Reduction In Tumor Volume Research Articles

Abstract 5345: Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines

Abstract The human leukocyte antigen (HLA) class I major histocompatibility complex (MHC) plays an integral role in immune surveillance by presenting intracellular antigen peptides on the cell surface, enabling recognition by cytotoxic T cells and subsequent elimination. Harnessing this intrinsic process for cancer immunotherapy is a promising therapeutic strategy; thus, developing preclinical models to evaluate the efficacy of novel peptide vaccines in vivo and ex vivo is critical. Previously, we developed a humanized MHC I mouse model (B-HLA-A2.1 mice), in which we successfully demonstrated efficacy of peptide vaccines as assessed by splenocyte IFN-γ production measured via ELISpot. Here, we provide evidence that B-HLA-A2.1 mice can also mount immune responses to NY-ESO-1 and WT1-Db126 peptides using the same assay. Additionally, immunization with WT1-Db126 at 7, 14, and 21 days prior to tumor inoculation with WT1-expressing MC38 colon cancer cells significantly reduced tumor volume. Additionally, we have generated two new humanized HLA models: B-HLA-A11.1 mice and B-HLA-A24.2 mice. Flow cytometric data demonstrate successful expression of the human HLAs on the cell surface of splenocytes isolated from both strains. Compared to wild-type C57BL/6 mice, analysis of leukocyte and lymphocyte subpopulations in the humanized mice indicates that the CD4/CD8 ratio is altered in favor of CD4+ T cells in both strains, similar to what was observed in B-HLA-A2.1 humanized mice. Despite these observed alterations, B-HLA-A24.2 mice were able to mount an immune response to peptide SART2 93-101, which was measured by splenocyte IFN-γ production. In summary, our data indicate that humanized HLA-A mice provide a powerful preclinical model for in vivo/ex vivo evaluation of novel peptide vaccines. Citation Format: Zhenlan Niu, Xuan Yu, Zhiyuan Shen, Jing Guo, Qingcong Lin, Hui Xu. Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5345.

Neoadjuvant immunotherapy based on PD-1/L1 Inhibitors for gastrointestinal tumor: a review of rationale and clinical advances.

The landscape of current tumor treatment has been revolutionized by the advent of immunotherapy based on PD-1/PD-L1 inhibitors. Leveraging its capacity to mobilize systemic anti-tumor immunity, which is primarily mediated by T cells, there is growing exploration and expansion of its potential value in various stages of clinical tumor treatment. Neoadjuvant immunotherapy induces a robust immune response against tumors prior to surgery, effectively facilitating tumor volume reduction, early eradication or suppression of tumor cell activity, and control of potential metastatic spread, to improve curative surgical resection rates and prevent tumor recurrence. This review delineates the theoretical basis of neoadjuvant immunotherapy from preclinical research evidence, discusses specific challenges in clinical application, and provides a comprehensive overview of clinical research progress in neoadjuvant immunotherapy for gastrointestinal tumors. These findings suggest that neoadjuvant immunotherapy has the potential to ameliorate immunosuppressive states and enhance cytotoxic T cell function while preserving lymphatic drainage in the preoperative period. However, further investigations are needed on specific treatment regimens, suitable patient populations, and measurable endpoints. Despite numerous studies demonstrating the promising efficacy and manageable adverse events of neoadjuvant immunotherapy in gastrointestinal tumors, the availability of high-quality randomized controlled trials is limited, which highlights the necessity for further research.

Transcatheter Arterial Embolization with Bleomycin-Lipiodol of Hepatic Hemangiomas: Safety, Efficacy and Predictors of Response.

