Microscopic Residual Disease Research Articles

Dual Function Antibody Conjugates for Multimodal Imaging and Photoimmunotherapy of Cancer Cells.

Precision imaging, utilizing molecular targeted agents, is an important tool in cancer diagnostics and guiding therapies. While there are limitations associated with single mode imaging probes, multimodal molecular imaging probes enabling target visualization through complementary imaging technologies provides an attractive alternative. However, there are several challenges associated with designing molecular probes carrying contrast agents for complementary multimodal imaging. Here, we propose a dual function antibody conjugate (DFAC) comprising an FDA approved photosensitizer Benzoporphyrin derivative (BPD) and a naphthalocyanine-based photoacoustic dye (SiNc(OH)) for multimodal infrared (IR) imaging. While fluorescence imaging, through BPD, provides sensitivity, complementing it with photoacoustic imaging, through SiNc(OH), provides a depth-resolved spatial resolution much beyond the optical diffusion limits of fluorescence measurements. Through a series of invitro experiments, we demonstrate the development and utilization of DFACs for multimodal imaging and photodynamic treatment of squamous cell carcinoma (A431) cell line. The proposed DFACs have potential use in precision imaging applications such as guiding tumor resection surgeries and photodynamic treatment of residual microscopic disease thereby minimizing local recurrence. The data demonstrated in this study merits further investigation for its preclinical and clinical translation.

Detection of glioma infiltration at the tumor margin using quantitative stimulated Raman scattering histology

In the management of diffuse gliomas, the identification and removal of tumor at the infiltrative margin remains a central challenge. Prior work has demonstrated that fluorescence labeling tools and radiographic imaging are useful surgical adjuvants with macroscopic resolution. However, they lose sensitivity at the tumor margin and have limited clinical utility for lower grade histologies. Fiber-laser based stimulated Raman histology (SRH) is an optical imaging technique that provides microscopic tissue characterization of unprocessed tissues. It remains unknown whether SRH of tissues taken from the infiltrative glioma margin will identify microscopic residual disease. Here we acquired glioma margin specimens for SRH, histology, and tumor specific tissue characterization. Generalized linear mixed models were used to evaluate agreement. We find that SRH identified residual tumor in 82 of 167 margin specimens (49%), compared to IHC confirming residual tumor in 72 of 128 samples (56%), and H&E confirming residual tumor in 82 of 169 samples (49%). Intraobserver agreements between all 3 modalities were confirmed. These data demonstrate that SRH detects residual microscopic tumor at the infiltrative glioma margin and may be a promising tool to enhance extent of resection.

TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study.

Simple SummaryThe status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients.In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

Establishment and Initial Experience of Clinical FLASH Radiotherapy in Canine Cancer Patients.

FLASH radiotherapy has emerged as a treatment technique with great potential to increase the differential effect between normal tissue toxicity and tumor response compared to conventional radiotherapy. To evaluate the feasibility of FLASH radiotherapy in a relevant clinical setting, we have commenced a feasibility and safety study of FLASH radiotherapy in canine cancer patients with spontaneous superficial solid tumors or microscopic residual disease, using the electron beam of our modified clinical linear accelerator. The setup for FLASH radiotherapy was established using a short electron applicator with a nominal source-to-surface distance of 70 cm and custom-made Cerrobend blocks for collimation. The beam was characterized by measuring dose profiles and depth dose curves for various field sizes. Ten canine cancer patients were included in this initial study; seven patients with nine solid superficial tumors and three patients with microscopic disease. The administered dose ranged from 15 to 35 Gy. To ensure correct delivery of the prescribed dose, film measurements were performed prior to and during treatment, and a Farmer-type ion-chamber was used for monitoring. Treatments were found to be feasible, with partial response, complete response or stable disease recorded in 11/13 irradiated tumors. Adverse events observed at follow-up ranging from 3-6 months were mild and consisted of local alopecia, leukotricia, dry desquamation, mild erythema or swelling. One patient receiving a 35 Gy dose to the nasal planum, had a grade 3 skin adverse event. Dosimetric procedures, safety and an efficient clincal workflow for FLASH radiotherapy was established. The experience from this initial study will be used as a basis for a veterinary phase I/II clinical trial with more specific patient inclusion selection, and subsequently for human trials.

