There is a strong rationale to combine radiotherapy with immune checkpoint inhibitors (ICIs). This study evaluates this combination before surgery in locally advanced rectal cancer (LARC). R-IMMUNE, a multicentric phase Ib/II trial, included patients with stage II/III LARC treated with a preoperative combination of radio-chemotherapy (45-50 Gy/25 fractions, 5FU 225 mg/m2/d, 5d/w from week 1 to 5) + atezolizumab 1200 mg/infusion (ATZ). The phase Ib evaluated a single infusion of ATZ at week 3. Phase II evaluated 4 infusions of ATZ at weeks 3, 6, 9 and 12. Surgery was planned for week 15. Safety and efficacy based on the pathological complete response (pCR) rate are primary objectives. Based on a two-stage Simon design, 33 patients (+3 for the replacement of non-evaluable patients) were required in phase II to detect an increase in pCR rate from 15% to 35% (α = 0.1, β = 0.1), with at least 8 pCRs to reject the null hypothesis. Six patients were included in phase Ib and 34 in phase II. This analysis covered 39 patients (median age 63 years, 56% male, 82% stage III, 12% MSI-H), excluding 1 phase II patient who is still undergoing treatment. A total of 193 adverse events (AEs) were reported, of which 29 (15%) were grade 3-4 and involved 19/39 (49%) of patients. Among gade 3-4 AEs, most frequent were urinary tract infections (6/29), blood disorders (5/29), post-operative anastomotic leaks/infections (4/29) and gastrointestinal disorders (4/29). Five patients presented immune-related AEs: 1 immune thrombocytopenia (grade 4), 2 endocrine disorders (grade 2) and 2 skin disorders (grade 1). So far, efficacy was assessed in 6 phase Ib patients and in 31 patients from the phase II (2 were excluded for protocol deviation). Respectively, 2/6 and 8/31 patients had a pCR. Overall, 10/37 (27%) patients had a pCR (including 2 MSI-H). An analysis of the nearly complete R-immune cohort confirmed an acceptable safety profile and met study efficacy objectives. The results warrant further investigations of ICIs combined with radiotherapy in LARC eventually within a total neoadjuvant treatment and organ preservation based strategies.

Cetuximab could mediate, independently from RAS mutation, an immunogenic tumor cell death and antitumor immune response. This trial explores the efficacy and safety of AVE, CET and IRI for the treatment of refractory MSS mCRC. Chemo-refractory (+anti-EGFR refractory if RAS wt) MSS, mCRC patients (pts) were enrolled in 3 cohorts (A: RAS wt, B & C: RAS mut) and treated with CET (500 mg/m2/Q2W), IRI (150 mg/m2/Q2W) and AVE (10 mg/kg/Q2W). Primary endpoints were safety, overall response rate (ORR) (cohorts A-B) and 6 months progression-free survival rate (6m-PFSR) (cohort C). Secondary and exploratory endpoints included disease control rate (DCR), PFS, OS and immunoscore (IS) biomarker. Based on a Simon 2-stage design (α=0.1; β=0.2) for ORR (cohorts A: P0/P1=0.15/0.33 – B: P0/P1=0.09/0.25) and 6m-PFSR (cohort C: P0/P1=0.15/0.31), 10+18 (A); 13+15 (B) and 14+25 (C) pts were needed. At least 2+5 (A); 2+3 (B) and 3+6 (C) pts must reach ORR (A-B) or 6m-PFSR (C) for efficacy objectives. Immunofluorescence (CD3, CD8 densities) was performed on baseline metastasis biopsies to generate IS. 57 pts (median 62 yrs, 73.7% male, 84.2% left-sided, 86.0% synchr. mCRC) were included and 55 pts treated. Any treatment-emergent adverse event (AE) grade >=3 occurred in 35 pts (63.6%; diarrhea in 11 pts, 20.0%). Immune-related AEs grade >=3 appeared in 2 pts (3.6%; 1 acute kidney injury, 1 cholangitis). Efficacy results are summarized. Table: 635PCharacteristicsCohort A (n=28)Cohort B (n=13)Cohort C (n=14)ORR, % (pts)21.4% (6/28)0.0% (0/13)0.0% (0/14)DCR, % (pts)50.0% (14/28)61.5% (8/13)42.9% (6/14)6m-PFSR, % (pts)25.0% (7/28)38.5% (5/13)7.1% (1/14)Median PFS, months (95%CI)3.6 (2.5-5.6)3.7 (2.7-6.4)2.8 (2.4-3.8)Median OS, months (95%CI)11.4 (5.3-15.6)10.1 (6.0-22.8)6.8 (5.3-9.7) Open table in a new tab Independently of RAS mutation, high IS was associated with greater tumor shrinkage (OR=8.3, p<0.01), DCR (OR=8.0, p=0.05), PFS (median 7.1 vs 3.1 months; HR=0.29, p<0.01) and OS (median 12.9 vs 7.2 months; HR=0.62, p=0.19). Despite good tolerability, AVETUXIRI trial did not reach its efficacy endpoint. IS could be a predictive biomarker for selecting patients with potential treatment benefits.

This trial explores the clinical efficacy and safety of AVE, CET and IRI for treatment refractory MSS mCRC. We aim at characterizing the immune response for biomarker discovery through associated translational research. MSS, chemorefractory (anti-EGFR refractory if RAS wt) mCRC patients (pts) were enrolled (RAS wt: 28 pts, RAS mut: 27 pts) and treated with CET and IRI from week 1(W1) and AVE from W3. Clinical objectives (safety, tumor response, disease control rate (DCR), PFS and OS) were presented separately. Exploratory endpoints include predictive efficacy biomarkers (immunoscore (IS), immune tumor microenvironment, gene expression profile (GEP), ctDNA) and modification overtime. Multiplex immunofluorescence (MIF), RNAseq and ctDNA analyses were done (sequential metastasis biopsies and plasma samples at W0, W3, W11). CD3, CD8, CD45RO, PD1, PD-L1cells densities were quantified. RNA-seq data were used to perform several analyses (DESeq2, GSEA, deconvolution, gene ontology). OncoSELECT panel (58 genes) was used to follow ctDNA variation over time (mean variant allele frequency). Among 55 treated pts, 95 biopsies (W0: 39, W3: 29, W11: 27) were available for MIF (table: W0 results). On 23 pts (1st stage), upregulation of adaptive immune response signature was associated with tumor shrinkage, PFS>6 and OS>12 months (p. adj= 0.00). Few modifications of immune cells and GEP were observed overtime (W0, W3, W11). ctDNA decrease (>10%) was associated with tumor response (p=0.04) and PFS (6.6 vs 3.4 months, p=0.08).Table: 2237PCharacteristicsIS (CD3/CD8) highCD3/PD1 highCD3/CD8/CD45RO/PD1 highHigh/others:pts10/2910/298/31RAS-wt/RAS-mut:OR, p-v1.39, p=0.730.82, p=0.990.83, p=0.99Tumor shrinkage: OR, p-v8.32, p=0.004.50, p=0.059.54, p=0.00DCR:OR, p-v8.02, p=0.053.16, p=0.265.55, p=0.12PFS:HR, p-v0.29, p=0.000.28, p=0.000.43, p=0.03OS:HR, p-v0.62, p=0.190.26, p=0.000.47, p=0.06 Open table in a new tab Independently of RAS mutation, existing adaptive immune response within metastases is associated with treatment benefit. ctDNA decrease is associated with tumor response.

Background and study aims: Neuroendocrine neoplasms (NENs) are relatively rare, with marked clinical and biological heterogeneity. Consequently, many controversial areas remain in diagnosis and optimal treatment stratification for NEN patients. We wanted to describe current clinical practice regarding controversial NEN topics and stimulate critical thinking and mutual learning among a Belgian multidisciplinary expert panel Patients and methods: A 3-round, Delphi method based project, coordinated by a steering committee (SC), was applied to a predefined multidisciplinary NEN expert panel studying the following controversial topics : factors guiding therapeutic decision making, the use of somatostatin analogues (SSA) in adjuvant setting, the interference between non-radioactive and radioactive SSAs, challenging small intestine neuroendocrine tumor (NET) cases, the approach of the carcinoid syndrome, the role of chemotherapy in well differentiated NET, the relevance of NET G3 and neuroendocrine carcinoma subclassification and the role of imaging techniques in NEN management. Results: A high level of consensus exists regarding the necessary diagnostic work-up, use of imaging techniques and interference between non-radioactive and radioactive SSAs. However, the prognostic impact of tumor functionality might be overrated and adequate diarrhea differential diagnostic work-up in these patients is underused. Significant differences are seen between individual experts and centers regarding treatment preferences both on the treatment modality level, as well as the choice of specific drugs (e.g. chemotherapy regimen). Conclusions: A Delphi-like multi-round expert discussion proves useful to boost critical thinking and discussion among experts of different background, as well as to describe current clinical practice and stimulate mutual learning in the absence of high-level scientific guidance.

Pathological response (PR) of resected CRCM after preop treatment is a recognized prognostic factor. Retrospective studies reported that BEV + oxaliplatin-based chemotherapy increased PR compared to irinotecan-based chemotherapy. In this trial, we aim to demonstrate that preop BEV + FOLFOX would increase PR. BEV-ONCO (NCT01858649) is a multicenter prospective randomized (1/1) phase II trial evaluating PR on resected CRCM after 3 to max 6 cycles of mFOLFOX (ARM A) or FOLFIRI (ARM B) + BEV (5mg/kg/2 weeks). Primary endpoint is the major pathological response rate (MPRR) defined as the % of patients presenting CRCMs with a mean tumor regression grade (TRG) <3. Secondary endpoints include DFS, OS, safety, complete PR, R0 resection rate and liver toxicity comprising sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH). 54 pts (27 per arm) are needed to detect a difference (alpha=0.05; beta=0.2) of MPRR proportion of 0.40 between treatment arms (two-sided Fisher's Exact test). Among 65 pts included between 06/2013 and 09/2018, 57 pts (28 ARM A / 29 ARM B) have had CRCM resection. Clinical and treatment characteristics were similar in both treatment arms (median age 60 y-old, 51% male, 33% RAS wt, 98% liver CRCM, 75% synchronous, median 2 CRCM/pt, median of 4 chemo cycles and 3 BEV cycles). 11/28 pts presented 1-month postop surgical complications in ARM A (39%, grade 3-4: 17.9%) and 9/29 pts in ARM B (31%, grade 3-4: 6.9%, p=0.58). MPRR was 32% in ARM A and 21% in ARM B (p=0.38). 4 pts presented complete PR (ARM A/B: 14%/0%, p=0.05). No difference between treatment arms was observed for R0 resection (ARM A/B: 89%/93%, p=0.80), SOS (ARM A/B: 54%/38%, p=0.50), NRH (ARM A/B: 21%/17%, p=0.75), DFS (ARM A/B: HR=1.14, 95%CI:0.58-2.21, p=0.71) and OS (ARM A/B: HR=1.38, 95%CI:0.48-4.00, p=0.55). Pts with PR among all CRCM (Max TRG≤3; 44% of pts) had a lower risk of relapse/death (DFS: HR=0.41, 95%CI=0.20-0.82, p=0.01) and death (OS: HR=0.34, 95%CI=0.10-1.11, p=0.07). This trial fails to demonstrate any significant difference of PR between BEV with FOLFOX or FOLFIRI but confirms PR as a prognostic factor.

BACKGROUND:Tumor lysis syndrome is a rare and potentially fatal complication of oncologic treatments, especially in solid tumors. To the best of our knowledge, tumor lysis syndrome has never been reported after trastuzumab and pertuzumab combination therapy. Knowledge of risk factors and active prevention proceedings is of utmost importance to avoid fatal outcomes.CASE PRESENTATION:We present the case of a chemo-naive 58-year-old Belgian woman developing hypovolemic shock and multiple organ failure due to tumor lysis syndrome after a single dose of trastuzumab and pertuzumab in the context of the treatment of a metastatic breast cancer and resulting in fatal outcome despite optimal management.CONCLUSIONS:Considering that targeted cancer therapies become increasingly effective, oncologists should be extremely cautious when treating patients at high risk of tumor lysis syndrome, even if they are not treated with cytotoxic chemotherapy, and determine appropriate prophylaxis.

Liver metastases in colorectal cancer patients decreases the expected 5 year survival rates by a factor close to nine. It is generally accepted that resection of liver metastases should be attempted whenever feasible. This manuscript addresses the optimal therapeutic plan regarding timing of resection of synchronous liver metastases and the use of chemotherapy in combination with resection of synchronous metachronous liver metastases. The aim is to pool all published results in order to attribute a level of evidence to outcomes and identify lacking evidence areas. A systematic search of guidelines, reviews, randomised controlled, observational studies and updating a meta-analysis was performed. Data were extracted and analysed. Data failed to demonstrate an effect of timing of surgery or use of chemotherapy on overall survival. Concomitant resection of liver metastases and the primary tumour may result in lower postoperative morbidity. Systemic peri-operative chemotherapy may improve progression free survival compared to surgery alone.

Background Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure and is an important supportive treatment for patients with advanced head and neck cancer. Although tumor seeding has been reported in various sites, seeding at the PEG exit site is a rare complication. Methods and Results We describe a clinical case in which squamous cell carcinoma of the hypopharynx implanted at the site of PEG insertion and was successfully removed by surgery. PEG was previously placed by the pull technique. A review of the literature, discussion of the mechanism of spread, and recommendations to avoid this complication are discussed. Conclusions To avoid this rare and poor prognostic complication, the pull technique should be avoided for PEG placement in any patient with head and neck squamous cell carcinoma. An alternative method such as the push technique should be preferred. (c) 2012 Wiley Periodicals, Inc. Head Neck, 2013

The diffuse infiltration by plasma cells in the liver is not uncommon in multiple myeloma (MM). However, a MM with hepatic mass is very unusual. We report a case of a 75-year-old male with hepatomegaly and a lesion occupying a voluminous space in the liver. A lambda light chain multiple myeloma was found in the check-up of this hepatic mass. We also provide a literature review.

"AORTIC MURAL THROMBI ASSOCIATED WITH ULCERATIVE COLITIS." Acta Clinica Belgica, 65(1), pp. 54–55