Nanoparticle albumin-bound (nab)-paclitaxel is paclitaxel linked to albumin nanoparticles, which makes it soluble and is an example of an application of nanotechnology for cancer treatment. The development of nanotechnology as a delivery system for nab-paclitaxel has improved the pharmacokinetics and pharmacodynamics of paclitaxel, in part by decreasing its hydrophobicity. Nab-paclitaxel in combination with gemcitabine has slightly improved survival in pancreatic cancer, compared to gemcitabine alone, as demonstrated in Phase III clinical trials. Cell cycle phase-specific drugs, such as nab-paclitaxel, which target cells in the G2/M phase of the cell cycle, can only have limited efficacy since the vast majority of cells in a tumor are quiescent in G0/G1 phase. Recent advances in our laboratory on how to decoy cancer cells to cycle and then trap them in a sensitive phase of the cell cycle, can, in the hopefully near future, allow drugs such as nab-paclitaxel to have high efficacy, even in a treatment-resistant tumor such as pancreatic cancer.

The present study reviews the use of tumor-specific antibodies conjugated to fluorescent dyes in preclinical and clinical studies to enhance visualization of primary tumors and metastases for fluorescence-guided surgery (FGS) in colorectal cancer (CRC). A search strategy was developed using the peer-reviewed National Center for Biotechnology Information (NCBI) database on PubMed. Studies using tumor-specific fluorescence imaging and FGS techniques on murine models of colorectal cell lines or patient-derived orthotopic xenograft (PDOX) colorectal cancer are reviewed. A total of 24 articles were identified that met the inclusion criteria, 21 preclinical and 3 clinical trials. The most widely used target antigen in preclinical and clinical trials was carcinoembryonic antigen (CEA). Mouse studies and clinical studies have demonstrated that the use of FGS in CRC can aid in decreased residual tumor and decreased rates of recurrence. As the mainstay of colorectal cancer treatment is surgery, the addition of intraoperative fluorescence imaging can help locate tumor margins, visualize occult micro-metastases, drive surgical decision making and improve patient outcomes.

Curative cancer surgery is dependent on the removal of all primary tumor and metastatic cancer cells. Preoperative imaging, intraoperative inspection and palpation, as well as pathological margin confirmation aid the surgeon, but these methods are lacking in sensitivity and can be highly subjective. Techniques in fluorescence-guided surgery (FGS) are emerging that selectively illuminate cancer cells, enhancing the distinction between tumors and surrounding tissues with the potential for single-cell sensitivity. FGS enhances tumor detection, surgical navigation, margin confirmation, and in some cases can be combined with therapeutic techniques to eliminate microscopic disease. In this review, we describe the preclinical developments and currently-used techniques for FGS.

Fluorescence-guided surgery can enhance the surgeon's ability to achieve a complete oncologic resection. There are a number of tumor-specific probes being developed with many preclinical mouse models to evaluate their efficacy. The current review discusses the different preclinical mouse models in the setting of probe evaluation and highlights the advantages of patient-derived orthotopic xenografts (PDOX) mouse models and genetic reporters to develop fluorescence-guided surgery.

Background

The success of a curative surgery for cancer is dependent on the complete removal of all cancer cells. Tumor visualization by the surgeon can be enhanced through fluorescent-antibody targeting. To further develop such technology, we selected humanized anti-carcinoembryonic antigen (CEA) conjugated to a near-infrared dye to target orthotopically-implanted human colon cancer in nude mice.

Materials and methods

The HT-29 human colon cancer cell line was grown in culture and subcutaneously injected in mice. After 3 wk of growth, tumors were resected and cut into 2 mm³ fragments that were sutured to the cecum of five additional nude mice for orthotopic implantation. The tumors were allowed to grow for 4 wk at which point 3 had successful orthotopic tumor growth and were selected for injection of the humanized anti-CEA antibody conjugated to the near-infrared dye IRDye800CW (anti-CEA-IRDye800CW). The antibody-dye conjugate (75 μg) was administered via tail vein injection. Images were obtained with the Pearl Trilogy Small Animal Imaging System with both 700 and 800 nm channels and evaluated using Image Studio.

Results

Laparotomy was performed 24 h after labeling the tumors. When imaged through the 800 nm channel, the tumors were observed to be strongly labeled with anti-CEA-IRDye800. At 48 h, laparotomy was repeated which again demonstrated strong labeling of the tumors through the 800 nm channel, but with a lower absolute intensity (in relative units), than at 24 h.

Conclusions

Humanized anti-CEA-IRDye800CW can rapidly and effectively label CEA-expressing human colon cancer in an orthotopic nude mouse model. Given the ability of this technology to target and label tumors with great specificity, the anti-CEA-IRDye800CW is currently being developed for clinical use in fluorescence-guided surgery.