Bilateral Wilms’ tumour: A ten-year experience of two academic centres in Johannesburg

Background. Nephroblastoma is the most common paediatric renal malignancy, affecting 1 in 10 000 children worldwide. Between 5% and 10% present bilaterally. Objective. To review two centre’s experience of bilateral Wilms’ tumour in order to improve future management practices. Methods. This was a retrospective case review of nephroblastomas treated at the Chris Hani Baragwanath and Charlotte Maxeke academic hospitals from 1 January 2003 to 31 December 2013. Results. Eighteen patients (8.04%) presented with bilateral disease and were younger than those with unilateral disease. Three patients presented with metachronous disease at a median age of 23 months; initial presentation was at a median age of 2 months. The remaining 15 patients presented with synchronous disease at a median age of 27 months. Treatment followed aspects of the SIOP 9 protocol. Two patients died before surgery. Thirteen kidneys were removed. Twelve patients underwent nephron-sparing surgery, with microscopically positive resection margins seen in six kidneys post surgery. Two patients with residual microscopic disease relapsed. Three kidneys demonstrated unfavourable histology. Nephroblastomatosis was identified in one kidney. Eight patients were alive and disease free and three were alive with disease. An overall and disease-free survival rate of 66.67% and 55.56%, respectively, was found for this cohort. Neither age >2 years nor metachronous disease was associated with a poorer prognosis. Conclusion. Bilateral nephroblastoma is a complex disease. The majority of patients in this series presented with advanced local disease. Relapse was more commonly influenced by the presence of microscopically positive margins than metastatic disease at presentation.

Hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal and appendiceal peritoneal metastases: lessons learned from PRODIGE 7.

The treatment for peritoneal metastases from appendiceal, colon and rectal cancer (MO1) has relied on cytoreductive surgery (CRS) to remove all visible evidence of disease plus a perioperative chemotherapy for the entire abdomen to eliminate microscopic residual disease. Using the results obtained from the PRODIGE 7 randomized controlled trial, methodological issues were discussed and possible improvements to the hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin were sought. Possible methodological and pharmacologic flaws were identified. Several methodological flaws included the sample size, cross-over option, neoadjuvant chemotherapy use and timing of the peritoneal disease evaluation. The sample size issue raised the question of what the minimal clinically relevant benefit we want in future trials. Neoadjuvant FOLFOX may have induced acquired drug resistance to oxaliplatin. Several pharmacological issues were identified including limited 5-fluorouracil exposure as well as limited oxaliplatin peritoneal exposure time. Insufficient 5-fluorouracil accompanied the oxaliplatin as only a bolus dose was used and continuous 5-FU infusion has previously been an integral part of oxaliplatin treatment. Finally, only approximately one-half of the oxaliplatin entered body tissues or tumor. Three suggestions from the lessons learned from a critique of PRODIGE 7 were offered as adjustments to the HIPEC protocol. The Efficacy of HIPEC, a perioperative FOLFOX or a return to HIPEC with mitomycin C were described.

Analysis of plasma KIM-1 as a biomarker for recurrence risk after resection for localized renal cell carcinoma.

342 Background: Recurrence is common after nephrectomy for renal cell carcinoma (RCC), but no circulating biomarkers are available to identify patients at highest risk of recurrence who may benefit from adjuvant therapy. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. Methods: Banked plasma samples were analyzed from the ECOG-ACRIN 2805 (ASSURE) trial evaluating adjuvant sunitinib, sorafenib, and placebo in resected high-risk RCC. KIM-1 levels were measured at trial enrollment 4-12 weeks post-nephrectomy (baseline) and on cycle 2 day 1 (C2D1) using a previously validated microbead assay. A lognormal accelerated failure time model was used to test for association between circulating KIM-1 and disease-free survival (DFS). Results: Plasma samples from 418 patients were analyzed. In univariable and multivariable analyses, higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms. This association remained independently significant after adjustment for Fuhrman grade, T-stage, N-stage, and tumor histology (survival time ratio 0.56 for 75th vs 25th percentile of KIM-1, 95% CI 0.42-0.73, p < 0.001). The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement. The addition of baseline KIM-1 improved the concordance of both the SSIGN and UISS prognostic models (SSIGN concordance 0.57 vs 0.43, p = 0.05; UISS concordance 0.60 vs 0.40, p = 0.0005). C2D1 KIM-1 was not an independent predictor for DFS after adjusting for baseline KIM-1. Conclusions: Elevated plasma KIM-1 level at post-nephrectomy baseline is associated with worse DFS in RCC. This is consistent with the hypothesis that post-nephrectomy plasma KIM-1 may be a biomarker for microscopic residual disease. The model was additionally adjusted for papillary and chromophobe histology, sex, and ECOG performance status. [Table: see text]

