Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets.

AIMS: Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets. METHODS AND RESULTS: In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]. CONCLUSION: This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

Limited wedge resection for T1 colon cancer (LIMERIC-II trial) - rationale and study protocol of a prospective multicenter clinical trial.

BACKGROUND: The sole presence of deep submucosal invasion is shown to be associated with a limited risk of lymph node metastasis. This justifies a local excision of suspected deep submucosal invasive colon carcinomas (T1 CCs) as a first step treatment strategy. Recently Colonoscopy-Assisted Laparoscopic Wedge Resection (CAL-WR) has been shown to be able to resect pT1 CRCs with a high R0 resection rate, but the long term outcomes are lacking. The aim of this study is to evaluate the safety, effectiveness and long-term oncological outcomes of CAL-WR as primary treatment for patients with suspected superficial and also deeply-invasive T1 CCs. METHODS: In this prospective multicenter clinical trial, patients with a macroscopic and/or histologically suspected T1 CCs will receive CAL-WR as primary treatment in order to prevent unnecessary major surgery for low-risk T1 CCs. To make a CAL-WR technically feasible, the tumor may not include > 50% of the circumference and has to be localized at least 25 cm proximal from the anus. Also, there should be sufficient distance to the ileocecal valve to place a linear stapler. Before inclusion, all eligible patients will be assessed by an expert panel to confirm suspicion of T1 CC, estimate invasion depth and subsequent advise which local resection techniques are possible for removal of the lesion. The primary outcome of this study is the proportion of patients with pT1 CC that is curatively treated with CAL-WR only and in whom thus organ-preservation could be achieved. Secondary outcomes are 1) CAL-WR's technical success and R0 resection rate for T1 CC, 2) procedure-related morbidity and mortality, 3) 5-year overall and disease free survival, 4) 3-year metastasis free survival, 5) procedure-related costs and 6) impact on quality of life. A sample size of 143 patients was calculated. DISCUSSION: CAL-WR is a full-thickness local resection technique that could also be effective in removing pT1 colon cancer. With the lack of current endoscopic local resection techniques for > 15 mm pT1 CCs with deep submucosal invasion, CAL-WR could fill the gap between endoscopy and major oncologic surgery. The present study is the first to provide insight in the long-term oncological outcomes of CAL-WR. TRIAL REGISTRATION: CCMO register (ToetsingOnline), NL81497.075.22, protocol version 2.3 (October 2022).

Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.

BACKGROUND: Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. METHODS: A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. RESULTS: 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %-36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02-1.14, for every increase of 500 µm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95-4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10-1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75-0.86). CONCLUSIONS: A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice.

Metabolic positron emission tomography/CT response after induction chemotherapy and chemo(re)irradiation is associated with higher negative resection margin rate in patients with locally recurrent rectal cancer.

AIM: Positron emission tomography (PET)/CT can be used to monitor the metabolic changes that occur after intensified treatment with induction chemotherapy and chemo(re)irradiation for locally recurrent rectal cancer (LRRC). This study aimed to analyse the correlation between the PET/CT response and final histopathological outcomes. METHODS: All LRRC patients who underwent induction chemotherapy prior to surgery between January 2010 and July 2020 and were monitored with pretreatment and post-treatment PET/CT were included. Visual qualitative analysis was performed, and patients were scored as having achieved a complete metabolic response (CMR), partial metabolic response (PMR) or no response (NR). The histopathological response was assessed according to the Mandard tumour regression (TRG) score and categorized as major (TRG 1-2), partial (TRG 3) or poor (TRG 4-5). The PET/CT and TRG categories were compared, and possible confounders were analysed. RESULTS: A total of 106 patients were eligible for analysis; 24 (23%) had a CMR, 54 (51%) had a PMR and 28 (26%) had NR. PET/CT response was a significant predictor of the negative resection margin rate, achieving 96% for CMR, 69% for PMR and 50% for NR. The overall accuracy between PET score and pathological TRG was 45%, and the positive predictive value for CMR was 63%. A longer interval between post-treatment PET/CT and surgery negatively influenced the predictive value. CONCLUSION: Metabolic PET/CT response evaluation after neoadjuvant treatment proves to be a complementary diagnostic tool to standard MRI in assessing tumour response, and may play a role for treatment planning in LRRC patients.

Active Surveillance Versus Immediate Surgery in Clinically Complete Responders After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Multicenter Propensity Matched Study.

OBJECTIVE: This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery. BACKGROUND: Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate. METHODS: Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes. RESULTS: Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14-1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44-2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively). CONCLUSION: In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.

