Synergistic anticancer immunity in metastatic triple-negative breast cancer through an in situ amplifying Peptide-Drug Conjugate.

Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvß3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a 'hot' tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies.

[Postoperative Imaging Findings of Colorectal Surgery: A Pictorial Essay]. / 대장 직장 ìˆ˜ìˆ ì˜ ìˆ˜ìˆ í›„ 영상 소견들: 임상화보.

Postoperative colorectal imaging studies play an important role in the detection of surgical complications and disease recurrence. In this pictorial essay, we briefly describe methods of surgery, imaging findings of their early and late complications, and postsurgical recurrence of cancer and inflammatory bowel disease.

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

Machine learning-based response assessment in patients with rectal cancer after neoadjuvant chemoradiotherapy: radiomics analysis for assessing tumor regression grade using T2-weighted magnetic resonance images.

PURPOSE: This study aimed to assess tumor regression grade (TRG) in patients with rectal cancer after neoadjuvant chemoradiotherapy (NCRT) through a machine learning-based radiomics analysis using baseline T2-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: In total, 148 patients with locally advanced rectal cancer(T2-4 or N+) who underwent MR imaging at baseline and after chemoradiotherapy between January 2010 and May 2021 were included. A region of interest for each tumor mass was drawn by a radiologist on oblique axial T2-weighted images, and main features were selected using principal component analysis after dimension reduction among 116 radiomics and three clinical features. Among eight learning models that were used for prediction model development, the model showing best performance was selected. Treatment responses were classified as either good or poor based on the MR-assessed TRG (mrTRG) and pathologic TRG (pTRG). The model performance was assessed using the area under the receiver operating curve (AUROC) to classify the response group. RESULTS: Approximately 49% of the patients were in the good response (GR) group based on mrTRG (73/148) and 26.9% based on pTRG (28/104). The AUCs of clinical data, radiomics models, and combined radiomics with clinical data model for predicting mrTRG were 0.80 (95% confidence interval [CI] 0.73, 0.87), 0.74 (95% CI 0.66, 0.81), and 0.75(95% CI 0.68, 0.82), and those for predicting pTRG was 0.62 (95% CI 0.52, 0.71), 0.74 (95% CI 0.65, 0.82), and 0.79 (95% CI 0.71, 0.87). CONCLUSION: Radiomics combined with clinical data model using baseline T2-weighted MR images demonstrated feasible diagnostic performance in predicting both MR-assessed and pathologic treatment response in patients with rectal cancer after NCRT.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Comparison of Four Diagnostic Guidelines for Hepatocellular Carcinoma Using Gadoxetic Acid-enhanced Liver MRI.

Background Noninvasive diagnostic guidelines for hepatocellular carcinoma (HCC) vary across different global geographic areas, especially regarding criteria about gadoxetic acid-enhanced MRI. Purpose To compare the diagnostic performance of four different international HCC diagnosis guidelines and readers' judgment in diagnosing HCC using gadoxetic acid-enhanced MRI in patients at high risk for HCC. Materials and Methods This retrospective study included patients who had not undergone treatment, were at risk for HCC, and who underwent gadoxetic acid-enhanced MRI from January 2015 to June 2018 from 11 tertiary hospitals in South Korea. Four radiologists independently reviewed focal liver lesions (FLLs) according to four guidelines: American Association for the Study of Liver Diseases (AASLD)/Liver Imaging Reporting and Data System (LI-RADS), Korean Liver Cancer Association-National Cancer Center (KLCA-NCC), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). Reader judgment (HCC or not HCC) was also recorded. Malignant FLLs were confirmed at pathology, and histologic and clinical follow-up data were used for benign FLLs. The guidelines' diagnostic performance was compared using generalized estimating equations. Additionally, the diagnostic odds ratio was assessed. Results A total of 2445 FLLs (median size, 27.4 mm) were analyzed in 2237 patients (mean age, 59 years ± 11 [SD]; 1666 male patients); 69.3% (1694 of 2445) were HCCs. KLCA-NCC showed the highest accuracy (80.0%; 95% CI: 78.7, 81.2; P = .001), with high sensitivity in Eastern guidelines (APASL, 89.1% [95% CI: 87.8, 90.3]; KLCA-NCC, 78.2% [95% CI: 76.6, 79.7]) and high specificity in Western guidelines (AASLD/LI-RADS, 89.6% [95% CI: 87.8, 91.2]; EASL, 88.1% [95% CI: 86.2, 89.9]) (P = .001). The diagnostic odds ratios were 20.7 (95% CI: 17.0, 25.3) for AASLD/LI-RADS, 18.9 (95% CI: 15.8, 22.6) for KLCA-NCC, 16.8 (95% CI: 13.8, 20.4) for EASL, and 8.9 (95% CI: 7.4, 10.7) for APASL. The readers' judgment demonstrated higher accuracy than that of the guidelines (accuracy, 86.0%; 95% CI: 84.9, 86.9; P = .001). Conclusion Among four different international HCC diagnosis guidelines, Eastern guidelines demonstrated higher sensitivity, whereas Western guidelines displayed higher specificity. KLCA-NCC achieved the highest accuracy, and AASLD/LI-RADS exhibited the highest diagnostic odds ratio. © RSNA, 2024 Supplemental material is available for this article.

