Tumor-positive Resection Margins Research Articles

ICG-Fluorescence Imaging for Margin Assessment During Minimally Invasive Colorectal Liver Metastasis Resection

Unintended tumor-positive resection margins occur frequently during minimally invasive surgery for colorectal liver metastases and potentially negatively influence oncologic outcomes. To assess whether indocyanine green (ICG)-fluorescence-guided surgery is associated with achieving a higher radical resection rate in minimally invasive colorectal liver metastasis surgery and to assess the accuracy of ICG fluorescence for predicting the resection margin status. The MIMIC (Minimally Invasive, Indocyanine-Guided Metastasectomy in Patients With Colorectal Liver Metastases) trial was designed as a prospective single-arm multicenter cohort study in 8 Dutch liver surgery centers. Patients were scheduled to undergo minimally invasive (laparoscopic or robot-assisted) resections of colorectal liver metastases between September 1, 2018, and June 30, 2021. All patients received a single intravenous bolus of 10 mg of ICG 24 hours prior to surgery. During surgery, ICG-fluorescence imaging was used as an adjunct to ultrasonography and regular laparoscopy to guide and assess the resection margin in real time. The ICG-fluorescence imaging was performed during and after liver parenchymal transection to enable real-time assessment of the tumor margin. Absence of ICG fluorescence was favorable both during transection and in the tumor bed directly after resection. The primary outcome measure was the radical (R0) resection rate, defined by the percentage of colorectal liver metastases resected with at least a 1 mm distance between the tumor and resection plane. Secondary outcomes were the accuracy of ICG fluorescence in detecting margin-positive (R1; <1 mm margin) resections and the change in surgical management. In total, 225 patients were enrolled, of whom 201 (116 [57.7%] male; median age, 65 [IQR, 57-72] years) with 316 histologically proven colorectal liver metastases were included in the final analysis. The overall R0 resection rate was 92.4%. Re-resection of ICG-fluorescent tissue in the resection cavity was associated with a 5.0% increase in the R0 percentage (from 87.4% to 92.4%; P < .001). The sensitivity and specificity for real-time resection margin assessment were 60% and 90%, respectively (area under the receiver operating characteristic curve, 0.751; 95% CI, 0.668-0.833), with a positive predictive value of 54% and a negative predictive value of 92%. After training and proctoring of the first procedures, participating centers that were new to the technique had a comparable false-positive rate for predicting R1 resections during the first 10 procedures (odds ratio, 1.36; 95% CI, 0.44-4.24). The ICG-fluorescence imaging was associated with changes in intraoperative surgical management in 56 (27.9%) of the patients. In this multicenter prospective cohort study, ICG-fluorescence imaging was associated with an increased rate of tumor margin-negative resection and changes in surgical management in more than one-quarter of the patients. The absence of ICG fluorescence during liver parenchymal transection predicted an R0 resection with 92% accuracy. These results suggest that use of ICG fluorescence may provide real-time feedback of the tumor margin and a higher rate of complete oncologic resection.

Adjuvant Therapy for Patients with a Tumor-Positive Resection Margin After Neoadjuvant Chemoradiotherapy and Esophagectomy

