MRI-detected extramural vascular invasion (mrEMVI) as the best predictive factor to identify candidates to total neoadjuvant therapy in locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: Chemotherapy in locally advanced rectal cancer (LARC) is shifting from an adjuvant setting to a total neoadjuvant therapy (TNT) strategy, that relies on distant metastases (DM) risk prediction. This study aims to assess the accuracy of magnetic resonance imaging-detected extramural vascular invasion (mrEMVI) as predictive factor for DM in LARC, compared with other MRI-detected and pathologic factors. METHODS: This retrospective single-center study analyzed data extracted from a series of consecutive patients curatively resected for rectal cancer at Mauriziano Hospital in Turin (Italy) from January 2013 to December 2018. RESULTS: Data from 69 patients were analyzed. MrEMVI was detected in 31 (44.9%) cases. Median follow-up was 39.9 months. DM and local recurrence occurred in 19 (27.5%) and 4 (5.8%) patients. One- and 3-year cumulative incidence of DM were 32.3% (95% confidence interval [CI]: 0.17-0.49) and 56.8% (95% CI: 0.35-0.74) in the mrEMVI-positive group and 5.4% (95% CI: 0.01-0.16) and 14.0% (95% CI: 0.05-0.27) in the mrEMVI-negative group (log-rank test, p < 0.001). In the multivariate analysis of MRI factors, mrEMVI was the only independent predictor of DM (HR: 3.59, CI: 1.21-10.69, p = 0.02). CONCLUSIONS: This study confirmed that mrEMVI is a powerful predictor of DM in LARC. It should be routinely reported and considered during multidisciplinary care strategy planning.

A close adherence to a stoma-therapeutic pathway improves immediate stoma-related outcomes and reduces the length of hospital stay.

PURPOSE: New stoma creation is related to a wide range of implications and stoma-related complications could occur frequently. The aim was to assess the impact of a close stoma-therapeutic-care pathway (STCP) in terms of length of stay, autonomy in the management of the pouch, readmission rate, and stoma-related complications. METHODS: Patients undergoing surgery for colorectal disease and first stoma creation from January 2017 to December 2020 were analyzed. All patients enrolled had joined the Enhanced Recovery after Surgery (ERAS) protocol. RESULTS: Among 143 enrolled, 56 (40%) did not completely follow the STCP (group A), whereas 87 (60%) demonstrated strict compliance (group B). The hospital stay lasted 8 days in group B and 11.5 in group A (p = 0.001). The first look at the stoma needed 1 day in group B and 3 days in group A (p < 0.001), emptying the pouch 2 days in group B and 5 days in group A (p < 0.001). Finally, the ability to change the pouch was 3 days in group B and 6 days in group A (p < 0.001). Nine (16.1%) stoma-related complications were counted in group A and 16 (18.4%) in group B, and 30-day readmission was 10.1% in group B and 11.5% in group A (p = 0.82 and p = 1, respectively, not significant). CONCLUSIONS: The STCP has been shown to reduce the hospital stay and to have a protective role making the patient autonomous in the management of the stoma.

Implementation of an enhanced recovery after surgery protocol for colorectal cancer in a regional hospital network supported by audit and feedback: a stepped wedge, cluster randomised trial.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are known to potentially improve the management and outcomes of patients undergoing colorectal surgery, with limited evidence of their implementation in hospital networks and in a large population. We aimed to assess the impact of the implementation of an ERAS protocol in colorectal cancer surgery in the entire region of Piemonte, Italy, supported by an audit and feedback (A&F) intervention. METHODS: A large, stepped wedge, cluster randomised trial enrolled patients scheduled for elective surgery at 29 general surgery units (clusters). At baseline (first 3 months), standard care was continued in all units. Thereafter, four groups of clusters began to adopt the ERAS protocol successively. By the end of the study, each cluster had a period in which standard care was maintained (control) and a period in which the protocol was applied (experimental). ERAS implementation was supported by initial training and A&F initiatives. The primary endpoint was length of stay (LOS) without outliers (>94th percentile), and the secondary endpoints were outliers for LOS, postoperative medical and surgical complications, quality of recovery and compliance with ERAS items. RESULTS: Of 2626 randomised patients, 2397 were included in the LOS analysis (1060 in the control period and 1337 in the experimental period). The mean LOS without outliers was 8.5 days during the control period (SD 3.9) and 7.5 (SD 3.5) during the experimental one. The adjusted difference between the two periods was a reduction of -0.58 days (95% CI -1.07, -0.09; p=0.021). The compliance with ERAS items increased from 52.4% to 67.3% (estimated absolute difference +13%; 95% CI 11.4%, 14.7%). No difference in the occurrence of complications was evidenced (OR 1.22; 95% CI 0.89, 1.68). CONCLUSION: Implementation of the ERAS protocol for colorectal cancer, supported by A&F approach, led to a substantial improvement in compliance and a reduction in LOS, without meaningful effects on complications. Trial registration number NCT04037787.

Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: a single institutional experience.

BACKGROUND: Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol. METHODS: Patients first received induction gemcitabine and oxaliplatin (GEMOX) (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)). Patients without disease progression then received gemcitabine twice weekly (50 mg/m(2) daily) concurrent with radiotherapy (50.4 grays) and were re-evaluated for resectability. RESULTS: Thirty-nine patients (15 with borderline resectable disease and 24 with unresectable disease) entered the study. The treatment was well tolerated. Disease control was obtained in 29 of 39 patients. Two patients progressed after GEMOX, and 7 progressed after CRT. After a median follow-up of 13 months, the median progression-free survival (PFS) was 10.2 months. The median PFS of patients with borderline resectable and unresectable disease was 16.6 and 9.1 months, respectively (P = .056). For the whole group, the median overall survival (OS) was 16.7 months (27.8 months for patients with borderline resectable disease, 13.3 for patients with unresectable disease; P = .045). Eleven patients (9 with borderline resectable disease and 2 with unresectable disease at diagnosis) underwent successful resection. Patients who underwent resection had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively). The median OS among resected and nonresected patients was 31.5 months and 12.3 months, respectively (P < .001). CONCLUSIONS: The current results indicated that induction GEMOX followed by CRT is feasible in patients with LAPC. Both those with borderline resectable disease and those with unresectable disease received clinical benefit, a chance to obtain resectability, and improved survival. The authors concluded that this protocol warrants further evaluation.

Laparoscopic versus open colectomy for TNM stage III colon cancer: results of a prospective multicenter study in Italy.

BACKGROUND AND PURPOSE: There is still debate about the practicality of performing laparoscopic colectomy instead of open colectomy for patients with curable cancer, although laparoscopic surgery is now being performed even for patients with advanced colon cancer. We compared the long-term results of laparoscopic versus open colectomy for TNM stage III carcinoma of the colon in a large series of patients followed up for at least 3 years. METHODS: The subjects of this prospective non-randomized multicentric study were 290 consecutive patients, who underwent open surgery (OS group; n = 164) or laparoscopic surgery (LS group; n = 126) between 1994 and 2005, at one of the four surgical centers. The same surgical techniques were used for the laparoscopic and open approaches to right and left colectomy. The distribution of TNM substages (III A, III B, IIIC) as well as the grading of carcinomas (G1, G2, G3) were similar in each arm of the study. The median follow-up periods were 76.9 and 58.0 months after OS and LS, respectively. RESULTS: There were 10 (6.1 %) versus 9 (7.1 %) deaths unrelated to cancer, 15 (9.1 %) versus 5 (4 %) cases of local recurrence, 7 (4.2 %) versus 5 (4 %) cases of peritoneal carcinosis, and 37 (22.5 %) versus 14 (11.1 %) cases of metastases in the OS and LS groups, respectively. There was also one case of port-site recurrence after LS (0.8 %). The OS group had a significantly higher probability of local recurrence and metastases (p < 0.001) with a significant higher probability of cancer-related death (p = 0.001) than the LS group. CONCLUSIONS: These findings support that LS is safe and effective for advanced carcinoma of the colon. Although the LS group in this study had a significantly better long-term outcome than the OS group, further investigations are needed to draw a definitive conclusion.

Has the Removing of the Mesentery during Ileo-Colic Resection an Impact on Post-Operative Complications and Recurrence in Crohn's Disease? Results from the Resection of the Mesentery Study (Remedy).

