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 Targeted real-time imaging during robot-assisted radical prostatectomy provides information on the localisation and extent of prostate cancer. We assessed the safety and feasibility of... Show moreBackground Targeted real-time imaging during robot-assisted radical prostatectomy provides information on the localisation and extent of prostate cancer. We assessed the safety and feasibility of the prostate-specific membrane antigen (PSMA)-targeted fluorescent tracer OTL78 in patients with prostate cancer.Methods In this single-arm, phase 2a, feasibility trial with an adaptive design was carried out in The Netherlands Cancer Institute, Netherlands. Male patients aged 18 years or older, with PSMA PET-avid prostate cancer with an International Society of Urological Pathology (ISUP) grade group of 2 or more, who were scheduled to undergo robot-assisted radical prostatectomy with or without extended pelvic lymph node dissection were eligible. All patients had a robot-assisted radical prostatectomy using OTL78. Based on timing and dose, patients received a single intravenous infusion of OTL78 (0 center dot 06 mg/kg 1-2 h before surgery [dose cohort 1], 0 center dot 03 mg/kg 1-2 h before surgery [dose cohort 2], or 0 center dot 03 mg/kg 24 h before surgery [dose cohort 3]). The primary outcomes, assessed in all enrolled patients, were safety and pharmacokinetics of OTL78. This study is completed and is registered in the European Trial Database, 2019-002393-31, and the International Clinical Trials Registry Platform, NL8552, and is completed.Findings Between lune 29, 2020, and April 1, 2021, 19 patients were screened for eligibility, 18 of whom were enrolled. The median age was 69 years (IQR 64-70) and median prostate-specific antigen concentration was 15 ng/mL (IQR 9 center dot 3-22 center dot 0). In 16 (89%) of 18 patients, robot-assisted radical prostatectomy was accompanied by an extended pelvic lymph node dissection. Three serious adverse events occurred in one (6%) patient: an infected lymphocele, a urosepsis, and an intraperitoneal haemorrhage. These adverse events were considered unrelated to the administration of OTL78 or intraoperative fluorescence imaging. No patient died, required a dose reduction, or required discontinuation due to drug-related toxicity. The dose-normalised maximum serum concentration (Cmax/dose) in patients was 84 center dot 1 ng/mL/mg for the 0 center dot 03 mg/kg dose and 79 center dot 6 ng/mL/mg for the 0 center dot 06 mg/kg dose, the half-life was 5 center dot 1 h for the 0 center dot 03 mg/kg dose and 4 center dot 7 h for the 0 center dot 06 mg/kg dose, the volume of distribution was 22 center dot 9 L for the 0 center dot 03 mg/kg dose and 19 center dot 5 L for the 0 center dot 06 mg/kg dose, and the clearance was 3 center dot 1 L/h for the 0 center dot 03 mg/kg dose and 3 center dot 0 L/h for the 0 center dot 06 mg/kg dose.Interpretation This first-in-patient study showed that OTL78 was well tolerated and had the potential to improve prostate cancer detection. Optimal dosing was 0 center dot 03 mg/kg, 24 h preoperatively. PSMA-directed fluorescence imaging allowed real-time identification of visually occult prostate cancer and might help to achieve complete oncological resections.Funding On Target Laboratories. 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
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
Simple Summary: We have developed a formulation for an innovative, quenched, cathepsin-targeted, fluorescent molecular probe to enhance resection quality for several solid-tumor cancers. Unlike... Show moreSimple Summary: We have developed a formulation for an innovative, quenched, cathepsin-targeted, fluorescent molecular probe to enhance resection quality for several solid-tumor cancers. Unlike other formulations for imaging probes or tracers in development and entering the clinic, which require systemic administration hours before the procedure, this current formulation is applied topically into the surgical cavity immediately after a standard of care resection. Within minutes of application, the probe activates in the presence of residual cancer in the surgical wound and provides a strong fluorescent signal that precisely delineates any remaining cancer, enabling a more complete resection. Utilization of this imaging gel formulation for topical application to detect breast cancer in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life. Background: Tumor-positive surgical margins during primary breast cancer (BCa) surgery are associated with a two-fold increase in the risk of local recurrence when compared with tumor-negative margins. Pathological microscopic evaluation of the samples only assesses about 1/10 of 1% of the entire volume of the removed BCa specimens, leading to margin under-sampling and potential local recurrence in patients with pathologically clean margins, i.e., false negative margins. In the case of tumor-positive margins, patients need to undergo re-excision and/or radiation therapy, resulting in increases in complications, morbidity, and healthcare costs. Development of a simple real-time imaging technique to identify residual BCa in the surgical cavity rapidly and precisely could significantly improve the quality of care. Methods: A small-molecule, fluorescently quenched protease-substrate probe, AKRO-QC-ICG, was tested as part of a thermosensitive imaging gel formulated for topical application and imaging of the BCa surgical cavity. Results: More than forty formulations of gel mixtures were investigated to enable easy fluid application and subsequent solidification once applied, preventing dripping and pooling in the surgical cavity. The final formulation was tested using human BCa orthotopic implants in nude and NSG patient-derived xenografts (PDX) mice. This formulation of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel was found to be a good solvent for the probe, with a desirable thermo-reversible solid-gel transition and mechanical strength for distribution of AKRO-QC-ICG on the surfaces of tissue. It demonstrated excellent ability to detect BCa tissue after 10 min exposure, with a high signal-to-noise ratio both in mouse xenografts and freshly excised human lumpectomy tissue. The in vivo efficacy of the AKRO-QC-ICG imaging gel to detect BCa revealed the levels of sensitivity/specificity = 0.92/1 in 12 nude mice, which was corroborated with the sensitivity/specificity = 0.94/1 in 10 PDX mice. Conclusions: Utilization of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel for topical application to detect BCa in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life. Show less