Clinicopathological characteristics predict lymph node metastases in ypT0-2 rectal cancer after chemoradiotherapy.

AIMS: Changes in rectal cancer treatment include increasing emphasis on organ preservation. Local excision after chemoradiotherapy (CRT) for rectal cancer with excellent clinical response reduces morbidity and mortality compared to total mesorectal excision, although residual lymph node metastases (LNM) may cause local recurrence. Our aim is to identify clinicopathological factors predicting the presence of residual LNM in rectal cancer patients with ypT0-2 tumours after neoadjuvant CRT. These risk factors may help to select patients who can be spared radical surgery without compromising oncological outcomes. METHODS AND RESULTS: Rectal cancer patients with ypT0-2 tumours after CRT and radical resection from five centres treated between June 1999 and February 2012 were included. Histopathology was reviewed extensively. Clinicopathological characteristics and their association with residual LNM were investigated. Of 657 consecutive CRT-treated rectal cancer patients 210 with ypT0-2 disease were included. Residual nodal disease was found in 44 cases (21.0%). Independent predictors of LNM were clinical nodal involvement (cN+ ) [odds ratio (OR): 2.79, 95% confidence interval (CI): 1.04-7.48, P = 0.042], high-grade histopathology assessed in the post-CRT resection specimen (OR: 6.46, 95% CI: 1.23-34.02, P = 0.028) and residual tumour diameter (RTD) ≥10 mm (OR: 2.54, 95% CI: 1.06-6.09, P = 0.036). An algorithm combining these factors stratified patients adequately according to LNM risk, independently of ypT category. CONCLUSIONS: Clinical nodal involvement, high-grade histopathology and RTD ≥10 mm are strong and independent predictors of residual nodal disease in rectal cancer patients with ypT0-2 tumours after CRT. Risk stratification based on these factors may help to identify patients suitable for organ preserving therapy and should be validated in appropriately selected populations.

Circumferential balloon-based radiofrequency ablation of Barrett's esophagus with dysplasia can be simplified, yet efficacy maintained, by omitting the cleaning phase.

BACKGROUND & AIMS: The current procedure for circumferential balloon-based radiofrequency ablation (c-RFA) for the removal of dysplastic Barrett's esophagus (BE) is labor intensive, comprising 2 ablation passes with a cleaning step to remove debris from the ablation zone and electrode. We compared the safety and efficacy of 3 different c-RFA ablation regimens. METHODS: We performed a prospective trial of consecutive patients with flat-type BE with high-grade dysplasia. Fifty-seven patients (45 men; age, 64 ± 15 y; 28 with prior endoscopic resection) were assigned randomly to groups that underwent c-RFA with a double application of RFA (12 J/cm(2)). The standard group received c-RFA, with device removal and cleaning, followed by c-RFA; the simple-with-cleaning group underwent c-RFA, with device cleaning without removal, followed by c-RFA; and the simple-no-cleaning group received 2 applications of c-RFA, and the device was not removed or cleaned. The primary outcome was surface regression of BE 3 months later, graded by 2 blinded expert endoscopists. Calculated sample size was 57 patients, based on a noninferiority design. RESULTS: Median BE surface regression at 3 months was 83% in the standard group, 78% in the simple-with-cleaning group, and 88% in the simple-no-cleaning group (P = .14). RF ablation time was 20 minutes (interquartile range [IQR], 18-25 min) for the standard group, 13 minutes (IQR, 11-15 min) for the simple-with-cleaning group, and 5 minutes (IQR, 5-9 min) for the simple-no-cleaning group (P < .01). The median number of introductions (RFA devices/endoscope) for the standard group was 7, vs 4 for the simple groups (P < .01). CONCLUSIONS: This randomized, prospective study suggests that c-RFA is easier and faster, but equally safe and effective, when the cleaning phase between ablations is omitted or simplified. Trialregister.nl, NTR 2495.

Focus on extralevator perineal dissection in supine position for low rectal cancer has led to better quality of surgery and oncologic outcome.

BACKGROUND: After abdominoperineal excision (APE), the presence of tumor cells in the circumferential resection margin (R1) and iatrogenic tumor perforations are still frequent and result in an increased rate of local recurrences. In this study, a standardized supine APE with an increased focus on the perineal dissection (sPPD) is compared to the customary supine APE. METHODS: From 2000 to 2010, a total of 246 patients underwent APE for rectal cancer (sPPD and customary supine APE). All patients were staged with preoperative magnetic resonance imaging (MRI) and received neoadjuvant treatment (n = 203) when margins were involved or threatened (cT3 + and T4). As a result of a quality improvement program in 2006, the surgical technique was modified: it became standardized, emphasis was placed on the perineal dissection, and pelvic dissection was limited to avoid false routes when following the total mesorectal excision planes deep into the pelvis. RESULTS: Overall, the percentage of involved circumferential resection margins (CRMs) was 10%. In the period before introducing sPPD, the R1 percentages for cT0-3 and cT4 tumors were 6.8 and 30.2%, compared to 2.2 and 5.7% after introduction of sPPD (P = 0.001). Risk factors for R1 resection were preoperative T4 tumors (14.9%, P = 0.011), tumor perforation (33.3%, P = 0.002), fistulating tumors (35.7%, P = 0.002), mucus-producing tumors (23.1%, P = 0.006), or bulky tumors (66.7%, P < 0.001). CONCLUSIONS: The objective of surgical treatment of low rectal cancer is to obtain negative resection margins and subsequently reduce the risk of local recurrence. A combination of the appropriate preoperative treatment and standardized surgical technique such as sPPD can achieve this goal.

T3+ and T4 rectal cancer patients seem to benefit from the addition of oxaliplatin to the neoadjuvant chemoradiation regimen.

BACKGROUND: To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters. METHODS: Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics. RESULTS: The data of 504 consecutive patients (n = 181 T3+, n = 323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P < .0001) when compared with the CORE scheme. Odds ratios for a R1 resection (3.74, 1.94, 1.14; P = .003) or CRM+ resection (3.78, 2.73, 1.34; P = .001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme. CONCLUSIONS: Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion.

Impact of ≥ 0.1-mm free resection margins on local intramural residual cancer after local excision of T1 colorectal cancer.

Background and study aims A free resection margin (FRM) > 1 mm after local excision of a T1 colorectal cancer (CRC) is known to be associated with a low risk of local intramural residual cancer (LIRC). The risk is unclear, however, for FRMs between 0.1 to 1 mm. This study evaluated the risk of LIRC after local excision of T1 CRC with FRMs between 0.1 and 1 mm in the absence of lymphovascular invasion (LVI), poor differentiation and high-grade tumor budding (Bd2-3). Patients and methods Data from all consecutive patients with local excision of T1 CRC between 2014 and 2017 were collected from 11 hospitals. Patients with a FRM ≥ 0.1 mm without LVI and poor differentiation were included. The main outcome was risk of LIRC (composite of residual cancer in the local excision scar in adjuvant resection specimens or local recurrence during follow-up). Tumor budding was also assessed for cases with a FRM between 0.1 and 1mm. Results A total of 171 patients with a FRM between 0.1 and 1 mm and 351 patients with a FRM > 1 mm were included. LIRC occurred in five patients (2.9 %; 95 % confidence interval [CI] 1.0-6.7 %) and two patients (0.6 %; 95 % CI 0.1-2.1 %), respectively. Assessment of tumor budding showed Bd2-3 in 80 % of cases with LIRC and in 16 % of control cases. Accordingly, in patients with a FRM between 0.1 and 1 mm without Bd2-3, LIRC was detected in one patient (0.8%; 95 % CI 0.1-4.4 %). Conclusions In this study, risks of LIRC were comparable for FRMs between 0.1 and 1 mm and > 1 mm in the absence of other histological risk factors.

Prognostic Implications of MRI-Detected EMVI and Tumor Deposits and Their Response to Neoadjuvant Therapy in cT3 and cT4 Rectal Cancer.

PURPOSE: Magnetic resonance imaging-detected extramural venous invasion (mrEMVI) and tumor deposits (TDs) are risk factors for the development of local recurrence and distant metastases (DMs) in rectal cancer. However, little is known about their response to neoadjuvant treatment and its relation to oncologic outcomes. This study evaluated the incidence and features of mrEMVI and TDs before and after neoadjuvant treatment in relation to the development of local recurrence and DMs. METHODS AND MATERIALS: Patients with cT3/4 rectal cancer without synchronous metastases who underwent surgery in a tertiary referral hospital were retrospectively analyzed. MRI scans were re-evaluated for the presence of mrEMVI, the occurrence of TDs, and response to neoadjuvant therapy (mr-vTRG). RESULTS: In total, 277 patients were included, of whom 163 (58.8%) presented with mrEMVI. TDs were present in 56.4% of mrEMVI-positive and 9.6% of mrEMVI-negative patients (P < .001). The 5-year DM rate was significantly higher in mrEMVI-positive patients with and without TDs (45.2% and 35.9%, respectively) compared with mrEMVI-negative patients (25.7%; P = .012). After neoadjuvant treatment, the 5-year DM rate of patients with mr-vTRG 3-5 was 46.1%, whereas good responders (mr-vTRG 1-2) had a DM rate similar to mrEMVI-negative patients (25.7% and 25.7%, respectively; P = .002). The occurrence of TDs and larger mrEMVI size resulted in a lower likelihood of regression of mrEMVI. CONCLUSIONS: The prevalence of mrEMVI and TDs in cT3-4 rectal cancer is high and is associated with worsened oncologic outcomes. mrEMVI regression (mr-vTRG 1-2), which occured in 25% of the cases, leads to oncologic outcomes similar to those in patients without mrEMVI on baseline MRI.

