What Is the Microbiome? A Description of a Social Network.

The gut microbiome has coevolved with its hosts over the years, forming a complex and symbiotic relationship. It is formed by what we do, what we eat, where we live, and with whom we live. The microbiome is known to influence our health by training our immune system and providing nutrients for the human body. However, when the microbiome becomes out of balance and dysbiosis occurs, the microorganisms within can cause or contribute to diseases. This major influencer on our health is studied intensively, but it is unfortunately often overlooked by the surgeon and in surgical practice. Because of that, there is not much literature about the microbiome and its influence on surgical patients or procedures. However, there is evidence that it plays a major role, showing that it needs to be a topic of interest for the surgeon. This review is written to show the surgeon the importance of the microbiome and why it should be taken into consideration when preparing or treating patients.

Re-Irradiation in Patients with Recurrent Rectal Cancer is Safe and Feasible.

BACKGROUND: There is no consensus yet for the best treatment regimen in patients with recurrent rectal cancer (RRC). This study aims to evaluate toxicity and oncological outcomes after re-irradiation in patients with RRC in our center. Clinical (cCR) and pathological complete response (pCR) rates and radicality were also studied. METHODS: Between January 2010 and December 2018, 61 locally advanced RRC patients were treated and analyzed retrospectively. Patients received radiotherapy at a dose of 30.0-30.6 Gy (reCRT) or 50.0-50.4 Gy chemoradiotherapy (CRT) in cases of no prior irradiation because of low-risk primary rectal cancer. In both groups, patients received capecitabine concomitantly. RESULTS: In total, 60 patients received the prescribed neoadjuvant (chemo)radiotherapy followed by surgery, 35 patients (58.3%) in the reRCT group and 25 patients (41.7%) in the long-course CRT group. There were no significant differences in overall survival (p = 0.82), disease-free survival (p = 0.63), and local recurrence-free survival (p = 0.17) between the groups. Patients in the long-course CRT group reported more skin toxicity after radiotherapy (p = 0.040). No differences were observed in late toxicity. In the long-course CRT group, a significantly higher cCR rate was observed (p = 0.029); however, there was no difference in the pCR rate (p = 0.66). CONCLUSIONS: The treatment of RRC patients with re-irradiation is comparable to treatment with long-course CRT regarding toxicity and oncological outcomes. In the reCRT group, less cCR was observed, although there was no difference in pCR. The findings in this study suggest that it is safe and feasible to re-irradiate RRC patients.

Mucus Microbiome of Anastomotic Tissue During Surgery Has Predictive Value for Colorectal Anastomotic Leakage.

OBJECTIVE: The aim of the present study is to investigate the association of gut microbiota, depending on treatment method, with the development of colorectal anastomotic leakage (AL). BACKGROUND: AL is a major cause for morbidity and mortality after colorectal surgery, but the mechanism behind this complication still is not fully understood. METHODS: Bacterial DNA was isolated from 123 "donuts" of patients where a stapled colorectal anastomosis was made and was analyzed using 16S MiSeq sequencing. In 63 patients, this anastomosis was covered with a C-seal, a bioresorbable sheath stapled to the anastomosis. RESULTS: In non-C-seal patients, AL development was associated with low microbial diversity (P = 0.002) and correspondingly with a high abundance of the dominant Bacteroidaceae and Lachnospiraceae families (P = 0.008 and 0.010, respectively). In C-seal samples, where AL rates were slightly higher (25% vs 17%), an association with the gut microbiota composition was almost undetectable. Only a few opportunistic pathogenic groups of low abundance were associated with AL in C-seal patients, in particular Prevotella oralis (P = 0.007). CONCLUSIONS: AL in patients without a C-seal can be linked to the intestinal microbiota, in particular with a low microbial diversity and a higher abundance of especially mucin-degrading members of the Bacteroidaceae and Lachnospiraceae families. In C-seal patients, however, it seems that any potential protective benefits or harmful consequences of the gut microbiota composition in regard to wound healing are negated, as progression to AL is independent of the initially dominant bacterial composition.

The OncoLifeS data-biobank for oncology: a comprehensive repository of clinical data, biological samples, and the patient's perspective.