To evaluate the safety, efficacy and predictors of response of transcatheter arterial embolization (TAE) to treat hepatic hemangiomas (HHs). A retrospective analysis was conducted of consecutive HH patients who received TAE with bleomycin-Lipiodol emulsion and gelatin sponge particles at three institutions from January 2014 to January 2021. TAE effectiveness was defined as more than 50% reduction of tumor volume. The effectiveness, safety, and CT changes of hemangiomas after TAE were assessed. Factors affecting TAE efficacy on tumor size were analyzed with logistic regression analysis. A total of 102 patients with 109 HHs were included. After treatment, both the tumor diameter and volume were significantly reduced from 8.5 ± 3.9 to 5.9 ± 3.8cm (P < 0.001) and 412.6 ± 742.3cm3 to 102.0 ± 232.7cm3 (P < 0.001), respectively. TAE effectiveness was achieved in 80.7% (88/109) of hemangiomas, which was characterized by progressive reduction in tumor volume over time with Lipiodol retention. Atypical enhancement pattern (tiny enhancing dots in the hepatic arterial and portal venous phase) (p = 0.001) and central arterioportal shunt (APS) (p = 0.002) associated with the tumor were independent predictors of TAE ineffectiveness. Postembolization syndrome and transient increase in liver enzymes were common without severe complications and death. TAE was safe and effective in reducing HH size. Lesion enhancement pattern and APS type were associated with TAE efficacy on tumor shrinkage. Level 3, non-controlled retrospective cohort study.

Dermatologic Effects of Selumetinib in Pediatric Patients with Neurofibromatosis Type 1: Clinical Challenges and Therapeutic Management.

Background: Plexiform neurofibromas (pNFs) are benign neoplasms, primarily originating from Schwann cells, posing challenges in patients with type 1 neurofibromatosis (NF1) due to pain, disfigurement, compression of vital structures and potential for malignancy. Selumetinib, a MEK1/2 inhibitor, has shown promising results in treating inoperable pNFs, with clinical trials demonstrating tumor volume reduction and improved patient-reported outcomes. Despite its efficacy, dermatologic toxicities may impact the quality of life and treatment adherence. Evaluating the frequency and spectrum of such effects is crucial for effective management. Methods: In a four-year retrospective and prospective study, pediatric NF1 patients with symptomatic, inoperable plexiform neurofibromas (pNFs) were treated with selumetinib. Eligibility criteria included significant morbidity, pNF size exceeding 3 cm or surgical inoperability, and performance status >70%. Hematological, liver, lung and cardiac assessments established baseline health. Selumetinib, orally administered at 25 mg/m2 twice, was administered for two years unless a response warranting extension occurred. Cutaneous AEs were documented and graded by severity according to CTCAE v5.0, with evaluations every three to six months. The impact on symptoms and pNF size was systematically recorded, and biopsies characterized histopathological features in those patients requiring surgery. Results: Twenty patients were enrolled, with an average age at therapy initiation of 11.6 years. Cutaneous side effects were common, with all patients experiencing at least one and a median of two per patient. Xerosis, paronychia and acneiform rash were prevalent. Notably, pre-pubertal individuals were more susceptible to xerosis. Acneiform rash had a higher incidence in older patients and those with skin phototypes II and III. Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. Hair abnormalities, including color changes and thinning, occurred, with female patients at higher risk for the latter. Paronychia presented challenges, necessitating various interventions, including surgical approaches. AEs led to treatment suspension in 20% of patients, with tumor rebound observed in 75%. Conclusions: According to our experience, successful management of selumetinib-induced cutaneous AEs requires tailored strategies including surgery. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.

Stereotactic radiotherapy for head and neck paragangliomas: How long should we wait for treatment response?

