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Press review
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Journal of Visceral Surgery (2017) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
Press review D. Goéré a,∗, A. Brouquet b a
Département de chirurgie oncologique, institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94800 Villejuif, France b Service de chirurgie digestive, hôpital du Kremlin-Bicêtre, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France 䊏
Anti-TNF therapy is associated with an increased risk of post-operative morbidity after surgery for Crohn’s disease Brouquet A, Maggiori L, Zerbib P, et al. Anti-TNF therapy is associated with an increased risk of postoperative morbidity after surgery for ileocolonic Crohn disease: results of a prospective nationwide cohort. Ann Surg 2016 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002017
Objective To determine the risk factors of morbidity after surgery for ileocolonic Crohn disease (CD). Summary of background data The risk factors of morbidity after surgery for CD, particularly the role of anti-TNF therapy, remain controversial and have not been evaluated in a large prospective cohort study. Methods From 2013 to 2015, data on 592 consecutive patients who underwent surgery for CD in 19 French specialty centers were collected prospectively. Possible relationships between anti-TNF and postoperative overall morbidity were tested by univariate and multivariate analysis. Because treatment by anti-TNF is possibly dependent on the characteristics of the patients and disease, a propensity score was calculated and introduced in the analysis using adjustment of the inverse probability of treatment-weighted method. Results Postoperative mortality, overall and intra-abdominal septic morbidity rates in the entire cohort were 0%, 29.7%, and 8.4%, respectively; 143 (24.1%) patients had received anti-TNF < 3 months prior to surgery. In the multivariate analysis, anti-TNF < 3 months prior to surgery was identified as an independent risk factor of the
∗
Corresponding author. E-mail address: [email protected] (D. Goéré).
overall postoperative morbidity (odds-ratio [OR] = 1.99; 95% confidence interval [CI] = 1.17—3.39, P = 0.011), with preoperative hemoglobin < 10 g/dL (OR = 4.77; 95% CI = 1.32—17.35, P = 0.017), operative time > 180 min (OR = 2.71; 95% CI = 1.54—4.78, P < 0.001) and recurrent CD (OR = 1.99; 95% CI = 1.13—3.36, P = 0.017). After calculating the propensity score and adjustment according to the inverse probability of treatment-weighted method, anti-TNF < 3 months prior to surgery remained associated with a higher risk of overall (OR = 2.98; 95% CI = 2.04—4.35, P < 0.0001) and intra-abdominal septic postoperative morbidities (OR = 2.22; 95% CI = 1.22—4.04, P = 0.009). Conclusions Preoperative anti-TNF therapy is associated with a higher risk of morbidity after surgery for ileocolonic CD. This information should be considered in the surgical management of these patients, particularly with regard to the preoperative preparation and indication of temporary defunctioning stoma. Comments 1. This study confirms that preoperative administration of anti-TNF can increase the risk of complications after surgery for ileocolic Crohn’s disease (CD). Even though existing publications are somewhat controversial, most of the recent literature points in the same direction as this current trial. 2. Interestingly, the question arises as to why some of the classic risk factors for postoperative complications such as preoperative malnutrition, perforated CD or corticosteroid administration do not stand out in this study. In dealing with this issue, the authors have shown that a temporary stoma could have limited the impact of these factors, largely recognized in published data. 3. It does not seem feasible to perform a controlled trial to evaluate the impact of preoperative anti-TNF on the risk of postoperative complications in patients undergoing surgery for ileocolic CD. Moreover, preoperative administration of anti-TNF reflects the severity of the disease and this association renders the study of the
1878-7886/$ — see front matter https://doi.org/10.1016/j.jviscsurg.2017.09.003 JVS-741; No. of Pages 8
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impact of anti-TNF on morbidity particularly delicate from a methodological viewpoint. Within this context, the authors proposed an original methodology based on a propensity score according to the inverse probability of treatment-weighted method, to limit the effect of confounding factors associated with the use of anti-TNF. 4. The patient characteristics of this French cohort are still under analysis to identify the risk factors for postoperative recurrence.
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Transanal minimally invasive surgery for local excision of benign and malignant rectal neoplasia Lee L, Burke JP, de Beche-Adams T, et al. Transanal minimally invasive surgery for local excision of benign and malignant rectal neoplasia: outcomes from 200 consecutive cases with midterm follow up. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002190
Objective This study describes the outcomes for 200 consecutive transanal minimally invasive surgery (TAMIS) local excision (LE) for rectal neoplasia. Background TAMIS is an advanced transanal platform that can result in high quality LE of rectal neoplasia. Methods Consecutive patients from July 1, 2009 to December 31, 2015 from a prospective institutional registry were analyzed. Indication for TAMIS LE was endoscopically unresectable benign lesions or histologically favorable early rectal cancers. The primary endpoints were resection quality, neoplasia recurrence, and oncologic outcomes. Kaplan-Meier survival analysis was used to describe diseasefree survival (DFS) for patients with rectal adenocarcinoma that did not receive immediate salvage radical surgery. Results There were 200 elective TAMIS LE procedures performed in 196 patients for 90 benign and 110 malignant lesions. Overall, a 7% margin positivity and 5% fragmentation rate was observed. The mean operative time for TAMIS was 69.5 minutes (SD 37.9). Postoperative morbidity was recorded in 11% of patients, with hemorrhage (9%), urinary retention (4%), and scrotal or subcutaneous emphysema (3%) being the most common. The mean follow up was 14.4 months (SD 17.4). Local recurrence occurred in 6%, and distant organ metastasis was noted in 2%. Mean time to local recurrence for malignancy was 16.9 months (SD 13.2). Cumulative DFS for patients with rectal adenocarcinoma was 96%, 93%, and 84% at 1-, 2-, and 3-years. Conclusions For carefully selected patients, TAMIS for local excision of rectal neoplasia is a valid option with low morbidity that maintains the advantages of organ preservation. Comments 1. This study confirms that TAMIS is an appropriate option for tumors of the mid and lower rectum amenable to local resection. The authors report one of the largest series of patients operated on with this technique, finding that the quality of excision was good and the risk of complication low. 2. The widespread availability of the technique should not call into question the selection and, in particular, oncologic criteria. The authors probably do not insist enough
on this point, all the more since half of the patients who had local recurrence after local excision refused a salvage proctectomy. This can be likened to selection and strategy failure. 3. As this is only a feasibility study, the results do not allow any conclusion as to the oncologic value of the procedure. The population was very heterogeneous with patients having both benign and malignant tumors, some having pre-operative treatment, others undergoing initial surgery, and the 14.4-month follow-up is too short to draw firm conclusions. 4. Although the results seem nearly the same as those obtained with TEM in other series, this study was not comparative and consequently, the results obtained do not allow to conclude that TAMIS is not inferior to TEM or even less, that the two treatments are equivalent. Of note, the mean distance of the tumor from the anal verge was 7 cm; TEM allows access to tumors located much higher.
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Roux-en-Y or Billroth II reconstruction after radical distal gastrectomy for gastric cancer So JB, Rao J, Wong AS, et al. Roux-en-Y or Billroth II reconstruction after radical distal gastrectomy for gastric cancer: a multicenter randomized controlled trial. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002229
Objective The aim of the study was to compare the clinical symptoms between Billroth II (B-II) and Roux-en-Y (R-Y) reconstruction after distal subtotal gastrectomy (DG) for gastric cancer. Background Surgery is the mainstay of curative treatment for gastric cancer. The technique for reconstruction after DG remains controversial. Both B-II and R-Y are popular methods. Methods This is a prospective multicenter randomized controlled trial. From October 2008 to October 2014, 162 patients who underwent DG were randomly allocated to B-II (n = 81) and R-Y (n = 81) groups. The primary endpoint is Gastrointestinal (GI) Symptoms Score 1 year after surgery. We also compared the nutritional status, extent of gastritis on endoscopy, and quality of life after surgery between the 2 procedures at 1 year. Results Operative time was significantly shorter for B-II than for R-Y [mean difference 21.5 minutes, 95% confidence interval (95% CI) 3.8—39.3, P = 0.019]. The B-II and R-Y groups had a peri-operative morbidity of 28.4% and 33.8%, respectively (P = 0.500) and a 30-day mortality of 2.5% and 1.2%, respectively (P = 0.500). GI symptoms score did not differ between R-Y versus B-II reconstruction (mean difference −0.45, 95% CI −1.21 to 0.31, P = 0.232). R-Y resulted in a lower median endoscopic grade for gastritis versus B-II (mean difference −1.32, 95% CI −1.67 to −0.98, P < 0.001). We noted no difference in nutritional status (R-Y versus B-II mean difference −0.31, 95% CI −3.27 to 2.65, P = 0.837) and quality of life at 1 year between the 2 groups too. Conclusion Although BII is associated with a higher incidence of heartburn symptom and higher median endoscopic grade for gastritis, BII and RY are similar in terms of overall GI
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Press review symptom score and nutritional status at 1 year after distal gastrectomy. Comments 1. The methodology in this trial is debatable. No hypothesis was proposed with regard to the main end-point and the authors did not indicate whether this was a superiority, non-inferiority, or equivalence study. This being said, it is difficult to determine if the sample size is adequate. 2. The questionable methodology limits the scope of results, even though some appear to be of interest, in particular, the risk of gastritis, which could have been the main endpoint of this trial. 3. It would have been particularly interesting to analyze the subgroup of patients with preoperative reflux disease to see if the Roux-en-Y anastomosis has any advantage in this category of patients. 4. The best way to perform Billroth II gastro-jejunostomy is still debated. The authors suggest to perform an isoperistaltic anastomosis but others [1] endorse the technique of anisoperistaltic anastomosis (afferent limb on the lesser curvature) to enhance the influx of biliopancreatic secretions at the level of the lesser curvature, and promote emptying of gastric contents by dependency, on the greater curvature. The authors did not discuss this point, which could have influenced the results of this study. Reference [1] J Visc Surg 2010;147(5):e273—83.