BACKGROUND: Understanding cancer heterogeneity, its temporal evolution over time, and the outcomes of guided treatment depend on accurate data collection in a context of routine clinical care. We have developed a hospital-based data-biobank for oncology, entitled OncoLifeS (Oncological Life Study: Living well as a cancer survivor), that links routine clinical data with preserved biological specimens and quality of life assessments. The aim of this study is to describe the organization and development of a data-biobank for cancer research. RESULTS: We have enrolled 3704 patients aged ≥ 18 years diagnosed with cancer, of which 45 with hereditary breast-ovarian cancer (70% participation rate) as of October 24th, 2019. The average age is 63.6 ± 14.2 years and 1892 (51.1%) are female. The following data are collected: clinical and treatment details, comorbidities, lifestyle, radiological and pathological findings, and long-term outcomes. We also collect and store various biomaterials of patients as well as information from quality of life assessments. CONCLUSION: Embedding a data-biobank in clinical care can ensure the collection of high-quality data. Moreover, the inclusion of longitudinal quality of life data allows us to incorporate patients' perspectives and inclusion of imaging data provides an opportunity for analyzing raw imaging data using artificial intelligence (AI) methods, thus adding new dimensions to the collected data.

Correspondence between primary and secondary care about patients with cancer: A qualitative mixed-methods analysis.

Cancer care is complex and involves many different healthcare providers, especially during diagnosis and initial treatment, and it has been reported that both general practitioners and oncology specialists experience difficulties with interdisciplinary communication. The aim of this qualitative study was to explore information sharing between primary and secondary care for patients with lung, breast or colorectal cancer. A qualitative content analysis of 50 medical files (419 documents) was performed, which identified 70 correspondence-related items. Six main topics were identified in most referral letters from primary to secondary care, but it was particularly notable that highly relevant information regarding the past medical history was often mixed with less relevant information. To lesser extents, the same held true for the medication list and presenting history. In the letters from specialists, nine topics were identified in most letters. Although information about actual treatment was always present, only limited detail, if any, was given about the intent of the treatment (curative or palliative) or the treatment alternatives. Interviews with nine healthcare providers confirmed these issues. These findings indicate that neither the initial referral nor the specialist correspondence is tailored to the needs of the recipient.

Fasciocutaneous Lotus Petal Flap for Perineal Wound Reconstruction after Extralevator Abdominoperineal Excision: Application for Reconstruction of the Pelvic Floor and Creation of a Neovagina.

BACKGROUND: The extralevator abdominoperineal excision (ELAPE) procedure creates an extensive soft tissue defect of the pelvic floor. It has been suggested that primary reconstruction reduces the risk of wound infection and delayed wound healing in this high-risk area. Use of myocutaneous flaps or omentoplasty are associated with functional limitations and complications. We performed the perineal variant of the lotus petal flap, which was originally described for vulvar reconstruction. We aimed to verify if application of the lotus petal flap in pelvic floor reconstruction after ELAPE meets the goals of an ideal reconstruction. METHODS: We performed a retrospective study of 28 patients who underwent the lotus petal flap procedure for pelvic floor reconstruction after ELAPE between January 2011 and March 2014. RESULTS: Median age was 62.1 years and 78.6 % of patients were female. In most patients the tumor was preoperatively irradiated (89.3 %) and in 28.6 % of the reconstructions a biological mesh was applied. No total flap loss occurred. Six (21.4 %) patients had no complications, while 13 (46.4 %) patients had minor complications (Clavien-Dindo grade I-II). Reoperation (Clavien-Dindo grade IIIb) was performed in nine patients (32.1 %), three of whom required a second lotus petal flap reconstruction. Median time until wound healing was 14 weeks. No additional surgery was performed for aesthetic problems. CONCLUSIONS: Reconstruction of the pelvic floor after ELAPE using the fasciocutaneous lotus petal flap has limited major complications, but still with a high incidence of minor wound complications. This retrospective cohort study shows limited consequences on form and function.

Intestinal microbiota and anastomotic leakage of stapled colorectal anastomoses: a pilot study.