Background and purposeStereotactic radiotherapy (SRT) is an effective treatment for head & neck (H&N) paragangliomas. Nevertheless, the timeline for achieving a tumor-volume-reduction (TVR) remains unclear. Materials and methodsSixty-three cases with H&N paragangliomas received definitive SRT and were evaluated retrospectively. Statistical Package for the Social Sciences (SPSS) v23.0 (IBM, Armonk, NY, USA) was used for statistics. ResultsSixty-eight lesions were irradiated, with glomus jugulotympanicum being the most common location (44 %). Median tumor diameter and volume were 3 cm (range, 1–7.6 cm) and 15.4 cm3 (range,1–185 cm3), respectively. Median dose was 25 Gy (range, 12–37.5 Gy) in 5 fractions (range, 1–5 fractions). Median follow-up was 40 months (range, 3–184 months). Treatment response, evaluated at a median 4.6 months post-SRT (range: 3–11 months), revealed TVR in 26 cases (41 %). During follow-up, 13 additional cases showed TVR, resulting in an overall TVR rate of 62 %. The median duration for attaining TVR was 9 months (range, 3–36 months) after SRT, and TVR occurred ≥ 12 months in 42 % of cases. Patients without prior surgery (p = 0.03) and with a longer follow-up (p = 0.04) demonstrated a higher rate of TVR. The likelihood of TVR tends to increase as the SRT dose increases (p = 0.06). Overall local control (LC) rate was 100 %. No ≥ grade 3 acute or late toxicities were observed. ConclusionWhile SRT demonstrates an excellent LC rate for H&N paragangliomas, it's important to note that the response to treatment may require time. TVR may last beyond the initial year of treatment in a substantial proportion of patients.

Efficacy of Cold Atmospheric Plasma vs. Chemotherapy in Triple-Negative Breast Cancer: A Systematic Review.

Breast cancer is a growing disease, with a high worldwide incidence and mortality rate among women. Among the various types, the treatment of triple-negative breast cancer (TNBC) remains a challenge. Considering the recent advances in cold atmospheric plasma (CAP) cancer research, our goal was to evaluate efficacy data from studies based on chemotherapy and CAP in TNBC cell lines and animal models. A search of the literature was carried out in the PubMed, Web of Science, Cochrane Library, and Embase databases. Of the 10,999 studies, there were fifty-four in vitro studies, three in vivo studies, and two in vitro and in vivo studies included. MDA-MB-231 cells were the most used. MTT, MTS, SRB, annexin-V/propidium iodide, trypan blue, and clonogenic assay were performed to assess efficacy in vitro, increasing the reliability and comprehensiveness of the data. There was found to be a decrease in cell proliferation after both chemotherapy and CAP; however, different protocol settings, including an extensive range of drug doses and CAP exposure times, were reported. For both therapies, a considerable reduction in tumor volume was observed in vivo compared with that of the untreated group. The treatment of TNBC cell lines with CAP proved successful, with apoptosis emerging as the predominant type of cellular death. This systematic review presents a comprehensive overview of the treatment landscape in chemotherapy and CAP regarding their efficacy in TNBC cell lines.

Short-term efficacy of oxaliplatin as interventional therapy for liver cancer, and its effect on serum CD163 and AFU

Purpose: To investigate the short-term effectiveness of oxaliplatin in the interventional treatment of liver cancer, and its effect on serum CD163 and α-L-glucosidase (AFU). &#x0D; Methods: Eighty liver carcinoma patients treated in The Affiliated Hospital of Shaoxing University, Shaoxing, China from January 2022 to January 2023 were allotted to 2 cohorts (each with 40 patients). Subjects in control group were treated with hepatic Transarterial Chemoembolization (TACE), while study group was treated with combination of hepatic TACE and oxaliplatin. Efficacy, serological indicators, health status and cancer-related fatigue were determined and compared between both cohorts. &#x0D; Results: DCR was significantly higher in study group than in the control. There were significantly reduced post-treatment amounts of CYFRA21-1, CA125 and VGEF in the study cohort, relative to pre-treatment and control levels (p &lt; 0.05). Post-treatment values of CD4+/CD8+ and CD4+ were significantly low, relative to levels before treatment, while CD8+ in both groups were significantly increased after treatment (p &lt; 0.05). However, post-treatment T lymphocyte level was comparable in both groups. There was significantly higher post-treatment KPS score in study cohort than pre-treatment and control scores, but RPFS score was significantly reduced, relative to the corresponding pre-treatment and control scores. Post-treatment serum amounts of CD163 and AFU were significantly down-regulated in both cohorts, with lower levels in the study cohort. &#x0D; Conclusion: The combined use of liver TACE and oxaliplatin produces good clinical outcome in the treatment of liver cancer. It is beneficial in reducing serum levels of CD163 and AFU, inhibits proliferation of tumor cells, reduces tumor volume, and improves cancer prognosis in patients.