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Indeterminate 18FDG-PET scan for extrahepatic disease before liver resection for metastatic colorectal cancer: a retrospective cohort study using a prospectively maintained database to analyze survival outcomes Wong GY, Kumar R, Beeke C, et al. Survival outcomes for patients with indeterminate 18FDG-PET scan for extrahepatic disease before liver resection for metastatic colorectal cancer: a retrospective cohort study using a prospectively maintained database to analyze survival outcomes for patients with indeterminate extrahepatic disease on 18FDG-PET scan before liver resection for metastatic colorectal cancer. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002170
Objective The aim of this study was to evaluate overall survival (OS) and cancer recurrence for patients with indeterminate positron emission tomography (PET) scan for extrahepatic disease (EHD) before liver resection (LR) for colorectal liver metastases (CLMs). Summary of background data Indeterminate EHD as determined by PET imaging indicates a probability of extrahepatic malignancy and potentially excludes patients from undergoing LR for CLM. Methods In a retrospective analysis of prospectively collected data from February 2006 to December 2014, OS for patients with indeterminate EHD on FDG-PET scan before LR for CLM was performed using standard survival analysis methods, including Kaplan-Meier estimator and Cox proportional hazard models for multivariate analysis. Postoperative imaging was used as reference to evaluate the association between indeterminate EHD and recurrence.
3 Results Of 267 patients with PET scans before LR, 197 patients had no EHD and 70 patients had indeterminate EHD. Median follow-up was 33 months. The estimated 5-year OS was 60.8% versus 59.4% for indeterminate and absent EHD, respectively (P = 0.625). Disease-free survival was comparable between both groups (P = 0.975) and overall recurrence was 57.1% and 59.5% for indeterminate and absent EHD, respectively (P = 0.742). About 16.9% of recurrence was associated with the site of indeterminate EHD, with 80% of associated recurrence occurring in the thorax. Conclusions The site of indeterminate EHD appears to have a predictive value for recurrence, with indeterminate EHD in the thorax having a higher probability of malignancy. The evidence in this report supports the critical evaluation of PET scan results and that patients are not denied potential curative LR unless the evidence for unresectable EHD is certain. Comments 1. The authors raise a very pertinent question that concerns a fairly common situation: more than 20% of patients undergoing operation for resectable liver metastases have extra-hepatic fixation on PET of indeterminate origin. 2. Given the retrospective nature of data, which warrants caution in interpretation, the main message is that indeterminate PET fixation should not influence the therapeutic strategy when liver metastases are resectable. 3. One of the main limitations of this study is the authors did not choose the appropriate denominator. In other terms, this series, dealing with surgical series only, did not take into account the patients that actually underwent operation because of indeterminate extra-hepatic fixation and it is difficult to imagine that there were no patients in this situation. One cannot eliminate the possibility that extra-hepatic fixation did not have any deleterious effect because of a selection bias. 4. The authors did not provide any details concerning the modalities of surveillance and the specific post-operative treatment of patients with indeterminate extra-hepatic PET fixation. The authors insist on the fact that recurrence was treated in the same way in both groups. Conversely, we do not know if patients with indeterminate extra-hepatic PET fixation had any specific post-operative treatment or even were managed any differently. 5. The last sentence of the conclusion of the summary concerning patients with non-resectable extra-hepatic disease obviously makes good sense. However, it is difficult to understand how this study demonstrates that non-resectable extra-hepatic disease is a contra-indication for curative management of liver metastases.
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Impact of enhanced recovery after surgery and fast track surgery pathways on healthcare-associated infections Grant MC, Yang D, Wu CL, et al. Impact of enhanced recovery after surgery and fast track surgery pathways on healthcare-associated infections: results from a systematic review and metaanalysis. Ann Surg 2017;265(1):68—79. http://dx.doi.org/10.1097/SLA.0000000000001703
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4 Objective The aim of this study was to establish if enhanced recovery after surgery (ERAS) and fast track surgery (FTS) protocols are associated with reduction in healthcareassociated infection (HAIs). Background Evidence suggests that prevention strategies for HAIs should be multifaceted and transdisciplinary. ERAS and FTS protocols are collaborative approaches to perioperative care, which reduce length of stay but may also be an effective strategy for reducing HAIs. Methods We performed a meta-analysis of randomized trials involving either ERAS or FTS for abdominal or pelvic surgery. Primary outcome included postoperative incidence of 3 major HAIs: lung infection (LI), urinary tract infection (UTI), and surgical site infection (SSI). Results Among all included trials, ERAS/FTS was associated with a significant reduction in postoperative LI [risk ratio (RR) = 0.38; 95% confidence interval (CI) = 0.23—0.61; P < 0.0001; I = 0%], UTI (RR = 0.42; 95% CI = 0.23—0.76; P = 0.004; I = 0%), and SSI (RR = 0.75; 95% CI = 0.58—0.98; P = 0.04; I = 0%) compared with conventional controls. Sensitivity analysis performed following the exclusion of high risk of bias publications did not appreciably affect these results. ERAS/FTS was also associated with a significant decrease in hospital length of stay (standard mean difference = −0.83; 95% CI = −0.92 to −0.75; P < 0.0001; P for heterogeneity < 0.0001, I = 93%). Subgroup analysis of trials involving colorectal surgery and open incision also resulted in significant reduction in all 3 HAIs among ERAS/FTS compared with conventional counterparts. Conclusions Our results suggest ERAS/FTS protocols are powerful tools to prevent HAIs. Further study is needed to establish the mechanism. Providers should consider adoption of similar transdisciplinary programs to reduce perioperative HAIs and at the same time improve the value of surgical care. Comments 1. It is now common knowledge that duration of hospital stay is not the best criterion to evaluate ERAS programs. This meta-analysis tends to show the added value of these programs with regard to the specific problem of hospital-acquired infections (HAI), responsible for additional public health care costs. This is therefore yet another argument to recommend such programs within our health care services. 2. One of the limitations of this meta-analysis, however, is the vagueness of the definition of the study criteria: in particular, it is not known whether readmissions for infectious complications treated outside the hospital where surgery was performed were included in the analysis, a parameter that obviously could have modified the results. 3. Another limitation of this meta-analysis comes from the fact that the authors did not study the relationship between compliance with the ERAS program and the risk of HAI. It would have been of interest to determine whether only those patients who adhered strictly to the protocol had any specific benefit as opposed whether just being included in the ERAS program was enough. 4. As indicated by the authors, evolving surgical techniques and in particular, the advent of minimally-invasive techniques have considerably reduced the risk of infective complications. In subgroup analysis, ERAS programs have
D. Goéré, A. Brouquet been shown to improve outcomes in patients undergoing traditional ‘‘open’’ surgery. Conversely there are not enough data available to study this effect in the subgroup of patients undergoing laparoscopic surgery, and it is not at all certain that this effect is as marked in this sub-group.