BACKGROUND: Anastomotic leakage (AL) after colorectal surgery is a severe complication, resulting in morbidity, reinterventions, prolonged hospital stay and, in some cases, death. Some technical and patient-related aetiological factors of AL are well established. In many cases, however, none of these factors seem to explain the occurrence of AL. Recent studies suggest that the intestinal microbiome plays a role in wound healing, diabetes and Crohn's disease. The aim of this study was to compare the intestinal microbiota of patients who developed AL with matched patients with healed colorectal anastomoses. METHODS: We investigated the microbiome in the doughnuts collected from 16 patients participating in the C-seal trial. We selected eight patients who developed AL requiring reintervention and eight matched controls without AL. We analysed the bacterial 16S rDNA of both groups with MiSeq sequencing. RESULTS: The abundance of Lachnospiraceae is statistically higher (P = 0.001) in patient group who did develop AL, while microbial diversity levels were higher in the group who did not develop AL (P = 0.037). Body mass index (BMI) was also positively associated with the abundance of the Lachnospiraceae family (P = 0.022). CONCLUSION: A correlation between the bacterial family Lachnospiraceae, low microbial diversity and anastomotic leakage, possibly in association with the BMI, was found. The relative abundance of the Lachnospiraceae family is possibly explained by the higher abundance of mucin-degrading Ruminococci within that family in AL cases (P = 0.011) as is similarly the case in IBD.

Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy.

BACKGROUND: Experience with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in a pioneer hospital resulted in a treatment protocol that has become the standard in the Netherlands. Outcome of CRS and HIPEC was reviewed to assure differences between the pioneer phase and the period wherein the Dutch HIPEC protocol was clinically implemented. METHODS: The first consecutive 100 CRS and HIPEC procedures performed in the Netherlands were included as pioneer cohort (1995-1999). Two-hundred and seventy-two procedures that were performed in three participating HIPEC centres after the implementation of the Dutch HIPEC protocol were included as the implementation cohort (2005-2012). Another 100 recent patients of the first centre were included as a control group (2009-2011). Indications for the CRS and HIPEC treatment were peritoneal carcinomatosis (PC) from colorectal carcinoma and pseudomyxoma peritonei (PMP). RESULTS: Of the 472 included procedures, 327 (69 %) procedures were performed for PC from colorectal carcinoma and 145 for PMP (31 %). Compared with the implementation phase, the pioneer phase was characterized by more affected abdominal regions (mean 4.3 vs. 3.5, p < 0.001), more resections (mean 3.8 vs. 3.4, p < 0.001), less macroscopic radical cytoreductions (66 vs. 86 %, p < 0.001) and more patients with major morbidity (grade III-V) (64 vs. 32 %, p < 0.001). Other determinants of morbidity were high tumour load and multiple organ resections. Outcome of the implementation phase was similar to the control group. CONCLUSIONS: This study determined that outcome had improved ever since the Dutch HIPEC protocol has been implemented based on completeness of cytoreduction and decreasing morbidity.

Increased primary health care use in the first year after colorectal cancer diagnosis.

OBJECTIVE: The view that the general practitioner (GP) should be more involved during the curative treatment of cancer is gaining support. This study aimed to assess the current role of the GP during treatment of patients with colorectal cancer (CRC). DESIGN: Historical prospective study, using primary care data from two cohorts. SETTING: Registration Network Groningen (RNG) consisting of 18 GPs in three group practices with a dynamic population of about 30,000 patients. SUBJECTS: Patients who underwent curative treatment for CRC (n = 124) and matched primary care patients without CRC (reference population; n = 358). MAIN OUTCOME MEASURES: Primary healthcare use in the period 1998-2009. FINDINGS: Patients with CRC had higher primary healthcare use in the year after diagnosis compared with the reference population. After correction for age, gender, and consultation behaviour, CRC patients had 54% (range 23-92%) more face-to-face contacts, 68% (range 36-108%) more drug prescriptions, and 35% (range -4-90%) more referrals compared with reference patients. Patients consulted their GP more often for reasons related to anaemia, abdominal pain, constipation, skin problems, and urinary infections. GPs also prescribed more acid reflux drugs, laxatives, anti-anaemic preparations, analgesics, and psycholeptics for CRC patients. CONCLUSIONS: The GP plays a significant role in the year after CRC diagnosis. This role may be associated with treatment-related side effects and psychological problems. Formal guidelines on the involvement of the GP during CRC treatment might ensure more effective allocation and communication of care between primary and secondary healthcare services.

Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol.

PURPOSE: This nationwide study evaluated results of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis of colorectal origin in the Netherlands following a national protocol. METHODS: In a multi-institutional study prospective databases of patients with peritoneal carcinomatosis (PC) from colorectal cancer and pseudomyxoma peritonei (PMP) treated according to the Dutch HIPEC protocol, a uniform approach for the CRS and HIPEC treatment, were reviewed. Primary end point was overall survival and secondary end points were surgical outcome and progression-free survival. RESULTS: Nine-hundred sixty patients were included; 660 patients (69 %) were affected by PC of colorectal carcinoma and the remaining suffered from PMP (31 %). In 767 procedures (80 %), macroscopic complete cytoreduction was achieved. Three-hundred and thirty one patients had grade III-V complications (34 %). Thirty-two patients died perioperatively (3 %). Median length of hospital stay was 16 days (range 0-166 days). Median follow-up period was 41 months (95 % confidence interval (CI), 36-46 months). Median progression-free survival was 15 months (95 % CI 13-17 months) for CRC patients and 53 months (95 % CI 40-66 months) for PMP patients. Overall median survival was 33 (95 % CI 28-38 months) months for CRC patients and 130 months (95 % CI 98-162 months) for PMP patients. Three- and five-year survival rates were 46 and 31 % respectively in case of CRC patients and 77 and 65 % respectively in case of PMP patients. CONCLUSIONS: The results underline the safety and efficacy of cytoreduction and HIPEC for PC from CRC and PMP. It is assumed the uniform Dutch HIPEC protocol was beneficial.

Thirty-seven patients treated with the C-seal: protection of stapled colorectal anastomoses with a biodegradable sheath.

PURPOSE: The present study was performed to get a better insight in the incidence of anastomotic leakage leading to reintervention when using the C-seal: a biodegradable sheath that protects the stapled colorectal anastomosis from leakage. METHODS: The C-seal is a thin walled tube-like sheath that forms a protective sheath within the bowel lumen. Thirty-seven patients undergoing surgery with creation of a stapled colorectal anastomosis with C-seal were analyzed. Follow-up was completed until 3 months after surgery. RESULTS: One patient (3%) developed anastomotic leakage leading to reintervention. None of the 37 anastomoses was dismantled. One patient was diagnosed with a rectovaginal fistula. In three patients (8%), a perianastomotic abscess spontaneously drained. CONCLUSION: The incidence of anastomotic leakage leading to reintervention when using the C-seal (3%) is lower than expected based on the literature (11%). We have currently set-up a multicenter randomized trial to confirm the efficiency of the C-seal (www.csealtrial.nl).

Economic analysis of open versus laparoscopic versus robot-assisted versus transanal total mesorectal excision in rectal cancer patients: A systematic review.

OBJECTIVES: Minimally invasive total mesorectal excision is increasingly being used as an alternative to open surgery in the treatment of patients with rectal cancer. This systematic review aimed to compare the total, operative and hospitalization costs of open, laparoscopic, robot-assisted and transanal total mesorectal excision. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) (S1 File) A literature review was conducted (end-of-search date: January 1, 2023) and quality assessment performed using the Consensus Health Economic Criteria. RESULTS: 12 studies were included, reporting on 2542 patients (226 open, 1192 laparoscopic, 998 robot-assisted and 126 transanal total mesorectal excision). Total costs of minimally invasive total mesorectal excision were higher compared to the open technique in the majority of included studies. For robot-assisted total mesorectal excision, higher operative costs and lower hospitalization costs were reported compared to the open and laparoscopic technique. A meta-analysis could not be performed due to low study quality and a high level of heterogeneity. Heterogeneity was caused by differences in the learning curve and statistical methods used. CONCLUSION: Literature regarding costs of total mesorectal excision techniques is limited in quality and number. Available evidence suggests minimally invasive techniques may be more expensive compared to open total mesorectal excision. High-quality economical evaluations, accounting for the learning curve, are needed to properly assess costs of the different techniques.

Evaluation of the use of decision-support software in carcino-embryonic antigen (CEA)-based follow-up of patients with colorectal cancer.