Some evidence suggests a reduction in clinical and surgical recurrence after mesenteric resection in Crohn's Disease (CD). The aim of the REsection of the MEsentery StuDY (Remedy) was to assess whether mesenteric removal during surgery for ileocolic CD has an impact in terms of postoperative complications, endoscopic and ultrasonographic recurrences, and long-term surgical recurrence. Among the 326 patients undergoing primary resection between 2009 and 2019 in two referral centers, in 204 (62%) the mesentery was resected (Group A) and in 122 (38%) it was retained (Group B). Median follow-up was 4.7 ± 3 years. Groups were similar in the peri-operative course. Endoscopic and ultrasonographic recurrences were 44.6% and 40.4% in Group A, and 46.7% and 41.2% in Group B, respectively, without statistically significant differences. The five-year time-to-event estimates, compared with the Log-rank test, were 3% and 4% for normal or thickened mesentery (p = 0.6), 2.8% and 4% for resection or sparing of the mesentery (p = 0.6), and 1.7% and 5.4% in patients treated with biological or immunosuppressants versus other adjuvant therapy (p = 0.02). In Cox's model, perforating behavior was a risk factor, and biological or immunosuppressant adjuvant therapy protective for surgical recurrence. The resection of the mesentery does not seem to reduce endoscopic and ultrasonographic recurrences, and the five-year recurrence rate.

Ulcerative enteritis. How the extension of ulcerative colitis to small bowel may jeopardize postcolectomy course: a case report and literature review.

Intestinal involvement in ulcerative colitis is generally limited to the colon and rectum. We describe a life-threatening case of ulcerative enteritis occurring after colectomy. Other 53 similar cases are reported in the literature. The aim of this narrative review was to focus on ulcerative enteritis characteristics and diagnostic workup. A 25-year-old boy affected by ulcerative colitis underwent a total colectomy in an urgent setting for septic shock. Postoperative course was characterized by elevated ileostomy output, raised up to 10 L/day. Critical clinical conditions required resuscitation therapy. After exclusion of surgical complications, intestinal infections, and histologic specimen revision, the patient underwent endoscopic examination. Ileal biopsies revealed ileal localization of ulcerative colitis. Steroid treatment was finally effective. After literature revision, we classified all cases of ulcerative enteritis in three groups, according to intestinal involvement pattern and timing of clinical manifestation after operation. Out of 54 cases, 18 occurred within 1 month since colectomy (early ileitis), 10 later on (late ileitis) and 26 do not involve ileus (nonileitis). Clinical manifestation is generally severe in the first group and mild and chronic in the others. Differential diagnoses of ulcerative enteritis are represented by infectious, immunological, toxic, and ischemic disorders. Those conditions excluded, ulcerative enteritis can be easily detected by endoscopic biopsies and treated with immunosuppressive agents. Long term surveillance seems important since recurrences are described. In conclusion, clinicians should suspect ulcerative enteritis in all patients with previous colectomy history that develop unexplained gastrointestinal syndromes, in order to avoid therapeutic delay.

Perioperative Care in Colorectal Cancer Surgery before a Structured Implementation Program of the ERAS Protocol in a Regional Network. The Piemonte EASY-NET Project.

BACKGROUND: In 2019, the Enhanced Recovery After Surgery (ERAS) protocol for colorectal cancer surgery was adopted by a minority of hospitals in Piemonte (4.3 million inhabitants, north-west Italy). The present analysis aims to compare the level of application of the ERAS protocol between hospitals already adopting it (ERAS, N = 3) with the rest of the regional hospitals (non-ERAS, N = 28) and to identify possible obstacles to its application. METHODS: All patients surgically treated for a newly diagnosed colorectal cancer during September-November 2019, representing the baseline period of a randomized controlled trial with a cluster stepped-wedge design, were included. Indicators of compliance to the ERAS items were calculated overall and for groups of items (preoperative, intraoperative and postoperative) and analyzed with a multilevel linear model adjusting for patients' characteristics, considering centers as random effects. RESULTS: Overall, the average level of compliance to the ERAS protocol was 56% among non-ERAS centers (N = 364 patients) and 80% among ERAS ones (N = 79), with a difference of 24% (95% CI: -41.4; -7.3, p = 0.0053). For both groups of centers, the lowest level of compliance was recorded for postoperative items (42% and 66%). Sex, age, presence of comorbidities and American Society of Anesthesiologists (ASA) score were not associated with a different probability of compliance to the ERAS protocol. CONCLUSIONS: Several items of the ERAS protocol were poorly adopted in colorectal surgery units in the Piemonte region in the baseline period of the ERAS Colon-Rectum Piemonte study and in the ERAS group. No relevant obstacles to the ERAS protocol implementation were identified at patient level.

