty-three patients presented IBD-CRC. Fifty were affected with ulcerative colitis (UC) and 13 with Crohn's disease (CD). CRC was diagnosed within 1.45 years since last endoscopic surveillance. Twelve patients (19%) had a diagnosis of primary sclerosing cholangitis. In matched analysis, IBD patients were diagnosed with CRC at younger age compared to sporadic CRC and were more likely to have right-sided CRC (40% versus 23.3%) and rare histological subtypes (19% versus 9.2%). No differences in 5-year overall (78.7 versus 80.9 months) and 5-year disease-free survival (74.5 versus 70.2 months) were noted. CONCLUSION: IBD-CRC patients were younger and more frequently had right-sided carcinomas compared to sporadic CRC. CRC in IBD patients did not show survival difference compared to matched-pair sporadic CRC patients without distant metastases after curative resection. Surveillance might be important for early detection of CRC in IBD patients.

Consensus statements on complete mesocolic excision for right-sided colon cancer-technical steps and training implications.

BACKGROUND: CME is a radical resection for colon cancer, but the procedure is technically demanding with significant variation in its practice. A standardised approach to the optimal technique and training is, therefore, desirable to minimise technical hazards and facilitate safe dissemination. The aim is to develop an expert consensus on the optimal technique for Complete Mesocolic Excision (CME) for right-sided and transverse colon cancer to guide safe implementation and training pathways. METHODS: Guidance was developed following a modified Delphi process to draw consensus from 55 international experts in CME and surgical education representing 18 countries. Domain topics were formulated and subdivided into questions pertinent to different aspects of CME practice. A three-round Delphi voting on 25 statements based on the specific questions and 70% agreement was considered as consensus. RESULTS: Twenty-three recommendations for CME procedure were agreed on, describing the technique and optimal training pathway. CME is recommended as the standard of care resection for locally advanced colon cancer. The essential components are central vascular ligation, exposure of the superior mesenteric vein and excision of an intact mesocolon. Key anatomical landmarks to perform a safe CME dissection include identification of the ileocolic pedicle, superior mesenteric vein and root of the mesocolon. A proficiency-based multimodal training curriculum for CME was proposed including a formal proctorship programme. CONCLUSIONS: Consensus on standardisation of technique and training framework for complete mesocolic excision was agreed upon by a panel of experts to guide current practice and provide a quality control framework for future studies.

Laparoscopic surgery for rectal cancer reveals comparable oncological outcome even in context of worse short-term results-long-term analysis of nearly 500 patients from two high-volume centers.

PURPOSE: Large randomized controlled trials have investigated the oncological value of the laparoscopic approach to colorectal cancer. Mainly, non-inferiority for the laparoscopic approach regarding long-term survival could be shown. Nevertheless, some recent trials revealed inferiority especially due to histopathological quality of specimen or location of the tumor in the rectum. The main objective of this study was to compare two historical patient collectives of specialized centers for either the laparoscopic or the open resection approach, regarding long-term survival and disease progression of rectal cancer according to tumor localization in a retrospective propensity score-matched analysis. METHODS: A retrospective analysis, based on two prospectively maintained institutional colorectal cancer databases, was performed. The database of the reference center in Erlangen maintained almost exclusively open operations whereas the database in Lübeck maintained to a vast majority laparoscopic operations. To adjust risk profiles, a 1:1 propensity score matching was performed. RESULTS: Seven hundred fifty-five patients of both centers (Erlangen, n = 507, Lübeck n = 248) were included. Propensity score matching resulted in two equalized groups with 248 patients. Regarding the postoperative complications, advantages for the open approach were seen. Analyzing the survival data, no differences in disease-free as well as overall survival were shown. Also, no differences in the overall loco-regional recurrence and distant metastasis rate were detected. CONCLUSION: In centers with adequate expertise, open and laparoscopic procedures result in equivalent oncologic long-term outcomes. Advantages for the open resected group concerning short-term results and complications were detected, due to remarkably low rates of anastomotic leakage.

