Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT)... Show moreBackground: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer. Show less
Background: Abdominal infections account for substantial morbidity after pancreatoduodenectomy. Contaminated bile is the presumed main risk factor, and prolonged antibiotic prophylaxis might... Show moreBackground: Abdominal infections account for substantial morbidity after pancreatoduodenectomy. Contaminated bile is the presumed main risk factor, and prolonged antibiotic prophylaxis might prevent these complications. This study compared organ/space infection (OSIs) rates in patients receiving perioperative versus prolonged antibiotic prophylaxis after pancreatoduodenectomy.Methods: Patients undergoing pancreatoduodenectomy in two Dutch centers between 2016 and 2019 were included. Perioperative prophylaxis was compared prolonged prophylaxis (cefuroxime and metronidazole for five days). The primary outcome was an isolated OSI: an abdominal infection without concurrent anastomotic leakage. Odds ratios (OR) were adjusted for surgical approach and pancreatic duct diameter.Results: OSIs occurred in 137 out of 362 patients (37.8%): 93 patients with perioperative and 44 patients with prolonged prophylaxis (42.5% versus 30.8%, P = 0.025). Isolated OSIs occurred in 38 patients (10.5%): 28 patients with perioperative and 10 patients with prolonged prophylaxis (12.8% versus 7.0%, P = 0.079). Bile cultures were obtained in 198 patients (54.7%). Patients with positive bile cultures showed higher isolated OSI rates with perioperative compared to prolonged prophylaxis (18.2% versus 6.6%, OR 5.7, 95% CI: 1.3-23.9).Conclusion: Prolonged antibiotics after pancreatoduodenectomy are associated with fewer isolated OSIs in patients with contaminated bile and warrant confirmation in a randomised controlled trial (Clinicaltrials.gov NCT0578431). Show less
BackgroundAbdominal infections account for substantial morbidity after pancreatoduodenectomy. Contaminated bile is the presumed main risk factor, and prolonged antibiotic prophylaxis might prevent... Show moreBackgroundAbdominal infections account for substantial morbidity after pancreatoduodenectomy. Contaminated bile is the presumed main risk factor, and prolonged antibiotic prophylaxis might prevent these complications. This study compared organ/space infection (OSIs) rates in patients receiving perioperative versus prolonged antibiotic prophylaxis after pancreatoduodenectomy.MethodsPatients undergoing pancreatoduodenectomy in two Dutch centers between 2016 and 2019 were included. Perioperative prophylaxis was compared prolonged prophylaxis (cefuroxime and metronidazole for five days). The primary outcome was an isolated OSI: an abdominal infection without concurrent anastomotic leakage. Odds ratios (OR) were adjusted for surgical approach and pancreatic duct diameter.ResultsOSIs occurred in 137 out of 362 patients (37.8%): 93 patients with perioperative and 44 patients with prolonged prophylaxis (42.5% versus 30.8%, P = 0.025). Isolated OSIs occurred in 38 patients (10.5%): 28 patients with perioperative and 10 patients with prolonged prophylaxis (12.8% versus 7.0%, P = 0.079). Bile cultures were obtained in 198 patients (54.7%). Patients with positive bile cultures showed higher isolated OSI rates with perioperative compared to prolonged prophylaxis (18.2% versus 6.6%, OR 5.7, 95% CI: 1.3–23.9).ConclusionProlonged antibiotics after pancreatoduodenectomy are associated with fewer isolated OSIs in patients with contaminated bile and warrant confirmation in a randomised controlled trial (Clinicaltrials.gov NCT0578431). Show less
Fluorescence-guided surgery (FGS) can play a key role in improving radical resection rates by assisting surgeons to gain adequate visualization of malignant tissue intraoperatively. Designed... Show moreFluorescence-guided surgery (FGS) can play a key role in improving radical resection rates by assisting surgeons to gain adequate visualization of malignant tissue intraoperatively. Designed ankyrin repeat proteins (DARPins) possess optimal pharmacokinetic and other properties for in vivo imaging. This study aims to evaluate the preclinical potential of epithelial cell adhesion molecule (EpCAM)-binding DARPins as targeting moieties for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of cancer. EpCAM-binding DARPins Ac2, Ec4.1, and non-binding control DARPin Off7 were conjugated to IRDye 800CW and their binding efficacy was evaluated on EpCAM-positive HT-29 and EpCAM-negative COLO-320 human colon cancer cell lines. Thereafter, NIRF and PA imaging of all three conjugates were performed in HT-29_luc2 tumor-bearing mice. At 24 h post-injection, tumors and organs were resected and tracer biodistributions were analyzed. Ac2-800CW and Ec4.1-800CW specifically bound to HT-29 cells, but not to COLO-320 cells. Next, 6 nmol and 24 h were established as the optimal in vivo dose and imaging time point for both DARPin tracers. At 24 h post-injection, mean tumor-to-background ratios of 2.60 ± 0.3 and 3.1 ± 0.3 were observed for Ac2-800CW and Ec4.1-800CW, respectively, allowing clear tumor delineation using the clinical Artemis NIRF imager. Biodistribution analyses in non-neoplastic tissue solely showed high fluorescence signal in the liver and kidney, which reflects the clearance of the DARPin tracers. Our encouraging results show that EpCAM-binding DARPins are a promising class of targeting moieties for pan-carcinoma targeting, providing clear tumor delineation at 24 h post-injection. The work described provides the preclinical foundation for DARPin-based bimodal NIRF/PA imaging of cancer. Show less
PurposeMetastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during... Show morePurposeMetastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during minimally invasive surgery. Intraoperative fluorescence imaging has the potential to overcome these challenges. The aim of this study was to assess feasibility of targeting CLM with the carcinoembryonic antigen (CEA) specific fluorescent tracer SGM-101.MethodsThis was a prospective, open-label feasibility study. The primary outcome was the number of CLM that showed a true positive fluorescence signal with SGM-101. Fluorescence positive signal was defined as a signal-to-background ratio (SBR) ≥ 1.5. A secondary endpoint was the CEA expression in the colorectal lung metastases, assessed with the immunohistochemistry, and scored by the total immunostaining score.ResultsThirteen patients were included in this study. Positive fluorescence signal with in vivo, back table, and closed-field bread loaf imaging was observed in 31%, 45%, and 94% of the tumors respectively. Median SBRs for the three imaging modalities were 1.00 (IQR: 1.00–1.53), 1.45 (IQR: 1.00–1.89), and 4.81 (IQR: 2.70–7.41). All tumor lesions had a maximum total immunostaining score for CEA expression of 12/12.ConclusionThis study demonstrated the potential of fluorescence imaging of CLM with SGM-101. CEA expression was observed in all tumors, and closed-field imaging showed excellent CEA specific targeting of the tracer to the tumor nodules. The full potential of SGM-101 for in vivo detection of the tracer can be achieved with improved minimal invasive imaging systems and optimal patient selection. Show less
Antibiotic prophylaxis varies substantially between institutes. The effect of prolonged antibiotic prophylaxis seems promising, particularly in patients undergoing pancreatoduodenectomy with... Show moreAntibiotic prophylaxis varies substantially between institutes. The effect of prolonged antibiotic prophylaxis seems promising, particularly in patients undergoing pancreatoduodenectomy with contaminated bile. This systematic review and meta-analysis demonstrated a beneficial effect of prolonged antibiotic prophylaxis after pancreatoduodenectomy in patients who had preoperative biliary drainage.Background Previous studies have reported conflicting results of prolonged antibiotic prophylaxis on infectious complications after pancreatoduodenectomy. This study evaluated the effect of prolonged antibiotics on surgical-site infections (SSIs) after pancreatoduodenectomy. Methods A systematic review and meta-analysis was undertaken of SSIs in patients with perioperative (within 24 h) versus prolonged antibiotic (over 24 h) prophylaxis after pancreatoduodenectomy. SSIs were classified as organ/space infections or superficial SSI within 30 days after surgery. ORs were calculated using a Mantel-Haenszel fixed-effect model. Results Ten studies were included in the qualitative analysis, of which 8 reporting on 1170 patients were included in the quantitative analysis. The duration of prolonged antibiotic prophylaxis varied between 2 and 10 days after surgery. Four studies reporting on 782 patients showed comparable organ/space infection rates in patients receiving perioperative and prolonged antibiotics (OR 1.35, 95 per cent c.i. 0.94 to 1.93). However, among patients with preoperative biliary drainage (5 studies reporting on 577 patients), organ/space infection rates were lower with prolonged compared with perioperative antibiotics (OR 2.09, 1.43 to 3.07). Three studies (633 patients) demonstrated comparable superficial SSI rates between patients receiving perioperative versus prolonged prophylaxis (OR 1.54, 0.97 to 2.44), as well as in patients with preoperative biliary drainage in 4 studies reporting on 431 patients (OR 1.60, 0.89 to 2.88). Conclusion Prolonged antibiotic prophylaxis is associated with fewer organ/space infection in patients who undergo preoperative biliary drainage. However, the optimal duration of antibiotic prophylaxis after pancreatoduodenectomy remains to be determined and warrants confirmation in an RCT.Lay Summary Almost 40 in 100 patients develop an infection after pancreatic surgery. This study collected research that studied the effect of prolonged antibiotics after pancreatic surgery on the number of infections after surgery. Research articles were selected if patients who received antibiotics only during surgery were compared with those who had prolonged antibiotics after surgery. Prolonged antibiotics means antibiotics for longer than 24 h after surgery. Comparing patients who had antibiotics during surgery and those who received prolonged antibiotics after surgery, this study focused on the number of abdominal infections and wound infections. Ten studies were selected, and these studies included 1170 patients in total. The duration of prolonged antibiotics ranged from 2 to 5 days after pancreatic surgery. Four studies (with 782 patients) showed comparable abdominal infections in patients who had antibiotics only during surgery and those who had prolonged antibiotics after surgery (OR 1.35, 95 per cent c.i. 0.94 to 1.93). However, for patients with a stent in the bile duct (5 studies on 577 patients), fewer abdominal infections were seen in patients who had prolonged antibiotics after surgery compared with patients who received antibiotics only during surgery (OR 2.09, 1.43 to 3.07). Three studies (633 patients) showed the same rate of wound infections in patients who had antibiotics only during surgery compared with those who received prolonged antibiotics after operation (OR 1.54, 0.97 to 2.44). The number of wound infections was also the same in patients with a stent in the bile duct (OR 1.60, 0.89 to 2.88). Prolonged antibiotics after pancreatic surgery seem to lower abdominal infections in patients who have a stent placed in the bile duct. However, the best duration of antibiotics is unclear; a decent study is needed. Show less
Vuijk, F.A.; Shahbazi, S.F.; Noortman, W.A.; Velden, F.H.P. van; Dibbets-Schneider, P.; Marinelli, A.W.K.S.; ... ; Geus-Oei, L.F. de 2023
ObjectiveIn this pilot study, we investigated the feasibility of response prediction using digital [F-18]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after... Show moreObjectiveIn this pilot study, we investigated the feasibility of response prediction using digital [F-18]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. MethodsRectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [F-18]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P <= 0.2, promising predictive features for response were selected. ResultsNineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Delta maximum standardized uptake value, Delta peak standardized uptake value corrected for lean body mass), were promising features. ConclusionBoth multiparametric MRI and [F-18]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT. Show less
Vuijk, F.A.; Shahbazi, S.F.; Noortman, W.A.; Velden, F.H.P. van; Dibbets-Schneider, P.; Marinelli, A.W.K.S.; ... ; Geus-Oei, L.F. de 2023
Objective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after... Show moreObjective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial.Methods Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [18F]FDG PET/CT before, 2 weeks into, and 6–8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P ≤ 0.2, promising predictive features for response were selected.Results Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features.Conclusion Both multiparametric MRI and [18F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT. Show less
The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive... Show moreThe lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcusbromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches. Show less
Huisman, B.W.; Cankat, M.; Bosse, T.; Vahrmeijer, A.L.; Rissmann, R.; Burggraaf, J.; ... ; Poelgeest, M.I.E. van 2023
BackgroundDifferentiating high-grade dysplasia (HGD) and T1 colorectal cancer (T1CRC) from low-grade dysplasia (LGD) in colorectal polyps can be challenging. Incorrect recognition of HGD or T1CRC... Show moreBackgroundDifferentiating high-grade dysplasia (HGD) and T1 colorectal cancer (T1CRC) from low-grade dysplasia (LGD) in colorectal polyps can be challenging. Incorrect recognition of HGD or T1CRC foci can lead to a need for additional treatment after local resection, which might not have been necessary if it was recognized correctly. Tumor-targeted fluorescence-guided endoscopy might help to improve recognition.ObjectiveSelecting the most suitable HGD and T1CRC-specific imaging target from a panel of well-established biomarkers: carcinoembryonic antigen (CEA), c-mesenchymal-epithelial transition factor (c-MET), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FRα), and integrin alpha-v beta-6 (αvβ6).MethodsEn bloc resection specimens of colorectal polyps harboring HGD or T1CRC were selected. Immunohistochemistry on paraffin sections was used to determine the biomarker expression in normal epithelium, LGD, HGD, and T1CRC (scores of 0–12). The differential expression in HGD-T1CRC components compared to surrounding LGD and normal components was assessed, just as the sensitivity and specificity of each marker.Results60 specimens were included (21 HGD, 39 T1CRC). Positive expression (score >1) of HGD-T1CRC components was found in 73.3%, 78.3%, and 100% of cases for CEA, c-MET, and EpCAM, respectively, and in <40% for FRα and αvβ6. Negative expression (score 0–1) of the LGD component occurred more frequently for CEA (66.1%) than c-MET (31.6%) and EpCAM (0%). The differential expression in the HGD-T1CRC component compared to the surrounding LGD component was found for CEA in 66.7%, for c-MET in 43.1%, for EpCAM in 17.2%, for FRα in 22.4%, and for αvβ6 in 15.5% of the cases. Moreover, CEA showed the highest combined sensitivity (65.0%) and specificity (75.0%) for the detection of an HGD-T1CRC component in colorectal polyps.ConclusionOf the tested targets, CEA appears the most suitable to specifically detect HGD and T1 cancer foci in colorectal polyps. An in vivo study using tumor-targeted fluorescence-guided endoscopy should confirm these findings. Show less
Introduction: Myxofibrosarcoma (MFS) is the most common soft-tissue sarcoma subtype in elderly patients. Local recurrence (LR) remains a major concern as the lack of intraoperative guidance and an... Show moreIntroduction: Myxofibrosarcoma (MFS) is the most common soft-tissue sarcoma subtype in elderly patients. Local recurrence (LR) remains a major concern as the lack of intraoperative guidance and an infiltrative growth pattern with long, slender tails hamper surgeons' ability to achieve adequate resection margins for MFS. Fluorescence-guided surgery (FGS) could overcome this concern by delineating tumor tissue during surgery. One of the most important steps to successful FGS is to define a tumor-specific biomarker that is highly overexpressed in tumor tissue while low or absent in adjacent healthy tissue. The aim of this study is to evaluate the expression of eight previously selected promising biomarkers for FGS in MFS tissue samples with adjacent healthy tissue using immunohistochemistry (IHC). Methods: The following eight biomarkers were stained in seventeen paraffin-embedded MFS samples: tumor endothelial marker-1 (TEM-1, also known as endosialin/CD248), vascular endothelial growth factor receptor-1 (VEGFR-1, also known as Flt-1), vascular endothelial growth factor receptor-2 (VEGFR-2, also known as Flk1), vascular endothelial growth factor-A (VEGF-A), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), platelet derived growth factor receptor-alpha (PDGFR-alpha), and cluster of differentiation 40 (CD40, also known as TNFRSF5). A pathologist specializing in sarcoma annotated the margin between the tumor and adjacent healthy tissue in each MFS tissue sample. Subsequently, we used an objective IHC scoring method to assess and compare the difference in staining intensity between the tumor and adjacent healthy tissue, which is crucial for the use of FGS. Results: TEM-1, VEGF-A, and PDGFR-alpha stained all MFS tumors, while the other biomarkers did not show expression in all MFS tumors. Ultimately, TEM-1 was identified as the most suitable biomarker for FGS in MFS based on higher tumor-to-background (TBR) staining intensity compared to VEGF-A and PDGFR-alpha, regardless of preoperative therapy. Conclusion: TEM-1-targeted FGS tracers should be further investigated to optimize MFS treatment. Show less
BackgroundDetermining the resectability of pancreatic cancer with vascular involvement on preoperative computed tomography imaging remains challenging, especially following preoperative... Show moreBackgroundDetermining the resectability of pancreatic cancer with vascular involvement on preoperative computed tomography imaging remains challenging, especially following preoperative chemotherapy and chemoradiotherapy. Intraoperative ultrasound (IOUS) may provide real-time additional information, but prospective multicenter series confirming its value are lacking. Patients and MethodsThis prospective multicenter study included patients undergoing surgical exploration for pancreatic cancer with vascular involvement. All patients underwent IOUS at the start of explorative laparotomy. Primary outcomes were resectability status as defined by the National Comprehensive Cancer Network and the extent of vascular involvement. ResultsOverall, 85 patients were included, of whom 74 (87%) were post preoperative chemotherapy, and mostly following FOLFIRINOX regimen (n = 57; 76%). On the basis of preoperative imaging, 34 (40%) patients were staged as resectable (RPC), 32 (38%) borderline resectable (BRPC), and 19 (22%) locally advanced pancreatic cancer (LAPC). IOUS changed the resectability status in 32/85 (38%) patients (p < 0.001), including 8/19 (42%) patients with LAPC who were downstaged (4 to BRPC, 4 to RPC), and 22/32 (69%) patients with BRPC who were downstaged to RPC. Among patients with presumed superior mesenteric artery (SMA) involvement, 20/28 (71%) had no SMA involvement on IOUS. In 15 of these 20 patients a pancreatic resection was performed, all with R0 SMA margin. ConclusionIOUS during surgical exploration for pancreatic cancer and vascular involvement downstaged the resectability status in over one-third of patients, which could facilitate progress during surgical exploration. This finding should be confirmed by larger studies, including detailed pathology assessment. Show less
Houvast, R.D.; Duijvenvoorde, M. van; Chua, J.; Vankemmelbeke, M.; Durrant, L.G.; Inderson, A.; ... ; Kuppen, P.J.K. 2023
Background: Targeted molecular imaging may improve tumor cell identification during diagnosis and resection of pancreatic ductal adenocarcinoma (PDAC). Although many molecular imaging biomarkers... Show moreBackground: Targeted molecular imaging may improve tumor cell identification during diagnosis and resection of pancreatic ductal adenocarcinoma (PDAC). Although many molecular imaging biomarkers are (over)expressed in PDAC, intertumoral heterogeneity of biomarker expression hampers universal tracer administration. Preoperative, patient-specific screening and selection of the most optimal biomarker could therefore improve tumor delineation. Objective: This study evaluated whether fine-needle biopsy (FNB) specimens could be used to preoperatively predict biomarker expression in the corresponding primary PDAC specimen. Methods: Expression of previously identified PDAC biomarkers alpha(v)beta(6), CEACAM5, EGFR, mesothelin, Le(a/c/x), and sdi-Le(a) on FNB and corresponding primary tumor (PT) specimens (n = 45) was evaluated using immunohistochemistry and quantified using a semi-automated image analysis workflow. Results: Biomarker expression on FNB and PT tissues showed high concordance ( increment H-score <= 50), i.e. was present in 62% of cases for alpha(v)beta(6), 61% for CEACAM5, 85% for EGFR, 69% for mesothelin, 76% for Le(a/c/x), and 79% for sdi-Le(a), indicating high concordance. Except for alpha(v)beta(6), biomarker expression on FNB tissues was positively correlated with PT expression for all biomarkers. Subgroup analyses showed that neoadjuvant therapy (NAT) had no major and/or significant effect on concordance, expression difference and, except for mesothelin, correlation of biomarker expression between FNB and PT tissues. Conclusion: This study demonstrated that biomarker expression in FNB tissues is predictive for PT expression, irrespective of the application of NAT. These findings thereby provide the foundation for the clinical application of an FNB-based biomarker-screening workflow, eventually facilitating a patient-specific approach of molecular imaging tracer administration in PDAC. Show less
Purpose: Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection.... Show morePurpose: Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection. This study evaluated cell surface biomarkers, partially selected via data-driven selection software, as potential targets for fluorescence-guided surgery in non-small cell lung cancers: adenocarcinomas (ADC), adenocarcinomas in situ (AIS), and squamous cell carcinomas (SCC). Procedures: Formalin-fixed paraffin-embedded tissue slides of resection specimens from 15 patients with ADC and 15 patients with SCC were used and compared to healthy tissue. Molecular targets were selected based on two strategies: (1) a data-driven selection using > 275 multi-omics databases, literature, and experimental evidence; and (2) the availability of a fluorescent targeting ligand in advanced stages of clinical development. The selected targets were carbonic anhydrase 9 (CAIX), collagen type XVII alpha 1 chain (collagen XVII), glucose transporter 1 (GLUT1), G protein-coupled receptor 87 (GPR87), transmembrane protease serine 4 (TMPRSS4), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FR alpha), integrin alpha v beta 6 (alpha v beta 6), and urokinase-type plasminogen activator receptor (uPAR). Tumor expression of these targets was assessed by immunohistochemical staining. A total immunostaining score (TIS, range 0-12), combining the percentage and intensity of stained cells, was calculated. The most promising targets in ADC were explored in six AIS tissue slides to explore its potential in non-palpable lesions. Results: Statistically significant differences in TIS between healthy lung and tumor tissue for ADC samples were found for CEA, EpCAM, FR alpha, alpha v beta 6, CAIX, collagen XVII, GLUT-1, and TMPRSS4, and of these, CEA, CAIX, and collagen XVII were also found in AIS. For SCC, EpCAM, uPAR, CAIX, collagen XVII, and GLUT-1 were found to be overexpressed. Conclusions: EpCAM, CAIX, and Collagen XVII were identified using concomitant use of data-driven selection software and clinical evidence as promising targets for intraoperative fluorescence imaging for both major subtypes of non-small cell lung carcinomas. Show less