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract.

Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability. Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated. Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10-6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.

Typical MR features and interpretation of perianal fistulas in patients with Crohn's disease.

Perianal fistulas in Crohn's disease (CD) are a poor prognostic phenotype requiring a combination of medical and surgical management. Perianal fistulas in CD are characterized by more complex and multi-branched fistulas, association with skin tags, and frequent presence of proctitis. A comprehensive approach with clinical examination, endoscopic and MR assessment is required, and in particular, MR interpretation provides detailed information on the type of fistula with its internal component and activity, secondary tracts and extension, internal, external openings, associated abscess, and presence of proctitis. Structured reporting of these items would be recommended for further discussion and management planning both at initial diagnosis and for disease monitoring during treatment follow-up. Management strategy would be individualized for each patient, and control of luminal disease activity could be an important determinant in the selection of treatment options. In this review, we provide an overview of the MRI evaluation of perianal fistulas in CD with a proposed structured MR report.

Assessing Active Bowel Inflammation in Crohn's Disease Using Intestinal Ultrasound: Correlation With Fecal Calprotectin.

AIM: To analyze the correlation between intestinal ultrasound (IUS) and serum and fecal biomarkers, and the characteristics of small bowel disease, for the assessment of active bowel inflammation. METHODS: Patients with Crohn's disease (CD) who underwent an initial IUS examination between July 2018 and November 2022 at our institution were included retrospectively. We divided small and large bowels into seven segments, and recorded the presence of active inflammation according to following criteria: bowel wall thickness ≥ mm with ≥1 of feature of active disease on IUS. The correlations between IUS-assessed activity and serum C-reactive protein (CRP, mg/dL) and fecal calprotectin (FC, µg/g) levels were analyzed. RESULTS: A total of 127 patients were included (mean age: 32.42 ± 12.07, M:F = 90:37, median disease duration 6 years [0-35]). Of them, 78 showed active bowel inflammation (61.4%), with inflammation distal to the terminal ileum being the most common disease location (n = 61, 78.2%). FC and serum CRP levels were significantly correlated with the number of segments with active inflammation (rho = 0.58, 0.48), number of segments with complications (r = 0.35, 0.31), and US activity score (r = 0.62, 0.54). With FC cutoff values of 100 and 150 µg/g, the concordance rates for patients with active small bowel disease were 78.7% (26/33) and 72.7% (24/33), respectively, which were better than those for other disease locations. CONCLUSIONS: Disease activity determined by IUS was significantly correlated with the biomarkers, with a better concordance rate in patients with active small bowel disease than in those with other disease locations with FC cut-off values of 100 and 150 µg/g.

Accelerometer-derived physical activity analysis of elderly osteoarthritis patients.

BACKGROUND: Because disability in Osteoarthritis (OA) may change physical activity (PA), which might affect the disease progression, it is important to measure a patient's daily PA to study the relationship between a patient's PA and disease progression. OBJECTIVE: The objective of the present study was to investigate the relationship between PA and patients with OA and people without OA using data from the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: Demographic study was conducted to obtain data of comorbidities of participants. PA was compared between the group with OA (OA group) and the group without OA (non-OA group). In addition, PAs of OA patients with comorbidities and those without comorbidities were compared. The cut-off of moderate to vigorous physical activity (MVPA) was obtained through a receiver operating characteristic (ROC) curve. RESULTS: In the demographic study, there were significantly more educated participants in the OA group (p < .001). Actigraph data showed a significant decrease in MVPA (p < .001) but a significant increase in light activity (p = .002) in the OA group. In addition, the OA group showed significantly lower light PA but significantly higher MVPA in ≥10 min bout length. OA patients with comorbidities showed higher MVPA than OA patients without comorbidities (p = .044). The cut-off point of MVPA was 7.071 min/day when ROC curve was conducted. CONCLUSIONS: The present study suggests that patients with OA and low activity need a certain level of physical activity and a cut-off point for MVPA is presented which accounts for comorbidities in OA patients.

