R1 Margin Status Research Articles

Long-term survival after resection of invasive pancreatic intraductal papillary mucinous neoplasm.

This study aimed to report the long-term outcomes after surgical resection for invasive (I) intraductal papillary mucinous neoplasm (IPMN) and to define prognostic factors for survival. We retrospectively evaluated all consecutive pancreatic resections performed IPMN between January 1, 2007, and December 31, 2022. Multivariate Cox analysis identified risk factors for survival. Surgery for IPMN was performed in 125 patients including 78 I-IPMN (62%). Ninety-day mortality rates was 1.6% (n = 2) with an overall morbidity rate of 44.4%. I-IPMN showed higher serum CA 19 - 9 serum values (p < 0.0001), more frequently jaundice (p = 0.008), more high-risk stigmata (p = 0.002) and diffuse IPMN form (p = 0.005) compared with non-invasive IPMN. The median overall survival for I-IPMN was 178.36 months (95% confidence interval [CI]: 87.01-NR) with overall survival rates at one, three, five, and 10 years of 91%, 75%, 72%, and 62%, respectively. Jaundice (hazard ratio [HR]: 4.23; 95% CI: 1.48-12.07; p = 0.006), T3 lesions (HR: 3.24; 95% CI: 1.65-6.39; p = 0.006), absence of lymph node involvement (HR: 0.15; 95% CI: 0.04-0.60; p = 0.0007), R1 margin status (HR: 2.96;95%CI:1.08-8:15;p = 0.03) and need for venous resection (HR: 4.30; 95% CI: 1.26-14.6; p = 0.006) were identified as independent risk factors for survival. Long-term survival and cure can be observed after surgical resection of pancreatic adenocarcinomas originating from I-IPMN when resected at early stage (Tis, T1, T2). I-IPMN spreading beyond pancreatic ducts (jaundice, T3 lesions, lymph nodes, Veins) have limited long-term survival.

Hospital readmissions after robotic hepatectomy for neoplastic disease: Analysis of risk factors, survival, and economical impact. A logistical regression and propensity score matched study

BackgroundAs the first comprehensive investigation into hospital readmissions following robotic hepatectomy for neoplastic disease, this study aims to fill a critical knowledge gap by evaluating risk factors associated with readmission and their impact on survival and the financial burden. MethodsThe study analyzed a database of robotic hepatectomy patients, comparing readmitted and non-readmitted individuals post-operatively using 1:1 propensity score matching. Statistical methods included Chi-square, Mann-Whitney U, T-test, binomial logistic regression, and Kaplan-Meier analysis. ResultsAmong 244 patients, 44 were readmitted within 90 days. Risk factors included hypertension (p ​= ​0.01), increased Child-Pugh score (p ​< ​0.01), and R1 margin status (p ​= ​0.05). Neoadjuvant chemotherapy correlated with lower readmission risk (p ​= ​0.045). Readmissions didn't significantly impact five-year survival (p ​= ​0.42) but increased fixed indirect hospital costs (p ​< ​0.01). ConclusionsReadmission post-robotic hepatectomy correlates with hypertension, higher Child-Pugh scores, and R1 margins. The use of neoadjuvant chemotherapy was associated with a lower admission rate due to less diffuse liver disease in these patients. While not affecting survival, readmissions elevate healthcare costs.

The definition of “R1” lymph node dissection status in patients undergoing curative-aim gastrectomy for gastric carcinoma: A proof of concept study

IntroductionThe aim of this study was to define and investigate the prognostic impact of “R1-Lymph-node dissection” during gastrectomy. MethodsThis was a retrospective study conducted with 499 patients undergoing curative-aim gastrectomy. We defined R1-Lymph dissection as an involvement of lymph node stations anatomically connected with lymph node stations outside the declared level of dissection (D1 to D2+). The primary outcomes were disease-free and disease-specific survival (DFS and DSS). ResultsAt multivariable analysis, the type of gastrectomy, pT and pN were associated with DFS, and the type of gastrectomy, R1-Margin status, R1-Lymph status, pT, pN and adjuvant therapy were associated with DSS. Moreover, pT and R1-Lymph status were the only factors associated with overall loco-regional recurrence. ConclusionsIn this study, we introduced the concept of R1-Lymph-node dissection, which was significantly associated with DSS and appeared to be a stronger prognostic factor for loco-regional recurrence than the R1 status on the resection margin.

Anatomic Variability in Patterns of Care for Locoregional Merkel Cell Carcinoma (MCC) Management at a Large Referral Center

<h3>Purpose/Objective(s)</h3> MCC is a rare cutaneous malignancy. This study evaluates patterns of care and outcomes for head and neck (HN) vs. non-HN (NHN) MCC at a large referral center. <h3>Materials/Methods</h3> We identified 144 locoregionally-confined MCC patients (pts) who received curative intent radiation therapy (RT) between 2003-2021. Clinicopathologic variables were described and time to relapse events were assessed by the Kaplan-Meier method. <h3>Results</h3> Of 144 pts, 80 (56%) had HN and 64 (44%) had NHN MCC. HN pts were older (median 70; IQR 66-76 vs. 65; IQR 57-73, p<0.001) and more likely male (63; 79% HN vs. 39; 61% NHN, p=0.03). Stage (I-II 42; 53% HN vs. 27; 42% NHN, p=0.24) and unknown primary presentation were similar (16; 20% HN vs. 7; 11% NHN, p=0.17). For pts with known primary tumor, wide local excision (WLE) after biopsy was less common in HN pts (46; 72% HN vs. 57; 100% NHN, p<0.001). Including 5 HN pts with excisional biopsies, R1 margin status was more common in the HN (15; 31% vs. 7; 13%, p=0.03), while all 13 definitive RT pts had HN disease. Most patients in this overall cohort received RT to the primary site (62; 96% HN vs. 55; 96% NHN) with a higher median dose for HN pts overall (60 Gy HN; IQR 56-60 Gy vs. 50 Gy NHN; IQR 56-60 Gy, p<0.001) as well as for pts having WLE (56 Gy HN; IQR 50-60 Gy vs. 50 Gy NHN; IQR 50-60). Similar rates of clinically LN+ disease were observed between cohorts (cLN+, 24; 30% HN vs. 18; 28% NHN, p=0.86), but HN pts had fewer LN dissections (LND, 14; 58% HN vs. 16; 89% NHN, p=0.024). Adjuvant nodal RT was delivered to most cLN+ pts (14; 100% HN vs. 14; 88% NHN, p=0.49) but this dose was higher for HN pts (med 59 Gy, IQR 52-60 Gy vs. med 50 Gy, IQR 50-54 Gy, p=0.013). For cLN- pts, fewer HN pts had sentinel lymph node biopsy (SLNB, 30; 54% HN vs. 42; 91% NHN, p<0.001). Of those SLN+ (11; 37% HN vs. 14, 33% NHN; p=0.81), only 1 HN pt and 2 NHN pts had completion LND. More HN pts received nodal RT for SLN+ disease (11; 100% HN vs. 9; 64% NHN, P=0.009) and elective nodal RT following N0 disease (4; 21% HN, med 46 Gy [IQR 46-53 Gy] vs 0% NHN, p=0.02). Nodal RT dose for cLN- pts trended higher in HN pts (med 52.5 Gy, IQR 46-60 Gy vs. 50 Gy, IQR 50-50.4 Gy, p=0.059). Median follow up was 40 months (IQR 22-58 mo) with similar outcomes for HN and NHN pts (3-yr LC 92% vs. 94%, p=0.85; 3-yr NC 83% vs. 79%, p=0.32; 3-yr DFS 64% vs. 60%, p=0.39). <h3>Conclusion</h3> Different treatment approaches exist for MCC pts at our institution based on tumor location. HN management historically relied more on comprehensive RT with higher doses whereas NHN management involves more comprehensive surgery and less RT. Anatomic limitations likely contributed to variation in practice. Despite differences in management tumor control outcomes are similar. Further study into the optimal approach to maximize disease control while limiting toxicity is warranted.

Radial and Longitudinal Margins in Surgery of Perihilar Cholangiocarcinoma: When R1 Definition Is Associated with Different Prognosis

Background: The purpose of study is to evaluate the impact of positive margins on long-term outcome of patients affected by perihilar cholangiocarcinoma (PHC) depending on the pattern of neoplastic infiltration (radial versus longitudinal) and to analyze predictive factors for survival specifically in the population of R1. Methods: Data regarding histopathological data were prospectively collected in patients submitted to surgery for PHC between 2004 and 2019 at San Raffaele Hospital, Milano. The outcome of patients with R1 (88 out of 264, 33.3% of the whole series) and R0 margins was compared. Within R1 group, the long term outcome was compared between patients with radial only infiltration (n=31), longitudinal only infiltration (n=30) and radial+longitudinal infiltration (n=27). Results: 3 years and 5 years long term survival was significantly different between the R0 (55% and 42% respectively) and the R1 group (42% and 18% respectively) with p<0.05. Within R1 group, patients with radial only and radial + longitudinal infiltration had a worse long term outcome compared with patients with longitudinal only infiltration(median DFS was 18 and 23 months respectively, p<0.05, while median OS was 33 and 39 months respectively, p<0.05). Together with R1 margin status, factors associated with long term outcome at multivariate analysis were nodal status, side of hepatectomy, grading and radial margin infiltration. Conclusion: Infiltration of radial resection margins in PHC is associated with a worse prognosis among patients with R1 margins and should be specifically taken into consideration to determine the indication for adjuvant treatments.

Adjuvant Chemotherapy Associated with Survival Benefit Following Neoadjuvant Chemotherapy and Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Population-Based Cohort Study

BackgroundData supporting the routine use of adjuvant chemotherapy (AC) compared with no AC (noAC) following neoadjuvant chemotherapy (NAC) and resection for pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to determine whether AC improves long-term survival in patients receiving NAC and resection.MethodsPatients receiving resection for PDAC following NAC from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). Patients with a survival rate of < 6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression analysis were performed to account for selection bias and analyze the impact of AC on overall survival.ResultsOf 4449 (68%) noAC patients and 2111 (32%) AC patients, 2016 noAC patients and 2016 AC patients remained after PSM. After matching, AC was associated with improved survival (median 29.4 vs. 24.9 months; p < 0.001), which remained after multivariable adjustment (HR 0.81, 95% confidence interval [CI] 0.75–0.88; p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (hazard ratio [HR] 0.80, 95% CI 0.72–0.90; p < 0.001), N1 (HR 0.76, 95% CI 0.67–0.86; p < 0.001), R0 margin status (HR 0.82, 95% CI 0.75–0.89; p < 0.001), R1 margin status (HR 0.77, 95% CI 0.64–0.93; p = 0.007), no neoadjuvant radiotherapy (NART; HR 0.84, 95% CI 0.74–0.96; p = 0.009), and use of NART (HR 0.80, 95% CI 0.73–0.88; p < 0.001). Stratified analysis by nodal, margin, and NART status demonstrated consistent results.ConclusionAC following NAC and resection is associated with improved survival, even in margin-negative and node-negative disease. These findings suggest completing planned systemic treatment should be considered in all resected PDACs previously treated with NAC.

Borderline or locally advanced pancreatic adenocarcinoma: A single center experience on the FOLFIRINOX induction regimen

IntroductionThis study aimed to determine the impact of FOLFIRINOX neoadjuvant therapy on patients with non-metastatic borderline/locally advanced (BL/LA) pancreatic ductal adenocarcinoma (PDAC), in current practice. Material and methodsFrom 2010 to 2017, 258 patients with BL/LA PDAC from a single high-volume institution received FOLFIRINOX neoadjuvant treatment. ResultsThe 258 patients received a median number of 6 cycles of FOLFIRINOX (range, 3–16); 98 (38%) patients underwent curative surgery, and 160 (62%) continued medical treatment. A venous resection was performed in 57 patients (58%), and an arterial resection in 12 (12%). The postoperative 30- and 90-day mortality rates were 6.1% and 8.2%, respectively. Adjuvant chemotherapy was performed in 57 patients (59%). The median overall survival (OS) in patients who did (n = 98) or did not (n = 160) undergo surgical resection were 39 months and 19 months, respectively (P < 0.001). In resected patients, the ASA 3 score (P < 0.01), venous resection (P < 0.01), hemorrhage (P < 0.01), and R1 margin status (P = 0.03) were found to negatively influence the OS. The median OS was significantly higher in patients who did not require a venous resection (not reached vs. 26.5 months, P < 0.001). ConclusionsNeoadjuvant FOLFIRINOX provided a survival benefit in BL/LA PDAC patients, particularly in those who did not ultimately require venous resection.

Prognostic Factors Change Over Time After Hepatectomy for Colorectal Liver Metastases: A Multi-institutional, International Analysis of 1099 Patients.

To evaluate the changing impact of genetic and clinicopathologic factors on conditional overall survival (CS) over time in patients with resectable colorectal liver metastasis. CS estimates account for the changing likelihood of survival over time and may reveal the changing impact of prognostic factors as time accrues from the date of surgery. CS analysis was performed in 1099 patients of an international, multi-institutional cohort. Three-year CS (CS3) estimates at the "xth" year after surgery were calculated as follows: CS3 = CS (x + 3)/CS (x). The standardized difference (d) between CS3 rates was used to estimate the changing prognostic power of selected variables over time. A d < 0.1 indicated very small differences between groups, 0.1 ≤ d < 0.3 indicated small differences, 0.3 ≤ d < 0.5 indicated moderate differences, and d ≥ 0.5 indicated strong differences. According to OS estimates calculated at the time of surgery, the presence of BRAF and KRAS mutations, R1 margin status, resected extrahepatic disease, patient age, primary tumor lymph node metastasis, tumor number, and carcinoembryonic antigen levels independently predicted worse survival. However, when temporal changes in the prognostic impact of these variables were considered using CS3 estimates, BRAF mutation dominated prognosis during the first year (d = 0.48), whereas surgeon-related variables (ie, surgical margin and resected extrahepatic disease) determined prognosis thereafter (d ≥ 0.5). Traditional clinicopathologic factors affected survival constantly, but only to a moderate degree (0.3 ≤ d < 0.5). The impact of genetic, surgery-related, and clinicopathologic factors on OS and CS3 changed dramatically over time. Specifically, BRAF mutation status dominated prognosis in the first year, whereas positive surgical margins and resected extrahepatic disease determined prognosis thereafter.

Propensity score analysis of non‐anatomicalversusanatomical resection of colorectal liver metastases

BackgroundThere are concerns that non‐anatomical resection (NAR) worsens perioperative and oncological outcomes compared with those following anatomical resection (AR) for colorectal liver metastases (CRLM). Most previous studies have been biased by the effect of tumour size. The aim of this study was to compare oncological outcomes after NAR versus AR.MethodsThis was a retrospective study of consecutive patients who underwent CRLM resection with curative intent from 1999 to 2016. Data were retrieved from a prospectively developed database. Survival and perioperative outcomes for NAR and AR were compared using propensity score analyses.ResultsSome 358 patients were included in the study. Median follow‐up was 34 (i.q.r. 16–68) months. NAR was associated with significantly less morbidity compared with AR (31·1 versus 44·4 per cent respectively; P = 0·037). Larger (hazard ratio (HR) for lesions 5 cm or greater 1·81, 95 per cent c.i. 1·13 to 2·90; P = 0·035) or multiple (HR 1·48, 1·03 to 2·12; P = 0·035) metastases were associated with poor overall survival (OS). Synchronous (HR 1·33, 1·01 to 1·77; P = 0·045) and multiple (HR 1·51, 1·14 to 2·00; P = 0·004) liver metastases, major complications after liver resection (HR 1·49, 1·05 to 2·11; P = 0·026) or complications after resection of the primary colorectal tumour (HR 1·51, 1·01 to 2·26; P = 0·045) were associated with poor disease‐free survival (DFS). AR was prognostic for poor OS only in tumours smaller than 30 mm, and R1 margin status was not prognostic for either OS or DFS. NAR was associated with a higher rate of salvage resection than AR following intrahepatic recurrence.ConclusionsNAR has at least equivalent oncological outcomes to AR while proving to be safer. NAR should therefore be the primary surgical approach to CRLM, especially for lesions smaller than 30 mm.

Validation of the New R-Status Definitions (1mm margin) for Pancreatic Adenocarcinoma resected by Distal or Total Pancreatectomy.

Background: The definitions for R0 and R1 margin status after resection for pancreatic cancer are controversial. Reported R0/R1 rates and associated survival are highly heterogeneous. A strict definition of R0 requiring a 1 mm free margin is accepted in major centers in Europe, but not internationally. We could recently show that the new R-status is an independent predictor of survival after pancreatoduodenectomy for cancer. The relevance of the R-status for cancers resected by distal pancreatectomy (DP) and total pancreatectomy (TP) remains unclear. Methods: A standardized protocol with evaluation of circumferential margins and the novel R definitions was introduced into clinical routine in 2005. From a prospective database, patients undergoing DP and TP for pancreatic adenocarcinoma between 01/2006 and 12/2014 were identified. The rates of R0, R1 (≤1mm) and R1 (direct) status and associated survival were assessed. Results: Of 535 patients with pancreatic adenocarcinoma treated with DP or TP, 122 (22.8%) had R0 and 401 (75.9%) had R1 resections, including 114 (21.3%) R1 (≤1mm) and 286 (53.4%) R1 (direct) resections. The R0 rate was 27.9 % after DP and 18.7% after TP. With R0, R1 (≤1mm) and R1 (direct) status the median survival times and five-year survival rates were 57.2, 23.2 and 16.9 months and 48.9, 16.2 and 11.5%, respectively (p<0.0001). Conclusion: The new R-status is confirmed as an important determinant of post-resection survival after DP and TP for pancreatic adenocarcinoma.

Radiation Therapy in Resectable Intrathoracic Sarcomas. A Rare Cancer Network Study

Intrathoracic sarcomas (ITS) are considered rare tumors and have a dismal prognosis. We investigated outcomes and risk factors for local control (LC), disease-free survival (DFS), and overall survival (OS) in patients with resected nonmetastatic ITS treated with or without adjuvant radiation therapy (RT) and/or chemotherapy. Patients from the Rare Cancer Network database were studied. A Kaplan-Meier estimate was used to assess survival curves, and Cox proportional hazards regression was used to assess risk factors for LC, DFS, and OS. Between 2000 and 2017, 121 patients met inclusion criteria. The primary site was lung in 30%, mediastinum in 34%, and pleura in 36%. Thirty-nine percent and 32% received RT and chemotherapy. Median follow-up was 34months (range, 2-141). LC, DFS, and OS at 10years were 52%, 18.7%, and 7.2%, respectively. In multivariate analysis, RT (P=.003) and R1 margin status (P=.041) retained a significant association with LC. Only R1 resection (P=.002) remained associated with an increased risk of death in multivariate analysis. Overall, 7 patients (6%) developed grade 3 treatment-related chronic toxicity events. This joint analysis revealed that OS remains modest in this group of patients, mainly given by the high risk of local and distant failure. Our results suggest that resected ITS can benefit from adjuvant RT.

Patterns of Care and Outcome Radiation-Induced Soft Tissue Sarcomas

Radiation therapy is used as a radical treatment for many cancers and is delivered in the neoadjuvant or adjuvant setting, frequently combined with other treatment modalities such as chemotherapy and surgery. However, radiation exposure is a well established risk factor for developing secondary malignancies. Soft-tissue sarcomas are the most common types of radiation-induced tumors in the general population. We have analyzed 510 patients from the French Sarcoma Group database. Prognostic factors for locoregional-free Survival (LRFS), metastases-free survival (MFS), and overall Survival (OS) were identified by univariate and multivariate analyses using a Cox regression model. Median overall survival for patients M0 with R0/R1 surgery was 65.1 months (95% CI, 50.0-98.4). The 5-year and 10-year OS rates were 52.9% (47.1-58.2) and 41.0% (34.2-47.7), respectively. On multivariate analysis, the predictors of worse OS were age, R1 margin status, grade 3 and size >55 mm. We report here the largest series of patients with radiation-induced soft-tissue sarcomas. We demonstrate that a majority of patients can be cured provided they are managed with adequate surgery.

The role of hepatectomy for synchronous liver metastases from pancreatic adenocarcinoma

BackgroundThe role of hepatectomy for patients with liver metastases from ductal adenocarcinoma of the pancreas (PLM) remains controversial. Therefore, the aim of our study was to examine the postoperative morbidity, mortality, and long-term survivals after liver resection for synchronous PLM. MethodsClinicopathological data of patients who underwent hepatectomy for PLM between 1993 and 2015 were assessed. Major endpoint of this study was to identify predictors of overall survival (OS). ResultsDuring the study period, 76 patients underwent resection for pancreatic cancer and concomitant hepatectomy for synchronous PLM. Pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 67%, 25%, and 8% of the patients, respectively. The median PLM size was 1 (1–13) cm and 36% of patients had multiple PLM. The majority of patients (96%) underwent a minor liver resection. After a median follow-up time of 130 months, 1-, 3-, and 5-year OS rates were 41%, 13%, and 7%, respectively. Postoperative morbidity and mortality rates were 50% and 5%, respectively. Preoperative and postoperative chemotherapy was administered to 5% and 72% of patients, respectively. In univariate analysis, type of pancreatic procedure (P = .020), resection and reconstruction of the superior mesenteric artery (P = .016), T4 stage (P = .086), R1 margin status at liver resection (P = .001), lymph node metastases (P = .016), poorly differentiated cancer (G3) (P = .037), no preoperative chemotherapy (P = .013), and no postoperative chemotherapy (P = .005) were significantly associated with worse OS. In the multivariate analysis, poorly differentiated cancer (G3) (hazard ratio [HR] = 1.87; 95% confidence interval [CI] = 1.08–3.24; P = .026), R1 margin status at liver resection (HR = 4.97; 95% CI = 1.46–16.86; P = .010), no preoperative chemotherapy (HR = 4.07; 95% CI = 1.40–11.83; P = .010), and no postoperative chemotherapy (HR = 1.88; 95% CI = 1.06–3.29; P = .030) independently predicted worse OS. ConclusionsLiver resection for PLM is feasible and safe and may be recommended within the framework of an individualized cancer therapy. Multimodal treatment strategy including perioperative chemotherapy and hepatectomy may provide prolonged survival in selected patients with metastatic pancreatic cancer.

SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases

Introduction: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role of in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for CLM. Methods: Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. Results: Of 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P< 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P=0.007), multiple tumors (HR 1.970; P=0.01), diameter greater than 3 cm (HR 1.752; P=0.017), R1 margin status (HR 2.452; P=0.014), RAS mutation (HR 2.044; P=0.002), and SMAD4 mutation (HR 2.773; P< 0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P=0.012) and was an independent predictor for worse OS (HR, 1.647; P=0.032). Conclusion: SMAD4 mutation is independently associated with worse outcomes in patients undergoing resection of CLM.

Effectiveness and Safety of Tissue Expander for Adjuvant Helical Tomotherapy in Curatively Resected Retroperitoneal Sarcoma.

We investigated the effectiveness and safety of using a tissue expander (TE) for adjuvant helical tomotherapy (HT) for curatively resected retroperitoneal sarcoma (RPS). This study was conducted with 60 RPS patients who underwent curative resection with or without TE insertion followed by HT from June 2009 to December 2016. Among the patients, TE was inserted in 37 (61.7%). The quality of TE insertion was evaluated. Median follow-up after surgery was 19.4 months (range=4.5-93.2 months). A higher biologically-equivalent dose (α/β=10) was used with patients who had TE insertion (median, 72.0 gray [Gy] vs. 67.1 Gy, p=0.02). The quality of TE insertion was excellent in 18 patients (48.6%), good in 10 (27.0%), fair in seven (18.9%), and poor in two (5.4%). Toxicity was not significantly different according to TE insertion. Local recurrence-free survival (LRFS) was 78.2%, and overall survival was 95.6% at 3 years. TE insertion was not a significant factor for LRFS (91.1% in TE vs. 62.9% in non-TE group at 3 years, p=0.62). In the subgroup of patients with R1 or unknown tumor margin status, however, LRFS was marginally higher in the TE insertion group (100.0% in TE vs. 62.9% non-TE group at 3 years, p=0.05). HT with TE insertion as adjuvant RT for curatively resected RPS was feasible with acceptable toxicity. In the patients with R1 or unknown tumor margin status, LRFS was marginally higher in the TE insertion group after HT.

SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases

IntroductionDorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-β signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM). MethodsBetween 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. ResultsOf 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P < 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P = 0.007), multiple tumors (HR 1.970; P = 0.01), diameter greater than 3 cm (HR 1.752; P = 0.017), R1 margin status (HR 2.452; P = 0.014), RAS mutation (HR 2.044; P = 0.002), and SMAD4 mutation (HR 2.773; P < 0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P = 0.012) and was an independent predictor for worse OS (HR, 1.647; P = 0.032). ConclusionSMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM.

The Prognostic Impact of Determining Resection Margin Status for Multiple Colorectal Metastases According to the Margin of the Largest Lesion.

Although the prognostic role of surgical margin status after resection of colorectal liver metastasis (CRLM) has been previously examined, controversy still surrounds the importance of surgical margin status in patients with multiple tumors. Patients who underwent curative-intent surgery for CRLM from 2000 to 2015 and who presented with multiple tumors were identified. Patients with R1 resection status determined by the closest resection margin of the non-largest tumor were classified as R1-Type 1; patients with R1 status determined by the resection margin of the largest tumor were defined as R1-Type 2. Data regarding surgical margin status, size of tumors, and overall survival (OS) were collected and assessed. A total of 251 patients met inclusion criteria; 156 patients (62.2%) had a negative margin (R0), 50 had an R1-type 1 (19.9%), and 45 had an R1-type 2 (17.9%) margin. Median and 5-year OS in the entire cohort was 56.4months and 48.0%, respectively. When all R1 (Type 1+Type 2) patients were compared with R0 patients, an R1 was not associated with worse prognosis (P=0.05). In contrast, when R1-type 2 patients were compared with R0 patients, an R1 was strongly associated with worse OS (P=0.009). On multivariate analysis, although the prognostic impact of all R1 was not associated with OS (hazard ratio [HR] 1.56; P=0.08), R1-Type 2 margin status independently predicted a poor outcome (HR 1.93; P=0.03). The impact of margin status varied according to the size of the tumor assessed. While R1 margin status defined according to the non-largest tumor was not associated with OS, R1 margin status relative to the largest index lesion was associated with prognosis.

Pancreatic Cancer Surgery: The New R-status Counts.

To assess the relevance of resection margin status for survival outcome after resection and adjuvant therapy for pancreatic cancer. The definitions for R0 and R1 margin status after resection for pancreatic cancer are controversial. The strict definition of R0 requiring a 1 mm tumor-free margin is not commonly accepted. Reported R0/R1 rates and associated survival are highly heterogeneous. A standardized protocol with rigorous assessment of circumferential margins and the R0 definition with a 1 mm free margin were introduced into clinical routine in 2005. From a prospective database, patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma between January 1, 2006 and December 12, 2012 were identified. The rates of R0 (≥1 mm margin), R1 (<1 mm clearance), and R1 (direct margin involvement) status and associated survival were assessed by uni- and multivariable analyses. Of 561 patients included, 112 patients (20.0%) had R0 and 449 patients (80.0%) had R1 resections, including 123 (21.9%) R1 (≤1 mm) and 326 (58.1%) R1 (direct) resections. A total of 438 (85.9%) received adjuvant therapy. With R0, R1 (<1 mm), and R1 (direct) status the median survival times and 5-year survival rates were 41.6, 27.5, and 23.4 months; and 37.7%, 30.1%, and 20.3%, respectively (P < 0.0001). By multivariable analysis, margin status was confirmed to be independently associated with survival. In the context of adjuvant therapy, the resection margin status remains an important independent determinant of postresection survival. R0/R1 resection rates and associated survival vary significantly with the definitions used. An international consensus is urgently needed to achieve comparability with respect to studies and protocols on patients with adjuvant therapy.

Pancreatic cancer surgery: The new R-status counts

Objective To assess the relevance of resection margin status for survival outcome after resection and adjuvant therapy for pancreatic cancer. Background The definitions for R0 and R1 margin status after resection for pancreatic cancer are controversial. The strict definition of R0 requiring a 1 mm tumor-free margin is not commonly accepted. Reported R0/R1 rates and associated survival are highly heterogeneous. Methods A standardized protocol with rigorous assessment of circumferential margins and the R0 definition with a 1 mm free margin were introduced into clinical routine in 2005. From a prospective database, patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma between January 1, 2006 and December 12, 2012 were identified. The rates of R0 (≥1 mm margin), R1 ( Results Of 561 patients included, 112 patients (20.0%) had R0 and 449 patients (80.0%) had R1 resections, including 123 (21.9%) R1 (≤1 mm) and 326 (58.1%) R1 (direct) resections. A total of 438 (85.9%) received adjuvant therapy. With R0, R1 ( Conclusions In the context of adjuvant therapy, the resection margin status remains an important independent determinant of postresection survival. R0/R1 resection rates and associated survival vary significantly with the definitions used. An international consensus is urgently needed to achieve comparability with respect to studies and protocols on patients with adjuvant therapy.

Impact of hypofractionated and standard fractionated chemoradiation before pancreatoduodenectomy for pancreatic ductal adenocarcinoma.

Previous studies have suggested that preoperative chemoradiation (CRT) is associated with an improved margin-negative resection rate among patients who undergo pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, the optimal preoperative regimen has not been established. All patients with PDAC who received chemotherapy and/or CRT followed by PD between 1999 and 2014 were retrospectively reviewed. The effects of 2 external-beam radiation regimens-a standard course of 50.4 Gy in 28 fractions and a hypofractionated course of 30 Gy in 10 fractions-were compared. Differences in clinicopathologic characteristics, locoregional recurrence (LR), and overall survival (OS) were assessed. Among 472 patients who received preoperative therapy, 224 (47.5%) received 30 Gy, 221 (46.8%) received 50.4 Gy, and 27 (5.7%) received chemotherapy alone. Patients who received 50.4 Gy were more likely to have advanced-stage disease and to have received induction and postoperative chemotherapy, but there was no difference in the R1 margin status, treatment effect, LR, or OS between the 2 radiation groups (all P values > .05). Patients who received preoperative CRT had a lower rate of LR than patients who received preoperative chemotherapy alone (P < .01). In a multivariate Cox proportional hazards analysis, 50.4 Gy was associated with OS and LR similar to those associated with 30 Gy, whereas the absence of preoperative radiation was associated with a higher rate of LR (odds ratio, 2.21; 95% confidence interval, 1.04-4.70) and similar OS. Preoperative hypofractionated CRT was associated with similar local control and OS in comparison with standard CRT in patients undergoing PD for PDAC. The use of chemotherapy alone without CRT was associated with poorer local control but similar survival. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2671-2679. © 2016 American Cancer Society.