Performance of gastrointestinal pathologists within a national digital review panel for Barrett's oesophagus in the Netherlands: results of 80 prospective biopsy reviews.

AIMS: The histopathological diagnosis of low-grade dysplasia (LGD) in Barrett's oesophagus (BO) is associated with poor interobserver agreement and guidelines dictate expert review. To facilitate nationwide expert review in the Netherlands, a web-based digital review panel has been set up, which currently consists of eight 'core' pathologists. The aim of this study was to evaluate if other pathologists from the Dutch BO expert centres qualify for the expert panel by assessing their performance in 80 consecutive LGD reviews submitted to the panel. METHODS: Pathologists independently assessed digital slides in two phases. Both phases consisted of 40 cases, with a group discussion after phase I. For all cases, a previous consensus diagnosis made by five core pathologists was available, which was used as reference. The following criteria were used: (1) percentage of 'indefinite for dysplasia' diagnoses, (2) percentage agreement with consensus diagnosis and (3) proportion of cases with a consensus diagnosis of dysplasia underdiagnosed as non-dysplastic. Benchmarks were based on scores of the core pathologists. RESULTS: After phase I, 1/7 pathologists met the benchmark score for all quality criteria, yet three pathologists only marginally failed the agreement with consensus diagnosis (score 68.3%, benchmark 69%). After a group discussion and phase II, 5/6 remaining aspirant panel members qualified with all scores within the benchmark range. CONCLUSIONS: The Dutch BO review panel now consists of 14 pathologists, who-after structured assessments and group discussions-can be considered homogeneous in their review of biopsies with LGD.

Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma.

AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow-up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2-3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy-eight patients had metastases. The risk of metastases was increased for tumors with 2-3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10-5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37-6.10). The prediction model demonstrated a good discriminative ability (c-statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice.

Multiple carcinomas in the hemodialysis access induced ischemic hand of a renal transplant patient.

Long term immunosuppression following organ transplantation promotes the onset of skin cancers. A renal transplant patient developed multiple hyperkeratotic nodi in the left hand and digital pain following prolonged immunosuppression. Several skin abnormalities were observed in an ischemic and atrophic left hand in the presence of a patent Cimino-Brescia arteriovenous fistula previously used for hemodialysis. Severe hand ischemia was confirmed by digital plethysmography. Pathological examination of all 7 excised skin lesions indicated manifestations of well differentiated squamous cell carcinomas (SCC). Severe loco-regional ischemia due to an intact hemodialysis access may enhance the toxic effects of chronic immunosuppressive medication. Oxidative stress may act as a co-carcinogenic factor for the development of SCC in renal transplant patients receiving immunosuppressive agents.

Interobserver, intraobserver, and interlaboratory variability in reporting pT4a colon cancer.

Clinical significance of the pT4 category in colon cancer is increasing with several therapeutic implications. The aim of this study was to evaluate variability in diagnosing pT4a colon cancer. Twelve pathologists classified 66 preselected scanned Hematoxylin/Eosin-stained slides with tumor cells at a distance of 25-1500 µm (n = 22), 0-25 µm (n = 22), or on (n = 22) the peritoneal surface. Inter- and intraobserver variability were calculated using Kappa statistics. For interlaboratory variability, pathology reports of pT3 and pT4a colon cancer were extracted from the Dutch Pathology Registry between 2012 and 2015. The proportion of pT4a (pT4a/(pT3+pT4a)) was compared between 33 laboratories. Potential risk of understaging was assessed by determining the average number of blocks taken from pT3 and pT4a N0-2M0 tumors with metachronous peritoneal metastasis. Interobserver variability among 12 pathologists was 0.50 (95%CI 0.41-0.60; moderate agreement). Intraobserver variability (8 pathologists) was 0.71 (substantial agreement). A total of 7745 reports with pT3 or pT4aN0-2M0 colon cancer from 33 laboratories were included for interlaboratory analysis. Median percentage of pT4a was 15.5% (range 3.2-24.6%). After adjustment for case mix, 8 labs diagnosed pT4a significantly less or more frequently than the median lab. Metachronous peritoneal metastases were histologically verified in 170 of 6629 pT3 and in 129 of 1116 pT4a tumors, with a mean number of blocks of 4.03(SD 1.51) and 4.78 (SD 1.76) taken from the primary tumors, respectively (p < 0.001). A substantial variability in diagnosing pT4a colon cancer exists, both at pathologist and laboratory level. Diagnosis of pT4a stage appears to be challenging and there is a need for standardizing assessment of this pathological entity.