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Antibiotics versus surgical therapy for uncomplicated appendicitis: systematic review and meta-analysis of controlled trials Harnoss JC, Zelienka, Probst P, et al. Antibiotics versus surgical therapy for uncomplicated appendicitis: systematic review and meta-analysis of controlled trials (PROSPERO 2015: CRD42015016882). Ann Surg 2017;265(5):889—900. http://dx.doi.org/10.1097/SLA.0000000000002039
Objective The aim was to investigate available evidence regarding effectiveness and safety of surgical versus conservative treatment of acute appendicitis. Summary of background data There is ongoing debate on the merits of surgical and conservative treatment for acute appendicitis. Methods A systematic literature search (Cochrane Library, Medline, Embase) and hand search of retrieved reference lists up to January 2016 was conducted to identify randomized and nonrandomized studies. After critical appraisal, data were analyzed using a random-effects model in a Mantel-Haenszel test or inverse variance to calculate risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). Results Four trials and four cohort studies (2551 patients) were included. We found that 26.5% of patients in the conservative group needed appendectomy within 1 year, resulting in treatment effectiveness of 72.6%, significantly lower than the 99.4% in the surgical group, (RR 0.75; 95% CI 0.7—0.79; P = 0.00001; I = 62%). Overall postoperative complications were comparable (RR 0.95; 95% CI 0.35—2.58; P = 0.91; I = 0%), whereas the rate of adverse events (RR 3.18; 95% CI 1.63—6.21; P = 0.0007; I = 1%) and the incidence of complicated appendicitis (RR 2.52; 95% CI 1.17—5.43; P = 0.02; I = 0%) were significantly higher in the antibiotic treatment group. Randomized trials showed significantly longer hospital stay in the antibiotic treatment group (RR 0.3; 95% CI 0.07—0.53; P = 0.009; I = 49%). Conclusions Although antibiotics may prevent some patients from appendectomies, surgery represents the definitive, onetime only treatment with a well-known risk profile, whereas the long-term impact of antibiotic treatment on patient quality of life and health care costs is unknown. This systematic review and meta-analysis helps physicians and patients in choosing between treatment options depending on whether they are risk averse or risk takers. Comments 1. Meta-analyses are certainly the ideal tool to try to answer this type of question, one that arises daily in the practice of so many surgeons. This is the third meta-analysis on the same topic. The methodology seems robust even if the inclusion of non-randomized cohort studies along with the four randomized controlled studies is debatable. 2. The authors underscore an important element in their discussion, in that the most appropriate endpoint to
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Press review answer this question would be to study patient quality of life. Unfortunately, these data are not available. 3. One of the main limitations of this meta-analysis is the heterogeneity of the studies included. The variability of the definition of uncomplicated appendicitis, the modalities of diagnosis, and in particular, the use of CT scan, and the type of antibiotic treatment are not comparable between the included studies, thus limiting the impact of results. 4. There are obviously several ways to interpret the outcome of this meta-analysis: one is that of the authors, i.e. medical treatment is less effective, results in more adverse events and, in particular, more patients with complicated appendicitis when operation is performed. Another interpretation would be that medical treatment avoids operation for more than 70% of patients with uncomplicated appendicitis, and the forms of appendicitis that resist medical treatment are more often complicated; but deferred management does not increase the overall risk of post-operative complication. All in all, it is not certain that this new analysis can definitively close the debate . . . 5. Certain authors consider that the ‘‘inferior’’ results of medical treatment compared with surgery in noncomplicated appendicitis are essentially related to a selection bias. Effectively, there are few data as to the selection criteria concerning both the diagnosis and comorbidity. All these elements can influence the efficacy and the safety of treatment and consequently the outcome of this analysis.
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Embryonic origin of primary colon cancer predicts pathologic response and survival in patients undergoing resection for colon cancer liver metastases Yamashita S, Brudvik KW, Kopetz SE, et al. Embryonic origin of primary colon cancer predicts pathologic response and survival in patients undergoing resection for colon cancer liver metastases. Ann Surg 2016 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002087
Background The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). Methods We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. Results Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs. 27%, P < 0.001; OS rate at 3 years: 46% vs. 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence
5 of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value 5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs. 78%, P = 0.003). Conclusions Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status. Comments 1. This study confirms the results of previous studies with regard to the poor prognostic impact of colorectal liver metastases (CRLM) of midgut (vs. hindgut) origin, irrespective of disease stage. These results can be explained by molecular [1,2], histological and bacterial [3] differences between these two localizations. Conversely, the negative impact of the localization on preoperative systemic chemotherapy has never been shown before. Likewise, in metastatic patients treated by anti-EGFR, survival is poorer in patients with cancers of midgut origin [4]. 2. The pejorative prognosis of midgut cancer is not only due to poorer response to chemotherapy since the same difference was found in the cohort of patients who did not have preoperative treatment. 3. For the authors, colon cancer and RAS status are two major prognostic factors in patients undergoing operation for CRLM. Of note, MSI and BRAF status were not taken into account because there are also major prognostic factors, with a higher incidence of mutated BRAF and MSI in mid-gut cancers. 4. Patients treated with anti-EGFR were not included in this study in order to homogenize the study population as much as possible without any treatment difference between the mutated and wild-type RAS patients. This, however, is not in accordance with the current European recommendations [5], which call for pre-operative bi-chemotherapy associated with anti-EGFR in wild-type RAS patients when a response is necessary to obtain an R0 resection. References [1] Br J Cancer 2015;112:1921—8. [2] Br J Cancer 2016;115:25—33. [3] Clin Transl Gastroenterol 2016;7(11):e200. [4] Ann Oncol 2017.doi: 10.1093. [5] Ann Oncol 2016;27:1386—422.
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Incidence of occult intrahepatic metastasis in hepatocellular carcinoma treated with transplantation corresponds to early recurrence rates after partial hepatectomy Aufhauser DD Jr1, Sadot E, Murken DR, at al. Incidence of occult intrahepatic metastasis in hepatocellular carcinoma treated with transplantation corresponds to early recurrence rates after partial hepatectomy. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002135
Objective This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC)
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6 lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. Summary of background data Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. Methods We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. Results In the OPTN and high-volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. Conclusion Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis. Comments 1. From a methodological viewpoint, this is a retrospective study, with a large number of patients transplanted for HCC. The two groups of patients (transplantation vs. resection) were obviously not comparable since the indications for resection differ from those for transplantation: patients in the resection group had more solitary and voluminous lesions, more viral B non-C hepatopathy, no underlying liver disease or cirrhosis. These differences represent major prognostic and predictive factors for recurrence and make it difficult to analyze the results of this study. Of note, sub-group analysis of the more homogeneous patients came to the same results as the overall analysis. 2. This study raises interesting questions that should have allowed to choose between transplantation and resection whenever the two options were possible; there are no available randomized studies to help answer this question. However, in spite of a large number of patients, the factors associated with the presence of multifocal HCC, not visible pre-operatively, were weak and did not influence therapeutic decision. 3. The authors concluded that transplantation was better. It has been shown that the prognosis of patients with HCC who are candidates for transplantation was better after initial transplantation compared to resection with salvage transplantation in case of recurrence [1]. 4. However, considering the limited availability of donor organs, it is disappointing that the authors did not discuss other alternatives such as surgery, chemo-embolization, or curative resection followed by secondary transplantation in patients at high risk for recurrence [2]. Currently, there are three therapeutic options for a CHILD A patient with a solitary HHC: surgical resection, transplantation, and local radiofrequency ablation; these options
D. Goéré, A. Brouquet must be discussed and integrated into a therapeutic program [3]. 5. As well, the authors could have discussed the potential absence of benefit of preoperative or perioperative treatment [4]. References [1] Ann Surg 2016;264:155—63. [2] Liver Transpl 2004;10:1294—300. [3] Lancet Oncol 2012;13:e11—22. [4] Cochrane Database Syst Rev 2009;21:CD001199.
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Laparoscopic lavage in the management of Hinchey grade III diverticulitis: a systematic review Marshall JR, Buchwald PL, Gandhi J, et al. Laparoscopic lavage in the management of Hinchey grade III diverticulitis: a systematic review. Ann Surg 2017;265:670—6. http://dx.doi.org/10.1097/SLA.0000000000002005
Objective To compare the outcomes of laparoscopic lavage and sigmoid resection in perforated diverticulitis with purulent peritonitis. Background Peritonitis secondary to perforated diverticulitis has conventionally been managed by resection and stoma formation. Case series have suggested that patients can be safely managed with laparoscopic lavage, resulting in reduced mortality and stoma formation. Recently, 3 randomized controlled trials have published contradictory conclusions. Methods MEDLINE from 1946 to present, Cochrane Database of Systematic Reviews, and Cochrane database of Registered clinical trials and EMBASE (all via OVID) were searched using the terms ‘‘laparoscopy’’ AND (‘‘primary resection’’ OR ‘‘Hartmann procedure’’, OR ‘‘sigmoidectomy’’), AND ‘‘Diverticulitis’’, AND ‘‘Peritonitis’’ AND ‘‘therapeutic irrigation’’ or ‘‘lavage’’ AND randomized controlled trial and any derivatives of those terms. We included all randomized controlled trials. Data were extracted from each study using a purpose-designed template. Statistical analysis was undertaken using Revman 5. Results Three randomized controlled trials were identified from 48 potential studies. The analysis included 307 patients of whom 159 underwent laparoscopic lavage. Overall, the rate of reintervention within 30 days postoperatively was 45/159 (28.3%) in the lavage group and 13/148 (8.8%) in the resection group (relative risk 3.01, 95% confidence interval 1.15—7.90). There was no significant difference in Intensive Care Unit admissions, 30- and 90-day mortality, or stoma rates at 12 months. Conclusion Laparoscopic lavage used in the management of Hinchey grade III diverticulitis leads to more reinterventions within 30 days postoperatively, but does not increase the 30- or 90-day mortality rates compared with sigmoid resection. Comments 1. Evaluation of peritoneal lavage without concomitant colonic resection is not new, but the debate continues. The authors of this meta-analysis found that laparoscopic lavage for the management of Hinchey grade III diverticulitis led to more re-interventions within 30 days post-operatively. However, of note, by re-intervention, they included all drainage procedures whether surgical
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Press review or via interventional radiology. More than one third of the so-called re-interventions (37.8%) in the lavage group were via interventional radiology. When interventional radiology drainage procedures were not included, there was no statistically significant difference found in the re-intervention rate between the two groups. 2. Concerning the evaluation criteria, none of the randomized trials had sufficient power to show a statistically significant difference in postoperative mortality or duration of hospital stay in intensive care. The definitive stoma rate was available in only two trials. The recently published results of the SCANDIV study found a statistically significantly higher stoma rate in the resection group (14% vs. 42%, P < 0.001) [1]. 3. One of the major points is that the complication and mortality rate related to stoma reversal are not included in any of these studies. The same holds true for the reinfection rate after lavage alone. 4. In conclusion, this meta-analysis does not allow any answer to the question. The indications for laparoscopic lavage without resection or resection remain difficult to define. The results of two other studies are awaited [2,3]. References [1] Br J Surg 2017. http://dx.doi.org/10.1002/bjs.10567. [2] LapLAND laparoscopic lavage for acute non-faeculent diverticulitis. https://www.clinicaltrials.gov/ct2/show/NCT01019239. [3] Laparoscopic-lavage Observational Study (LLOS).