Correlation between Harris hip score and gait analysis through artificial intelligence pose estimation in patients after total hip arthroplasty.

BACKGROUND: Recently, open pose estimation using artificial intelligence (AI) has enabled the analysis of time series of human movements through digital video inputs. Analyzing a person's actual movement as a digitized image would give objectivity in evaluating a person's physical function. In the present study, we investigated the relationship of AI camera-based open pose estimation with Harris Hip Score (HHS) developed for patient-reported outcome (PRO) of hip joint function. METHOD: HHS evaluation and pose estimation using AI camera were performed for a total of 56 patients after total hip arthroplasty in Gyeongsang National University Hospital. Joint angles and gait parameters were analyzed by extracting joint points from time-series data of the patient's movements. A total of 65 parameters were from raw data of the lower extremity. Principal component analysis (PCA) was used to find main parameters. K-means cluster, X-squared test, Random forest, and mean decrease Gini (MDG) graph were also applied. RESULTS: The train model showed 75% prediction accuracy and the test model showed 81.8% reality prediction accuracy in Random forest. "Anklerang_max", "kneeankle_diff", and "anklerang_rl" showed the top 3 Gini importance score in the Mean Decrease Gini (MDG) graph. CONCLUSION: The present study shows that pose estimation data using AI camera is related to HHS by presenting associated gait parameters. In addition, our results suggest that ankle angle associated parameters could be key factors of gait analysis in patients who undergo total hip arthroplasty.

Botulinum toxin injection strategy of intractable and relapsed piriformis syndrome: A case report.

RATIONALE: Piriformis syndrome (PS) is neuromuscular disorder caused by sciatic nerve compression by piriformis muscle and related to sciatic-type pain. When the conservative care fails, local injection or surgery can be also performed into piriformis. In recent years, botulinum toxin (BoNT) has also been considered as a new therapeutic option of piriformis syndrome. PATIENT CONCERNS: A man in his late 40s came to pain clinic for left low back pain. The symptom was aggravated with sitting position. DIAGNOSIS: Piriformis syndrome. INTERVENTIONS: The patient underwent BoNT injection with 100 IU with 2 mL into piriformis muscle for piriformis syndrome treatment, and his pain was relieved. However, it recurred 8 months later. BoNT injection was repeated with 100 IU with 5 mL. OUTCOMES: At the time of this writing, his pain was reduced for 2 years without any medication. LESSONS: We report a case of treating relapsed piriformis syndrome with BoNT injection of different dilution volume, suggesting that the higher the dilution volume, the more effective for therapeutic effect of BoNT.

Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer.

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.

Metronomic dose-finding approach in oral chemotherapy by experimentally-driven integrative mathematical modeling.

In conventional chemotherapy, maximum tolerated dose approach is considered as a first-line medication for cancer treatment in clinics. In contrast to the conventional chemotherapy which has heavy tumor burdens arising from high dose treatment, metronomic chemotherapy (MCT) engages relatively low dose without drug-free breaks, and is recognized as a promising strategy for a long-term management of the disease. Although doxorubicin (DOX), an anthracycline anti-cancer drug, showed a potential of maintenance effect in vitro, further study on in vivo-relevant concentration to achieve tumor suppression with no toxicity is required to apply the MCT in clinicals. Therefore, the objective of this study was to identify an optimal MCT regimen of DOX by determining concentration-response relationships of tumor suppression (pharmacodynamic; PD) and cardiac toxicity (toxicodynamic; TD). Utilizing an oral DOX formulation complexed with deoxycholic acid (DOX/DOCA complex) which has enhanced bioavailability, physiologically-based pharmacokinetic (PBPK) model was linked to TD and PD models to generate drug profiles from the combined PK, TD, and PD parameters. The integrated model was validated for various scenarios of administration route, formulation, dose, and frequency. The established mathematical model facilitated calculations of adequate in vivo-relevant dosages and intervals, suggesting the optimum oral metronomic regimen of DOX. It is expected to serve as a useful guideline for the design and evaluation of oral DOX formulations in future preclinical/clinical studies.