BackgroundApproximately 4–9% of patients have a tumor-positive resection margin after neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Although it is associated with decreased survival, Western guidelines do not recommend adjuvant treatment.ObjectiveThe aim of this study was to assess the proportion of patients who received adjuvant therapy, and to evaluate overall survival (OS) after esophagectomy in patients with a tumor-positive resection margin.MethodsPatients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) esophageal cancer between 2015 and 2022, and treated with nCRT followed by irradical esophagectomy, were selected from the Netherlands Cancer Registry. The primary outcome was the proportion of patients with a tumor-positive resection margin who started adjuvant treatment ≤16 weeks after esophagectomy, including chemotherapy/radiotherapy, immunotherapy, or targeted therapy. OS was calculated from the date of surgery until the date of death or last day of follow-up.ResultsOverall, 376 patients were included in our study, of whom 357 were treated with nCRT. Of these 357 patients, 98.3% had a microscopically irradical resection and 1.7% had a macroscopically irradical resection. Approximately 72.3% of tumors showed a partial response (Mandard 2–3) and 11.8% showed little/no pathological response (Mandard 4–5) to nCRT. One of 357 patients underwent adjuvant chemoradiotherapy and 39 patients (61%) underwent adjuvant immunotherapy (nivolumab). The median and 5-year OS rate of all patients was 16.4 months (95% confidence interval 13.1–19.8) and 21%, respectively.ConclusionReal-world population-level data showed that no patients with a tumor-positive resection margin underwent adjuvant therapy following nCRT and esophagectomy prior to 2021. Interestingly, 61% of patients were treated with adjuvant nivolumab in 2021–2022. OS after irradical esophagectomy is poor and long-term data will explore the added value of nivolumab.

453. TREATMENT AND SURVIVAL OF PATIENTS WITH A POSITIVE RESECTION MARGIN AFTER NEOADJUVANT CHEMORADIOTHERAPY AND ESOPHAGECTOMY

Abstract Background Esophagectomy after neoadjuvant chemoradiotherapy (nCRT) is associated with a tumor-positive resection margin in 4–9% of patients. Although survival in patients with a positive margin is decreased, Western guidelines do not recommend adjuvant systemic/local treatment after esophagectomy. The aim of this study was to assess whether patients underwent adjuvant therapy, regardless the lack of evidence from guidelines, and to evaluate the overall survival (OS) in patients that underwent esophagectomy and had a positive resection margin. Methods All patients diagnosed with resectable (cT2-4a/cTxN0–3/NxM0) esophageal or junctional cancer that underwent nCRT followed by esophagectomy between 2015 and 2021 were selected from the Netherlands’ Cancer Registry. Included were patients with a tumor-positive resection margin. The primary endpoint was the proportion of patients that started adjuvant treatment ≤16 weeks after esophagectomy, including chemotherapy, radiotherapy, immunotherapy or targeted therapy. Secondary outcome OS was calculated from date of surgery until date of death or last day of follow-up, using the Kaplan Meier method. Results Among the 300 included patients, 98.7% had a microscopically irradical resection (R1), while 1.3% had a macroscopically irradical resection (R2). The median age was 67 (interquartile range 60–72) years and WHO 0–1 (89.3%). Esophagectomy was performed open (8.3%), laparoscopically (57.7%) or robot-assisted (33%) and via transthoracic (89.7%) or transhiatal approach (8.7%). Some 71% of tumors had a partial response (Mandard category 1–3) or no pathological response (Mandard 4–5; 12.7%) to nCRT. One patient underwent external radiotherapy after esophagectomy. Twenty patients (7%) underwent adjuvant immunotherapy (nivolumab), despite their irradical resection. Median OS of all patients was 18.6 months (95% CI 14.7–22.4). Conclusion Real-world population level data showed that 7% of patients were treated with adjuvant immunotherapy, despite lack of evidence of the benefit thereof in patients with an irradical resection. This underlines the need for better neoadjuvant therapy leading to less irradical resections, as well as prospective studies evaluating adjuvant therapy in patients with an irradical resection.

Risk Factors for Tumor Positive Resection Margins After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: Results from the Dutch Upper GI Cancer Audit: A Nationwide Population-Based Study.