Unplanned Excision of Extremity and Trunk Wall Soft Tissue Sarcoma: To Re-resect or Not to Re-resect?

The need for systematic reexcision in patients who underwent unplanned excision (UE) for extremity and superficial trunk soft tissue sarcoma (ESTSTS) has been questioned. We investigated the outcome of patients who underwent reexcision for ESTSTS compared with primarily resected at our institution and the prognostic impact of microscopic residual disease (MR) in the reexcision specimen. Primary ESTSTS patients surgically treated at our institution between 1997 and 2017 were divided in three groups: primarily resected (A), reexcised after macroscopically complete UE (B), and incomplete UE (C). Weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR), and distant metastasis (CCI-DM) were calculated and compared. In group B, multivariable models were performed to assess factors associated with the outcomes. A total of 1962 patients were identified: 1076,697 and 189 in groups A, B, and C, respectively. Overall median follow-up was 85 months. Seven-year weighted-OS was 73.8%, 84.1%, and 80.7% (p < 0.001) for groups A, B, and C respectively. Seven-year CCI-LR and DM were 5.0% and 25.3%, 12.1% and 15.8%, and 13.6% and 29.4% (both p < 0.001) for groups A, B, and C, respectively. At multivariable analysis, the presence MR was associated with LR (p < 0.001) but not with OS nor CCI-DM. UE and the presence of MR at pathology in reexcision specimen are associated to a higher risk of LR but not to a higher risk of DM or lower OS. After macroscopic complete UE, postponing reexcision until a LR occurs may be considered on an individualized basis.

Infant malignant ectomesenchymoma masquerading as inguinal hernia in two patients

Infant malignant ectomesenchymoma masquerading as inguinal hernia in two patients

Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles

The dissemination of tumor metastasis in the peritoneal cavity, also called peritoneal metastasis (PM) or carcinomatosis, represents a late stage of gastrointestinal and gynecological cancer with very poor prognosis, even when cytoreductive surgery is effective, due to residual microscopic disease. Photodynamic therapy (PDT) in the management of peritoneal metastasis has been clinically limited by the low tumor selectivity of photosensitizers (PS) and important adverse effects. Here, we propose extracellular nanovesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) as the fourth generation of immune active PS vectors that are able to target peritoneal metastasis with superior selectivity, potentiate PDT cytotoxicity at the tumor site without affecting healthy tissues, modulate the tumor microenvironment of immunocompetent colorectal and ovarian carcinomatosis models, and promote an antitumor immune response. A pioneering strategy was developed for high yield, large-scale production of MSC-EVs encapsulating the drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC) that is compatible with requirements of clinical translation and also preserves the topology and integrity of naturally produced EVs. Intraperitoneal injection of EVs-mTHPC showed an impressive enhancement of tumoral selectivity in comparison to the free drug and to the liposomal formulation Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor proliferation was significantly decreased after PDT with EVs-mTHPC. Overall EVs vectorization of mTHPC afforded important tumoral selectivity while overcoming the PDT toxicity of the free drug and prolonged mice survival in the colorectal carcinomatosis model. MSC-EVs produced by our scalable manufacturing method appears like the clinically relevant fourth-generation PDT vehicle to overcome current limitations of PDT in the treatment of peritoneal metastasis and promote a hot tumor immune environment in PM.

Simulating drug penetration during hyperthermic intraperitoneal chemotherapy

Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after debulking cytoreductive surgery. During HIPEC, a limited number of catheters are used to administer and drain fluid containing chemotherapy (41–43 °C), yielding heterogeneities in the peritoneum. Large heterogeneities may lead to undertreated areas, increasing the risk of recurrences. Aiming at intra-abdominal homogeneity is therefore essential to fully exploit the potential of HIPEC. More insight is needed into the extent of the heterogeneities during treatments and assess their effects on the efficacy of HIPEC. To that end we developed a computational model containing embedded tumor nodules in an environment mimicking peritoneal conditions. Tumor- and treatment-specific parameters affecting drug delivery like tumor size, tumor shape, velocity, temperature and dose were assessed using three-dimensional computational fluid dynamics (CFD) to demonstrate their effect on the drug distribution and accumulation in nodules. Clonogenic assays performed on RKO colorectal cell lines yielded the temperature-dependent IC50 values of cisplatin (19.5–6.8 micromolar for 37–43 °C), used to compare drug distributions in our computational models. Our models underlined that large nodules are more difficult to treat and that temperature and velocity are the most important factors to control the drug delivery. Moderate flow velocities, between 0.01 and 1 m/s, are optimal for the delivery of cisplatin. Furthermore, higher temperatures and higher doses increased the effective penetration depth with 69% and 54%, respectively. We plan to extend the software developed for this study toward patient-specific treatment planning software, capable of mapping and assist in reducing heterogeneous flow patterns.

Demonstration of treatment planning software for hyperthermic intraperitoneal chemotherapy in a rat model

Background Hyperthermic intraperitoneal chemotherapy (HIPEC) is administered to treat residual microscopic disease after cytoreductive surgery (CRS). During HIPEC, fluid (41–43 °C) is administered and drained through a limited number of catheters, risking thermal and drug heterogeneities within the abdominal cavity that might reduce effectiveness. Treatment planning software provides a unique tool for optimizing treatment delivery. This study aimed to investigate the influence of treatment-specific parameters on the thermal and drug homogeneity in the peritoneal cavity in a computed tomography based rat model. Method We developed computational fluid dynamics (CFD) software simulating the dynamic flow, temperature and drug distribution during oxaliplatin based HIPEC. The influence of location and number of catheters, flow alternations and flow rates on peritoneal temperature and drug distribution were determined. The software was validated using data from experimental rat HIPEC studies. Results The predicted core temperature and systemic oxaliplatin concentration were comparable to the values found in literature. Adequate placement of catheters, additional inflow catheters and higher flow rates reduced intraperitoneal temperature spatial variation by −1.4 °C, −2.3 °C and −1.2 °C, respectively. Flow alternations resulted in higher temperatures (up to +1.5 °C) over the peritoneal surface. Higher flow rates also reduced the spatial variation of chemotherapy concentration over the peritoneal surface resulting in a more homogeneous effective treatment dose. Conclusion The presented treatment planning software provides unique insights in the dynamics during HIPEC, which enables optimization of treatment-specific parameters and provides an excellent basis for HIPEC treatment planning in human applications.

Conservative management of rhabdomyosarcoma of uterine cervix: A case series

Background: Rhabdomyosarcoma (RMS) of the uterine cervix is a rare disease, usually affects pediatric and adolescent girls. Excellent treatment outcomes have been reported with combined modality treatment employing surgery, chemotherapy, and radiation therapy. Fertility-sparing treatment options can be considered in young patients without compromising outcome. Aim: This study aimed to analyze the outcome of patients with cervical RMS who were managed conservatively. Materials and Methods: We retrospectively reviewed the clinical and pathologic data of all patients with cervical RMS who were registered at our institution during 1995–2010. Long-term outcome data of patients who had conservative surgery were analyzed. Results: During this period, six patients with cervical RMS were registered. Five patients, managed conservatively, were eligible for analysis. The median age was 20 years (range: 14–21 years). Excessive vaginal discharge was the most common presenting symptom (n = 3). All patients initially had either a polypectomy (n = 4) or gross tumor resection (n = 1) followed by received chemotherapy with VAC regimen (Vincristine, Actinomycin-D and Cyclophosphamide). One patient received local radiation (HDR brachytherapy) for microscopic residual disease. All patients were disease-free at the completion of primary therapy. At a median follow-up of 10 years, four patients remain relapse-free; three, having retained fertility, had successful pregnancies and healthy children. One patient developed ovarian failure consequent to radiation treatment but remains disease free. One patient developed local recurrence, 8 years after primary treatment, and underwent salvage hysterectomy followed by second-line chemotherapy. This patient too remains disease-free, 3 years after salvage treatment. Conclusion: RMS of the uterine cervix is highly curable in early stages. The focus now is on improving the quality of life by reducing treatment-related morbidity and late effects. Fertility preservation approaches should be considered in young females with RMS of cervix.

Microscopic Peritoneal Residual Disease after Complete Macroscopic Cytoreductive Surgery for Advanced High Grade Serous Ovarian Cancer.

Background: Epithelial ovarian cancers (EOC) are usually diagnosed at an advanced stage and managed by complete macroscopic cytoreductive surgery (CRS) and systemic chemotherapy. Peritoneal recurrence occurs in 60% of patients and may be due to microscopic peritoneal metastases (mPM) which are neither eradicated by surgery nor controlled by systemic chemotherapy. The aim of this study was to assess and quantify the prevalence of residual mPM after complete macroscopic CRS in patients with advanced high-grade serous ovarian cancer (HGSOC). Methods: A prospective study conducted between 1 June 2018 and 10 July 2019 in a single referent center accredited by the European Society of Gynecological Oncology for advanced EOC management. Consecutive patients presenting with advanced HGSOC and eligible for complete macroscopic CRS were included. Up to 13 peritoneal biopsies were taken from macroscopically healthy peritoneum at the end of CRS and examined for the presence of mPM. A mathematical model was designed to determine the probability of presenting at least one mPM after CRS. Results: 26 patients were included and 26.9% presented mPM. There were no differences in characteristics between patients with or without identified mPM. After mathematical analysis, the probability that mPM remained after complete macroscopic CRS in patients with EOC was 98.14%. Conclusion: Microscopic PM is systematically present after complete macroscopic CRS for EOC and could be a relevant therapeutic target. Adjuvant locoregional strategies to conventional surgery may improve survival by achieving microscopic CRS.

Postoperative Radiotherapy for Cutaneous Squamous Cell Carcinoma in Patients With Microscopic Residual Disease

This case series assesses data from patients with microscopic residual disease to examine postoperative radiotherapy outcomes.

Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1–JNK axis

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

Narrative review on serous primary peritoneal carcinoma of unknown primary site: four questions to be answered.

Serous peritoneal papillary carcinoma (SPPC) represents a particular cancer of unknown primary (CUP) entity that arises in the peritoneal surface lining the abdomen and pelvis without a discriminative primary tumor site. In this review, we discuss the validity of SPPC as a distinct entity. Clinically, patients with SPPC are older, have higher parity and later menarche, are more often obese and probably have poorer survival compared to those with primary ovarian cancer. Pathologically, SPPC is more anaplastic and multifocal, unlike primary ovarian cancer which is commonly unifocal. Biologically, it presents a higher expression of proliferative signals and similar cell cycle and DNA repair protein expression. These differences hint towards SPPC and primary ovarian cancer being as a spectrum of disease. Patients with SPPC are traditionally managed similarly to stage III–IV ovarian cancer. The recommended approach integrates aggressive cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and systemic chemotherapy to remove the macroscopic tumor, eradicate the microscopic residual disease, and control the microscopic metastasis. However, the available evidence lacks proper randomized or prospective studies on SPPC and is limited to retrospective series. The diligent identification of SPPC is warranted to design specific clinical trials that eventually evaluate the impact of the new therapeutics on this distinct entity.

The Landmark Series: Chemotherapy for Non-Metastatic Colon Cancer.

Micrometastatic disease that is present at the time of surgery is responsible for the overwhelming majority of deaths in patients with what is otherwise perceived to be local and regional colon cancer. The goal of perioperative therapy is to eliminate microscopic residual disease that would otherwise be left behind following surgery. A secondary goal specific to neoadjuvant (preoperative) therapy is to downstage tumors deemed potentially not amenable to an R0 resection on the basis of a suspected T4b primary (locally invading into a surrounding structure). In this landmark series paper, we review the current standard for perioperative therapy in patients with colon cancer.

Positive histologic margins is a risk factor of recurrence after ileocaecal resection in Crohn’s disease

IntroductionSurgical resection is not curative in Crohn’s disease (CD) and, recurrence after surgery is a common situation. The identification of patients at high risk of recurrence remains disappointing in clinical practice. ObjectiveTo evaluate the impact of residual microscopic disease on margins on the risk of recurrence after ileocaecal resection in CD. Patients and methodsAll patients who underwent ileocaecal resection between January 1992 and December 2016 were prospectively identified. Demographic data, clinical, surgical and histological variables were retrospectively collected. Positive histologic margin was assessed prospectively and defined by the presence of acute inflammatory lesions on margins: erosion, ulceration, chorion infiltration by neutrophils, cryptic abscesses or cryptitis. ResultsOne hundred twenty five patients were included, with a median follow-up of 8 years (Interquartile Range (IQR), 4.3–15.2). Half (49.6%, n = 62) were women, and the median age at surgery was 33 years (IQR, 24–42). Fifty-six (44.8%) had positive inflammatory margins. Five years after surgery, respectively 29 (51%) and 23 (34%) patients with positive and negative margins had clinical recurrence (p = 0.034). At the end of the follow-up, respectively 60% (n = 34) and 47% (n = 33) patients had clinical recurrence (p = 0.07). CD-related hospitalizations were observed in respectively 37.5% (n = 21) and 18.8% (n = 13) with positive and negative margins (p = 0.02). Fourteen patients (25%) with positive intestinal margins had surgical recurrence at the end of the follow-up compared to 5 patients (7%) with negative margins (p = 0.04). Multivariate analysis confirmed that positive intestinal margin was independently associated with surgical recurrence (OR, 4.7 (CI95%, 1.4–15.3), p = 0.01). ConclusionPositive histologic margin was associated with an increased risk of clinical and surgical recurrence after ileocaecal resection for Crohn’s disease.

SURG-07. DETECTION OF GLIOMA INFILTRATION AT THE TUMOR MARGIN USING QUANTITATIVE STIMULATED RAMAN SCATTERING MICROSCOPY

Abstract BACKGROUND Differentiating neoplastic tumor tissues from normal brain at the infiltrative tumor margin remains challenging. Stimulated Raman scattering microscopy (SRM) is a rapid, label-free technique that provides microscopic imaging of unprocessed tissues. However, it has never been studied as a tool to enhance extent of resection. METHODS In this single center study, patients with WHO II-IV gliomas undergoing surgical resection were included. Margin samples were taken with corresponding stereotactic coordinates. Each tumor margin sample was analyzed using (1) H&amp;E, (2) SRM, and (3) immunohistochemical (IHC) stains for IDH1-R132H or p53. Specimens were imaged fresh with SRM, inked for orientation and placed in formalin for routine processing. Stained slides were scored by 3-neuro-pathologists using a semiquantitative 2-tiered scoring system for the presence or absence of residual tumor. SRM microscopy images were segmented into cellularity. The intraobserver measure of agreement between modalities for each pathologist was calculated using Cohen’s kappa. RESULTS A total of 31 patients and 179 margin specimens were acquired. Postoperative MRI confirmed that 169 (94%) of glioma margin sample coordinates were indeed at the tumor margins (10 of 179 were not true margins). All 10 samples which were not true margins were identified as having residual tumor by SRM. IHC semiquantitative scoring of margin specimen confirmed 72 of 128 samples (56%) had residual tumor. Similarly, H&amp;E-scoring confirmed 82 of 169 samples (49%) and 82 of 167 samples (49%) by SRM-scoring had residual tumor. Intraobserver agreements between all 3 modalities confirmed agreement: IHC-SRM was near perfect (K-0.84, CI-0.750-0.94); IHC-H&amp;E substantial, (K-0.67 CI-0.54-0.80); SRM-H&amp;E agreement substantial (K-0.72 CI-0.62-0.83). Margin samples with residual tumor demonstrated higher tissue cellularity when compared with samples without tumor (p&amp;lt; 0.0001). CONCLUSIONS SRM allows for identification of residual microscopic disease at the infiltrative tumor margin and therefore may be a promising tool to enhance extent of resection.