Caspase-3 mediated switch therapy of self-triggered and long-acting prodrugs for metastatic TNBC.

Triple-negative breast cancer (TNBC) is characterized by its highly heterogeneous microenvironment and propensity for aggressive behavior, both of which represent, along with poor prognosis and high incidence of relapse, the main challenges of curing the disease. Although recent progress in targeted chemotherapy combinations has shown promising outcomes, conventional targeted chemotherapeutic approaches have relied on exploiting the expression of certain molecules or proteins overexpressed on cancer cells as drug targets, which have demonstrated limited clinical benefit against metastatic cancers. Here, we describe a tumoral caspase-3 mediated peptide-doxorubicin conjugates (PDC) switch therapy that adopts two different caspase-3 cleavable PDCs, RGDEVD-DOX (TPD1) and EMC-KGDEVD-DOX (MPD1), for targeting metastatic triple-negative breast cancer (mTNBC). First, using TPD1, an integrin αVß3 based targeted strategy was utilized to target tumor cells or tumor vasculature associated with the highly malignant progression of mTNBC. TPD1 triggered the tumor cell-specific initial apoptosis and the induction of caspase-3 expression in the target tumor site. Then MPD1 was administered sequentially, which is an albumin-binding prodrug, and activated by induced caspase-3 in order to maintain the tumoral caspase-3 level and release the cytotoxic payload. The PDC switch therapy markedly accumulated doxorubicin in the tumor site and augmented tumor-specific in situ amplification of apoptosis. Importantly, the PDC switch therapy exerted a bystander killing effect on the neighboring cancer cells thus demonstrating potent therapeutic efficacy against both local and metastatic cancers. Given the limited therapeutic outcomes with conventional targeted therapies, our strategy of regulating the expression of caspase-3 level as a drug target could provide as a more durable and effective alternative in the treatment of highly heterogeneous mTNBC.

A novel oral metronomic chemotherapy provokes tumor specific immunity resulting in colon cancer eradication in combination with anti-PD-1 therapy.

In this study, we investigated the immune-modulating effects of a novel metronomic chemotherapy (MCT) featuring combined oral oxaliplatin (OXA) and pemetrexed (PMX) for colon cancer. OXA and PMX were ionically complexed with lysine derivative of deoxycholic acid (DCK), and incorporated into nanoemulsions or colloidal dispersions, yielding OXA/DCK-NE and PMX/DCK-OP, respectively, to improve their oral bioavailabilities. MCT was not associated with significant lymphotoxicity whereas the maximum tolerated dose (MTD) afforded systemic immunosuppression. MCT was associated with more immunogenic cell death and tumor cell MHC-class I expression than was MTD. MCT improved the tumor antigen presentation of dendritic cells and increased the number of functional T cells in the tumor. MCT also helped to enhance antigen-specific memory responses both locally and systemically. By combining MCT with anti-programmed cell death protein-1 (αPD-1) therapy, the tumor volume was suppressed by 97.85 ± 84.88% compared to the control, resulting in a 95% complete response rate. Upon re-challenge, all tumor-free mice rejected secondary tumors, indicating the induction of a tumor specific memory response. Thus, MCT using an OXA and PMX combination, together with αPD-1, successfully treated colon cancer by activating both innate and adaptive immune cells and elicited tumor-specific long-term immune memory while avoiding toxicity caused by MTD treatment.

Comparison of epidural, spinal, and saddle block for holmium laser enucleation of prostate (HoLEP): A prospective randomized, comparative study.

BACKGROUND: Holmium laser enucleation of the prostate (HoLEP) has become an important treatment modality for benign prostate hypertrophy. The aim of the present study was to compare regional anesthesia methods for HoLEP operation and to determine the optimal technique. METHODS: Sixty patients with American Society of Anesthesiologists scores of I-III were randomly allocated into 3 groups. Patients in group E received an epidural block with 75 mg of bupivacaine plus 50 µg of fentanyl. In group S, 15 mg of bupivacaine and 50 µg fentanyl were used for spinal anesthesia. In group SA, patients received saddle block with 15 mg of bupivacaine and 50 µg of fentanyl. RESULTS: Time to T10 dermatome block and to maximal level block were longest in group E (P < .05), and maximal sensorial block level was higher in group E than group SA (P < .05). There was a significant difference in postoperative motor block, but no difference in systolic blood pressure and heart rate. CONCLUSION: Among 3 techniques, saddle block might be preferable in HoLEP because an adequate sensorial level was achieved with lower motor block and stable hemodynamics.