BACKGROUND: Surgical orthotopic implantation of human colon cancer tissue to the ceca of mice has been used to mimic behavior of cancer in human patients for the development of precision cancer medicine. However, with the current method of serosal surface implantation (SSI) of pieces of human colon cancer tissue, cancer cells are exposed to the peritoneum, which can artificially increase the rate of peritoneal carcinomatosis (PC) during the disease course. The objective of the present study was to introduce a tumor-sealing method (TSM) and compare it with SSI for the ability to produce clinically-relevant metastases without artificial PC. MATERIALS AND METHODS: HCT116 colon cancer cells transfected with green fluorescence protein (GFP) were cultured and then injected into the subcutaneous layer of athymic nude mice. Subcutaneous tumors were allowed to grow sufficiently to supply adequate tumor for orthotopic implantation. For SSI, a 1 mm3-sized tumor fragment was sutured to partially torn serosa of the cecum. For TSM, the blind end of the cecum was folded over the tumor fragment and sealed with sutures. At 20 days after implantation, all mice were opened to visualize PC by intravital fluorescence imaging. At necropsy, distant metastasis was investigated using frozen section of whole blocks of organs. RESULTS: At 20 days after implantation, PC rates in the SSI group and the TSM group were 80% (12/15) and 20% (3/15), respectively (p<0.001). The liver metastasis rate was 41.7% (5/12) in the SSI group and 50% (5/10) in the TSM group (p=0.696). The lung metastasis rate was 0% (0/12) in the SSI group and 10% (1/10) in the TSM group (p=0.201). The mean survival of mice without PC on the 20th day was significantly longer than that of mice with PC on the 20th day (69.1±14.7 vs. 44.5±12.4 days, p=0.001). CONCLUSION: These results suggest that TSM might be a more patient-like and useful method as a model of metastatic colon cancer than SSI.

Background

Hospital-based addiction care focuses on assessing and diagnosing substance use disorders, managing withdrawal, and initiating medications for addiction treatment. Hospital harm reduction is generally limited to prescribing naloxone. Hospitals can better serve individuals with substance use disorders by incorporating harm reduction education and equipment provision as essential addiction care. We describe the implementation of a hospital intervention that provides harm reduction education and equipment (e.g., syringes, pipes, and fentanyl test strips) to patients via an addiction consult team in an urban, safety-net hospital.

Methods

We performed a needs assessment to determine patient harm reduction needs. We partnered with a community-based organization who provided us harm reduction equipment and training. We engaged executive, regulatory, and nursing leadership to obtain support. After ensuring regulatory compliance, training our team, and developing a workflow, we implemented this harm reduction program that provides education and equipment to individuals whose substance use goals do not include abstinence.

Results

During a 12-month period we provided 195 individuals harm reduction kits.

Conclusions

This intervention allowed us to advance hospital-based addiction care, better educate and engage patients, staff, and clinicians, and reduce stigma. By establishing a community harm reduction partner, obtaining support from hospital leadership, and incorporating feedback from staff, clinicians, and patients, we successfully implemented harm reduction education and equipment provision in a hospital setting as part of evidence-based addiction care.

Trial registration

Commentary, none.

Background

Our laboratory has previously developed fluorescence-guided surgery of pancreatic and other cancers in orthotopic mouse models. Laparoscopic surgery is being used more extensively in surgical oncology. This report describes the efficacy of laparoscopic fluorescence-guided surgery of pancreatic cancer in an orthotopic mouse model.

Study design

Mouse models of human pancreatic cancer were established with fragments of the BxPC-3 red fluorescent protein-expressing human pancreatic cancer using surgical orthotopic implantation. Mice were randomized to bright-light laparoscopic surgery (BLLS) or to fluorescence-guided laparoscopic surgery (FGLS). Fluorescence-guided laparoscopic surgery was performed with a light-emitting diode light source through a 495-nm emission filter in order to resect the primary tumors and any additional separate submillimeter tumor deposits within the pancreas, the latter of which was not possible with BLLS. Tumors were labeled with anti-CEA AlexaFluor 488 antibodies 24 hours before surgery with intravenous injection. Perioperative fluorescence images were obtained to evaluate tumor size. Mice were followed postoperatively to assess for recurrence and at termination to evaluate tumor burden.

Results

At termination, the FGLS-treated mice had less pancreatic tumor volume than the BLLS-treated mice (5.75 mm(2) vs 28.43 mm(2), respectively; p = 0.012) and lower tumor weight (21.1 mg vs 174.4 mg, respectively; p = 0.033). Fluorescence-guided laparoscopic surgery compared with BLLS also decreased local recurrence (50% vs 80%, respectively; p = 0.048) and distant recurrence (70% vs 95%, respectively; p = 0.046). More mice in the FGLS group than the BLLS group were free of tumor at termination (25% vs 5%, respectively). Median disease-free survival was lengthened from 2 weeks with BLLS (95% CI, 1.635-2.365) to 7 weeks with FGLS (95% CI, 5.955-8.045; p = 0.001).

Conclusions

Fluorescence-guided laparoscopic surgery is more effective than BLLS and, therefore, has important potential for surgical oncology.

Mucins (MUC1-MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal cancers. MUC1, MUC2, MUC4, MUC5AC, and MUC6 are currently the most widely covered in the literature regarding their role in the progression from normal colonic tissue to cancer.