To identify risk factors for tumor positive resection margins after neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for esophageal cancer. Esophagectomy after nCRT is associated with tumor positive resection margins in 4-9% of patients. This study evaluates potential risk factors for positive resection margins after nCRT followed by esophagectomy. All patients who underwent an elective esophagectomy following nCRT in 2011-2017 in the Netherlands were included. A multivariable logistic regression was performed to assess the association between potential risk factors and tumor positive resection margins. In total, 3900 patients were included. Tumor positive resection margins were observed in 150 (4%) patients. Risk factors for tumor positive resection margins included tumor length (in centimeters, OR:1.1, 95% CI: 1.0-1.1), cT4-stage (OR:3.0, 95% CI: 1.2 - 6.7) and an Ivor Lewis esophagectomy (OR:1.6, 95% CI: 1.0 - 2.6). Predictors associated with a lower risk of tumor positive resection margins were; squamous cell carcinoma (OR:0.4, 95% CI: 0.2 - 0.7), distal tumors (OR:0.5, 95% CI: 0.3 - 1.0), minimally invasive surgery (OR:0.6, 95% CI: 0.4 - 0.9) and a hospital volume of >60 esophagectomies per year (OR:0.6, 95%CI: 0.4 - 1.0). In this nationwide cohort study, tumor and surgical related factors (tumor length, histology, cT-stage, tumor location, surgical procedure, surgical approach, hospital volume) were identified as risk factors for tumor positive resection margins after nCRT for esophageal cancer. These results can be used to improve the radical resection rate by careful selection of patients and surgical approach and are a plea for centralization of esophageal cancer care.

Self-intensified synergy of a versatile biomimetic nanozyme and doxorubicin on electrospun fibers to inhibit postsurgical tumor recurrence and metastasis

Tumor-positive resection margins after surgery can result in tumor recurrence and metastasis. Although adjuvant postoperative radiotherapy and chemotherapy have been adopted in clinical practice, they lack efficacy and result in unavoidable side effects. Herein, a self-intensified in-situ therapy approach using electrospun fibers loaded with a biomimetic nanozyme and doxorubicin (DOX) is developed. The fabricated PEG-coated zeolite imidazole framework-67 (PZIF67) is demonstrated as a versatile nanozyme triggering reactions in cancer cells based on endogenous H2O2 and •O2−. The PZIF67-generated •OH induces reactive oxygen species (ROS) overload, implementing chemodynamic therapy (CDT). The O2 produced by PZIF67 inhibits the expression of hypoxia-up-regulated proteins, thereby suppressing tumor progression. PZIF67 also catalyzes the degradation of glutathione, further disturbing the intracellular redox homeostasis and enhancing CDT. Furthermore, the introduced DOX not only kills cancer cells individually, but also replenishes the continuously consumed substrates for PZIF67-catalyzed reactions. The PZIF67-weakened drug resistance strengthens the cytotoxicity of DOX. The combined application of PZIF67 and DOX also suppresses metastasis-associated genes. Both in vitro and in vivo results demonstrate that the self-intensified synergy of PZIF67 and DOX on electrospun fibers efficiently prevents postsurgical tumor recurrence and metastasis, offering a feasible therapeutic regimen for operable malignant tumors.

Enhancing the Contrast of Tumor Imaging for Image-Guided Surgery Using a Tumor-Targeting Probiotic with the Continuous Expression of a Biomarker.

Tumor recurrence commonly results from tumor-positive resection margins and metastatic lesions. The complete removal of tumor-positive margins is particularly essential in clinics. Thus, we designed a strategy based on Escherichia coli Nissle 1917 (EcN) nitroreductase (NTR) with a polyethylene glycol (PEG) polymer coating (PC-EcN-NTR) to specifically target and colonize in tumors for high-contrast tumor imaging by providing a large amount of NTR as biomarkers in situ. NTR is a favorable biomarker for tumor detection and imaging. The nfsB-encoding plasmid with a 16S promoter was transfected into EcN for the continuous and stable expression of NTR (E. coli. NfsB). PC-EcN-NTR can accumulate and proliferate for a long time in tumors to substantially express NTR. When the NTR-activated fluorescence (FL) probe was sprayed on the tumor, the tumor region showed fluorescence signals within 5 min. Compared to the tumor without colonization with bacteria, the PC-EcN-NTR-colonized tumors displayed 3.15× enhanced fluorescence signals. Furthermore, the fluorescence signals of the whole tumor can last at least 3 h, which is suitable for a long and meticulous surgical operation. More importantly, in the PC-EcN-NTR-harboring tumor, obvious FL appeared even at the very edge (approximately 200 μm away from the edge) of the tumor tissue. A TCF-Based near-infrared-II fluorescent probe (probe 2) was designed and synthesized. Results similar to those of probe 1 were observed when probe 2 was used for in vivo tumor imaging, which further proved the generality of the enhancing ability of the tumor-targeting probiotic. This strategy will hopefully guide the surgical resection of tumors via monitoring intense NTR activity. It may spur the use of tumor-targeting probiotic and enzyme-activated fluorescent probes for the processes of tumor diagnosis and image-guided surgery.

Use of Image-Guided Surgical Navigation during Resection of Locally Recurrent Rectal Cancer.

Surgery for locally recurrent rectal cancer (LRRC) presents several challenges, which is why the percentage of inadequate resections of these tumors is high. In this exploratory study, we evaluate the use of image-guided surgical navigation during resection of LRRC. Patients who were scheduled to undergo surgical resection of LRRC who were deemed by the multidisciplinary team to be at a high risk of inadequate tumor resection were selected to undergo surgical navigation. The risk of inadequate surgery was further determined by the proximity of the tumor to critical anatomical structures. Workflow characteristics of the surgical navigation procedure were evaluated, while the surgical outcome was determined by the status of the resection margin. In total, 20 patients were analyzed. For all procedures, surgical navigation was completed successfully and demonstrated to be accurate, while no complications related to the surgical navigation were discerned. Radical resection was achieved in 14 cases (70%). In five cases (25%), a tumor-positive resection margin (R1) was anticipated during surgery, as extensive radical resection was determined to be compromised. These patients all received intraoperative brachytherapy. In one case (5%), an unexpected R1 resection was performed. Surgical navigation during resection of LRRC is thus safe and feasible and enables accurate surgical guidance.

The impact of performing gastric cancer surgery during holiday periods. A population-based study using Dutch upper gastrointestinal cancer audit (DUCA) data

Existing literature suggests inferior quality of oncologic surgery during holiday periods. This study aimed to investigate the impact of holiday periods on surgical treatment of gastric cancer in the Netherlands. This nationwide study included all gastric cancer patients undergoing potentially curative surgery registered in the Dutch Upper Gastrointestinal Cancer Audit (DUCA). For each patient it was established whether they underwent surgery during or outside the 11 Dutch holiday weeks, based on date and region of surgery. Separate, single-day holidays were not included. Baseline and treatment characteristics were compared using descriptive statistics. Time from diagnosis to treatment and short-term surgical outcomes were compared using multilevel multivariable logistic regression analyses. To prevent bias from recent advancements, analyses were repeated in a recent cohort of patients (2015-2018). Between 2011-2018, 3440 patients were included in the DUCA. Some 555 (16.1%) patients underwent surgery during 11 holiday weeks. There were no differences in patient, tumor and treatment characteristics and time to treatment between holidays and non-holidays. Tumor-positive resection margins (R1/R2 vs R0) occurred more frequent during holidays (aOR:1.47, 95%CI:1.07-2.04). Subgroup analyses in a recent cohort of patients also found higher tumor-positive resection margins (aOR:1.59, 95%CI:1.01-2.43) and higher failure-to-rescue rates (aOR:2.55, 95%CI:1.18-5.49) during holidays. Even though time to treatment and patient, tumor and treatment characteristics were comparable between holidays and non-holidays, tumor-positive resection margin and failure-to-rescue rates were higher during holidays. This suggests that steps must be taken to keep specialized and dedicated gastric cancer expertise up to standard during holiday periods.

Near-Infrared Fluorescence Tumor-Targeted Imaging in Lung Cancer: A Systematic Review.

Lung cancer is the most common cancer type worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype. Non-disseminated NSCLC is mainly treated with surgical resection. The intraoperative detection of lung cancer can be challenging, since small and deeply located pulmonary nodules can be invisible under white light. Due to the increasing use of minimally invasive surgical techniques, tactile information is often reduced. Therefore, several intraoperative imaging techniques have been tested to localize pulmonary nodules, of which near-infrared (NIR) fluorescence is an emerging modality. In this systematic review, the available literature on fluorescence imaging of lung cancers is presented, which shows that NIR fluorescence-guided lung surgery has the potential to identify the tumor during surgery, detect additional lesions and prevent tumor-positive resection margins.

Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors

PurposeRadical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims to assess the feasibility of urokinase plasminogen activator receptor (uPAR) targeting antibody fragments for FGS in a direct comparison with their parent IgG in various relevant in vivo models.ProceduresHumanized anti-uPAR monoclonal antibody MNPR-101 (uIgG) was proteolytically digested into F(ab’)2 and Fab fragments named uFab2 and uFab. Surface plasmon resonance (SPR) and cell assays were used to determine in vitro binding before and after fluorescent labeling with IRDye800CW. Mice bearing subcutaneous HT-29 human colonic cancer cells were imaged serially for up to 120 h after fluorescent tracer administration. Imaging characteristics and ex vivo organ biodistribution were further compared in orthotopic pancreatic ductal adenocarcinoma (BxPc-3-luc2), head-and-neck squamous cell carcinoma (OSC-19-luc2-GFP), and peritoneal carcinomatosis (HT29-luc2) models using the clinical Artemis fluorescence imaging system.ResultsUnconjugated and conjugated uIgG, uFab2, and uFab specifically recognized uPAR in the nanomolar range as determined by SPR and cell assays. Subcutaneous tumors were clearly identifiable with tumor-to-background ratios (TBRs) > 2 after 72 h for uIgG-800F and 24 h for uFab2-800F and uFab-800F. For the latter two, mean fluorescence intensities (MFIs) dipped below predetermined threshold after 72 h and 36 h, respectively. Tumors were easily identified in the orthotopic models with uIgG-800F consistently having the highest MFIs and uFab2-800F and uFab-800F having similar values. In biodistribution studies, kidney and liver fluorescence approached tumor fluorescence after uIgG-800F administration and surpassed tumor fluorescence after uFab2-800F or uFab-800F administration, resulting in interference in the abdominal orthotopic mouse models.ConclusionsIn a side-by-side comparison, FGS with uPAR-targeting antibody fragments compared with the parent IgG resulted in earlier tumor visualization at the expense of peak fluorescence intensity.

A Standardized Framework for Fluorescence-Guided Margin Assessment for Head and Neck Cancer Using a Tumor Acidosis Sensitive Optical Imaging Agent

PurposeIntra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery.ProceduresThirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology.ResultsAll six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion.ConclusionOur specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity.

Multiphoton tomography in differentiation of morphological and molecular subtypes of breast cancer: A quantitative analysis.

In this study multiphoton tomography, based on second harmonic generation (SHG), and two-photon-excited fluorescence (TPEF) was used to visualize both the extracellular matrix and tumor cells in different morphological and molecular subtypes of human breast cancer. It was shown, that quantified assessment of the SHG based imaging data has great potential to reveal differences of collagen quantity, organization and uniformity in both low- and highly- aggressive invasive breast cancers. The values of quantity and uniformity of the collagen fibers distribution were significantly higher in low-aggressive breast cancer compared to the highly-aggressive subtypes, while the value representing collagen organization was lower in the former type. Additionally, it was shown, that TPEF detection of elastin fibers and amyloid protein may be used as a biomarker of detection the low-aggressive breast cancer subtype. Thus, TPEF/SHG imaging offers the possibility of becoming a useful tool for the rapid diagnosis of various subtypes of breast cancer during biopsy as well as for the intraoperative determinination of tumor-positive resection margins.

Intraoperative Assessment of the Resection Specimen Facilitates Achievement of Adequate Margins in Oral Carcinoma.

