Vy9V82 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing... Show moreVy9V82 T cells are effector cells with proven antitumor efficacy against a broad range of cancers. This study aimed to assess the antitumor activity and safety of a bispecific antibody directing Vy9V82 T cells to EGFR-expressing tumors. An EGFR-V82 bispecific T-cell engager (bsTCE) was generated, and its capacity to activate Vy9V82 T cells and trigger antitumor activity was tested in multiple in vitro, in vivo, and ex vivo models. Studies to explore safety were conducted using cross-reactive surrogate engagers in nonhuman primates (NHP). We found that Vy9V82 T cells from peripheral blood and tumor specimens of patients with EGFR thorn cancers had a distinct immune checkpoint expres-sion profile characterized by low levels of PD-1, LAG-3, and TIM-3. Vy9V82 T cells could be activated by EGFR-V82 bsTCEs to mediate lysis of various EGFR thorn patient-derived tumor samples,and substantial tumor growth inhibition and improved survival were observed in in vivo xenograft mouse models using peripheral blood mononuclear cells (PBMC) as effector cells. EGFR-V82 bsTCEs exerted preferential activity toward EGFR thorn tumor cells and induced downstream activation of CD4 thorn and CD8 thorn T cells and natural killer (NK) cells without concomitant activation of suppressive regulatory T cells observed with EGFR-CD3 bsTCEs. Administration of fully cross-reactive and half-life extended surrogate engagers to NHPs did not trigger signals in the safety parameters that were assessed. Considering the effector and immune-activating properties of Vy9V82 T cells, the preclinical efficacy data and acceptable safety profile reported here provide a solid basis for testing EGFR-V82 bsTCEs in patients with EGFR thorn malignancies. Show less
Background. Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of... Show moreBackground. Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level.Methods. Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (=7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those undergoing only rectal resection.Results. Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874).Conclusion. Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research. Show less
Background Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal... Show moreBackground Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC). Methods Using gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort (n = 20). Results ADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 [95% CI 1.11-1.96], P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 [95% CI 1.06-3.00], P = 0.030) and mesenchymal subtype tumors (HR 2.12 [95% CI 1.25-3.60], P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers. Conclusions Here we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum. Show less
Background In the recent years two innovative approaches have become available for minimally invasiveen blocresections of large non-pedunculated rectal lesions (polyps and early cancers). One is... Show moreBackground In the recent years two innovative approaches have become available for minimally invasiveen blocresections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. Methods Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. Discussion This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for theen blocresection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. Show less
Background: Although self-expandable metal stent (SEMS) placement as bridge to surgery (BTS) in patients with left-sided obstructing colonic cancer has shown promising short-term results, it is... Show moreBackground: Although self-expandable metal stent (SEMS) placement as bridge to surgery (BTS) in patients with left-sided obstructing colonic cancer has shown promising short-term results, it is used infrequently owing to uncertainty about its oncological safety. This population study compared long-term oncological outcomes between emergency resection and SEMS placement as BTS.Methods: Through a national collaborative research project, long-term outcome data were collected for all patients who underwent resection for left-sided obstructing colonic cancer between 2009 and 2016 in 75 Dutch hospitals. Patients were identified from the Dutch Colorectal Audit database. SEMS as BTS was compared with emergency resection in the curative setting after 1: 2 propensity score matching.Results: Some 222 patients who had a stent placed were matched to 444 who underwent emergency resection. The overall SEMS-related perforation rate was 7.7 per cent (17 of 222). Three-year locoregional recurrence rates after SEMS insertion and emergency resection were 11-4 and 13.6 per cent (P= 0-457), disease-free survival rates were 58-8 and 52.6 per cent (P= 0-175), and overall survival rates were 74-0 and 68-3 per cent (P= 0.231), respectively. SEMS placement resulted in significantly fewer permanent stomas (23.9 versus 45.3 per cent; P < 0-001), especially in elderly patients (29.0 versus 57.9 per cent; P < 0-001). For patients in the SEMS group with or without perforation, 3-year locoregional recurrence rates were 18 and 11.0 per cent (P= 0.432), disease-free survival rates were 49 and 59.6 per cent (P= 0-717), and overall survival rates 61 and 75.1 per cent (P= 0.529), respectively.Conclusion: Overall, SEMS as BTS seems an oncologically safe alternative to emergency resection with fewer permanent stomas. Nevertheless, the risk of SEMS-related perforation, as well as permanent stoma, might influence shared decision-making for individual patients. Show less