Predictivity of early and late assessment for post-surgical recurrence of Crohn's disease: Data from a single-center retrospective series.

BACKGROUND AND AIMS: Post-surgical recurrence of Crohn's disease (CD) after ileocolonic resection is common. Early identification of features associated with recurrence is a standard procedure of postoperative management, but the prognostic role of such features when detected at later time points is unclear. We compared the predictivity for Crohn's disease recurrence of common clinical-instrumental variables when assessed early (<12 months) or late (>36 months) after surgery. METHODS: This retrospective study considered CD patients who had ileocolonic resection and were followed for a median of 7.6 years. Clinical characteristics, post-surgical therapy, endoscopy recurrence (Rutgeerts' score ≥i2) and ultrasound features were compared between subgroups who had a early or late post-surgical assessment. Univariate and multivariate analyses were done to identify variables associated with recurrence (clinical and surgical). RESULTS: Of 201 patients, 70 (32%) had a early and 39 (19%) had a late post-surgical assessment. The Early and Late subgroups had similar clinical characteristics. Overall, clinical relapse was observed in 131 patients (66%), surgical relapse in 31 (16%), endoscopic recurrence in 149 (75%) and ultrasonographic recurrence in 132 (66%), without significant differences in frequencies between subgroups. By Cox proportional hazard regression, endoscopic recurrence was a significant predictor of clinical recurrence overall (HR=2.31, P = 0.002) and in the Early (HR=3.85, P = 0.002) but not Late subgroup. DISCUSSION: The most informative postoperative CD assessment is the one done within the first year of surgery. Later endoscopic evaluations have no prognostic value and should be done only for clinical needs or for research purposes.

Prospective, randomised, multicentre, open-label trial, designed to evaluate the best timing of closure of the temporary ileostomy (early versus late) in patients who underwent rectal cancer resection and with indication for adjuvant chemotherapy: the STOMAD (STOMa closure before or after ADjuvant therapy) randomised controlled trial.

INTRODUCTION: Temporary ileostomy is a valuable aid in reducing the severity of complications related to rectal cancer surgery. However, it is still unclear what is the best timing of its closure in relation to the feasibility of an adjuvant treatment, especially considering patient-reported outcomes and health system costs. The aim of the study is to compare the results of an early versus late closure strategy in patients with indication to adjuvant chemotherapy after resection for rectal cancer. METHODS AND ANALYSIS: This is a prospective multicentre randomised trial, sponsored by Rete Oncologica Piemonte e Valle d'Aosta (Oncology Network of Piedmont and Aosta Valley-Italy). Patients undergone to rectal cancer surgery with temporary ileostomy, aged >18 years, without evidence of anastomotic leak and with indication to adjuvant chemotherapy will be enrolled in 28 Network centres. An early closure strategy (between 30 and 40 days from rectal surgery) will be compared with a late one (after the end of adjuvant therapy). Primary endpoint will be the compliance to adjuvant chemotherapy with and without ileostomy. Complications associated with stoma closure as well as quality of life, costs and oncological outcomes will be assessed as secondary endpoints. ETHICS AND DISSEMINATION: The trial will engage the Network professional teams in a common effort to improve the treatment of rectal cancer by ensuring the best results in relation to the most correct use of resources. It will take into consideration both the patients' point of view (patient-reported outcome) and the health system perspective (costs analysis). The study has been approved by the Ethical Review Board of Città della Salute e della Scienza Hospital in Turin (Italy). The results of the study will be disseminated by the Network website, medical conferences and peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04372992.

A retrospective study on efficacy of the ERAS protocol in patients undergoing surgery for Crohn disease: A propensity score analysis.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) offers many benefits for patients with colorectal cancer. However, its application to patients with Crohn's disease (CD) is questioned. AIM: The aim of this propensity-matched study was to validate the results of ERAS protocol on CD patients. METHODS: Patients undergoing ileocolic resection for primary or relapsed CD from 2007 to 2018 were retrospectively analyzed and propensity-matched into two equal groups (ERAS vs standard of care). Demographic characteristics, length of stay, bowel function, oral intake, and perioperative morbidity were analyzed. RESULTS: Ninety four out of 299 patients were selected for analysis. No significant difference was observed for age, gender, American Society of Anesthesiologists score, body mass index, previous surgery and therapy, operative time and laparoscopy. The median length of stay in ERAS and non-ERAS groups was 6 and 8 days (p < 0.001). Median postoperative days of first bowel movement and solid oral intake were day 1 and day 2 p < 0,001, and day 2 and day 4.5 p < 0,001 in ERAS and non-ERAS group, respectively. No statistically differences in other postoperative outcomes were shown. CONCLUSIONS: ERAS implementation showed decreased length of stay, faster bowel function restoration and earlier solid oral intake in patients who underwent laparoscopic or open ileocolic resection for primary or relapsing CD.