BACKGROUND: The present paper is a first evaluation of the use of "CEAwatch", a clinical support software system for surgeons for the follow-up of colorectal cancer (CRC) patients. This system gathers Carcino-Embryonic Antigen (CEA) values and automatically returns a recommendation based on the latest values. METHODS: Consecutive patients receiving follow-up care for CRC fulfilling our in- and exclusion criteria were identified to participate in this study. From August 2008, when the software was introduced, patients were asked to undergo the software-supported follow-up. Safety of the follow-up, experiences of working with the software, and technical issues were analyzed. RESULTS: 245 patients were identified. The software-supported group contained 184 patients; the control group contained 61 patients. The software was safe in finding the same amount of recurrent disease with fewer outpatient visits, and revealed few technical problems. Clinicians experienced a decrease in follow-up workload of up to 50% with high adherence to the follow-up scheme. CONCLUSION: CEAwatch is an efficient software tool helping clinicians working with large numbers of follow-up patients. The number of outpatient visits can safely be reduced, thus significantly decreasing workload for clinicians.

The C-seal trial: colorectal anastomosis protected by a biodegradable drain fixed to the anastomosis by a circular stapler, a multi-center randomized controlled trial.

BACKGROUND: Anastomotic leakage is a major complication in colorectal surgery and with an incidence of 11% the most common cause of morbidity and mortality. In order to reduce the incidence of anastomotic leakage the C-seal is developed. This intraluminal biodegradable drain is stapled to the anastomosis with a circular stapler and prevents extravasation of intracolonic content in case of an anastomotic dehiscence.The aim of this study is to evaluate the efficacy of the C-seal in reducing anastomotic leakage in stapled colorectal anastomoses, as assessed by anastomotic leakage leading to invasive treatment within 30 days postoperative. METHODS: The C-seal trial is a prospective multi-center randomized controlled trial with primary endpoint, anastomotic leakage leading to re-intervention within 30 days after operation. In this trial 616 patients will be randomized to the C-seal or control group (1:1), stratified by center, anastomotic height (proximal or distal of peritoneal reflection) and the intention to create a temporary deviating ostomy. Interim analyses are planned after 50% and 75% of patient inclusion. Eligible patients are at least 18 years of age, have any colorectal disease requiring a colorectal anastomosis to be made with a circular stapler in an elective setting, with an ASA-classification < 4. Oral mechanical bowel preparation is mandatory and patients with signs of peritonitis are excluded. The C-seal student team will perform the randomization procedure, supports the operating surgeon during the C-seal application and achieves the monitoring of the trial. Patients are followed for one year after randomization en will be analyzed on an intention to treat basis. DISCUSSION: This Randomized Clinical trial is designed to evaluate the effectiveness of the C-seal in preventing clinical anastomotic leakage.

Cost analysis and cost-effectiveness of open versus laparoscopic versus robot-assisted versus transanal total mesorectal excision in patients with rectal cancer: a protocol for a systematic review.

INTRODUCTION: Nowadays, most rectal tumours are treated open or minimally invasive, using laparoscopic, robot-assisted or transanal total mesorectal excision. However, insight into the total costs of these techniques is limited. Since all three techniques are currently being performed, including cost considerations in the choice of treatment technique may significantly impact future healthcare costs. Therefore, this systematic review aims to provide an overview of evidence regarding costs in patients with rectal cancer following open, laparoscopic, robot-assisted and transanal total mesorectal excision. METHODS AND ANALYSIS: A systematic search will be conducted for papers between January 2000 and March 2022. Databases PubMed/MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library databases will be searched. Study selection, data extraction and quality assessment will be performed independently by four reviewers and discrepancies will be resolved through discussion. The Consensus Health Economic Criteria list will be used for assessing risk of bias. Total costs of the different techniques, consisting of but not limited to, theatre, in-hospital and postoperative costs, will be the primary outcome. ETHICS AND DISSEMINATION: No ethical approval is required, as there is no collection of patient data at an individual level. Findings will be disseminated widely, through peer-reviewed publication and presentation at relevant national and international conferences. TRIAL REGISTRATION NUMBER: CRD42021261125.