The therapeutic effect of ultrasound targeted destruction of schisandrin A contrast microbubbles on liver cancer and its mechanism.

The aim of the study was to explore the therapeutic effect of ultrasound targeted destruction of schisandrin A contrast microbubbles on liver cancer and its related mechanism. The Span-PEG microbubbles loaded with schisandrin A were prepared using Span60, NaCl, PEG-1500, and schisandrin A. The loading rate of schisandrin A in Span-PEG composite microbubbles was determined by ultraviolet spectrophotometry method. The Walker-256 cell survival rate of schisandrin A was determined by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay. The content of schisandrin A in the cells was determined by high performance liquid chromatography. Ultrasound imaging was used to evaluate the therapeutic effect in situ. Enzyme linked immunosorbent assay (ELISA) was used to measure the content of inflammatory factors in serum. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of experimental animals in each group. Immunohistochemistry was used to detect the expression of hypoxia inducible factor-1α (HIF-1α), vascular endothlial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) in tumor tissues, and western blot was used to detect the protein expression of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway in tumor tissues. The composite microbubbles were uniform in size, and the particle size distribution was unimodal and stable, which met the requirements of ultrasound contrast agents. The loading rate of schisandrin A in Span-PEG microbubbles was 8.84 ± 0.14%, the encapsulation efficiency was 82.24±1.21%. The IC50 value of schisandrin A was 2.87 μg/mL. The drug + microbubbles + ultrasound (D+M+U) group had the most obvious inhibitory effect on Walker-256 cancer cells, the highest intracellular drug concentration, the largest reduction in tumor volume, the most obvious reduction in serum inflammatory factors, and the most obvious improvement in pathological results. The results of immunohistochemistry showed that HIF-1α, VEGF and VEGFR-2 protein decreased most significantly in D+M+U group (P < 0.01). WB results showed that D+M+U group inhibited the PI3K/AKT/mTOR signaling pathway most significantly (P < 0.01). Schisandrin A had an anti-tumor effect, and its mechanism might be related to the inhibition of the PI3K/AKT/mTOR signaling pathway. The schisandrin A microbubbles could promote the intake of schisandrin A in tumor cells after being destroyed at the site of tumor under ultrasound irradiation, thus playing the best anti-tumor effect.

Retrospective Analysis of the Efficacy and Safety of Ultrasound-Guided Radiofrequency Ablation in the Treatment of Papillary Thyroid Microcarcinoma: A Follow-Up Study of Continuous Postoperative Surveillance and Large-Sample Data.

To retrospectively evaluate the efficacy and safety of ultrasound-guided radiofrequency ablation (RFA) in the treatment of papillary thyroid microcarcinoma (PTMC) through a follow-up study of continuous postoperative surveillance and large-sample data. The efficacy of ultrasound-guided RFA was evaluated by measuring the tumor volume reduction rate (VRR), tumor disappearance rate, and disease progression in 358 patients with low-risk unifocal PTMC who underwent ultrasound-guided RFA at Hangzhou Weja Hospital, while the safety was evaluated by measuring their complications. The VRR was -745.69 ± 1012.69 (%), -150.35 ± 395.5 (%), 46.47 ± 138.74 (%), 92.95 ± 27.88 (%), 97.78 ± 10.99 (%), and 99.27 ± 3.82 (%), respectively, at 1, 3, 6, 12, 18, and 24 months after RFA. The corresponding tumor disappearance rate was 1.68%, 9.78%, 43.85%, 82.68%, 92.59%, and 95.63%, respectively. No local recurrence, new tumors, lymph node metastasis, distant metastasis, and deaths caused by recurrent/metastatic PTMC were found at the last follow-up. Except for 3 cases (0.84%) with thickening or hoarseness of voice and 3 cases (0.84%) with coughing during drinking water, no other complications were found. Ultrasound-guided RFA has good efficacy and safety for the treatment of low-risk unifocal PTMC and can be promoted for use in patients who meet the required indications.

A quinoxaline-based derivative exhibited potent and selective anticancer activity with apoptosis induction in PC-3 cells through Topo II inhibition

Quinoxaline constitutes a variety of derivatives that exhibit a range of biological characteristics, including anti-inflammatory and antitumor effects, and their importance in therapeutic chemistry is rising. The cytotoxicity effects of four quinoxaline compounds (I, II, III, and IV) against liver cancer cells (HepG2), prostate cancer cells (PC-3), and normal cells (Vero) were evaluated using the MTT assay. Compounds III and IV had the most anti-proliferative effects and highly selective indices against PC-3 cells with IC50 values of 4.11 and 2.11 µM, respectively. The apoptotic cell death for compounds III and IV in PC-3 cells was investigated using cell cycle, Annexin V-FITC/PI double staining-based flow cytometry, and DNA fragmentation assay. Compounds III or IV arrested the cell cycle at the S phase and caused apoptosis in PC-3 cells. Compounds III and IV showed inhibitory effects against topoisomerase II enzyme with IC50 values 21.98 and 7.529 µM, respectively, when compared to doxorubicin as a reference drug. Western Blot analysis displayed that compound IV treatment has significantly upregulated the pro-apoptotic proteins (p53, caspase-3, caspase-8) and downregulated the anti-apoptotic protein Bcl-2 in PC-3 cells in a dose-dependent manner, leading to cell apoptosis. The molecular docking study exhibited that compound IV had a good binding affinity for inhibiting topoisomerase II, consistent with the apoptotic mechanism. In vivo study using Ehrlich solid tumor model demonstrated that compound IV significantly reduced tumor volume and weight in vivo with minimal toxicity. This study reveals significant evidence for the antitumor efficacy of compound IV against prostate cancer cells as a topoisomerase II inhibitor. Communicated by Ramaswamy H. Sarma

Operative treatment of pulmonary primitive neuroectodermal tumor: a case report and literature review

BackgroundPulmonary primitive neuroectodermal tumor (PNET), a member of the Ewing sarcoma family of tumors, is a rare malignancy that is associated with a grim prognosis. To date, fewer than 30 cases of pulmonary PNET have been reported. In this case report, we present the clinical details of a 12-year-old girl with pulmonary PNET who underwent surgical treatment. We also conducted an analysis and summary of other relevant studies and the surgical outcomes.Case presentationIn May 2018, a 12-year-old girl was admitted with symptoms of cough and blood-tinged phlegm. A computed tomography scan revealed a large mass, measuring 12.9 cm × 8.1 cm, in the right middle and lower lungs. A percutaneous lung biopsy confirmed poorly differentiated tumor cells with a nested growth pattern. Immunohistochemical staining demonstrated positive expression of CD99, CD56, Vimentin, and Synaptophysin. The patient was diagnosed with pulmonary PNET. Following three cycles of neoadjuvant chemotherapy, a substantial reduction in tumor volume was observed. Subsequently, the patient underwent a surgical procedure involving pneumonectomy and partial resection of the left atrium with the assistance of cardiopulmonary bypass. The patient was discharged 37 days after surgery. During a three-year follow-up period, she exhibited no signs of tumor recurrence and has successfully returned to school.ConclusionsThis case highlights the successful management of an advanced PNET with neoadjuvant chemotherapy, pneumonectomy, and partial resection of the left atrium employing cardiopulmonary bypass. The patient remained disease-free after three years. Our analysis of surgically treated cases indicates that neoadjuvant chemotherapy can contribute to improved prognoses for PNET patients. It is crucial to emphasize that complete surgical excision remains the cornerstone of treatment, underscoring the importance of surgeons considering radical surgical approaches whenever feasible for patients with pulmonary PNETs.

Tectoridin inhibits the growth of bladder cancer by regulating PI3K/MAPK pathway through RAB27B.

