May 2024

This is a preclinical evaluation of a novel coenzyme-R conjugated near-infrared fluorochrome tracer for the detection of metabolically active cancer cells. The authors demonstrate that this tracer specifically localizes to highly proliferative tumor cells both in vitro and in vivo, suggesting its viability as a tracer for intraoperative molecular imaging to facilitate oncologic resections and evaluate the metabolic response to systemic therapies.

Summary: Intraoperative molecular imaging (IMI) requires appropriate molecular targeted fluorochromes to detect and facilitate the removal of cancer cells during surgery. The Sodium Multivitamin Transporter (SMVT) is a key transporter of coenzyme-R (CR), which is integral to the cellular metabolism of malignant cells. In this study, the authors perform a preclinical evaluation of (CR)-S0456, a high-affinity SMVT-targeted ligand linked to a near-infrared (NIR) fluorophore, for the detection of metabolically active cancer cells.

Spectrophysical analysis of (CR)-S0456 demonstrated non-inferior optical properties compared to other FDA-approved fluorophores. In vitro studies using five cell lines of varying proliferative potential showed universal yet variable (CR)-S0456 uptake, with fluorescence intensity directly correlating with cellular proliferative potential.

Fibrosarcoma cell lines were treated with various metabolic inhibitors to evaluate the effect of altered cellular metabolic activity on (CR)-S0456 uptake. Treatment of fibrosarcoma cell lines with Omipalisib, a PI3K/mTOR inhibitor that decreases cellular proliferation, resulted in the lowest (CR)-S0456 uptake. Further in vitro analysis of Omipalisib-treated fibrosarcoma cells revealed decreased expression of SMVT by Western blot analysis, decreased cell viability by DAPI nuclear staining and MTT assay, and decreased (CR)-S0456 uptake, which taken together, suggest that decreases in cellular proliferation correspond with decreased SMVT expression, limiting (CR)-S0456 absorbance.

In vivo studies with athymic fibrosarcoma flank xenograft mice demonstrated no (CR)-S0456 uptake in the lung, heart, pancreas, and brain. There was background uptake in normal liver, colon, small intestine, kidneys, and stomach, yet greater uptake in tumor xenografts. Fibrosarcoma xenograft mice treated with Omipalisib and injected with (CR)-S0456 showed no tumor fluorescence compared with untreated xenograft mice. Analysis of xenograft tumor lysates revealed decreased expression of mTOR, pAKT, and SMVT in the Omipalisib-treated group, which correlated with decreased intratumoral (CR)-S0456 fluorescence.

These findings demonstrate that (CR)-S0456 localizes intracellularly through SMVT and treatment with chemotherapeutic agents alters key cellular metabolic pathways leading to decreased SMVT expression and (CR)-S0456 uptake in both in vitro and in vivo models. Furthermore, (CR)-S0456 demonstrates high NIR fluorescence affinity and specificity for SMVT-expressing tumors with no background uptake in the lungs, making (CR)-S0456 a potentially attractive tracer for IMI-guided pulmonary oncologic resections. Limitations of this study include the inability of in vitro models to perfectly replicate the human tumor microenvironment. Additionally, neoadjuvant cancer treatments may cause metabolic alterations that can lead to non-localization and lack of fluorescence of (CR)-S0456, thereby limiting its use in those clinical situations. This study also assumes that SMVT expression is relatively uniform across tumor types; however, there could be some variability within tumors or patients that might affect the utility of this tracer. Future studies may benefit from assessing the interactions between (CR)-S0456 and other common treatments, such as radiation therapy and immunotherapy, as well as the performance of this tracer in tumors with extremely low SMVT expression or those that have developed resistance to metabolic interventions.

Bottom Line: The use of (CR)-S0456 demonstrates high NIR fluorescence specificity for SMVT-expressing tumors, with its uptake correlating with coenzyme-R metabolic activity and cellular proliferative potential. Given that this tracer is not taken up by normal lung parenchyma, it may be a particularly useful target for IMI-guided pulmonary oncologic resections as well as a viable assessment tool for metabolic response to systemic therapies.

This is a matched retrospective cohort study that used Medicare claims data to compare general surgery outcomes at flagship systems, flagship hospitals, and flagship hospital affiliates to matched controls. They found that patients treated at flagship hospitals had significantly lower mortality rates than those treated at flagship hospital affiliates.

Summary: The study aims to compare surgical outcomes at flagship hospitals and their affiliates within flagship systems to matched controls outside these systems. Despite the perception that flagship hospital affiliates offer similar quality care as flagship hospitals, it is unknown if this translates to better surgical outcomes for patients. Medicare claims data of patients aged 66 years and older who underwent inpatient general surgery procedures between 2018 and 2019 were used to compare surgical outcomes of patients treated at flagship system hospitals to those treated at hospitals within the same hospital referral regions (HRRs) but outside the flagship system. Optimal subset matching was used to match patients in flagship system hospitals to control patients outside the flagship system who underwent the same procedure within the same HRR, accounting for demographic, socioeconomic factors, and comorbidities. The primary outcome was 30-day mortality.

Overall, there were 32,228 closely matched pairs across 35 of the largest HRRs. Patients at flagship system hospitals had significantly lower rates of 30-day mortality than matched controls [3.79% vs. 4.36%, difference=−0.57% (95% CI: −0.86%, −0.28%), P<0.001]. Similarly, patients at flagship hospitals (15,571/32,228 pairs) had lower mortality rates than control patients [3.30% (flagship hospitals) vs. 4.41% (controls), difference=−1.11% (95% CI: −1.53%, −0.70%), P<0.001]. However, general surgery patients at affiliate hospitals in flagship systems did not have significantly different rates of 30-day mortality compared with control patients receiving the same procedure at within-HRR hospitals outside the flagship system [4.25% (affiliate hospitals) vs. 4.32% (controls), difference=−0.07% (95% CI: −0.48%, 0.35%), P=0.77]. Finally, rates of 30-day mortality were significantly lower at flagship hospitals versus controls compared with affiliate hospitals versus controls [difference-in-differences=−1.05% (95% CI: −1.62%, −0.47%), P<0.001]. Of note, 30-day mortality was lower for patients with multimorbidity treated at flagship system hospitals versus matched controls, while no significant difference was observed for patients without multimorbidity.

The results of this study demonstrate that while Medicare patients undergoing inpatient general surgery at flagship system hospitals had lower rates of 30-day mortality compared to their matched controls at hospitals outside the flagship system who underwent the same procedure within the same HRR, these differences were driven almost entirely by flagship hospitals and almost entirely by lower mortality for older patients with multimorbidity in those hospitals. This study was limited by its inclusion of 35 of the largest HRRs with higher numbers of beds, resident-to-bed ratios, and high technology capabilities compared with the average hospital across the nation, indicating they were likely better resourced, which may skew results. It is additionally limited by its use of fee-for-service Medicare claims data, which may not be reflective of the general population. Similarly, there may also be an element of unmeasured confounding, as the Medicare claims data lacks some granularity and would thereby limit the number of covariables they were able to match on.

Bottom Line: Flagship hospitals may demonstrate significantly lower mortality rates for general surgery patients compared to both flagship hospital affiliates and other hospitals within the same region. However, affiliation with a flagship system alone may not necessarily result in improved surgical outcomes. Flagship system affiliation alone does not guarantee or imply improved surgical outcomes.

This retrospective, single-institution study investigates clinical features that can distinguish gastrointestinal stromal tumors (GIST) from other subepithelial gastric tumors (SGTs). This study identifies key characteristics, such as tumor location and specific imaging features, that help differentiate GISTs from non-GIST SGTs.

Summary: Subepithelial gastric tumors (SGTs) encompass various pathologies, with gastrointestinal stromal tumors (GISTs) being the most prevalent. Traditionally, surgical resection is preferred due to the malignant potential of GISTs. However, distinguishing GISTs from other non-GIST SGTs based on clinical features has been challenging.

This study retrospectively analyzed 253 patients treated between 2000 and 2020 to identify distinguishing clinical features of GISTs compared to non-GIST SGTs, such as heterotopic pancreas, leiomyoma, schwannoma, and lipoma. The study included patients with histologically confirmed SGTs, excluding those without a preoperative diagnosis of SGT. The primary outcome was the identification of clinical features differentiating GIST from non-GIST SGTs.

Among the 253 patients, 79.1% had GISTs, while 20.9% had non-GIST SGTs. GISTs were more frequently located in the body of the stomach (51.0% vs. 26.4% in non-GISTs; P < 0.001), while leiomyomas were predominantly found in the cardia/fundus (86.4% vs. 33.8%; P < 0.001). Specific imaging features, such as intraperitoneal bleeding, cystic appearance on EUS, and calcifications, were highly specific for GISTs. A histologic diagnosis of GIST was independently associated with increasing age (OR 1.09, 95% CI: 1.04 – 1.15), Black race (OR 8.81, 95% CI: 2.23 – 34.89), heterogeneous appearance on CT scan (OR 13.64, 95% CI: 1.21 – 154.04), and ulceration on upper endoscopy (OR 14.94, 95% CI: 1.17 – 191.60). The study also found that biopsy methods did not significantly impact the accuracy of preoperative histologic diagnosis.

This study demonstrates that clinical features, such as tumor location, imaging characteristics, and patient demographics, can effectively differentiate GISTs from other SGTs. A proposed diagnostic algorithm based on these features can guide more targeted biopsy and surgical decisions, potentially reducing unnecessary surgeries and associated morbidities.

Limitations of this study include its generalizability, as these data are from a single institution and may not represent the population at large. There was also a fairly small number of non-GIST SGTs (n = 53), which could impact statistical power. Lastly, this study relies on imaging technologies available during the study period (2000-2020), which may not reflect current advancements in imaging and biopsy techniques.

Bottom line: Clinical features, including tumor location and specific imaging characteristics, can distinguish GISTs from other subepithelial gastric tumors, aiding in better clinical decision-making and potentially reducing unnecessary surgeries.

This proof-of-concept study utilizes an imaging technology to differentiate between tumor and normal tissue in real-time biopsies. They found that when combined with a near-infrared tracer (cancer marker), needle-based confocal laser endomicroscopy (imaging modality with cellular-level resolution) was able to detect malignant cells in biopsy samples.

Summary: When cancer is suspected in a patient, small nodules in different parts of the body are often biopsied to rule out malignancy due to ease of accessibility. However, the diagnostic yield of these biopsies is low; similarly, another drawback is that current medical technology does not provide real-time diagnostic information. Different technologies, such as intraoperative molecular imaging, have been studied to improve diagnostic capability for biopsies. Recently, this group demonstrated the ability to macroscopically differentiate between tumor and normal tissue during resection of solid tumors using optical near-infrared tracers (NIR) when they were systemically administered prior to surgery.

In this current study, the cancer detection capabilities of NIR tracers were integrated with the cellular-level resolution of needle-based confocal laser microscopy (nCLE) to detect cancer at the cellular level in real-time during biopsy. In this analysis, single malignant cells were detected at a ratio of 1:1000 when co-cultured with normal fibroblasts, which is important in lung cancers, as there are large amounts of non-malignant cells including tumor-associated fibrosis. NIR-nCLE was tested and proven effective in guiding transthoracic and transbronchial tumor biopsy in a murine animal model. This imaging modality was then implemented in human resection specimens that had undergone NIR tracer-guided lung cancer resection as part of an ongoing Phase 1 clinical trial. NIR-nCLE was shown to be effective in diagnosing malignancy in this human sample specific to ground glass opacities.

This study highlights the feasibility and promise of an imaging technique that can provide real-time in vivo optical detection of cancer at the cellular level. This has the ability to greatly improve diagnostic accuracy of biopsies for small nodules suspicious for malignancy. Potentially even more importantly, the cellular resolution of this imaging modality produces a binary result allowing imaging interpretation by non-experts in real-time.

Limitations of this study include the need for NIR-nCLE to be tested in human models in vivo to assess the impact of respiration, circulation, and motion artifact on the technology. Additionally, the use of fluorescence signals is subject to tumor heterogeneity (some tumors may not express the tracer) and the dynamic fluorescence scale (the scale is adjusted to the highest intensity in that single field), which can result in false negatives and false positives, respectively. There is also no mention of cost and accessibility, which may be prohibitive of uptake at some healthcare facilities, particularly in low-resource settings.

Bottom line: This study utilizes an imaging technology to effectively differentiate between tumor and normal tissue at the cellular level while performing biopsies of pulmonary nodules. These findings lay the foundation for an imaging modality that has promise to guide biopsy of nodules suspicious for malignancy in vivo.