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A multi-institutional comparison of perioperative outcomes of robotic and open pancreaticoduodenectomy Zureikat AH, Postlewait LM, Liu Y, et al. A multi-institutional comparison of perioperative outcomes of robotic and open pancreaticoduodenectomy. Ann Surg 2016;264:640—9. http://dx.doi.org/10.1097/SLA.0000000000001869
Objectives Limited data exist comparing robotic and open approaches to pancreaticoduodenectomy (PD). We performed a multicenter comparison of perioperative outcomes of robotic PD (RPD) and open PD (OPD). Methods Perioperative data for patients who underwent postlearning curve PD at 8 centers (8/2011—1/2015) were assessed. Univariate analysis of clinicopathologic and treatment factors were performed, and multivariable models were constructed to determine associations of operative approach (RPD or OPD) with perioperative outcomes. Results Of the 1028 patients, 211 (20.5%) underwent RPD (4.7% conversions) and 817 (79.5%) underwent OPD. As compared with OPD, RPD patients had higher body mass index, rates of prior abdominal surgery, and softer pancreatic remnants, whereas OPD patients had a higher percentage of pancreatic ductal adenocarcinoma cases, and greater proportion of nondilated (< 3 mm) pancreatic ducts. On multivariable analysis, as compared with OPD, RPD was associated with longer operative times [mean difference = 75.4 minutes, 95% confidence interval (CI) 17.5—133.3, P = 0.01], reduced blood loss (mean difference = −181 mL, 95% CI −355—(−7.7), P = 0.04) and reductions in major complications (odds ratio = 0.64, 95% CI 0.47—0.85, P = 0.003). No associations were demonstrated
7 between operative approach and 90-day mortality, clinically relevant postoperative pancreatic fistula and wound infection, length of stay, or 90-day readmission. In the subset of 522 (51%) pancreatic ductal adenocarcinomas, operative approach was not a significant independent predictor of margin status or suboptimal lymphadenectomy (< 12 lymph nodes harvested). Conclusions Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed. Comments 1. This is the largest series of robotic-assisted pancreatoduodenectomies. The methodological analysis is based on multivariate analysis with the Generalized Estimating Equation model (GEE model) because of the disparity between the two groups and co-variables. Matching and analysis by a propensity score would have allowed comparing the two groups with more robust outcome data. 2. While these results are interesting, they are not very ‘‘exportable’’ and only seem to be accessible to expert centers with high volume referrals in pancreatic surgery. Effectively, even though this is a multicenter study, the patients in the RPD group originated from two centers only, with 79% from one center in Pittsburgh. Therefore a center effect has most likely contributed to the good results reported herein. 3. Effectively, in the 2015 multicenter analysis originating from the American National Cancer Database (NCDB), comparing the immediate postoperative outcome of 983 patients who underwent mini-invasive pancreatic surgery (laparoscopy ± robotic-assisted) to 6078 who underwent open surgery [1], the conclusions were that the miniinvasive approach was associated with an increased complication rate and a 30% conversion rate. The 4.8% conversion rate in the current series attests to the expertise of the two centers performing the RPD. 4. These results underscore the importance of training and expertise in pancreatic surgery centers that want to start mini-invasive pancreatic surgery programs. Reference [1] Ann Surg 2015;262:372—7.
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RAS mutation clinical risk score to predict survival after resection of colorectal liver metastases Brudvik KW, Jones RP, Giuliante F, et al. RAS mutation clinical risk score to predict survival after resection of colorectal liver metastases. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002319
Objective To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). Background The t-CS relies on the following factors: primary tumor nodal status, disease free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. Methods Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors
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available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analysis were used to compare the t-CS and the mCS. The m-CS was validated in an international multicenter cohort of 608 patients. Results A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis > 50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. Conclusions Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM. Comments 1. The authors have defined a new prognostic score for patients having undergone operation for colorectal liver metastasis (CRLM) by substituting the RAS mutation status for three items of the traditional Fong score (number of metastases > 1, CEA > 200, delay < 12 months). The score is simple, easy to calculate, reproducible, and allows correct classification of patients. 2. As the data were retrospective, and in order to improve the strength of the analysis, the authors tested their results on an external cohort. Of note, certain results were not confirmed in the external validation cohort, in particular, there was no statistically significant difference found in survival between the patients with a score equal to 2 (n = 184) and those with a score equal to 3 (n = 28). 3. As is the case with all scores, certain prognostic factors were not included, in order to facilitate the calculation and to improve the robustness. Thus, the response to preoperative chemotherapy, the presence of extrahepatic metastases, and BRAF and MSI status were not integrated. This does not necessarily mean that these factors cannot be integrated individually and that they should not influence therapeutic decisions. 4. This article confirms the major prognostic impact of RAS mutation status in patients undergoing operation for CRLM. However, at this stage, the clinical impact of this score remains limited and confirmation on a prospective series is necessary.
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ImmunoScore Signature: a prognostic and predictive tool in gastric cancer Jiang Y, Zhang Q, Hu Y, et al. ImmunoScore signature: a prognostic and predictive tool in gastric cancer. Ann Surg 2016 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002116
Objective We postulated that the ImmunoScore (IS) could markedly improve the prediction of postsurgical survival and chemotherapeutic benefits in gastric cancer (GC). Summary of background data A prediction model for GC patients was developed using data from 879 consecutive patients. Methods The expression of 27 immune features was detected in 251 specimens by using immunohistochemistry, and a 5feature-based ISGC was then constructed using the LASSO Cox regression model. Testing and validation cohorts were included to validate the model. Results Using the LASSO model, we established an ISGC classifier based on 5 features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. Significant differences were found between the high-ISGC and low-ISGC patients in the training cohort in 5-year disease-free survival (45.0% vs. 4.4%, respectively; P < 0.001) and 5-year overall survival (48.8% vs. 6.7%, respectively; P < 0.001). Multivariate analysis revealed that the ISGC classifier was an independent prognostic factor. A combination of ISGC and tumor, node, and metastasis (TNM) had better prognostic value than TNM stage alone. Further analysis revealed that stages II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. Finally, we constructed 2 nomograms to predict which patients with stages II and III GC might benefit from adjuvant chemotherapy after surgery. Conclusions The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value of the TNM staging system. Moreover, the ISGC might be a useful predictive tool to identify stages II and III GC patients who would benefit from adjuvant chemotherapy. Comments 1. From a methodological viewpoint, the quality of the pathology and statistical analysis seems good. However, of note, these data were collected retrospectively, therefore a prospective validation is necessary. 2. The immunohistochemical analysis was performed on biopsy or operative specimens. The authors did not allude to the possibility of difficulties in the immunohistochemcial interpretation of biopsies or that tumor heterogeneity that could have distorted the results. 3. Another biological prognostic factor should be integrated into this analysis: the MSI status. Microsatellite instability, a characteristic that could correspond to a better prognosis and a different response to treatments, is described in 15—20% of patients. 4. It seems that patients did not receive any preoperative chemotherapy; therefore there is no information as to the possible modifications of the immunologic infiltrate after chemotherapy and its value. 5. In practical terms, however, immunoscores are difficult to use, mainly because of the time necessary to read and interpret the specimens and the paucity of competent pathologists. Standardization of the technique and a computerized data-processing are needed today.