BackgroundInadequate resection margins in oral cavity squamous cell carcinoma have an adverse effect on patient outcome. Intraoperative assessment provides immediate feedback enabling the surgeon to achieve adequate resection margins. The goal of this study was to evaluate the value of specimen-driven intraoperative assessment by comparing the margin status in the period before and the period after the introduction of specimen-driven assessment as a standard of care (period 2010–2012 vs period 2013–2017).MethodsA cohort of patients surgically treated for oral squamous cell carcinoma at the Erasmus MC Cancer Institute, Rotterdam, between 2010–2012 was studied retrospectively and compared to results of a prospectively collected cohort between 2013–2017. The frequency, type and results of intraoperative assessment of resection margins were analyzed.ResultsOne hundred seventy-four patients were included from 2010–2012, 241 patients were included from 2013–2017. An increase in the frequency of specimen-driven assessment was seen between the two periods, from 5% in 2010–2012 to 34% in 2013–2017. When performing specimen-driven assessment, 16% tumor-positive resection margins were found in 2013–2017, compared to 43% tumor-positive resection margins overall in 2010–2012. We found a significant reduction of inadequate resection margins for specimen-driven intraoperative assessment (p < 0.001). Also, tumor recurrence significantly decreased, and disease-specific survival improved when performing specimen-driven intraoperative assessment.ConclusionsSpecimen-driven intraoperative assessment improves resection margins and consequently, the outcome of oral cancer patients. We advocate this method as standard of care.

Fifty Years of Surgery for Pancreatic Cancer.

The surgical treatment of pancreatic cancer (PDAC) has seen sweeping changes during the past 5 decades. Up to the middle of the 20th century resection rates were below 5%, but the numbers of curative resections for PDAC are now continuously increasing due to improved neoadjuvant treatment concepts as well as progress in surgical techniques and perioperative management. During the same period, mortality rates after pancreatic surgery have decreased considerably and are now less than 5%. One of the most important cornerstones of reduced mortality has been the concentration of PDAC surgery in specialized centers. In addition, the management of postoperative complications has improved greatly as a result of optimized interdisciplinary teamwork. Adjuvant chemotherapy has become the reference treatment in resected PDAC, achieving significantly prolonged survival. Moreover, the concept of borderline resectable PDAC has emerged to characterize tumors with increased risk for tumor-positive resection margins or worse outcome. The best treatment strategy for borderline resectable PDAC is currently under debate, whereas neoadjuvant therapy has become established as a beneficial treatment option for patients with locally advanced PDAC, enabling conversion surgery in up to 60% of cases. This review article summarizes the principal changes in PDAC surgery during the past 50 years.

Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery

Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in- and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences.

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.

Prevention of Anastomotic Leakage in Ovarian Cancer Debulking Surgery and Its Impact on Overall Survival.

The aim of this retrospective study was to investigate the impact of anastomotic leakage on survival rate and to define potential factors of risk and protection from bowel anastomotic leakage in patients with bowel segment resection treated for epithelial ovarian cancer in an accredited high-volume center. Data of 136 patients treated with bowel resection between 2010 and 2017 were collected. All operations were performed by three accredited gynecological oncologists and by two specialized colorectal surgeons. Survival and anastomotic leakage rates were analyzed as per preoperative treatment, number and localization of anastomoses, grading of ovarian cancer, and protective loop ileostomy. In total, anastomotic leakage was observed in 23 out of 165 anastomoses (13.9%), representing 23 anastomotic leakages in 136 patients (16.9%). The 30-day mortality rate was 0.73%. There was no statistically significant difference in anastomotic leakage rate depending on localization and number of anastomoses (p=0.634). Patients with a protective loop ileostomy (n=22/136 patients) had no anastomotic leakage (0.0%, p=0.021). The anastomotic leakage rate was significantly different in patients without protective loop ileostomy depending on bevacizumab administration [no bevacizumab: 15/111 (13.5%) vs. bevacizumab administration: 4/8 (50.0%), p=0.007]. Tumor-positive resection margins in bowel segments were an independent prognostic factor (relative risk=6.3; 95% confidence intervaI=3.1-12.9). In this data set, protective loop ileostomy likely reduced the anastomotic leakage rate after bowel resection in selected cases of ovarian cancer treated with debulking surgery. Especially in patients treated with bevacizumab, protective loop ileostomy should be considered. There was no significant impact of leakage rate on overall survival.