Bladder cancer (BC) is a common and malignant tumor of the urinary tract, and its treatment options are limited. Tectoridin (TEC) has antitumor activity against prostate and colon cancer, but its effects on BC are poorly understood. BC cells were treated with increasing concentrations of TEC, and its effects on cell proliferation, migration, invasiveness, and apoptosis were assessed. Xenograft mouse model was used to evaluate the influences of TEC on BC tumor growth. Western blot analysis was conducted to explore the downstream pathways affected by TEC. TEC treatment decreased BC cell viability in a dose-dependent manner (IC50 ≈ 25 μM), and inhibited cell proliferation, migration, and invasiveness while promoting apoptosis. Clinical analysis revealed high expression of RAB27B in BC tumor tissues, particularly in advanced stages, correlating with an unfavorable prognosis. In vitro experiments demonstrated that TEC suppressed the PI3K/MAPK pathway by targeting RAB27B, and overexpression of RAB27B counteracted the antitumor effects of TEC. In xenograft models, TEC administration suppressed tumor growth, reduced tumor volume, inhibited cell proliferation, and suppressed the PI3K/MAPK pathway, highlighting its potential as an inhibitor of tumor growth. TEC suppresses BC tumor growth by targeting RAB27B and inactivating the PI3K/MAPK signaling and may provide a promising therapeutic target for BC treatment.

Secretome from Magnetically Stimulated Muscle Exhibits Anticancer Potency: Novel Preconditioning Methodology Highlighting HTRA1 Action.

Briefly (10 min) exposing C2C12 myotubes to low amplitude (1.5 mT) pulsed electromagnetic fields (PEMFs) generated a conditioned media (pCM) that was capable of mitigating breast cancer cell growth, migration, and invasiveness in vitro, whereas the conditioned media harvested from unexposed myotubes, representing constitutively released secretome (cCM), was less effective. Administering pCM to breast cancer microtumors engrafted onto the chorioallantoic membrane of chicken eggs reduced tumor volume and vascularity. Blood serum collected from PEMF-exposed or exercised mice allayed breast cancer cell growth, migration, and invasiveness. A secretome preconditioning methodology is presented that accentuates the graded anticancer potencies of both the cCM and pCM harvested from myotubes, demonstrating an adaptive response to pCM administered during early myogenesis that emulated secretome-based exercise adaptations observed in vivo. HTRA1 was shown to be upregulated in pCM and was demonstrated to be necessary and sufficient for the anticancer potency of the pCM; recombinant HTRA1 added to basal media recapitulated the anticancer effects of pCM and antibody-based absorption of HTRA1 from pCM precluded its anticancer effects. Brief and non-invasive PEMF stimulation may represent a method to commandeer the secretome response of muscle, both in vitro and in vivo, for clinical exploitation in breast and other cancers.

Abstract A017: Cell-specific photodynamic therapy for high grade gliomas

Abstract A017: Cell-specific photodynamic therapy for high grade gliomas

Significance of navigated transcranial magnetic stimulation and tractography to preserve motor function in patients undergoing surgery for motor eloquent gliomas

Resection of gliomas in or close to motor areas is at high risk for morbidity and development of surgery-related deficits. Navigated transcranial magnetic stimulation (nTMS) including nTMS-based tractography is suitable for presurgical planning and risk assessment. The aim of this study was to investigate the association of postoperative motor status and the spatial relation to motor eloquent brain tissue in order to increase the understanding of postoperative motor deficits.Patient data, nTMS examinations and imaging studies were retrospectively reviewed, corticospinal tracts (CST) were reconstructed with two different approaches of nTMS-based seeding. Postoperative imaging and nTMS-augmented preoperative imaging were merged to identify the relation between motor positive cortical and subcortical areas and the resection cavity.38 tumor surgeries were performed in 36 glioma patients (28.9% female) aged 55.1 ± 13.8 years. Mean distance between the CST and the lesion was 6.9 ± 5.1 mm at 75% of the patient-individual fractional anisotropy threshold and median tumor volume reduction was 97.7 ± 11.6%. The positive predictive value for permanent deficits after resection of nTMS positive areas was 66.7% and the corresponding negative predictive value was 90.6%. Distances between the resection cavity and the CST were higher in patients with postoperative stable motor function. Extent of resection and distance between resection cavity and CST correlated well.The present study strongly supports preoperative nTMS as an important surgical tool for preserving motor function in glioma patients at risk.