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Journal of Visceral Surgery (2017) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
Press review D. Goéré a,∗, A. Brouquet b a
Département de chirurgie oncologique, institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94800 Villejuif, France b Service de chirurgie digestive, hôpital du Kremlin-Bicêtre, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France 䊏
Anti-TNF therapy is associated with an increased risk of post-operative morbidity after surgery for Crohn’s disease Brouquet A, Maggiori L, Zerbib P, et al. Anti-TNF therapy is associated with an increased risk of postoperative morbidity after surgery for ileocolonic Crohn disease: results of a prospective nationwide cohort. Ann Surg 2016 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002017
Objective To determine the risk factors of morbidity after surgery for ileocolonic Crohn disease (CD). Summary of background data The risk factors of morbidity after surgery for CD, particularly the role of anti-TNF therapy, remain controversial and have not been evaluated in a large prospective cohort study. Methods From 2013 to 2015, data on 592 consecutive patients who underwent surgery for CD in 19 French specialty centers were collected prospectively. Possible relationships between anti-TNF and postoperative overall morbidity were tested by univariate and multivariate analysis. Because treatment by anti-TNF is possibly dependent on the characteristics of the patients and disease, a propensity score was calculated and introduced in the analysis using adjustment of the inverse probability of treatment-weighted method. Results Postoperative mortality, overall and intra-abdominal septic morbidity rates in the entire cohort were 0%, 29.7%, and 8.4%, respectively; 143 (24.1%) patients had received anti-TNF < 3 months prior to surgery. In the multivariate analysis, anti-TNF < 3 months prior to surgery was identified as an independent risk factor of the
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Corresponding author. E-mail address: [email protected] (D. Goéré).
overall postoperative morbidity (odds-ratio [OR] = 1.99; 95% confidence interval [CI] = 1.17—3.39, P = 0.011), with preoperative hemoglobin < 10 g/dL (OR = 4.77; 95% CI = 1.32—17.35, P = 0.017), operative time > 180 min (OR = 2.71; 95% CI = 1.54—4.78, P < 0.001) and recurrent CD (OR = 1.99; 95% CI = 1.13—3.36, P = 0.017). After calculating the propensity score and adjustment according to the inverse probability of treatment-weighted method, anti-TNF < 3 months prior to surgery remained associated with a higher risk of overall (OR = 2.98; 95% CI = 2.04—4.35, P < 0.0001) and intra-abdominal septic postoperative morbidities (OR = 2.22; 95% CI = 1.22—4.04, P = 0.009). Conclusions Preoperative anti-TNF therapy is associated with a higher risk of morbidity after surgery for ileocolonic CD. This information should be considered in the surgical management of these patients, particularly with regard to the preoperative preparation and indication of temporary defunctioning stoma. Comments 1. This study confirms that preoperative administration of anti-TNF can increase the risk of complications after surgery for ileocolic Crohn’s disease (CD). Even though existing publications are somewhat controversial, most of the recent literature points in the same direction as this current trial. 2. Interestingly, the question arises as to why some of the classic risk factors for postoperative complications such as preoperative malnutrition, perforated CD or corticosteroid administration do not stand out in this study. In dealing with this issue, the authors have shown that a temporary stoma could have limited the impact of these factors, largely recognized in published data. 3. It does not seem feasible to perform a controlled trial to evaluate the impact of preoperative anti-TNF on the risk of postoperative complications in patients undergoing surgery for ileocolic CD. Moreover, preoperative administration of anti-TNF reflects the severity of the disease and this association renders the study of the
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impact of anti-TNF on morbidity particularly delicate from a methodological viewpoint. Within this context, the authors proposed an original methodology based on a propensity score according to the inverse probability of treatment-weighted method, to limit the effect of confounding factors associated with the use of anti-TNF. 4. The patient characteristics of this French cohort are still under analysis to identify the risk factors for postoperative recurrence.
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Transanal minimally invasive surgery for local excision of benign and malignant rectal neoplasia Lee L, Burke JP, de Beche-Adams T, et al. Transanal minimally invasive surgery for local excision of benign and malignant rectal neoplasia: outcomes from 200 consecutive cases with midterm follow up. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002190
Objective This study describes the outcomes for 200 consecutive transanal minimally invasive surgery (TAMIS) local excision (LE) for rectal neoplasia. Background TAMIS is an advanced transanal platform that can result in high quality LE of rectal neoplasia. Methods Consecutive patients from July 1, 2009 to December 31, 2015 from a prospective institutional registry were analyzed. Indication for TAMIS LE was endoscopically unresectable benign lesions or histologically favorable early rectal cancers. The primary endpoints were resection quality, neoplasia recurrence, and oncologic outcomes. Kaplan-Meier survival analysis was used to describe diseasefree survival (DFS) for patients with rectal adenocarcinoma that did not receive immediate salvage radical surgery. Results There were 200 elective TAMIS LE procedures performed in 196 patients for 90 benign and 110 malignant lesions. Overall, a 7% margin positivity and 5% fragmentation rate was observed. The mean operative time for TAMIS was 69.5 minutes (SD 37.9). Postoperative morbidity was recorded in 11% of patients, with hemorrhage (9%), urinary retention (4%), and scrotal or subcutaneous emphysema (3%) being the most common. The mean follow up was 14.4 months (SD 17.4). Local recurrence occurred in 6%, and distant organ metastasis was noted in 2%. Mean time to local recurrence for malignancy was 16.9 months (SD 13.2). Cumulative DFS for patients with rectal adenocarcinoma was 96%, 93%, and 84% at 1-, 2-, and 3-years. Conclusions For carefully selected patients, TAMIS for local excision of rectal neoplasia is a valid option with low morbidity that maintains the advantages of organ preservation. Comments 1. This study confirms that TAMIS is an appropriate option for tumors of the mid and lower rectum amenable to local resection. The authors report one of the largest series of patients operated on with this technique, finding that the quality of excision was good and the risk of complication low. 2. The widespread availability of the technique should not call into question the selection and, in particular, oncologic criteria. The authors probably do not insist enough
on this point, all the more since half of the patients who had local recurrence after local excision refused a salvage proctectomy. This can be likened to selection and strategy failure. 3. As this is only a feasibility study, the results do not allow any conclusion as to the oncologic value of the procedure. The population was very heterogeneous with patients having both benign and malignant tumors, some having pre-operative treatment, others undergoing initial surgery, and the 14.4-month follow-up is too short to draw firm conclusions. 4. Although the results seem nearly the same as those obtained with TEM in other series, this study was not comparative and consequently, the results obtained do not allow to conclude that TAMIS is not inferior to TEM or even less, that the two treatments are equivalent. Of note, the mean distance of the tumor from the anal verge was 7 cm; TEM allows access to tumors located much higher.
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Roux-en-Y or Billroth II reconstruction after radical distal gastrectomy for gastric cancer So JB, Rao J, Wong AS, et al. Roux-en-Y or Billroth II reconstruction after radical distal gastrectomy for gastric cancer: a multicenter randomized controlled trial. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002229
Objective The aim of the study was to compare the clinical symptoms between Billroth II (B-II) and Roux-en-Y (R-Y) reconstruction after distal subtotal gastrectomy (DG) for gastric cancer. Background Surgery is the mainstay of curative treatment for gastric cancer. The technique for reconstruction after DG remains controversial. Both B-II and R-Y are popular methods. Methods This is a prospective multicenter randomized controlled trial. From October 2008 to October 2014, 162 patients who underwent DG were randomly allocated to B-II (n = 81) and R-Y (n = 81) groups. The primary endpoint is Gastrointestinal (GI) Symptoms Score 1 year after surgery. We also compared the nutritional status, extent of gastritis on endoscopy, and quality of life after surgery between the 2 procedures at 1 year. Results Operative time was significantly shorter for B-II than for R-Y [mean difference 21.5 minutes, 95% confidence interval (95% CI) 3.8—39.3, P = 0.019]. The B-II and R-Y groups had a peri-operative morbidity of 28.4% and 33.8%, respectively (P = 0.500) and a 30-day mortality of 2.5% and 1.2%, respectively (P = 0.500). GI symptoms score did not differ between R-Y versus B-II reconstruction (mean difference −0.45, 95% CI −1.21 to 0.31, P = 0.232). R-Y resulted in a lower median endoscopic grade for gastritis versus B-II (mean difference −1.32, 95% CI −1.67 to −0.98, P < 0.001). We noted no difference in nutritional status (R-Y versus B-II mean difference −0.31, 95% CI −3.27 to 2.65, P = 0.837) and quality of life at 1 year between the 2 groups too. Conclusion Although BII is associated with a higher incidence of heartburn symptom and higher median endoscopic grade for gastritis, BII and RY are similar in terms of overall GI
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Press review symptom score and nutritional status at 1 year after distal gastrectomy. Comments 1. The methodology in this trial is debatable. No hypothesis was proposed with regard to the main end-point and the authors did not indicate whether this was a superiority, non-inferiority, or equivalence study. This being said, it is difficult to determine if the sample size is adequate. 2. The questionable methodology limits the scope of results, even though some appear to be of interest, in particular, the risk of gastritis, which could have been the main endpoint of this trial. 3. It would have been particularly interesting to analyze the subgroup of patients with preoperative reflux disease to see if the Roux-en-Y anastomosis has any advantage in this category of patients. 4. The best way to perform Billroth II gastro-jejunostomy is still debated. The authors suggest to perform an isoperistaltic anastomosis but others [1] endorse the technique of anisoperistaltic anastomosis (afferent limb on the lesser curvature) to enhance the influx of biliopancreatic secretions at the level of the lesser curvature, and promote emptying of gastric contents by dependency, on the greater curvature. The authors did not discuss this point, which could have influenced the results of this study. Reference [1] J Visc Surg 2010;147(5):e273—83.