Prognostic subdivision of pT2 rectal carcinomas.

PURPOSE: The aim of the present study is to explore the prognostic impact of a subdivision of pT2 by the depth of invasion into the muscularis propria in rectal carcinomas. METHODS: Data from 269 consecutive patients with rectal carcinoma treated with primary tumor resection and lymph node dissection between 1986 and 2012 were analyzed with respect to locoregional and distant recurrence, disease-free survival, and overall survival. The depth of invasion into the muscularis propria of pT2 carcinomas was categorized by the pathologist into two groups: pT2a, invasion into the inner half of the muscularis propria; pT2b, invasion into the outer half of the muscularis propria. RESULTS: One hundred nineteen of the 269 patients (44.2%) were classified pT2a and 150 patients (55.8%) were classified pT2b. In univariate analysis, significant differences between pT2a and pT2b carcinomas were found for locoregional recurrences (5-year rates 5.3 vs 14.0%; p = 0.025), distant metastases (14.1 vs 18.7%; p = 0.026), disease-free survival (78.2 vs 62.5%; p = 0.022), and overall survival (87.4 vs 72.5%; p = 0.013). In multivariate Cox regression analysis, the pT2 subdivision was found to be an independent risk factor for locoregional recurrence (hazard ratio 2.6; p = 0.023), disease-free survival (HR 1.4; p = 0.022), and overall survival (HR 1.5; p = 0.020), but only marginally for distant metastasis (HR 1.7; p = 0.083). Other independent prognostic factors were lymph node status, lymphatic invasion, and grading. CONCLUSIONS: The depth of invasion into the muscularis propria is an independent prognostic factor for pT2 rectal carcinomas that will support decision-making for preoperative, surgical, and postoperative treatment.

Patient's quality of life after surgery and radiotherapy for extremity soft tissue sarcoma - a retrospective single-center study over ten years.

BACKGROUND AND OBJECTIVES: The purpose of this study is to analyze major complication rates and different aspects of health-related quality of life (HRQoL) in extremity soft tissue sarcoma (STS) patients treated with or without radio (chemo) therapy and surgery. METHODS: We performed a retrospective analysis of all patients who underwent Extremity STS excision from 2004 to 2014 (182 patients included). Patients' data were collected from patients' records. HRQoL was assessed by using EORTC QLQ-C30. RESULTS: A total of 182 patients underwent sarcoma resection. After neoadjuvant radiochemotherapy (RCT), the major-complication rate amounted to 28% (vs. 7%, no radiotherapy, p <  0.001). Major-complication rates after adjuvant radiotherapy (RT) occurred in 8% (vs. 7%, no radiotherapy, p = 0.265). Comparison QoL scores between treating with neoadjuvant RCT or without RT revealed significant worse scores with neoadjuvant RCT. Further stratification of disease control of these patients showed significant reduced scores in the group of disease-free patients with neoadjuvant RCT compared to irradiated disease-free patients. DISCUSSION: To date, there have only been a few investigations of QoL in STS. Retrospective study on quality of life have limitations, like a lack of baseline evaluation of QoL. Patient candidated to radiation therapy could have had worse QoL baseline due to more advanced disease. Disease status of the patients who answered the questionnaires could have been an influence of QoL and we could show reduced scores in the group of disease-free patients with neoadjuvant RCT, but not for the patients with recurrence or metastasis, so it is very hard to discriminate whether radiation therapy could really have an impact or not. CONCLUSION: This study might assist in further improving the understanding of QoL in STS patients and may animate for prospective studies examining the oncological therapies impact on HRQoL.

The influence of tumour site on prognosis in metastatic colorectal carcinomas with primary tumour resection.

PURPOSE: The aim of our study was to compare the characteristics and prognosis between right- and left-sided metastatic colorectal carcinomas. METHODS: Data from 937 patients with stage IV colorectal carcinomas (synchronous distant metastasis) who had a resection of the primary tumour between 1985 and 2014 were analysed. Carcinomas in the caecum to transverse colon were defined as right-sided (n = 250; 26.7%). They were compared to tumours located from the splenic flexure to the rectum categorised as left-sided (n = 687; 73.3%). RESULTS: In right-sided carcinomas, we observed significantly more female patients (50.8 vs 36.2%; p < 0.001), more unfavourable histological types (24.0 vs 8.6%; p < 0.001), more M1c carcinomas (metastases to the peritoneum ± others; 32.0 vs 14.4%; p < 0.001) and more emergencies (11.6 vs 7.1%; p = 0.029), while multimodal treatment was utilised in fewer patients (51.6 vs 63.8%; p = 0.001) and curative resections were less frequently (24.1 vs 35.4%; p = 0.002). Prognosis was significantly worse in patients with right-sided carcinomas (2-year-survival 27.2 vs 44.6%, p < 0.01). This difference was more pronounced after R2 resection (15.3 vs 29.7%; p < 0.001), than after macroscopic curative resection (2-year-survival 63.9 vs 71.9%; p = 0.106). In multivariate Cox regression analysis, tumour site was found to be an independent prognostic factor for overall survival (HR 1.2; 95% CI 1.0-1.5; p = 0.012). During the three 10-year periods, the prognosis improved equally in patients with right- and left-sided carcinomas, while the differences in survival remained identical. CONCLUSIONS: In a surgical patient cohort undergoing primary tumour resection, significant differences in prognosis were observed between patients with metastatic right- and left-sided colorectal carcinomas.

Variations in the Vascular Anatomy of the Right Colon and Implications for Right-Sided Colon Surgery.

BACKGROUND: Knowledge of the normal pattern and variations of the blood supply of the right colon is crucial for better outcomes after colon surgery. OBJECTIVE: The purpose of this study was to describe the precise vascular anatomy of the right colon according to surgical perspective. DESIGN: Adult fresh cadavers were dissected between January 2013 and October 2015, focusing on the venous and arterial anatomy of the right side of the colon. SETTINGS: Macroscopic anatomical dissections were performed on 111 adult fresh cadavers with emphasis on the vascular anatomy of the right colon. The colic tributaries of the superior mesenteric artery and vein were documented in writing. Furthermore, the dissections were recorded with a video camera. RESULTS: The incidence of colic arteries arising from the superior mesenteric artery included ileocolic artery, 100%; right colic artery, 33.3%; middle colic artery, 100%; and accessory middle colic artery, 11,7%. All 111 cadavers had a single ileocolic vein, which drained into the superior mesenteric vein in 103 cases (92.8%), into the gastro-pancreatico-colic trunk in 7 cases (6.3%), and into the jejunal trunk in 1 case (0.9%). The drainage site of the ileocolic vein to the superior mesenteric vein varied, and in 9% of cases the ileocolic vein did not accompany the ileocolic artery. The gastro-pancreatico-colic trunk was detected in 87 cases (78.4%); with several forms of the origin of the respective branches, the gastropancreatic trunk was detected in 24 cases (21.6), and the classic gastrocolic trunk of Henle was not detected. Variations were found in the formation and drainage routes of other venous colic tributaries of the superior mesenteric vein. LIMITATIONS: This study is limited by its use of cadavers in that it is impossible to trace each vessel to its origin in live surgery. CONCLUSIONS: Surgeons must watch, observe, and bear in mind that vascular variations can occur. Awareness of these complex variations may improve the quality of surgery and may prevent devastating complications during right-sided colon resections.

Survival analysis in rectal carcinoma after neoadjuvant chemoradiation: various methods with different results.