Safety and effectiveness of SGM-101, a fluorescent antibody targeting carcinoembryonic antigen, for intraoperative detection of colorectal cancer: a dose-escalation pilot study.

BACKGROUND: Tumour-targeted fluorescence imaging has the potential to advance current practice of oncological surgery by selectively highlighting malignant tissue during surgery. Carcinoembryonic antigen (CEA) is overexpressed in 90% of colorectal cancers and is a promising target for colorectal cancer imaging. We aimed to assess the tolerability of SGM-101, a fluorescent anti-CEA monoclonal antibody, and to investigate the feasibility to detect colorectal cancer with intraoperative fluorescence imaging. METHODS: We did an open-label, pilot study in two medical centres in the Netherlands. In the dose-escalation cohort, we included patients (aged ≥18 years) with primary colorectal cancer with increased serum CEA concentrations (upper limit of normal of ≥3 ng/mL) since diagnosis, who were scheduled for open or laparoscopic tumour resection. In the expansion cohort, we included patients (aged ≥18 years) with recurrent or peritoneal metastases of colorectal cancer, with increasing serum concentrations of CEA since diagnosis, who were scheduled for open surgical resection. We did not mask patients, investigators, or anyone from the health-care team. We assigned patients using a 3 + 3 dose design to 5 mg, 7·5 mg, or 10 mg of SGM-101 in the dose-escalation cohort. In the expansion cohort, patients received a dose that was considered optimal at that moment of the study but not higher than the dose used in the dose-escalation cohort. SGM-101 was administered intravenously for 30 min to patients 2 or 4 days before surgery. Intraoperative imaging was done to identify near-infrared fluorescent lesions, which were resected and assessed for fluorescence. The primary outcome was tolerability and safety of SGM-101, assessed before administration and continued up to 12 h after dosing, on the day of surgery, the first postoperative day, and follow-up visits at the day of discharge and the first outpatient clinic visit. Secondary outcomes were effectiveness of SGM-101 for detection of colorectal cancer, assessed by tumour-to-background ratios (TBR); concordance between fluorescent signal and tumour status of resected tissue; and diagnostic accuracy in both cohorts. This trial is registered with the Nederlands Trial Register, number NTR5673, and ClinicalTrials.gov, number NCT02973672. FINDINGS: Between January, 2016, and February, 2017, 26 patients (nine in the dose-escalation cohort and 17 in the expansion cohort) were included in this study. SGM-101 did not cause any treatment-related adverse events, although three possibly related mild adverse events were reported in three (33%) of nine patients in the dose-escalation cohort and five were reported in three (18%) of 17 patients in the expansion cohort. Five moderate adverse events were reported in three (18%) patients in the expansion cohort, but they were deemed unrelated to SGM-101. No changes in vital signs, electrocardiogram, or laboratory results were found after administration of the maximum dose of 10 mg of SGM-101 in both cohorts. A dose of 10 mg, administered 4 days before surgery, showed the highest TBR (mean TBR 6·10 [SD 0·42] in the dose-escalation cohort). In the expansion cohort, 19 (43%) of 43 lesions were detected using fluorescence imaging and were not clinically suspected before fluorescent detection, which changed the treatment strategy in six (35%) of 17 patients. Sensitivity was 98%, specificity was 62%, and accuracy of fluorescence intensity was 84% in the expansion cohort. INTERPRETATION: This study presents the first clinical use of CEA-targeted detection of colorectal cancer and shows that SGM-101 is safe and can influence clinical decision making during the surgical procedure for patients with colorectal cancer. FUNDING: Surgimab.

Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement.

CONTEXT: -The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. OBJECTIVE: -To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. DATA SOURCES: -Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. CONCLUSIONS: -The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.