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Indeterminate 18FDG-PET scan for extrahepatic disease before liver resection for metastatic colorectal cancer: a retrospective cohort study using a prospectively maintained database to analyze survival outcomes Wong GY, Kumar R, Beeke C, et al. Survival outcomes for patients with indeterminate 18FDG-PET scan for extrahepatic disease before liver resection for metastatic colorectal cancer: a retrospective cohort study using a prospectively maintained database to analyze survival outcomes for patients with indeterminate extrahepatic disease on 18FDG-PET scan before liver resection for metastatic colorectal cancer. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002170
Objective The aim of this study was to evaluate overall survival (OS) and cancer recurrence for patients with indeterminate positron emission tomography (PET) scan for extrahepatic disease (EHD) before liver resection (LR) for colorectal liver metastases (CLMs). Summary of background data Indeterminate EHD as determined by PET imaging indicates a probability of extrahepatic malignancy and potentially excludes patients from undergoing LR for CLM. Methods In a retrospective analysis of prospectively collected data from February 2006 to December 2014, OS for patients with indeterminate EHD on FDG-PET scan before LR for CLM was performed using standard survival analysis methods, including Kaplan-Meier estimator and Cox proportional hazard models for multivariate analysis. Postoperative imaging was used as reference to evaluate the association between indeterminate EHD and recurrence.
3 Results Of 267 patients with PET scans before LR, 197 patients had no EHD and 70 patients had indeterminate EHD. Median follow-up was 33 months. The estimated 5-year OS was 60.8% versus 59.4% for indeterminate and absent EHD, respectively (P = 0.625). Disease-free survival was comparable between both groups (P = 0.975) and overall recurrence was 57.1% and 59.5% for indeterminate and absent EHD, respectively (P = 0.742). About 16.9% of recurrence was associated with the site of indeterminate EHD, with 80% of associated recurrence occurring in the thorax. Conclusions The site of indeterminate EHD appears to have a predictive value for recurrence, with indeterminate EHD in the thorax having a higher probability of malignancy. The evidence in this report supports the critical evaluation of PET scan results and that patients are not denied potential curative LR unless the evidence for unresectable EHD is certain. Comments 1. The authors raise a very pertinent question that concerns a fairly common situation: more than 20% of patients undergoing operation for resectable liver metastases have extra-hepatic fixation on PET of indeterminate origin. 2. Given the retrospective nature of data, which warrants caution in interpretation, the main message is that indeterminate PET fixation should not influence the therapeutic strategy when liver metastases are resectable. 3. One of the main limitations of this study is the authors did not choose the appropriate denominator. In other terms, this series, dealing with surgical series only, did not take into account the patients that actually underwent operation because of indeterminate extra-hepatic fixation and it is difficult to imagine that there were no patients in this situation. One cannot eliminate the possibility that extra-hepatic fixation did not have any deleterious effect because of a selection bias. 4. The authors did not provide any details concerning the modalities of surveillance and the specific post-operative treatment of patients with indeterminate extra-hepatic PET fixation. The authors insist on the fact that recurrence was treated in the same way in both groups. Conversely, we do not know if patients with indeterminate extra-hepatic PET fixation had any specific post-operative treatment or even were managed any differently. 5. The last sentence of the conclusion of the summary concerning patients with non-resectable extra-hepatic disease obviously makes good sense. However, it is difficult to understand how this study demonstrates that non-resectable extra-hepatic disease is a contra-indication for curative management of liver metastases.
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Impact of enhanced recovery after surgery and fast track surgery pathways on healthcare-associated infections Grant MC, Yang D, Wu CL, et al. Impact of enhanced recovery after surgery and fast track surgery pathways on healthcare-associated infections: results from a systematic review and metaanalysis. Ann Surg 2017;265(1):68—79. http://dx.doi.org/10.1097/SLA.0000000000001703
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4 Objective The aim of this study was to establish if enhanced recovery after surgery (ERAS) and fast track surgery (FTS) protocols are associated with reduction in healthcareassociated infection (HAIs). Background Evidence suggests that prevention strategies for HAIs should be multifaceted and transdisciplinary. ERAS and FTS protocols are collaborative approaches to perioperative care, which reduce length of stay but may also be an effective strategy for reducing HAIs. Methods We performed a meta-analysis of randomized trials involving either ERAS or FTS for abdominal or pelvic surgery. Primary outcome included postoperative incidence of 3 major HAIs: lung infection (LI), urinary tract infection (UTI), and surgical site infection (SSI). Results Among all included trials, ERAS/FTS was associated with a significant reduction in postoperative LI [risk ratio (RR) = 0.38; 95% confidence interval (CI) = 0.23—0.61; P < 0.0001; I = 0%], UTI (RR = 0.42; 95% CI = 0.23—0.76; P = 0.004; I = 0%), and SSI (RR = 0.75; 95% CI = 0.58—0.98; P = 0.04; I = 0%) compared with conventional controls. Sensitivity analysis performed following the exclusion of high risk of bias publications did not appreciably affect these results. ERAS/FTS was also associated with a significant decrease in hospital length of stay (standard mean difference = −0.83; 95% CI = −0.92 to −0.75; P < 0.0001; P for heterogeneity < 0.0001, I = 93%). Subgroup analysis of trials involving colorectal surgery and open incision also resulted in significant reduction in all 3 HAIs among ERAS/FTS compared with conventional counterparts. Conclusions Our results suggest ERAS/FTS protocols are powerful tools to prevent HAIs. Further study is needed to establish the mechanism. Providers should consider adoption of similar transdisciplinary programs to reduce perioperative HAIs and at the same time improve the value of surgical care. Comments 1. It is now common knowledge that duration of hospital stay is not the best criterion to evaluate ERAS programs. This meta-analysis tends to show the added value of these programs with regard to the specific problem of hospital-acquired infections (HAI), responsible for additional public health care costs. This is therefore yet another argument to recommend such programs within our health care services. 2. One of the limitations of this meta-analysis, however, is the vagueness of the definition of the study criteria: in particular, it is not known whether readmissions for infectious complications treated outside the hospital where surgery was performed were included in the analysis, a parameter that obviously could have modified the results. 3. Another limitation of this meta-analysis comes from the fact that the authors did not study the relationship between compliance with the ERAS program and the risk of HAI. It would have been of interest to determine whether only those patients who adhered strictly to the protocol had any specific benefit as opposed whether just being included in the ERAS program was enough. 4. As indicated by the authors, evolving surgical techniques and in particular, the advent of minimally-invasive techniques have considerably reduced the risk of infective complications. In subgroup analysis, ERAS programs have
D. Goéré, A. Brouquet been shown to improve outcomes in patients undergoing traditional ‘‘open’’ surgery. Conversely there are not enough data available to study this effect in the subgroup of patients undergoing laparoscopic surgery, and it is not at all certain that this effect is as marked in this sub-group.
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Antibiotics versus surgical therapy for uncomplicated appendicitis: systematic review and meta-analysis of controlled trials Harnoss JC, Zelienka, Probst P, et al. Antibiotics versus surgical therapy for uncomplicated appendicitis: systematic review and meta-analysis of controlled trials (PROSPERO 2015: CRD42015016882). Ann Surg 2017;265(5):889—900. http://dx.doi.org/10.1097/SLA.0000000000002039
Objective The aim was to investigate available evidence regarding effectiveness and safety of surgical versus conservative treatment of acute appendicitis. Summary of background data There is ongoing debate on the merits of surgical and conservative treatment for acute appendicitis. Methods A systematic literature search (Cochrane Library, Medline, Embase) and hand search of retrieved reference lists up to January 2016 was conducted to identify randomized and nonrandomized studies. After critical appraisal, data were analyzed using a random-effects model in a Mantel-Haenszel test or inverse variance to calculate risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). Results Four trials and four cohort studies (2551 patients) were included. We found that 26.5% of patients in the conservative group needed appendectomy within 1 year, resulting in treatment effectiveness of 72.6%, significantly lower than the 99.4% in the surgical group, (RR 0.75; 95% CI 0.7—0.79; P = 0.00001; I = 62%). Overall postoperative complications were comparable (RR 0.95; 95% CI 0.35—2.58; P = 0.91; I = 0%), whereas the rate of adverse events (RR 3.18; 95% CI 1.63—6.21; P = 0.0007; I = 1%) and the incidence of complicated appendicitis (RR 2.52; 95% CI 1.17—5.43; P = 0.02; I = 0%) were significantly higher in the antibiotic treatment group. Randomized trials showed significantly longer hospital stay in the antibiotic treatment group (RR 0.3; 95% CI 0.07—0.53; P = 0.009; I = 49%). Conclusions Although antibiotics may prevent some patients from appendectomies, surgery represents the definitive, onetime only treatment with a well-known risk profile, whereas the long-term impact of antibiotic treatment on patient quality of life and health care costs is unknown. This systematic review and meta-analysis helps physicians and patients in choosing between treatment options depending on whether they are risk averse or risk takers. Comments 1. Meta-analyses are certainly the ideal tool to try to answer this type of question, one that arises daily in the practice of so many surgeons. This is the third meta-analysis on the same topic. The methodology seems robust even if the inclusion of non-randomized cohort studies along with the four randomized controlled studies is debatable. 2. The authors underscore an important element in their discussion, in that the most appropriate endpoint to
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Press review answer this question would be to study patient quality of life. Unfortunately, these data are not available. 3. One of the main limitations of this meta-analysis is the heterogeneity of the studies included. The variability of the definition of uncomplicated appendicitis, the modalities of diagnosis, and in particular, the use of CT scan, and the type of antibiotic treatment are not comparable between the included studies, thus limiting the impact of results. 4. There are obviously several ways to interpret the outcome of this meta-analysis: one is that of the authors, i.e. medical treatment is less effective, results in more adverse events and, in particular, more patients with complicated appendicitis when operation is performed. Another interpretation would be that medical treatment avoids operation for more than 70% of patients with uncomplicated appendicitis, and the forms of appendicitis that resist medical treatment are more often complicated; but deferred management does not increase the overall risk of post-operative complication. All in all, it is not certain that this new analysis can definitively close the debate . . . 5. Certain authors consider that the ‘‘inferior’’ results of medical treatment compared with surgery in noncomplicated appendicitis are essentially related to a selection bias. Effectively, there are few data as to the selection criteria concerning both the diagnosis and comorbidity. All these elements can influence the efficacy and the safety of treatment and consequently the outcome of this analysis.
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Embryonic origin of primary colon cancer predicts pathologic response and survival in patients undergoing resection for colon cancer liver metastases Yamashita S, Brudvik KW, Kopetz SE, et al. Embryonic origin of primary colon cancer predicts pathologic response and survival in patients undergoing resection for colon cancer liver metastases. Ann Surg 2016 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002087
Background The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). Methods We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. Results Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs. 27%, P < 0.001; OS rate at 3 years: 46% vs. 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence
5 of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value 5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs. 78%, P = 0.003). Conclusions Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status. Comments 1. This study confirms the results of previous studies with regard to the poor prognostic impact of colorectal liver metastases (CRLM) of midgut (vs. hindgut) origin, irrespective of disease stage. These results can be explained by molecular [1,2], histological and bacterial [3] differences between these two localizations. Conversely, the negative impact of the localization on preoperative systemic chemotherapy has never been shown before. Likewise, in metastatic patients treated by anti-EGFR, survival is poorer in patients with cancers of midgut origin [4]. 2. The pejorative prognosis of midgut cancer is not only due to poorer response to chemotherapy since the same difference was found in the cohort of patients who did not have preoperative treatment. 3. For the authors, colon cancer and RAS status are two major prognostic factors in patients undergoing operation for CRLM. Of note, MSI and BRAF status were not taken into account because there are also major prognostic factors, with a higher incidence of mutated BRAF and MSI in mid-gut cancers. 4. Patients treated with anti-EGFR were not included in this study in order to homogenize the study population as much as possible without any treatment difference between the mutated and wild-type RAS patients. This, however, is not in accordance with the current European recommendations [5], which call for pre-operative bi-chemotherapy associated with anti-EGFR in wild-type RAS patients when a response is necessary to obtain an R0 resection. References [1] Br J Cancer 2015;112:1921—8. [2] Br J Cancer 2016;115:25—33. [3] Clin Transl Gastroenterol 2016;7(11):e200. [4] Ann Oncol 2017.doi: 10.1093. [5] Ann Oncol 2016;27:1386—422.
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Incidence of occult intrahepatic metastasis in hepatocellular carcinoma treated with transplantation corresponds to early recurrence rates after partial hepatectomy Aufhauser DD Jr1, Sadot E, Murken DR, at al. Incidence of occult intrahepatic metastasis in hepatocellular carcinoma treated with transplantation corresponds to early recurrence rates after partial hepatectomy. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002135
Objective This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC)
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6 lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. Summary of background data Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. Methods We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. Results In the OPTN and high-volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. Conclusion Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis. Comments 1. From a methodological viewpoint, this is a retrospective study, with a large number of patients transplanted for HCC. The two groups of patients (transplantation vs. resection) were obviously not comparable since the indications for resection differ from those for transplantation: patients in the resection group had more solitary and voluminous lesions, more viral B non-C hepatopathy, no underlying liver disease or cirrhosis. These differences represent major prognostic and predictive factors for recurrence and make it difficult to analyze the results of this study. Of note, sub-group analysis of the more homogeneous patients came to the same results as the overall analysis. 2. This study raises interesting questions that should have allowed to choose between transplantation and resection whenever the two options were possible; there are no available randomized studies to help answer this question. However, in spite of a large number of patients, the factors associated with the presence of multifocal HCC, not visible pre-operatively, were weak and did not influence therapeutic decision. 3. The authors concluded that transplantation was better. It has been shown that the prognosis of patients with HCC who are candidates for transplantation was better after initial transplantation compared to resection with salvage transplantation in case of recurrence [1]. 4. However, considering the limited availability of donor organs, it is disappointing that the authors did not discuss other alternatives such as surgery, chemo-embolization, or curative resection followed by secondary transplantation in patients at high risk for recurrence [2]. Currently, there are three therapeutic options for a CHILD A patient with a solitary HHC: surgical resection, transplantation, and local radiofrequency ablation; these options
D. Goéré, A. Brouquet must be discussed and integrated into a therapeutic program [3]. 5. As well, the authors could have discussed the potential absence of benefit of preoperative or perioperative treatment [4]. References [1] Ann Surg 2016;264:155—63. [2] Liver Transpl 2004;10:1294—300. [3] Lancet Oncol 2012;13:e11—22. [4] Cochrane Database Syst Rev 2009;21:CD001199.
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Laparoscopic lavage in the management of Hinchey grade III diverticulitis: a systematic review Marshall JR, Buchwald PL, Gandhi J, et al. Laparoscopic lavage in the management of Hinchey grade III diverticulitis: a systematic review. Ann Surg 2017;265:670—6. http://dx.doi.org/10.1097/SLA.0000000000002005
Objective To compare the outcomes of laparoscopic lavage and sigmoid resection in perforated diverticulitis with purulent peritonitis. Background Peritonitis secondary to perforated diverticulitis has conventionally been managed by resection and stoma formation. Case series have suggested that patients can be safely managed with laparoscopic lavage, resulting in reduced mortality and stoma formation. Recently, 3 randomized controlled trials have published contradictory conclusions. Methods MEDLINE from 1946 to present, Cochrane Database of Systematic Reviews, and Cochrane database of Registered clinical trials and EMBASE (all via OVID) were searched using the terms ‘‘laparoscopy’’ AND (‘‘primary resection’’ OR ‘‘Hartmann procedure’’, OR ‘‘sigmoidectomy’’), AND ‘‘Diverticulitis’’, AND ‘‘Peritonitis’’ AND ‘‘therapeutic irrigation’’ or ‘‘lavage’’ AND randomized controlled trial and any derivatives of those terms. We included all randomized controlled trials. Data were extracted from each study using a purpose-designed template. Statistical analysis was undertaken using Revman 5. Results Three randomized controlled trials were identified from 48 potential studies. The analysis included 307 patients of whom 159 underwent laparoscopic lavage. Overall, the rate of reintervention within 30 days postoperatively was 45/159 (28.3%) in the lavage group and 13/148 (8.8%) in the resection group (relative risk 3.01, 95% confidence interval 1.15—7.90). There was no significant difference in Intensive Care Unit admissions, 30- and 90-day mortality, or stoma rates at 12 months. Conclusion Laparoscopic lavage used in the management of Hinchey grade III diverticulitis leads to more reinterventions within 30 days postoperatively, but does not increase the 30- or 90-day mortality rates compared with sigmoid resection. Comments 1. Evaluation of peritoneal lavage without concomitant colonic resection is not new, but the debate continues. The authors of this meta-analysis found that laparoscopic lavage for the management of Hinchey grade III diverticulitis led to more re-interventions within 30 days post-operatively. However, of note, by re-intervention, they included all drainage procedures whether surgical
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Press review or via interventional radiology. More than one third of the so-called re-interventions (37.8%) in the lavage group were via interventional radiology. When interventional radiology drainage procedures were not included, there was no statistically significant difference found in the re-intervention rate between the two groups. 2. Concerning the evaluation criteria, none of the randomized trials had sufficient power to show a statistically significant difference in postoperative mortality or duration of hospital stay in intensive care. The definitive stoma rate was available in only two trials. The recently published results of the SCANDIV study found a statistically significantly higher stoma rate in the resection group (14% vs. 42%, P < 0.001) [1]. 3. One of the major points is that the complication and mortality rate related to stoma reversal are not included in any of these studies. The same holds true for the reinfection rate after lavage alone. 4. In conclusion, this meta-analysis does not allow any answer to the question. The indications for laparoscopic lavage without resection or resection remain difficult to define. The results of two other studies are awaited [2,3]. References [1] Br J Surg 2017. http://dx.doi.org/10.1002/bjs.10567. [2] LapLAND laparoscopic lavage for acute non-faeculent diverticulitis. https://www.clinicaltrials.gov/ct2/show/NCT01019239. [3] Laparoscopic-lavage Observational Study (LLOS).