PURPOSE: Survival is an important indicator of outcome quality in rectal carcinoma. The 5-year survival rate is the typical outcome measurement. In patients with neoadjuvant chemoradiation followed by curative surgery, 7 years of follow-up is recommended. Different methods of survival analysis lead to different results. Here, we compared four different methods. METHODS: The data of 439 patients with rectal carcinoma treated with neoadjuvant chemoradiation followed by curative total mesorectal excision (TME) surgery between 1995 and 2010 were analysed. After stratifying by stage, relative survival (RS), cancer-related survival (CRS), overall survival (OS) and disease-free survival (DFS) were compared. In particular, the 3-year disease-free survival rate was compared to the 5- and 7-year overall survival rates. RESULTS: In the total cohort, the 5-year survival rates ranged from 90% (RS), over 84% (CRS) and 83% (OS) to 72% (DFS). Depending on the stage of disease, the differences between the 5-year survival rates varied between 10 and 32 percentage points. The differences were lowest in UICC stage y0 and highest in UICC stage yIV. The 3-year DFS-rate was always lower (worse) than the 5-year OS rate and higher (better) than the 7-year OS rate, with the exception of stage yIV. CONCLUSIONS: Comparisons of survival are only meaningful if the same methods are applied. The 3-year rate of DFS was always worse than the rate of 5-year OS. Therefore, the 3-year rate of DFS appears to be a useful surrogate indicator in rectal carcinoma treatment studies.

Forty-Two Years' Experience with Pulmonary Resections of Metastases from Colorectal Cancer.

Background Pulmonary metastasectomy is a commonly performed surgery in patients with controlled metastatic colorectal cancer (CRC). We reviewed our long-term single institution experience with lung resections for colorectal metastases to assess the factors influencing patient survival. Materials and Methods A cohort of 220 patients (138 men and 82 women; median age, 59 years) who underwent complete pulmonary metastasectomy for CRC with curative intent between 1972 and 2014 was retrospectively analyzed. The impact of factors related to primary tumor, metastases, and associated therapy on patient survival was assessed. Results Two postoperative inhospital deaths occurred. The median interoperative interval was 26 months. The overall 5-year survival rate after pulmonary metastasectomy was 49.4%. In univariable analysis, bilateral pulmonary metastases (log rank p = 0.02), multiple metastases (log rank p = 0.005), and stage IV UICC (the International Union Against Cancer) CRC at the time of initial presentation (log rank p = 0.008) were significantly associated with poor outcome. Multivariable Cox analysis demonstrated that stage IV CRC (p = 0.02) and multiple metastases (p = 0.0019) were statistically significant predictors of survival after the pulmonary metastasectomy. There was no significant difference in survival between patients with high versus low preoperative carcinoembryonic antigen serum level (p = 0.149), high versus low preoperative carbohydrate antigen 19-9 serum level (p = 0.291), and primary tumor location in rectum versus colon (p = 0.845). Conclusion Patients with unilateral metastasis and stages I to III primary tumor benefited most from pulmonary metastasectomy for CRC.

Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.

BACKGROUND: Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. METHODS: In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. FINDINGS: Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. INTERPRETATION: Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. FUNDING: German Cancer Aid.

Anatomy of the transverse colon revisited with respect to complete mesocolic excision and possible pathways of aberrant lymphatic tumor spread.

PURPOSE: Although lymph node metastases to pancreatic and gastroepiploic lymph node stations in transverse colon cancer have been described, the mode of lymphatic spread in this area remains unclear. This study was undertaken to describe possible pathways of aberrant lymphatic spread in the complex anatomic area of the proximal superior mesenteric artery and vein, the greater omentum, and the lower pancreatic border. METHODS: Abdominal specimens obtained from four cadaveric donors were dissected according to the principles of complete mesocolic excision. The vascular architecture of the transverse colon was scrutinized in search of possible pathways of lymphatic spread to the pancreatic and gastroepiploic lymph nodes. RESULTS: Vascular connections between the transverse colon and the greater omentum at the level of both the hepatic and the splenic flexures could be identified. In addition, small vessels running from the transverse mesocolon to the lower pancreatic border in the area between the middle colic artery and the inferior mesenteric vein were demonstrated. Moreover, venous tributaries to the gastrocolic trunk could be exposed to highlight its surgical importance as a guiding structure for complete mesocolic excision. CONCLUSION: The technical feasibility to clearly separate embryologic compartments by predefined tissue planes in complete mesocolic excision was confirmed. However, the vicinity of all three endodermal intestinal segments (foregut, midgut, and hindgut) obviously gives way to vascular connections that might serve as potential pathways for lymphatic metastatic spread of transverse colon cancer.