Clinical selection strategy for and evaluation of intra-operative brachytherapy in patients with locally advanced and recurrent rectal cancer.

BACKGROUND AND PURPOSE: A radical resection of locally advanced rectal cancer (LARC) or recurrent rectal cancer (RRC) can be challenging. In case of increased risk of an R1 resection, intra-operative brachytherapy (IOBT) can be applied. We evaluated the clinical selection strategy for IOBT. MATERIALS AND METHODS: Between February 2007 and May 2018, 132 LARC/RRC patients who were scheduled for surgery with IOBT standby, were evaluated. By intra-operative inspection of the resection margin and MR imaging, it was determined whether a resection was presumed to be radical. Frozen sections were taken on indication. In case of a suspected R1 resection, IOBT (1 × 10 Gy) was applied. Histopathologic evaluation, treatment and toxicity data were collected from medical records. RESULTS: Tumour was resected in 122 patients. IOBT was given in 42 patients of whom 54.8% (n = 23) had a histopathologically proven R1 resection. Of the 76 IOBT-omitted R0 resected patients, 17.1% (n = 13) had a histopathologically proven R1 resection. In 4 IOBT-omitted patients, a clinical R1/2 resection was seen. In total, correct clinical judgement occurred in 72.6% (n = 88) of patients. In LARC, 58.3% (n = 14) of patients were overtreated (R0, with IOBT) and 10.9% (n = 5) were undertreated (R1, without IOBT). In RRC, 26.5% (n = 9) of patients were undertreated. CONCLUSION: In total, correct clinical judgement occurred in 72.6% (n = 88). However, in 26.5% (n = 9) RRC patients, IOBT was unjustifiedly omitted. IOBT is accompanied by comparable and acceptable toxicity. Therefore, we recommend IOBT to all RRC patients at risk of an R1 resection as their salvage treatment.

Back-Table Fluorescence-Guided Imaging for Circumferential Resection Margin Evaluation Using Bevacizumab-800CW in Patients with Locally Advanced Rectal Cancer.

Negative circumferential resection margins (CRM) are the cornerstone for the curative treatment of locally advanced rectal cancer (LARC). However, in up to 18.6% of patients, tumor-positive resection margins are detected on histopathology. In this proof-of-concept study, we investigated the feasibility of optical molecular imaging as a tool for evaluating the CRM directly after surgical resection to improve tumor-negative CRM rates. Methods: LARC patients treated with neoadjuvant chemoradiotherapy received an intravenous bolus injection of 4.5 mg of bevacizumab-800CW, a fluorescent tracer targeting vascular endothelial growth factor A, 2-3 d before surgery (ClinicalTrials.gov identifier: NCT01972373). First, for evaluation of the CRM status, back-table fluorescence-guided imaging (FGI) of the fresh surgical resection specimens (n = 8) was performed. These results were correlated with histopathology results. Second, for determination of the sensitivity and specificity of bevacizumab-800CW for tumor detection, a mean fluorescence intensity cutoff value was determined from the formalin-fixed tissue slices (n = 42; 17 patients). Local bevacizumab-800CW accumulation was evaluated by fluorescence microscopy. Results: Back-table FGI correctly identified a tumor-positive CRM by high fluorescence intensities in 1 of 2 patients (50%) with a tumor-positive CRM. For the other patient, low fluorescence intensities were shown, although (sub)millimeter tumor deposits were present less than 1 mm from the CRM. FGI correctly identified 5 of 6 tumor-negative CRM (83%). The 1 patient with false-positive findings had a marginal negative CRM of only 1.4 mm. Receiver operating characteristic curve analysis of the fluorescence intensities of formalin-fixed tissue slices yielded an optimal mean fluorescence intensity cutoff value for tumor detection of 5,775 (sensitivity of 96.19% and specificity of 80.39%). Bevacizumab-800CW enabled a clear differentiation between tumor and normal tissue up to a microscopic level, with a tumor-to-background ratio of 4.7 ± 2.5 (mean ± SD). Conclusion: In this proof-of-concept study, we showed the potential of back-table FGI for evaluating the CRM status in LARC patients. Optimization of this technique with adaptation of standard operating procedures could change perioperative decision making with regard to extending resections or applying intraoperative radiation therapy in the case of positive CRM.