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A multi-institutional comparison of perioperative outcomes of robotic and open pancreaticoduodenectomy Zureikat AH, Postlewait LM, Liu Y, et al. A multi-institutional comparison of perioperative outcomes of robotic and open pancreaticoduodenectomy. Ann Surg 2016;264:640—9. http://dx.doi.org/10.1097/SLA.0000000000001869
Objectives Limited data exist comparing robotic and open approaches to pancreaticoduodenectomy (PD). We performed a multicenter comparison of perioperative outcomes of robotic PD (RPD) and open PD (OPD). Methods Perioperative data for patients who underwent postlearning curve PD at 8 centers (8/2011—1/2015) were assessed. Univariate analysis of clinicopathologic and treatment factors were performed, and multivariable models were constructed to determine associations of operative approach (RPD or OPD) with perioperative outcomes. Results Of the 1028 patients, 211 (20.5%) underwent RPD (4.7% conversions) and 817 (79.5%) underwent OPD. As compared with OPD, RPD patients had higher body mass index, rates of prior abdominal surgery, and softer pancreatic remnants, whereas OPD patients had a higher percentage of pancreatic ductal adenocarcinoma cases, and greater proportion of nondilated (< 3 mm) pancreatic ducts. On multivariable analysis, as compared with OPD, RPD was associated with longer operative times [mean difference = 75.4 minutes, 95% confidence interval (CI) 17.5—133.3, P = 0.01], reduced blood loss (mean difference = −181 mL, 95% CI −355—(−7.7), P = 0.04) and reductions in major complications (odds ratio = 0.64, 95% CI 0.47—0.85, P = 0.003). No associations were demonstrated
7 between operative approach and 90-day mortality, clinically relevant postoperative pancreatic fistula and wound infection, length of stay, or 90-day readmission. In the subset of 522 (51%) pancreatic ductal adenocarcinomas, operative approach was not a significant independent predictor of margin status or suboptimal lymphadenectomy (< 12 lymph nodes harvested). Conclusions Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed. Comments 1. This is the largest series of robotic-assisted pancreatoduodenectomies. The methodological analysis is based on multivariate analysis with the Generalized Estimating Equation model (GEE model) because of the disparity between the two groups and co-variables. Matching and analysis by a propensity score would have allowed comparing the two groups with more robust outcome data. 2. While these results are interesting, they are not very ‘‘exportable’’ and only seem to be accessible to expert centers with high volume referrals in pancreatic surgery. Effectively, even though this is a multicenter study, the patients in the RPD group originated from two centers only, with 79% from one center in Pittsburgh. Therefore a center effect has most likely contributed to the good results reported herein. 3. Effectively, in the 2015 multicenter analysis originating from the American National Cancer Database (NCDB), comparing the immediate postoperative outcome of 983 patients who underwent mini-invasive pancreatic surgery (laparoscopy ± robotic-assisted) to 6078 who underwent open surgery [1], the conclusions were that the miniinvasive approach was associated with an increased complication rate and a 30% conversion rate. The 4.8% conversion rate in the current series attests to the expertise of the two centers performing the RPD. 4. These results underscore the importance of training and expertise in pancreatic surgery centers that want to start mini-invasive pancreatic surgery programs. Reference [1] Ann Surg 2015;262:372—7.
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RAS mutation clinical risk score to predict survival after resection of colorectal liver metastases Brudvik KW, Jones RP, Giuliante F, et al. RAS mutation clinical risk score to predict survival after resection of colorectal liver metastases. Ann Surg 2017 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002319
Objective To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). Background The t-CS relies on the following factors: primary tumor nodal status, disease free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. Methods Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors
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available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analysis were used to compare the t-CS and the mCS. The m-CS was validated in an international multicenter cohort of 608 patients. Results A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis > 50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. Conclusions Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM. Comments 1. The authors have defined a new prognostic score for patients having undergone operation for colorectal liver metastasis (CRLM) by substituting the RAS mutation status for three items of the traditional Fong score (number of metastases > 1, CEA > 200, delay < 12 months). The score is simple, easy to calculate, reproducible, and allows correct classification of patients. 2. As the data were retrospective, and in order to improve the strength of the analysis, the authors tested their results on an external cohort. Of note, certain results were not confirmed in the external validation cohort, in particular, there was no statistically significant difference found in survival between the patients with a score equal to 2 (n = 184) and those with a score equal to 3 (n = 28). 3. As is the case with all scores, certain prognostic factors were not included, in order to facilitate the calculation and to improve the robustness. Thus, the response to preoperative chemotherapy, the presence of extrahepatic metastases, and BRAF and MSI status were not integrated. This does not necessarily mean that these factors cannot be integrated individually and that they should not influence therapeutic decisions. 4. This article confirms the major prognostic impact of RAS mutation status in patients undergoing operation for CRLM. However, at this stage, the clinical impact of this score remains limited and confirmation on a prospective series is necessary.
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ImmunoScore Signature: a prognostic and predictive tool in gastric cancer Jiang Y, Zhang Q, Hu Y, et al. ImmunoScore signature: a prognostic and predictive tool in gastric cancer. Ann Surg 2016 [Epub ahead of print]. http://dx.doi.org/10.1097/SLA.0000000000002116
Objective We postulated that the ImmunoScore (IS) could markedly improve the prediction of postsurgical survival and chemotherapeutic benefits in gastric cancer (GC). Summary of background data A prediction model for GC patients was developed using data from 879 consecutive patients. Methods The expression of 27 immune features was detected in 251 specimens by using immunohistochemistry, and a 5feature-based ISGC was then constructed using the LASSO Cox regression model. Testing and validation cohorts were included to validate the model. Results Using the LASSO model, we established an ISGC classifier based on 5 features: CD3invasive margin (IM), CD3center of tumor (CT), CD8IM, CD45ROCT, and CD66bIM. Significant differences were found between the high-ISGC and low-ISGC patients in the training cohort in 5-year disease-free survival (45.0% vs. 4.4%, respectively; P < 0.001) and 5-year overall survival (48.8% vs. 6.7%, respectively; P < 0.001). Multivariate analysis revealed that the ISGC classifier was an independent prognostic factor. A combination of ISGC and tumor, node, and metastasis (TNM) had better prognostic value than TNM stage alone. Further analysis revealed that stages II and III GC patients with high-ISGC exhibited a favorable response to adjuvant chemotherapy. Finally, we constructed 2 nomograms to predict which patients with stages II and III GC might benefit from adjuvant chemotherapy after surgery. Conclusions The ISGC classifier could effectively predict recurrence and survival of GC, and complemented the prognostic value of the TNM staging system. Moreover, the ISGC might be a useful predictive tool to identify stages II and III GC patients who would benefit from adjuvant chemotherapy. Comments 1. From a methodological viewpoint, the quality of the pathology and statistical analysis seems good. However, of note, these data were collected retrospectively, therefore a prospective validation is necessary. 2. The immunohistochemical analysis was performed on biopsy or operative specimens. The authors did not allude to the possibility of difficulties in the immunohistochemcial interpretation of biopsies or that tumor heterogeneity that could have distorted the results. 3. Another biological prognostic factor should be integrated into this analysis: the MSI status. Microsatellite instability, a characteristic that could correspond to a better prognosis and a different response to treatments, is described in 15—20% of patients. 4. It seems that patients did not receive any preoperative chemotherapy; therefore there is no information as to the possible modifications of the immunologic infiltrate after chemotherapy and its value. 5. In practical terms, however, immunoscores are difficult to use, mainly because of the time necessary to read and interpret the specimens and the paucity of competent pathologists. Standardization of the technique and a computerized data-processing are needed today.