Prognostic significance of lymph node metastases in pancreatic head cancer treated with extended lymphadenectomy: not just a matter of numbers.

BACKGROUND: The prognostic significance of variables related to nodal involvement (node status, number of disease-positive nodes [posNn], node ratio [Nr], and site of nodal metastases) in patients with resected pancreatic head cancer remains poorly defined. METHODS: Clinical, operative, and pathologic data, including indexes of the burden and extent of nodal involvement, were analyzed in a consecutive series of 77 patients who underwent resection with extended lymphadenectomy for adenocarcinoma of the pancreatic head. RESULTS: Fifty-nine patients (77%) were found to have lymph node (LN) metastases. Median LN count, posNn, and Nr were 28 (10-54), 4 (1-29), and 14% (2%-55%), respectively. Twenty-six patients (44% of N1) had metastases limited to node level (NL) 1 (i.e., peripancreatic nodes); metastases up to NL2 (nodes along main arteries and hepatic hilum) and NL3 (preaortic nodes) were found in 21 (36%) and 12 (20%) patients, respectively. Interestingly, survival of patients with positive LN limited to NL1 was similar to that of node-negative patients (P = 0.407). posNn, Nr, and NL were all significant predictors of survival (P < 0.015). posNn and Nr proved to be an accurate proxy of NL involvement. The best cutoff of posNn was 2 and of and Nr was 10%. CONCLUSIONS: The level of nodal metastatic spread is a statistically significant prognostic factor in cancer of the pancreatic head. Both posNn and Nr are accurate proxy of NL and may improve patients' risk stratification.

A novel patient-centered protocol to reduce hospital readmissions for dehydration after ileostomy.

Early hospital readmission for dehydration represents a relevant problem among patients with diverting or terminal ileostomy. The aim of the study was to evaluate the efficacy of a new multidisciplinary individualized multistep protocol in terms of reduction of hospital readmission for dehydration. Since January 2016, our institution adopted a new protocol for patients with ileostomy. Protocol key points were: preoperative personalized education in stoma management; early recognition of dehydration symptoms; multidisciplinary counseling; patient autonomy in stoma management through post-operative recall schedule. The study compared a series of consecutive patients treated before (2014-2015) and after (2016-2017) the protocol application. The primary endpoint was hospital readmission rate after protocol use. The secondary endpoint was the identification of possible risk factors for readmission. The entire cohort was composed of 296 patients, 129 in the protocol group and 167 in the control one. The two groups were homogeneous for baseline characteristics. Hospital readmission rate within 30 days post-discharge for dehydration dropped from 9 to 3.9% after protocol application. Specifically, the number of avoided potential readmissions was 29/129 (22.4%). The number needed to treat (NNT) was 20. Univariate analysis identified three relevant variables: patient comorbidities, diuretics use as risk factors and protocol application as the protective one. The multivariate analysis confirmed patient comorbidity as the risk factor. Dehydration related to ileostomy is a potentially avoidable problem, by employing preventive strategies, especially in high-risk patients. Our new protocol could be a simple and cost-saving method, effective in preventing hospital readmissions.

Laparoscopic vs open restorative proctocolectomy with IPAA for ulcerative colitis: Impact of surgical technique on creating a well functioning pouch.