24 - Prognostic value of tumor positive resection margin, rapid biochemical relapse and fast disease progression in low-risk prostate cancer following radical prostatectomy: A long-term follow up

24 - Prognostic value of tumor positive resection margin, rapid biochemical relapse and fast disease progression in low-risk prostate cancer following radical prostatectomy: A long-term follow up

Population-Based Study on Risk Factors for Tumor-Positive Resection Margins in Patients with Gastric Cancer

BackgroundRadical gastrectomy is the cornerstone of the treatment of locally advanced gastric cancer. This study was designed to evaluate factors associated with a tumor-positive resection margin after gastrectomy and to evaluate the influence of hospital volume.MethodsIn this Dutch cohort study, patients with junctional or gastric cancer who underwent curative gastrectomy between 2011 and 2017 were included. The primary outcome was incomplete tumor removal after the operation defined as the microscopic presence of tumor cells at the resection margin. The association of patient and disease characteristics with incomplete tumor removal was tested with multivariable regression analysis. The association of annual hospital volume with incomplete tumor removal was tested and adjusted for the patient- and disease characteristics.ResultsIn total, 2799 patients were included. Incomplete tumor removal was seen in 265 (9.5%) patients. Factors associated with incomplete tumor removal were: tumor located in the entire stomach (odds ratio (OR) [95% confidence interval (CI): 3.38 [1.91–5.96] reference: gastroesophageal junction), cT3, cT4, cTx (1.75 [1.20–2.56], 2.63 [1.47–4.70], 1.60 [1.03–2.48], reference: cT0-2), pN+ (2.73 [1.96–3.80], reference: pN−), and diffuse and unknown histological subtype (3.15 [2.14–4.46] and 2.05 [1.34–3.13], reference: intestinal). Unknown differentiation grade was associated with complete tumor removal (0.50 [0.30–0.83], reference: poor/undifferentiated). Compared with a hospital volume of < 20 resections/year, 20–39, and > 39 resections were associated with lower probability for incomplete tumor removal (OR 0.56 [0.42–0.76] and 0.34 [0.18–0.64]).ConclusionsTumor location, cT, pN, histological subtype, and tumor differentiation are associated with incomplete tumor removal. The association of incomplete tumor removal with an annual hospital volume of < 20 resections may underline the need for further centralization of gastric cancer care in the Netherlands.

Salvage surgery for advanced stage head and neck squamous cell carcinoma following radiotherapy or chemoradiation

Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma (HNSCC) is known to result in poor prognosis. As there are only small and heterogeneous studies available with wide variety in outcome measures, our purpose was to select and pool literature according to specific criteria. Systematic review and meta-analysis of clinical outcome after salvage surgery for recurrent advanced stage HNSCC following primary radiotherapy or chemoradiation. 16 of 3956 screened studies were included for analysis (729 patients). Pooled 5-year OS was 37% (95% CI 30-45%, 12 studies, 17 outcome measurements, 540 patients). Outcome was presented for larynx (6 studies, 397 patients), hypopharynx (2 studies, 47 patients), larynx and hypopharynx combined (3 studies, 69 patients) or separately (1 study, 134 patients), oral cavity (1 study, 11 patients), oropharynx (1 study, 34 patients) and multiple subsites combined (2 studies, 37 patients). There was no significant difference in survival outcome between subsites (pheterogeneity=0.8116). The pooled tumor-positive resection margin rate was 32% and pooled re-operation rate 17%. Complication rates from the pooled data were: fistulas 33%, wound infections 24% and flap failure 3%. Treatment-related mortality rate was 1% and mean hospital stay was 23 days. Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma after primary (chemo)radiotherapy is a good last resort curative treatment option, resulting in 37% overall survival at 5 years. As data from advanced stage non-laryngeal tumors were sparse, no solid conclusions can be drawn with regard to outcome differences between tumor subsites.