Simple Summary Prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging is increasingly being used for (re)staging in prostate cancer. Although PSMA suggests specificity to prostate cancer... Show moreSimple Summary Prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging is increasingly being used for (re)staging in prostate cancer. Although PSMA suggests specificity to prostate cancer, previous preclinical studies and case reports have shown this protein to be overexpressed by multiple other tumor types. This study aims to investigate the applicability of a PSMA-targeted PET/CT tracer to detect gastrointestinal cancers, including colon, pancreatic and gastric cancer. Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [F-18]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [F-18]DCFPyL and [F-18]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [F-18]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUVmax of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUVmax and TBR on [F-18]FDG PET/CT were significantly higher than on [F-18]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUVmax on [F-18]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [F-18]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [F-18]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers. Show less
Purpose: To assess the quantitative minimal ablation margin (MAM) in patients with colorectal liver metastases (CRLM) treated with percutaneous thermal ablation (TA) and correlate the quantitative... Show morePurpose: To assess the quantitative minimal ablation margin (MAM) in patients with colorectal liver metastases (CRLM) treated with percutaneous thermal ablation (TA) and correlate the quantitative MAM with local tumour recurrence (LTR).Method: Thirty-nine of 143 patients with solitary or multiple CRLM who underwent a first percutaneous TA procedure between January 2011 and May 2020 were considered eligible for study enrolment. Image fusion of pre-and post-ablation scans and 3D quantitative MAM assessment was performed using the in-house developed semi-automatic rigid MRI/CECT-CECT co-registration software deLIVERed. The quantitative MAM was analysed and correlated with LTR.Results: Eighteen (46 %) patients were additionally excluded from further analyses due to suboptimal co -registration (quality co-registration score < 3). The quality of co-registration was considered sufficient in 21 (54 %) patients with a total of 29 CRLM. LTR was found in 5 of 29 (17 %) TA-treated CRLM. In total, 12 (41 %) negative MAMs were measured (mean MAM-4.7 +/- 2.7 mm). Negative MAMs were significantly more frequently seen in patients who developed LTR (100 %) compared to those without LTR (29 %; p = 0.003). The median MAM of patients who developed LTR (-6.6 mm (IQR-9.5 to-4.6)) was significantly smaller compared to the median MAM of patients without LTR (0.5 mm (IQR-1.8 to 3.0); p < 0.001). The ROC curve showed high accuracy in predicting LTR for the quantitative MAM (area under the curve of 0.975 +/- 0.029).Conclusion: This study demonstrated the feasibility of 3D quantitative MAM assessment, using deLIVERed co -registration software, to assess technical success of TA in patients with CRLM and to predict LTR. Show less
Background: Muscle attenuation (MA) and visceral adipose tissue (VAT) have not yet been included in the currently used alternative Fistula Risk Score (a-FRS). The aim of this study was to examine... Show moreBackground: Muscle attenuation (MA) and visceral adipose tissue (VAT) have not yet been included in the currently used alternative Fistula Risk Score (a-FRS). The aim of this study was to examine the added value of these parameters as predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in the a-FRS after pancreatoduodenectomy compared to Body Mass Index (BMI). Methods: A single center retrospective cohort study was performed in patients who underwent pancreatoduodenectomy between 2009 and 2018. The a-FRS model was reproduced, MA and VAT were both combined and separately added to the model instead of BMI using logistic regression analysis. Model discrimination was assessed by ROC-curves. Results: In total, 329 patients were included of which 55 (16.7%) developed CR-POPF. The a-FRS model showed an AUC of 0.74 (95%CI: 0.68-0.80). In this model, BMI was not significantly associated with CR-POPF (p = 0.16). The MA + VAT model showed an AUC of 0.81 (95%CI: 0.75-0.86). VAT was significantly associated with CR-POPF (per cm2, OR: 1.01; 95%CI: 1.00-1.01; p < 0.001). The AUC of the MA + VAT model differed significantly from the AUC of the a-FRS model (p = 0.001). Conclusion: Visceral adipose tissue is of added value in the a-FRS compared to BMI in predicting CRPOPF in patients undergoing pancreatoduodenectomy. Show less
The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after... Show moreThe majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients. Show less