Surgery along the embryological planes for colon cancer: a systematic review of complete mesocolic excision.

BACKGROUND: Complete mesocolic excision (CME) for colonic cancer offers a surgical specimen of higher quality, with higher number of lymph nodes compared to conventional colectomy. However, evidence on oncological outcomes is limited. The aim of the present study is to review recent literature and provide more information regarding the effect of CME colectomy on short- and long-term outcomes. METHOD: PubMed and MEDLINE databases were searched, and articles in English reporting data on CME were reviewed. Intraoperative events; postoperative morbidity and mortality; histopathological characteristics, including macroscopic assessment, number, and status of retrieved lymph nodes; and oncological outcomes were the end-points. RESULTS: Thirty-two studies were analyzed. As regards the macroscopic assessment, a larger specimen (p = 0.02) that contains a higher number of lymph nodes (p < 0.00001) is acquired after CME. Two studies report a higher disease-free survival, in stage I and II and particularly in stage III disease after CME. CME by laparoscopy offers comparable outcomes, as regards intraoperative blood loss and immediate postoperative morbidity and mortality rates. Specimen quality is similar after either approach, for cancers located at the right and left colon, but not at the transverse colon. CONCLUSION: There is strong evidence that CME offers a longer central pedicle that contains more lymph nodes than conventional surgery for colon cancer. CME represents the surgical background for the maximum lymph node harvest, an important quality marker for the surgical outcome. However, and according to present data, there is limited evidence that colectomy in terms of CME leads to improved long-term oncological outcomes.

The impact of surgical quality on prognosis in patients undergoing rectal carcinoma surgery after preoperative chemoradiation.

PURPOSE: The aim of the study was to analyse the impact of surgical quality on the prognosis of rectal carcinoma patients who underwent preoperative long-term chemoradiation and TME surgery. METHODS: In a total of 314 patients, four quality indicators, including plane of surgery, pathological circumferential resection margin (pCRM), intraoperative local tumour cell dissemination and anastomotic leakage, were analysed with respect to locoregional recurrence, distant metastasis and overall survival. RESULTS: In 260 (82.8 %) of the patients, all four quality indicators were fulfilled. In 30 (9.6 %) of the patients, at least one quality indicator was not fulfilled; in 24 (7.6 %) of the patients, the data were not complete. Locoregional recurrence was significantly increased in patients who underwent surgery in the muscularis propria plane, who had a pCRM ≤ 1 mm or who experienced local tumour cell dissemination. In patients who had at least one quality indicator that was not fulfilled (suboptimal surgical quality), the 5-year rate of locoregional recurrence in those patients was 23.1 % compared to 4.8 % in patients who underwent optimal surgery (P = 0.001). In multivariate analysis, suboptimal surgery (hazard ratio (HR) 3.9; P = 0.020), abdominoperineal excision (HR 4.7; P = 0.003) and poor regression of primary tumours (HR 8.5; P < 0.001) were identified as independent prognostic factors for locoregional recurrence. In contrast to type of surgical treatment, ypT, ypN and regression grade, the quality of surgery did not significantly influence distant metastasis or overall survival. CONCLUSIONS: Even after preoperative chemoradiation, the surgical quality still has a strong impact on local control in patients with rectal carcinoma.

Robotic liver surgery for minor hepatic resections: a comparison with laparoscopic and open standard procedures.