Radiosurgical Decompression of Trigeminal Nerve and Its Correlation with Functional Outcome in Tumor-Related Trigeminal Neuralgia

BackgroundThe target selection during gammaknife radiosurgery(GKRS) in cases of tumor related trigeminal neuralgia(TRTGN) is always debatable. Here we discuss the correlation of regression of tumor size, degree of release of the nerve with long term pain control. MethodsTotal 50 cases of TRTGN were treated with GKRS (tumor was targeted) during the period March 2012 and March 2023. Post GKRS radiology was categorised in to three types(Type 1 – tumor volume remained same/reduced, additional segment of nerve not seen, Type 2 – tumor volume reduced, additional segment of trigeminal nerve seen but tumor still adherent to the nerve, Type 3 – tumor volume reduced, adjacent nerve seen completely separated from tumor). Pre and post GKRS pain score(BNI I to III –good, BNI IV&V – poor) was correlated with the above subgroups. ResultAt a median follow up of 46.5 months 18 cases have type 1, 23 showed type 2 and 9 showed type 3 radiological response. Ten(55.5%) patients with type 1, 15(65.21%) with type 2 and 7(77.8%) with type 3 responses had good pain control. The outcome among these three was not statistically significant(p=0.519).Five patients with type 3 radiological response were off medication which was statistically better than type 1 radiological response with three patients(p = 0.012) and type2 radiological response with two patients(p = 0.002). ConclusionPost GKRS tumor volume reduction may show good pain control in TRTGN. This further allows visualization of additional segment of nerve that can be targeted in the second session for treating recurrent or failed cases.

The role and molecular mechanism of NOP16 in the pathogenesis of nasopharyngeal carcinoma.

We aimed to explore the effects of NOP16 on the pathogenesis of nasopharyngeal carcinoma (NPC) and the related mechanism. In this study, the expression level of NOP16 in NPC tissues and adjacent tissues was measured by qRT-polymerase chain reaction(PCR) and immunohistochemistry (IHC)tests. In the in vitro study, the expression levels of NOP16 and RhoA/phosphatidylinositol 3-kinase(PI3K)/Akt/c-Myc and IKK/IKB/NF-κB signalling pathway-related proteins in NPC cells were measured by qRT-PCR and Western blot (WB). CCK8 assays and colony formation assays were used to detect cell proliferation. Transwell assays were used to detect the migration and invasion ability of NPC cells. Flow cytometry and WB were used to measure the level of apoptosis. For the in vivo study, NPC xenograft models were established in nude mice, and tumour weight and volume were recorded. The expression levels of NOP16 and RhoA/PI3K/Akt/c-Myc signalling pathway-related proteins and mRNAs were measured by immunofluorescence, qRT-PCR and WB experiments. In clinical samples, the results of qRT-PCR and IHC experiments showed that the expression level of NOP16 was significantly increased in NPC tissues. In the in vitro study, the results of qRT-PCR and WB experiments showed that NOP16 was significantly increased in NPC cells. The CCK8 assay, colony formation assay, transwell assay and flow cytometry results showed that knocking out NOP16 inhibited the proliferation, migration and invasion of NPC cells and increased apoptosis. WB results showed that knocking out NOP16 inhibited the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB signalling pathways. These effects were reversed by 740Y-P (PI3K activator). In the in vivo study, knockdown of NOP16 reduced tumour volume and weight and inhibited the RhoA/PI3K/Akt/c-Myc signalling pathway. In conclusion, knockdown of NOP16 inhibited the proliferation, migration and invasion of NPC cells and induced apoptosis by inhibiting the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB pathways, leading to the malignant phenotype of NPC.

Enhanced Anti-tumor Effect of Flavopiridol in Combination With Gemcitabine in Pancreatic Cancer.

The efficacy of current chemotherapies for pancreatic ductal adenocarcinoma (PDAC) is still unsatisfactory. Flavopiridol inhibits multiple cyclin-dependent kinases, causing cell cycle arrest and inducing cancer cell apoptosis. This study aimed to evaluate the anti-tumor effect of flavopiridol and gemcitabine in PDAC in vitro and in vivo. PANC-1 and MIA PaCa-2 cell lines were treated with gemcitabine and flavopiridol alone, in combination, and sequentially, and cell proliferation, apoptosis, and the cell cycle were evaluated. Proteins related to cell cycle progression (cyclin A, CDK2, E2F-1, and p53) were quantified using western blotting. A xenograft mouse model was generated, and the effects of gemcitabine and flavopiridol, administered alone or in combination, were evaluated by measuring tumor volume and apoptosis degree using the TUNEL assay. Sequential administration of gemcitabine and flavopiridol suppressed PDAC cell proliferation and induced apoptosis. Flavopiridol treatment led to an increase in the number of cells in the S and a decrease in those in the G0/G1 phases. Gemcitabine increased and decreased the number of S- and G2/M-phase cells, respectively. Furthermore, flavopiridol treatment decreased cyclin A and CDK2 expression and increased E2F-1 expression. In a xenograft mouse model, the combined administration of gemcitabine and flavopiridol demonstrated the most significant reduction in tumor volume and induction of apoptosis. Flavopiridol potentiates the anti-tumor activity of gemcitabine by inducing cell cycle arrest and apoptosis. Its synergistic inhibition of PDAC cell proliferation, when combined with gemcitabine, positions flavopiridol as a promising candidate for cancer treatment.

Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma

BackgroundIn the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244.MethodsTo directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments.ResultsCD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244−/− bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors.ConclusionOur study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.

Biomechanical imaging biomarker during chemoradiotherapy predicts treatment response in head and neck squamous cell carcinoma

Objective. For response-adapted adaptive radiotherapy (R-ART), promising biomarkers are needed to predict post-radiotherapy (post-RT) responses using routine clinical information obtained during RT. In this study, a patient-specific biomechanical model (BM) of the head and neck squamous cell carcinoma (HNSCC) was proposed using the pre-RT maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose (FDG) and tumor structural changes during RT as evaluated using computed tomography (CT). In addition, we evaluated the predictive performance of BM-driven imaging biomarkers for the treatment response of patients with HNSCC who underwent concurrent chemoradiotherapy (CCRT). Approach. Patients with histologically confirmed HNSCC treated with definitive CCRT were enrolled in this study. All patients underwent CT two times as follows: before the start of RT (pre-RT) and 3 weeks after the start of RT (mid-RT). Among these patients, 67 patients who underwent positron emission tomography/CT during the pre-RT period were included in the final analysis. The locoregional control (LC), progression-free survival (PFS), and overall survival (OS) prediction performances of whole tumor stress change (TS) between pre- and mid-RT computed using BM were assessed using univariate, multivariate, and Kaplan–Meier survival curve analyses, respectively. Furthermore, performance was compared with the pre and post-RT SUVmax, tumor volume reduction rate (TVRR) during RT, and other clinical prognostic factors. Main results. For both univariate, multivariate, and survival curve analyses, the significant prognostic factors were as follows (p < 0.05): TS and TVRR for LC; TS and pre-RT FDG-SUVmax for PFS; and TS only for OS. In addition, for 2 year LC, PFS, and OS prediction, TS showed a comparable predictive performance to post-RT FDG-SUVmax. Significance. BM-driven TS is an effective prognostic factor for tumor treatment response after CCRT. The proposed method can be a feasible functional imaging biomarker that can be acquired during RT using only routine clinical data and may provide useful information for decision-making during R-ART.