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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations.

PURPOSE: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease. EXPERIMENTAL DESIGN: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets. RESULTS: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer. CONCLUSIONS: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation.

A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.

UNLABELLED: Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples ("xenopatients") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need. SIGNIFICANCE: Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting.