Distal Tumors Research Articles

A Self-Amplifying Photodynamic Biomedicine for Cascade Immune Activation Against Triple-Negative Breast Cancer.

The efficacy of immunotherapy in triple-negative breast cancer (TNBC) is significantly hindered by its low immunogenicity and immunosuppressive tumor microenvironment. Non-invasive photodynamic therapy (PDT) is increasingly recognized as a potential immunotherapeutic stimulant in the treatment of TNBC. However, photodynamic immunotherapy is constrained by tumor hypoxia and excessive inflammation suppression during the course of treatment. Herein, a simple and efficacious biomedicine is formulated to overcome adverse influences by amplifying photodynamic immunotherapy, thereby stimulating the systemic immune response. Specifically, the approach targeted tumor delivery by employing specific agents such as the photosensitizer (verteporfin), the hypoxic ameliorator (atovaquone), and the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) signaling blocker (celecoxib). More importantly, the biomedicine effectively ameliorated hypoxia and inhibited COX-2/PGE2 signaling, thereby amplifying PDT-induced immunogenic cell death. This, in turn, enhanced the efficacy of photodynamic immunotherapy and triggered a robust immune response cascade. Notably, the self-amplifying photodynamic biomedicine significantly inhibited primary tumors, distal tumors, lung metastases, and post-operative recurrence while maintaining high biocompatibility. To sum up, the work provides a viable cascade stimulation approach and an efficient biomedical nanoplatform, offering a novel strategy for photodynamic immunotherapy of TNBC in the clinic.

Coevolution of Atypical BRAF and KRAS Mutations in Colorectal Tumorigenesis

Abstract BRAF mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non–class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (n = 6,605 tumors) compared class 1 (n = 709, 10.7% of colorectal cancers), class 2 (n = 31, 0.47%), and class 3 (n = 81, 1.22%) mutations. Class 2–mutant and class 3–mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; P < 0.001), often at atypical sites (KRAS noncodon 12/13/61, NRAS, or NF1). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker BRAF driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical BRAF mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup. Implications: The heterogeneous nature of BRAF-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.

Hyaluronan-coated gold nanoshells for enhanced synergistic effect and immunogenic cell response of chemo-photothermal therapy on lung cancer.

Lung cancer (LC) is the predominant cause of cancer-related fatalities globally, with the highest death rates in both genders, primarily attributed to smoking. The non-kinase transmembrane cell surface glycoprotein, CD44, enhances LC cell migration and invasion, leading to drug resistance and an unfavorable prognosis. This research formulated a cisplatin-loaded gold nanoshell (HCP@GNS) integrated with hyaluronan (HCP@GNS@HA) to enhance targeting capability and realize a synergistic effect of chemo-photothermal therapy (chemo-PTT) against LC. The coating of hyaluronic acid (HA) facilitated the uptake of HCP@GNS@HA into CD44-rich cancer cells, maintaining the superior photothermal conversion capacity of HCP@GNS nanoparticles for hyperthermia and photothermal eradication of tumor tissues under near-infrared exposure. As a nanocarrier, HCP@GNS@HA exhibited high biocompatibility and hemocompatibility, showing stronger cytotoxicity than either the free drug or photothermal therapy alone when combined with NIR irradiation, especially at high cis-diamminedichloroplatinum (II) (CDDP) concentrations. The chemo-PTT mediated by HCP@GNS@HA effectively curtailed tumor growth without adverse effects, significantly mobilizing B cells, DC cells, macrophages, natural killer (NK) cells, and NKT cells in the distal tumor against tumor growth. In conclusion, the developed hyaluronic acid (HA)-coated gold nanoshells could potentially serve as a promising candidate for nanomedicine, tackling both primary and distal LC growth.

The efficacy of open transanal drainage tube against anastomotic leakage in left-sided colorectal cancer surgery: a propensity score matching study

Background/AimThe effectiveness of a transanal drainage tube (TAT) for the prevention of anastomotic leakage after double stapling technique (DST) anastomosis in colorectal cancer has been reported. Previously, TATs had been placed and connected to drainage bags. It was considered that a higher decompression effect could be expected by inserting an open-type TAT, without connection to a drainage bag. In this study, the relation between anastomotic leakage and the application of this type of TAT in left-sided colorectal cancer surgery was investigated, using propensity score matching (PSM).Materials and methodsFrom January 2016 to July 2023, 233 consecutive patients underwent radical surgery for sigmoid colon and rectal cancers and reconstruction using DST at Osaka Metropolitan University Hospital. Patients were divided into two groups: those who had a closed TAT inserted (CLOSED group), and those who had an open TAT inserted (OPEN group).ResultsOverall, open TATs were inserted in 43 patients, and closed TATs were inserted in 190 patients. PSM was performed between the OPEN and CLOSED groups on the basis of the following 13 factors: age, sex, BMI, diabetes mellitus (DM), smoking history, modified Glasgow prognostic score (mGPS), ASA-PS, location of distal tumor edge, operative procedure, surgical approach, operative time, intraoperative blood loss, and pathological stage. The multivariate analysis of significant factors identified a BMI of 25 or more, a location of distal edge on middle to lower rectum, and a closed TAT, as independent risk factors for anastomotic leakage (HR: 8.72; p = 0.038, HR: 10.06; p = 0.034 and HR: 17.43; p = 0.033).ConclusionAn open TAT may be effective in preventing anastomotic leakage in left-sided colorectal cancer surgery.

Accelerating Tumor Immunotherapy Through a Synergistic Strategy of Increasing Throttle and Relaxing Brake.

Tumor immunotherapy has been widely used clinically, but it is still hindered by weak antitumor immunity and immunosuppressive tumor microenvironment (TME). Here, a kind of simple disodium hydrogen phosphate nanoparticle (Na2HPO4 NP) is prepared to "accelerate" tumor immunotherapy by "increasing throttle" and "relaxing brake" simultaneously. The obtained Na2HPO4 NPs release a large amount of Na+ and HPO42- ions within tumor cells, thereby activating the caspase 1/GSDMD-mediated pyroptosis pathway to achieve immune activation. Meanwhile, alkalescent Na2HPO4 NPs can further consume lactic acid through acid-base neutralization, and regulate adenosine (Ado) metabolism via nanomaterial-induced biocatalytic process to relieve two-tier immunosuppression. Collectively, Na2HPO4 NPs effectively activate the antitumor immune process in vivo, and dramatically inhibit primary and distal tumor growth. This work will provide unique inspiration and strategy for the regulation of both positive and negative directions in immunotherapy.

Accelerating Tumor Immunotherapy Through a Synergistic Strategy of Increasing Throttle and Relaxing Brake

Tumor immunotherapy has been widely used clinically, but it is still hindered by weak antitumor immunity and immunosuppressive tumor microenvironment (TME). Here, a kind of simple disodium hydrogen phosphate nanoparticle (Na2HPO4 NP) is prepared to "accelerate" tumor immunotherapy by "increasing throttle" and "relaxing brake" simultaneously. The obtained Na2HPO4 NPs release a large amount of Na+ and HPO42‐ ions within tumor cells, thereby activating the caspase 1/GSDMD‐mediated pyroptosis pathway to achieve immune activation. Meanwhile, alkalescent Na2HPO4 NPs can further consume lactic acid through acid‐base neutralization, and regulate adenosine (Ado) metabolism via nanomaterial‐induced biocatalytic process to relieve two‐tier immunosuppression. Collectively, Na2HPO4 NPs effectively activate the antitumor immune process in vivo, and dramatically inhibit primary and distal tumor growth. This work will provide unique inspiration and strategy for the regulation of both positive and negative directions in immunotherapy.

Doxorubicin prodrug for γ-glutamyl transpeptidase imaging and on-demand cancer therapy.

The γ-glutamyl transpeptidase (γ-GGT) is an important tumor marker, which has been reported to be firmly associated with the developmental stage of liver cancer. Therefore, it makes sense to image and monitor γ-GGT level and design γ-GGT-responsive prodrug for integrated diagnosis and treatment of liver cancer. Herein, we prepare a doxorubicin (Dox) prodrug for imaging γ-GGT and on-demand treating liver cancer. When γ-GGT exists, the γ-glutamyl group will be cut off to liberate free Dox for monitoring cancer progression and killing tumor cells. Fortunately, little Dox is released due to the low level of γ-GGT in normal cells, which improves the safety and efficiency of chemotherapy. To further improve the tumor targeted ability, Dox prodrug is loaded in hyaluronic acid modified liposome nanoparticles to form the nano-prodrug. Then nano-prodrug is enriched in the tumor by binding to the high expressed CD44 on cancer cells. With the assistance of anti-PD-L1, nano-prodrug effectively inhibits the growth of proximal and distal tumors.

Facile integration of a binary nano-prodrug with αPD-L1 as a translatable technology for potent immunotherapy of TNBC.

Immune checkpoint blockers (ICBs)-based immunotherapy is a favorable approach for efficient triple-negative breast cancer (TNBC) treatment. However, the therapeutic efficacy of ICBs is greatly compromised by immunosuppressive tumor microenvironments (TMEs) and low expression levels of programmed cell death ligand-1 (PD-L1). Herein, we constructed an amphiphilic prodrug by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond, which can self-assemble into GEM-MSA-2 (G-M) nanoparticles (NPs) with a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Notably, the immunogenic cell death (ICD)-triggering effect of GEM together with the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation properties of MSA-2 enables efficient infiltration of non-exhausting T cells and repolarization of macrophages from M2 to M1 types in the tumor microenvironment for transforming a cold tumor to a hot one. Most importantly, G-M NPs treatment increases the PD-L1 expression levels, thus providing a unique opportunity for further integration with anti-PD-L1 monoclonal antibody (αPD-L1) for eliciting stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge. Overall, this study presents a minimalist nano-prodrug combined with αPD-L1 as a simple yet robust translatable nanotechnology for potent chemo-immunotherapy of TNBC. STATEMENT OF SIGNIFICANCE: Enhancing the therapeutic efficacy of αPD-L1 for tumor immunotherapy via a translatable technology remains a challenge. We report herein facile integration of a binary nano-prodrug with αPD-L1 for potent immunotherapy of TNBC. An amphiphilic prodrug is constructed by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond. The resulting self-assembled GEM-MSA-2 (G-M) nanoparticles (NPs) show a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Besides the induced immunogenic cell death (ICD) and activated cGAS-STING pathway, G-M NPs increase the PD-L1 expression levels, providing a unique opportunity for further integration with αPD-L1 to elicit stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge.

Recurrent Tracheal Schwannomas: A Case Report and Literature Review

ABSTRACT Tracheal schwannomas are rare benign tumors in pediatric age group. We report a case of recurrent distal tracheal tumor in a 12 year old boy successfully managed with resection under cardiopulmonary bypass and review the relevant literature.

MRI of the Rectum: A Decade into DISTANCE, Moving to DISTANCED.

Over the past decade, advancements in rectal cancer research have reshaped treatment paradigms. Historically, treatment for locally advanced rectal cancer has focused on neoadjuvant long-course chemoradiotherapy, followed by total mesorectal excision. Interest in organ preservation strategies has been strengthened by the introduction of total neoadjuvant therapy with improved rates of complete clinical response. The administration of systemic induction chemotherapy and consolidation chemoradiotherapy in the neoadjuvant setting has introduced a new dimension to the treatment landscape and patients now face a more intricate decision-making process, given the expanded therapeutic options. This complexity underlines the importance of shared decision-making and brings to light the crucial role of radiologists. MRI, especially high-spatial-resolution T2-weighted imaging, is heralded as the reference standard for rectal cancer management because of its exceptional ability to provide staging and prognostic insights. A key evolution in MRI interpretation for rectal cancer is the transition from the DISTANCE mnemonic to the more encompassing DISTANCED-DIS, distal tumor boundary; T, T stage; A, anal sphincter complex; N, nodal status; C, circumferential resection margin; E, extramural venous invasion; D, tumor deposits. This nuanced shift in the mnemonic captures a wider range of diagnostic indicators. It also emphasizes the escalating role of radiologists in steering well-informed decisions in the realm of rectal cancer care.

Physical Activity and Quality of Life After Distal Femur Tumor Resection and Limb Salvage.

Background/Objectives: Distal femur tumor resection with limb salvage is a demanding procedure that offers hope for patients by preserving the limb rather than opting for amputation. While limb salvage can improve both physical function and psychological well-being, there's limited knowledge on how active patients remain afterward and how their Quality of Life (QoL) is affected, especially regarding physical activities and sports. This study investigates the quality of life of the patients through the development of motor activity, focusing on both physical and sporting activity of the above-mentioned individuals and their physical abilities to participate in activities of daily and sporting life after surgery. Methods: This study involved 16 patients aged 19-47 years who had undergone surgical resection and replacement of the distal femur for the treatment of sarcoma and were selected by random sampling from a total of 72 patients who had undergone a similar procedure. To explore the topic in depth, the researchers followed the triangulation method. From July 2023 to February 2024, we used surveys and interviews to explore their physical activity (PA) levels, sports participation, and QoL. This study included the International Physical Activity (PA) Questionnaire (IPAQ), the University of California and Los Angeles (UCLA) Activity Score, and semi-structured interviews. The data were analyzed using the statistical software packages SPSS 25 and Excel. Results: Most participants reported moderate to high levels of PA, according to IPAQ, and continued engaging in sports, with swimming, walking, and stair climbing being the most common activities. No significant relationship was found between their PA levels and factors such as age, BMI, or the side of the affected limb. Interviews showed that patients' motivation and their surgeon's guidance played key roles in their return to regular activities, though many exercised less frequently or intensely than recommended. Conclusions: Patients who undergo limb salvage surgery following distal femur tumor removal generally maintain a good level of physical activity, which supports their QoL. Encouraging these patients to stay active and even engage in sports appears feasible, especially when guided by medical professionals. These findings highlight the potential benefits of tailored rehab programs to improve long-term health and QoL in sarcoma survivors, although larger studies are needed for more comprehensive insights.

Study of surgical feasibility and outcome of laparoscopic surgery in malignant rectal tumors

ABSTRACT Objective To assess the viability, limitations, technical challenges, and outcomes of malignant rectal tumors laparoscopic mesorectal resection with the assessment of postoperative continence. Patients and Methods The study involved 20 people who had malignant rectal tumors. All patients underwent laparoscopic mesorectal resection. Data were recorded and investigated during Preoperative, operative, and postoperative periods. Results Low anterior, anterior, and intersphincteric resections were performed in 30%, 7%, and 35% of patients, respectively. The mean operative period lasted was on average of 3.10 ± 0.72 h. Only one case (5%) showed postoperative complications. The peristalsis became audible after one to two days, on an average of 1.65 ± 0.49 days. The hospital staying mean duration was 4.25 ± 0.72. Only for 7 patients with intersphincteric resection, the mean Wexner score was 3.0 ± 1.91 after the closure of ileostomy. Patients who underwent low anterior resection had significantly longer postoperative hospital stays (p = 0.020). There was a substantial relationship between the number of both the resected lymph nodes (LN) and the involved ones (p < 0.001). Conclusion Laparoscopic mesorectal excision for rectal tumors is superior nowadays on traditional open approach, has no increased operative time and has privileges of decreasing postoperative pain, decreasing complications, decreasing the hospital stay, early recovery and fast first bowel motion and helps for better visualization and resection of all related lymph nodes. Intersphincteric mesorectal excision of rectal tumors is preferred for all patients below 60 years old with distal rectal tumors regardless of the tumor lower edge’s extended length from the anal verge as long as the external sphincters are preserved.

Gastric partitioning versus gastrojejunostomy for gastric outlet obstruction due to unresectable gastric cancer: randomized clinical trial.

Gastric outlet obstruction due to unresectable tumours is usually managed with a gastrojejunostomy. Unfortunately, the unsatisfactory outcomes of this procedure have led to the search for alternatives, including gastric partitioning. Monocentric, randomized, parallel, open-label trial that included patients with obstructive, unresectable distal gastric tumours. The objective was to compare gastric partitioning to gastrojejunostomy, considering the gastric outlet obstruction scoring system scale as the main outcome. Randomization was performed using computer-generated software available online and after the application of the informed consent term, the allocation group was revealed to the surgeon before the surgical procedure. Over 7 years, 90 patients were initially randomized. After applying the inclusion and exclusion criteria, 25 patients were included in the gastrojejunostomy group and 27 in the partitioning group. Both groups were similar regarding initial clinical characteristics including sex, age, weight, clinical performance, and the acceptance of oral diet. Surgery duration, length of hospital stay, postoperative complications, and 30- and 90-day mortality rates were similar between groups. Acceptance of normal diet was more frequently reached by patients in the partitioning group (96% versus 72%; P = 0.022). During outpatient follow-up, maintenance of oral intake and weight was similar between groups. Patients in the partitioning group received more frequent red blood cell transfusions (81% versus 52%; P = 0.024). There was no difference regarding the administration of palliative chemotherapy lines and survival. In the multivariable analysis, the inability to eat a full diet (P = 0.035) and the absence of palliative chemotherapy after the procedure (P = 0.001) were associated with worse survival. Gastric partitioning provided a better return of the ability to accept food orally. There was no difference regarding postoperative complications and long-term survival. NCT02065803, clinicaltrials.gov.

Evaluating functional outcomes and quality of life in musculoskeletal tumor patients with distal femoral megaprostheses: a case-control study

BackgroundEndoprosthetic knee replacement using megaprostheses has become a common strategy for preserving joint function in patients with distal femur tumors. While existing literature has primarily focused on surgical techniques, complications, and implants, recent improvements in patient survival rates have sparked increased interest in the long-term functional outcomes associated with this treatment.MethodsThis case-control study evaluated functional outcomes—Timed Up and Go (TUG), 6-Minute Walk Test (6MWT), knee flexor and extensor muscle strength, and sagittal knee range of motion—and health-related quality of life (SF-36) between patients with distal femoral megaprostheses (n = 31) and healthy controls (n = 48). Participants performed the TUG and 6MWT equipped with an inertial measurement unit. Additionally, bivariate Spearman correlations were calculated within the patient group to assess relationships between Musculoskeletal Tumour Society (MSTS) scores and functional outcomes.ResultsPatients performed significantly worse than controls in the TUG test, with longer completion times (Mean Difference: -3.3 s; 95% CI: -5.7 to -0.9; p = 0.008), reduced rotational speed during the middle turn (Mean Difference: 16°/s; 95% CI: 7 to 25; p < 0.001) and final turn (Mean Difference: 22°/s; 95% CI: 9 to 34; p < 0.001), and lower vertical acceleration during the Sit-to-Stand phase (Mean Difference: 1.3 m/s²; 95% CI: 0.1 to 2.5; p = 0.032). In the 6MWT, patients walked 86 m less on average than controls (95% CI: 35 to 136; p = 0.002). Knee range of motion was significantly reduced, with median flexion of 90.2° (range: 5–125) in patients versus 136.4° (range: 115–150) in controls (p < 0.001, Z = -7.268). Muscle strength was also markedly lower in patients (p < 0.001). The SF-36 revealed significant differences in the Physical Component Summary (Mean Difference 95% CI: 15.5 [10.0 to 20.9]; p < 0.001), while no significant differences were found in the Mental Component Summary (p > 0.05). In patient group, bivariate Spearman correlations indicated a very strong positive association between MSTS scores and knee extension strength (ρ = 0.710; p < 0.001), and strong positive correlations with sagittal knee range of motion (ρ = 0.472; p = 0.015), total walking distance in 6MWT (ρ = 0.474; p = 0.019), and final turn rotational speed in TUG (ρ = 0.439; p = 0.032).ConclusionOur findings demonstrate a strong association between knee extensor strength and range of motion with overall functional performance, as reflected in MSTS scores. While nearly 75% of patients achieved scores classified as “good” to “excellent,” objective measures from the TUG and 6MWT revealed significant performance deficits compared to healthy controls, likely due to limitations in knee extensor strength and range of motion. These results highlight the need for targeted rehabilitation strategies focused on enhancing muscle strength and range of motion to optimize long-term functional recovery in these patients.

Is tumour location a dominant risk factor of recurrence in early rectal cancer?

Impact of rectal tumour location on risk of lymph node metastases (LNM) and recurrence in early RC is poorly studied and elusive. Tumour location as a prognostic factor may contribute to optimise management of early RC in the future. The aim of this study was to investigate rectal tumour location as an independent predictor of oncologic outcome in early rectal cancer (RC). Retrospective multicentre national cohort study on prospectively collected data on all patients with T1-T2 RC, undergoing surgical resection between 2009 and 2021. Tumour location was categorised as distal (0-5cm), mid (5-10cm), and proximal (10-16cm), measured from the anal verge. Incidence of LNM in the 2424 included T1-T2 RC patients was 18.2%, 17.3% and 21.6% for distal, mid and proximal tumours, respectively. Recurrence was detected in 130 (7.6%) out of 1705 patients available for recurrence analyses (60-month median follow-up). Incidence of recurrence was twice as high in distal (11.4%) compared to proximal (5.6%) tumours and was 8.3% in mid located tumours. Distal (HR 2.051, CI 1.248-3.371, P < 0.05) and mid (HR 1.592, CI 1.061-2.388, P < 0.05) tumour location were significant risk factors of recurrence in uni- and multivariate Cox regression analyses. This study shows that tumour location significantly affects incidence of recurrence in early RC, with an increasing risk for mid and especially distal location, found to be a predominant risk factor of recurrence. Our findings stress the need for an increased awareness on differences in oncologic outcome related to tumour location in early RC.

Self-delivering RNAi immunotherapeutic PH-762 silences PD-1 to generate local and abscopal antitumor efficacy.

Immunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086). PH-762 pharmacology was characterized in vitro, and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy. PH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo, IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity. These data support PH-762 as a promising candidate for neoadjuvant immunotherapy in clinical studies.

Remolding the tumor microenvironment by bacteria augments adoptive T cell therapy in advanced-stage solid tumors

The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells. Here, we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment. Our study reveals that intratumor injection of E. coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5, together facilitating tumor infiltration of adoptively transferred T cells. The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy. This combinatorial therapy, consisting of E. coli adjuvant and adoptive T-cell therapy, effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors. Notably, this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination. This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors, including melanoma and hepatocellular carcinoma, by converging attacks from both inside and outside the tumor tissues.

Cryo-thermal therapy reshaped the tumor immune microenvironment to enhance the efficacy of adoptive T cell therapy

BackgroundAdoptive cell therapies (ACT) exhibit excellent efficacy in hematological malignancy. However, its application in solid tumors still has many challenges partly due to the tumor immune microenvironment. Cryo-thermal therapy (CTT) can induce an acute inflammatory response and remold the immune environment, providing an appropriate environment for the activation of adaptive immunity. However, it remains unclear whether CTT can enhance the efficacy of ACT.MethodsA bilateral B16F10 tumor-bearing mouse model was used to assess whether CTT could enhance the efficacy of ACT. The right large tumor was subjected to CTT, and the left small tumor was collected for flow cytometry, RNA-seq, immunohistochemistry and TCR Vβ sequencing. Finally, bilateral B16F10 tumor-bearing mice and 4T1 tumor-bearing mice were used to assess the efficacy after CTT combined with ACT.ResultsCTT dramatically reshaped the immune microenvironment in distal tumors to an acute inflammatory state by promoting innate cell infiltration, increasing cytokine production by macrophages and DCs. The remodeling of the tumor immune microenvironment further enhanced the antitumor efficiency of ACT by increasing the proliferation of T cells, promoting activation of the effector functions of T cells and boosting the expansion of TCR clones.ConclusionsOur results suggest that CTT can significantly reshape the tumor immunosuppressive microenvironment and convert “cold tumors” into “hot tumors,” thereby enhancing ACT-induced immune responses and maximizing the therapeutic effect of ACT.

HPB SO54 - Outcomes of Isolated Bile Duct Resection for Cholangiocarcinoma; More Than 15 Years Experience in a Single Tertiary HPB Centre

Abstract Background Cholangiocarcinoma of the extrahepatic biliary tree usually requires a major resection to achieve clear margins with adequate lymphadenectomy. For perihilar tumours this involves extended liver resection with bile duct resection whilst distal tumours require pancreaticoduodenectomy. Occasionally a combination of both (hepato-pancreaticoduodenectomy) is required. These procedures are associated with high morbidity and mortality. In a small number of patients, cholangiocarcinoma is confined to the extrahepatic bile duct with no involvement of the liver or pancreas and a bile duct resection alone is an option. We reviewed the outcomes of patients who underwent bile duct resection for cholangiocarcinoma in our unit. Method We identified all patients who underwent bile duct resection and hepaticojejunostomy for cholangiocarcinoma between June 2007 and June 2023 in our centre from a prospectively maintained database. Patient demographics, complications, histology, resection margin status, follow-up, recurrence, and survival were recorded. Time to recurrence and overall survival were analysed using Kaplan Meier analysis. Results Thirteen patients underwent bile duct resection and hepaticojejunostomy for cholangiocarcinoma. 12 (92%) were male and the median (range) age was 72 (41-82). No patients received neoadjuvant treatment. 3 (23%) patients developed postoperative complications with 1 (7.7%) perioperative mortality. R0 margin was achieved in 6 (46%). The median (range) postoperative stay was 7 (5-25) days. 8 (61.5%) patients received adjuvant chemotherapy. 7 patients (53.8%) developed recurrent disease at a median of 12 (IQR 8-54) months following surgery. The most common sites of recurrence were the liver (23.1%) followed by local recurrence (15.4%). The median survival was 38 (IQR 20-95) months. Conclusion Extrahepatic bile duct resection with hepaticojejunostomy is an option for patients with cholangiocarcinoma of the extrahepatic bile duct without macroscopic involvement of the liver or pancreas. In our series this procedure was associated with a low morbidity and perioperative mortality with acceptable recurrence rates and overall survival despite only modest R0 resection rates. Isolated bile duct resection with hepaticojejunostomy should be considered for tumours without macroscopic involvement of the liver or pancreas, especially in patients of borderline fitness for a more extensive resection.

Preferential activation of type I interferon-mediated antitumor inflammatory signaling by CuS/MnO2/diAMP nanoparticles enhances anti-PD-1 therapy for sporadic colorectal cancer

Converting the “cold” tumor microenvironment (TME) to a “hot” milieu has become the prevailing approach for enhancing the response of immune-excluded/immunosuppressed colorectal cancer (CRC) patients to immune checkpoint blockade (ICB) therapy. During this process, inflammation accompanied by different kinds of chemokines/cytokines inevitably occurs. However, some activated inflammatory signals exhibit protumor potency. Therefore, strategies that preferentially activate antitumor inflammatory signaling rather than tumor-promoting signaling need to be developed. Herein, we constructed a STING agonist-loaded CuS/MnO2 bimetallic nanosystem, termed diAMP-BCM. BCM with an optimized Cu/Mn ratio efficiently promoted the activation of proinflammatory signaling, and in combination with the STING agonist diAMP, diAMP-BCM controllably activated tumoricidal inflammatory signaling in APCs. DiAMP-BCM can efficiently generate ROS and promote the activation of STING, which induces the apoptosis of cancer cells and promotes the recruitment of monocytes while facilitating the polarization of macrophages and maturation of DCs. MC38 and CT26 CRC models were established to evaluate the in vivo antitumor effects of diAMP-BCM. Combined with ICB therapy, diAMP-BCM enables the rebuilding of tumor milieus with efficient tumor growth inhibition and alleviation of T-cell exhaustion, particularly in distal tumors, in sporadic colorectal cancer therapy. This study established a nanoplatform to promote the preferential activation of antitumor inflammatory signaling, rebuild the T-cell repertoire and alleviate T-cell exhaustion to enhance cancer ICB immunotherapy.Graphical