Background
Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when ...none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor.
Methods
A dose-escalation study was performed to assess safety and feasibility of targeting and identifying PDAC in a tumor-specific manner using cetuximab-IRDye800 in patients undergoing surgical resection for pancreatic cancer. Patients received a loading dose of 100 mg of unlabeled cetuximab before infusion of cetuximab-IRDye800 (50 mg or 100 mg). Multi-instrument fluorescence imaging was performed throughout the surgery in addition to fluorescence and photoacoustic imaging ex vivo.
Results
Seven patients with resectable pancreatic masses suspected to be PDAC were enrolled in this study. Fluorescence imaging successfully identified tumor with a significantly higher mean fluorescence intensity in the tumor (0.09 ± 0.06) versus surrounding normal pancreatic tissue (0.02 ± 0.01), and pancreatitis (0.04 ± 0.01;
p
< 0.001), with a sensitivity of 96.1% and specificity of 67.0%. The mean photoacoustic signal in the tumor site was 3.7-fold higher than surrounding tissue.
Conclusions
The safety and feasibilty of intraoperative, tumor-specific detection of PDAC using cetuximab-IRDye800 with multimodal molecular imaging of the primary tumor and metastases was demonstrated.
Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. ...The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown.
In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death.
The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval CI, 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group.
Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.).
Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug ...delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-immunogenic, functionalized polylactic acid (PLA) MBs for use in targeted cancer therapy. Our previous studies have shown that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with two different PEGylation methods and was best achieved using incorporation of PEG–PLA at 5 wt % and for a LipidPEG at 1 wt %. Capitalizing on this, we now attach a targeting ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively induces tumor cell death upon binding to cancer cell-specific surface receptors, initiating a transmembrane apoptosis signal. Additionally, the functionalized MBs were designed to coencapsulate doxorubicin (Dox) that can be released from the polymer shell in response to ultrasound focused at the tumor site, shielding healthy tissues from toxicity while increasing the potency and efficiency of treatment to the tumor tissue. Ligation of TRAIL reduced the encapsulation efficiency for Dox compared to those of their non-ligated counterparts (p < 0.0001) by approximately 34% for 100% PLA, 23% for 5 wt % PEG–PLA, and 30% for the 1 wt % LipidPEG platform. All platforms exhibited a burst effect (<7%, p < 0.0001), and sustained release lasted for over 150 h. This work has resulted in a choice of effective ultrasound-triggered, non-immunogenic, targeted drug delivery agents for potential use in cancer therapy. These platforms have many advantages over the systemic administration of chemotherapeutic drugs and represent a promising treatment to better serve the population with solid cancerous tumors as a whole.
Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can potentially facilitate ...the visualization of involved peritumoral LNs and guide the locoregional extent of nodal dissection. Here, the efficacy of targeted intraoperative fluorescent imaging was examined in the detection of metastatic lymph nodes (LNs) during resection of pancreatic ductal adenocarcinoma (PDAC).
A dose-escalation prospective study was performed to assess feasibility of tumor detection within peripancreatic LNs using cetuximab-IRDye800 in PDAC patients. Fluorescent imaging of dissected LNs was analyzed ex vivo macroscopically and microscopically and fluorescence was correlated with histopathology.
A total of 144 LNs (72 in the low-dose and 72 in the high-dose cohort) were evaluated. Detection of metastatic LNs by fluorescence was better in the low-dose (50 mg) cohort, where sensitivity and specificity was 100% and 78% macroscopically, and 91% and 66% microscopically. More importantly, this method was able to detect occult foci of tumor (measuring < 5 mm) with a sensitivity of 88% (15/17 LNs).
This study provides proof of concept that intraoperative fluorescent imaging with cetuximab-IRDye800 can facilitate the detection of peripancreatic lymph nodes often containing subclinical foci of disease.
Head and neck cancers become a severe threat to human's health nowadays and represent the sixth most common cancer worldwide. Surgery remains the first-line choice for head and neck cancer patients. ...Limited resectable tissue mass and complicated anatomy structures in the head and neck region put the surgeons in a dilemma between the extensive resection and a better quality of life for the patients. Early diagnosis and treatment of the pre-malignancies, as well as real-time in vivo detection of surgical margins during en bloc resection, could be leveraged to minimize the resection of normal tissues. With the understanding of the head and neck oncology, recent advances in optical hardware and reagents have provided unique opportunities for real-time pre-malignancies and cancer imaging in the clinic or operating room. Optical imaging in the head and neck has been reported using autofluorescence imaging, targeted fluorescence imaging, high-resolution microendoscopy, narrow band imaging and the Raman spectroscopy. In this study, we reviewed the basic theories and clinical applications of optical imaging for the diagnosis and treatment in the field of head and neck oncology with the goal of identifying limitations and facilitating future advancements in the field.
Identification of lymph node (LN) metastasis is essential for staging of solid tumors, and as a result, surgeons focus on harvesting significant numbers of LNs during ablative procedures for ...pathological evaluation. Isolating those LNs most likely to harbor metastatic disease can allow for a more rigorous evaluation of fewer LNs. Here we evaluate the impact of a systemically injected, near-infrared fluorescently-labeled, tumor-targeting contrast agent, panitumumab-IRDye800CW, to facilitate the identification of metastatic LNs in the ex vivo setting for head and neck cancer patients. Molecular imaging demonstrates a significantly higher mean fluorescence signal in metastatic LNs compared to benign LNs in head and neck cancer patients undergoing an elective neck dissection. Molecular imaging to preselect at-risk LNs may thus allow a more rigorous examination of LNs and subsequently lead to improved prognostication than regular neck dissection.
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor type and is associated with a high mortality rate borne out of such affording a survival rate of only 15 months. GBM ...aggressiveness is associated with the overexpression of epidermal growth factor receptor (EGFR) and its mutants. Targeting GBM with therapeutics is challenging because the blood-brain barrier (BBB) permits primarily select small-molecule entities across its semipermeable blockade. However, recent preclinical data suggest that large biomolecules, such as the anti-EGFR antibody therapeutic, cetuximab, could be capable of bypassing the BBB despite the relative enormity of its size. As such, we set forth to establish the feasibility of utilizing an EGFR-targeting near-infrared-I (NIR-I) fluorescent construct in the form of an immunoconjugate (cetuxmimab-IRDye800) to achieve visual differentiation between diseased brain tissue arising from a low-passage
patient-derived
GBM cell line (GBM39) and healthy brain tissue
via
utilizing orthotopic
intracranial
murine GBM39 tumor models for
in vivo
and
ex vivo
evaluation such that by doing so would establish proof of concept for ultimately facilitating its
in vivo
fluorescence-guided resection and
ex vivo
surgical back-table pathological confirmation in the clinic. As anticipated, we were not capable of distinguishing between malignant tumor tissue and healthy tissue in resected intact and slices of whole brain
ex vivo
under white-light illumination (WLI) due to both the diseased tissue and healthy tissue appearing virtually identical to the unaided eye. However, we readily observed over an average 6-fold enhancement in the fluorescence emission in the resected intact whole brain
ex vivo
when performing NIR-I fluorescence imaging (FLI) on the cohort of GBM39 tumor models that were administered the immunoconjugate compared to controls. In all, we laid the initial groundwork for establishing that NIR-I fluorescent immunoconjugates (theranostics) such as cetuximab-IRDye800 can bypass the BBB to visually afford GBM39 tumor tissue differentiation for its image-guided surgical removal.
Fluorescent immunoconjugate cetuximab-IRDye800 bypasses the blood-brain-barrier to afford visualization of patient-derived GBM39 brain tumor tissue for facilitating its fluorescence-guided resection.
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