Ultrasonography of the distal common bile duct: An easy-to-perform technique for better visualization.

BACKGROUND AND STUDY AIMS: No standard ultrasonography (US) method exists for visualizing the distal common bile duct (CBD). The supine HD view is usually adopted for CBD evaluation, but duodenal or colonic gas shadowing can affect this view. PATIENTS AND METHODS: We developed and evaluated an easy-to-perform technique, the supine distal CBD view, applying the US protocol for the distal CBD evaluation. Five reviewers checked the visibility of the distal CBD and cystic duct, as well as each view's image quality and influencing factors. RESULTS: The visibility of the distal CBD was enhanced on the supine distal CBD view (86.0%-94.6%) versus the supine hepatoduodenal view (40.8%-82.1%), with less variability among the reviewers. The image quality of the supine distal CBD view was superior to that of the supine HD view (2.52 ± 0.67 vs. 1.93 ± 0.86, respectively; p < 0.01). The depth of the distal CBD from the surface was significantly larger in the patients with nonvisible distal CBDs. CONCLUSION: We present a user-friendly, easy-to-perform US view for locating and visualizing the distal CBD. With this technique, the distal CBD can be evaluated without changing a patient's position or increasing the duration of the procedure.

Caspase-cleavable peptide-doxorubicin conjugate in combination with CD47-antagonizing nanocage therapeutics for immune-mediated elimination of colorectal cancer.

Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8+ T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.2% (p < 0.001) tumor growth inhibition in an established CRC model. T cell-mediated elimination of tumors was also confirmed by the tumor-specific activation of T cells detected by IFNγ and tumor-free mice were observed (95%) that bared a memory response when re-challenged. The strategically developed MPD-1 is an ideal adjuvant to immunotherapy and the combination with FS nanocage triggers potent immunity against MSS CRC. In summary, we present an approach to initiate and stimulate immune-mediated eradication of cancer cells using synergistic immunogenic agents targeting the MSS CRC.

Anticoagulation therapy promotes the tumor immune-microenvironment and potentiates the efficacy of immunotherapy by alleviating hypoxia.

PURPOSE: Here, this study verifies that cancer-associated thrombosis (CAT) accelerates hypoxia, which is detrimental to the tumor immune microenvironment by limiting tumor perfusion. Therefore, we designed an oral anticoagulant therapy to improve the immunosuppressive tumor microenvironment and potentiate the efficacy of immunotherapy by alleviating tumor hypoxia. EXPERIMENTAL DESIGN: A novel oral anticoagulant (STP3725) was developed to consistently prevent CAT formation. Tumor perfusion and hypoxia were analyzed with or without treating STP3725 in wild-type and P selectin knockout mice. Immunosuppressive cytokines and cells were analyzed to evaluate the alteration of the tumor microenvironment. Effector lymphocyte infiltration in tumor tissue was assessed by congenic CD45.1 mouse lymphocyte transfer model with or without anticoagulant therapy. Finally, various tumor models including K-Ras mutant spontaneous cancer model were employed to validate the role of the anticoagulation therapy in enhancing the efficacy of immunotherapy. RESULTS: CAT was demonstrated to be one of the perfusion barriers, which fosters immunosuppressive microenvironment by accelerating tumor hypoxia. Consistent treatment of oral anticoagulation therapy was proved to promote tumor immunity by alleviating hypoxia. Furthermore, this resulted in decrease of both hypoxia-related immunosuppressive cytokines and myeloid-derived suppressor cells while improving the spatial distribution of effector lymphocytes and their activity. The anticancer efficacy of αPD-1 antibody was potentiated by co-treatment with STP3725, also confirmed in various tumor models including the K-Ras mutant mouse model, which is highly thrombotic. CONCLUSIONS: Collectively, these findings establish a rationale for a new and translational combination strategy of oral anticoagulation therapy with immunotherapy, especially for treating highly thrombotic cancers. The combination therapy of anticoagulants with immunotherapies can lead to substantial improvements of current approaches in the clinic.