BACKGROUND: Minimally invasive liver surgery is increasing worldwide. The benefit of the robot in this scenario is currently controversially discussed. We compared our robotic cases vs. laparoscopic and open minor hepatic resections and share the experience. MATERIAL AND METHODS: From 2011 to 2015, ten patients underwent robotic and 19 patients underwent laparoscopic minor liver resections in the Department of Surgery, University Hospital Erlangen. These patients were compared to a case-matched control group of 53 patients. The perioperative prospectively collected data were analyzed retrospectively. RESULTS: Blood loss was significantly decreased in the robotic (306 ml) and laparoscopic (356 ml) vs. the open (903 ml) surgery group (p = 0.001). Mean tumor size was 4.1-4.8 cm in all groups (p = 0.571). Negative surgical margins were present in 94 % of the open and 100 % of the laparoscopic and robotic group (p = 0.882). Time for surgery was enlarged for robotic (321 min) vs. laparoscopic (242 min) and open (186 min) surgery (p = 0.001). Postoperative hospitalization was decreased after robotic (7 days) and laparoscopic (8 days) vs. open (10 days) surgery (p = 0.004). Total morbidity was 17 % for open, 16 % for laparoscopic, and 1 % for robotic cases (p = 0.345). Postoperative pain medication and elevation of liver enzymes were remarkably lower after minimally invasive vs. open procedures. CONCLUSION: Minimally invasive liver surgery can be performed safely for minor hepatic resections and should be considered whenever possible. Minor liver resections can be performed by standard laparoscopy equivalent to robotic procedures. Nevertheless, the robot adds a technical upgrade which may have benefits for challenging cases and major liver surgery.

Repeated cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with recurrent peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become the treatment of choice for resectable peritoneal carcinomatosis (PC) and improved the survival of these patients. The situation changes if PC recurs and repeated CRS with HIPEC is considered. The patient selection and outcome of the repeated approach has not been well described. We analyzed our cohort and share the experiences. METHODS: Ninety-three CRS/HIPEC procedures, performed in 85 patients during the period 2001-2013, were examined in a retrospective analysis. Type of primary, ECOG status, peritoneal cancer index (PCI), completeness of cytoreduction (CC), duration of hospitalization, postoperative morbidity, mortality, and disease-free/overall survival were reviewed. RESULTS: Six patients (7%) underwent a second CRS/HIPEC (median interval between the two procedures: 26 months, range 8-61) including two patients with mesotheliomas, one patient with ovarian adenocarcinoma, one patient with leiomyosarcoma of uterus, one patient with colon adenocarcinoma, and one patient with appendiceal adenocarcinoma. The last two patients underwent a third CRS/HIPEC, 25 and 36 months, after the second procedure. The median PCI was 14 (range, 4-26) during the first and 20 (range, 7-39) during the second CRS/HIPEC of these patients. Completeness of cytoreduction score of 0 (CC-0) was achieved in all first procedures and in 67% of second procedures (CC-0; n=4 and CC-1; n=2). A CC-0 score was possible in both of the third procedures. The mean operating time was 444 min (range, 198-642) and 427 min (range, 239-617) during the first and the second procedure. Median intensive care unit (ICU) was 2 days, and hospital stay after second CRS/HIPEC was 17 days (range, 7-50). The 30-day morbidity after repeated CRS/HIPEC was 33% (16% for grade III-IV complications), and there was no 30-day mortality neither after the second nor after the third CRS/HIPEC. Median disease-free interval between first CRS/HIPEC and peritoneal recurrence was 17 months (range, 8-30). Median disease-free survival of 18 months (range, 4-33) was achieved after the second CRS/HIPEC. After a median follow-up of 74 months (range, 39-151), all patients are alive with disease (n=5) or disease free (n=1) under chemotherapy. CONCLUSIONS: In experienced centers, repeated CRS/HIPEC can be performed with safety. Patient selection and correct timing is of particular importance in achieving control of the disease. Repeated CRS/HIPEC should be considered as treatment option for selected patients with recurrent PC.

Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis.

Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%-15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients' informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort.

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. METHODS: In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. INTERPRETATION: Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. FUNDING: German Cancer Aid (Deutsche Krebshilfe).