BACKGROUND: Patients with ulcerative colitis are often young, and proctocolectomy with restorative ileo-pouch anal anastomosis is a crucial act that can improve or worsen the quality of the rest of their lives. The literature is scant on long-term functional outcomes after laparoscopy. The purpose of this study was to investigate results in terms of pouch function after standardized total laparoscopic technique compared with open intervention. MATERIALS AND METHODS: This was a retrospective comparative study. Cases were collected from the prospectively-maintained database of the Unit of General and Oncologic Surgery, XXX, Torino, Italy. Patients treated between May 2005 and May 2015 with three-stage laparoscopic or open proctocolectomy and ileo-pouch anal anastomosis were enrolled. The primary study endpoint was the percentage of well-functioning pouches. Secondary endpoints were postoperative early and late outcomes such as morbidity and pouch survival. RESULTS: Of the 78 patients identified, 48 underwent the open technique and 30 underwent laparoscopy. Median follow-up was 4 years. The overall complication rates were 19% and 13% (p = 0.5), and there were major complications (Clavien-Dindo III-IV) in 14.6% and 13.3% of patients in the open and laparoscopic groups, respectively (p = 0.8). Late complications occurred in 26 patients. Nine (18.8%) and 5 (16.7%) patients had pouchitis (p = 0.8), and 6 (12.5%) and 2 (6.7%) had cuffitis in the open and laparoscopic groups, respectively (p = 0.70). Pouch failure occurred in 2 patients (4.2%) in the open group and 2 (6.7%) in the laparoscopic group. The pouch was observed to be functioning very well in 18 patients (37.5%) in the open group and in 17 patients (56%) in the laparoscopic group (p = 0.09). The study was limited by its retrospective, nonrandomized design. CONCLUSION: Our data demonstrated similar early and late results after total laparoscopic and open proctocolectomy, in particular concerning pouch function.

Extended lymphadenectomy and vein resection for pancreatic head cancer: outcomes and implications for therapy.

HYPOTHESIS: An aggressive strategy that includes extended lymphadenectomy and vein resection may improve the results of surgical treatment of pancreatic head cancer. DESIGN: Nonrandomized control trial. SETTING: Tertiary care referral center. PATIENTS: The study included 149 consecutive patients undergoing macroscopically curative resection for periampullary adenocarcinoma from January 1, 1988, to December 31, 1998. INTERVENTIONS: A standard resection was performed in 122 cases; an extended lymphadenectomy in 37. Twenty-four patients underwent venous resection. MAIN OUTCOME MEASURES: Data on surgical mortality, morbidity, and postoperative outcome, pathological findings, and long-term survival were analyzed. RESULTS: In-hospital and 60-day operative mortality was 5.4%. Morbidity was 37.5%. Mortality, morbidity, and postoperative stay were nonsignificantly modified by extended lymphadenectomy or venous resection. Extended resection permitted the identification of a significantly higher percentage of nodal metastases beyond the peripancreatic node groups. In patients undergoing vein resection, a significantly higher rate of positive retroperitoneal margin was found. In the 100 patients with ductal adenocarcinoma, the median overall survival and the 5-year actuarial survival rate were 15 months and 8.4%, respectively. A trend toward a better survival was observed in the first 2 years after operation in the extended resection group compared with the standard resection group. Nodal status was the most powerful predictor of overall survival by multivariate analysis. CONCLUSIONS: Extended lymphadenectomy and vein resection did not adversely affect postoperative mortality and morbidity. Patients who required a vein resection were less likely to receive a microscopically curative pancreatectomy. Extended resection permitted better pathological staging and was associated with an early advantage in survival, but long-term survival was possible only in patients with favorable prognostic factors.

Liver resection for hilar cholangiocarcinoma: in-hospital mortality and longterm survival.

BACKGROUND: Extended surgical procedures are the only chance of longterm survival for patients with Klatskin tumors, but high mortality rates have been reported. The type of treatment for Bismuth type l-II carcinomas is still a matter of discussion. STUDY DESIGN: We performed a single-unit, retrospective study analyzing 36 patients who underwent resectional surgery for Klatskin tumor. RESULTS: An associated liver resection was performed in 88.9% of our patients; most of them had a major hepatectomy. The in-hospital mortality rate was 2.8%. Three- and 5-year survival rates were 40.8% and 27.2%, respectively. But the group of patients with Bismuth type I-II carcinomas undergoing hepatectomy had markedly better longterm outcomes than those undergoing hilar resection (p = 0.04): 54.5% versus 0% at 5 years, respectively; none of the patients who had only resection of bile duct confluence were alive at 2 years. Lymph node metastases were found in 38.8% of our patients; nodal involvement was not a major prognostic factor. CONCLUSIONS: Achievement of low in-hospital mortality rates is possible in specialized surgical departments. Aggressive surgical approaches can allow better longterm results in the subset of Bismuth type I-II carcinomas.

Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas.

PURPOSE: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti-EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC). EXPERIMENTAL DESIGN: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab. RESULTS: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment. CONCLUSIONS: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses.