Tumor Growth Rate Research Articles

Mechanistic target of rapamycin (mTOR) regulates self-sustained quiescence, tumor indolence, and late clinical metastasis in a Beclin-1-dependent manner

ABSTRACT Self-sustained quiescence (SSQ) has been characterized as a stable but reversible non-proliferative cellular state that limits the cloning of cultured cancer cells. By developing refined clonogenic assays, we showed here that cancer cells in SSQ can be selected with anticancer agents and that culture at low cell density induced SSQ in pancreas and prostate adenocarcinoma cells. Pre-culture of cells in 3D or their pretreatment with pharmacological inhibitors of mechanistic target of rapamycin (mTOR) synergize with low cell density for induction of SSQ in a Beclin-1-dependent manner. Dissociated pancreatic adenocarcinoma (PAAD) cells rendered defective for SSQ by down-regulating Beclin-1 expression exhibit higher tumor growth rate when injected subcutaneously into mice. Conversely, dissociated PAAD cells in SSQ promote the formation of small indolent tumors that eventually transitioned to a rapid growth phase. Ex vivo clonogenic assays showed that up to 40% of clonogenic cancer cells enzymatically dissociated from resected fast-growing tumors could enter SSQ, suggesting that SSQ could significantly impact the proliferation of cancer cells that are naturally dispersed from tumors. Remarkably, the kinetics of clinical metastatic recurrence in 124 patients with pancreatic adenocarcinoma included in the TGCA-PAAD project could be predicted from Beclin-1 and Cyclin-A2 mRNA levels in their primary tumor, Cyclin A2 mRNA being a marker of both cell proliferation and mTOR complex 1 activity. Overall, our data show that SSQ is likely to promote the late development of clinical metastases and suggest that identifying new agents targeting cancer cells in SSQ could help improve patient survival.

LPCAT1 functions as an oncogene in cervical cancer through mediating JAK2/STAT3 signaling

Cervical cancer is a major gynecological tumor worldwide. Unfortunately, the molecular mechanisms involved in cervical cancer tumorigenesis still requires more clarification. Lysophosphatidylcholine acyltransferase 1 (LPCAT1), an enzyme involved in phosphatidylcholine metabolism, has been reported to regulate the proliferation, epithelial-mesenchymal transition (EMT) and recurrence of malignancies. Here in our study, we found that LPAT1 was over-expressed in clinical cervical cancer tissues, and its high expression was closely correlated with poor outcomes of patients. We further showed that LPCAT1 knockdown remarkably restrained the proliferation, migration and invasion of cervical cancer cells, while it significantly induced apoptosis. RNA-seq and bioinformatics assays initially showed that interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) pathway was a key mechanism for LPCAT1 to regulate cervical cancer progression. LPCAT1 silence strongly decreased IL-6, p-Janus kinase 2 (JAK2) and p-STAT3 expression levels in cervical cancer cells. Similarly, the expression levels of IL-6/STAT3 target genes were also highly down-regulated in cervical cancer cells with LPCAT1 deletion. Importantly, we found that human recombinant IL-6 addition considerably abolished the function of LPCAT1-knockdown to suppress the proliferation and EMT process in cervical cancer cells, accompanied with mitigated apoptotic cell death. Furthermore, our animal experiment results validated that stable LPCAT1 deletion efficiently reduced the tumor growth rates of xenograft mouse models and lung metastasis in vivo. Collectively, all our findings revealed that LPCAT1 may be a promising alternative prognostic biomarker and therapeutic target for cervical cancer through regulating JAK2/STAT3 signaling pathway.

A Novel Bone Contouring Technique Using Multiple Tangential Shaving for Conservative Management of Craniofacial Fibrous Dysplasia.

This study aimed to propose a novel surgical technique, named multiple tangential shaving of bone contour, for the conservative management of craniofacial fibrous dysplasia. We retrospectively reviewed 17 patients who underwent conservative management of craniofacial fibrous dysplasia using multiple tangential shaving technique between July 2005 and December 2020. Demographics, tumor characteristics, and surgery-related factors were investigated. All patients underwent preoperative (T0) and postoperative computed tomography scans taken at least twice within 1 month for immediate assessment (T1) and at least 12 months postoperatively for long-term assessment (T2). Clinical outcomes, including tumor recurrence, perioperative complications, and physician measure of esthetic outcomes (Whitaker score), were investigated. This technique was applied for contouring of the zygomatic-maxillary and calvarial bone for patients aged between 16 and 60 years (mean age: 26y). The mean±SD tumor volume reduction was 15.5±8.95cm 3 , and the postoperative mean±SD tumor growth rate was 5.52±6.26% per year. Satisfactory outcome was obtained in terms of esthetics with a mean±SD Whitaker score of 1.41±0.62. Patients required a mean operation time of 1.67±0.43 hours and a mean number of shaving operations of 1.35±0.61 during the follow-up period. Five of 17 patients required reoperation because of the tumor recurrence (N=4) and to correct new-onset diplopia after surgery (N=1). In conclusion, the multiple tangential shaving technique allows an easy approach for conservative management of craniofacial fibrous dysplasia. An acceptable rate of tumor recurrence and esthetic outcomes can be obtained by selecting the appropriate candidate for a conservative approach.

Proposal for multiple new lesions as complement of hyperprogressive disease in NSCLC patients treated with PD-1/PD-L1 immunotherapy

BackgroundHyperprogressive disease (HPD) is a progression pattern of rapid increase in tumor burden during immunotherapy. However, current HPD definitions are mainly based on the diameter of target lesions. How to take new lesions into account remains unknown. MethodsIn this retrospectively analysis, 393 patients received PD-1/PD-L1 inhibitors monotherapy. 237 patients were eligible for HPD evaluation based on tumor growth rate (TGR) ratio, ΔTGR or tumor growth kinetic (TGK) ratio. Among them, 214 patients were eligible for evaluation of new lesions. The impact of new lesions on overall survival (OS) was investigated by Kaplan-Meier methods. The optimal threshold for new lesion number was investigated by one-year time-dependent receiver operating characteristic (ROC) curves. Developing more than one new lesions (n ≥ 2) was defined as multiple new lesions (MNL). New HPD was redefined as both developing MNL and meeting the requirement of current HPD definitions (TGR ratio, ΔTGR or TGK ratio). The survival difference between the newly defined HPD and non-HPD patients was investigated. ResultsHPD occurred in 5.1–18.1 % patient based on current definitions (TGR ratio, 15.6 %; ΔTGR, 5.1 %; TGK ratio, 18.1 %). However, there is no significant difference between OS of HPD and non-HPD patient. New lesion was associated with a shorter median OS in PD（with or without HPD) patients (6.1 vs 18.9 months, p = 0.001). Time-dependent ROC analysis suggested that the optimal threshold for new lesion number in survival prediction was two. After the redefinition of HPD, New HPD patients had a significantly shorter median OS compared with non-HPD patients (TGR ratio with MNL: 5.6 vs 11.8 months, p < 0.001; ΔTGR with MNL: 5.0 vs 11.4 months, p = 0.034; TGK ratio with MNL: 5.7 vs 12.3 months, p < 0.001; respectively). ConclusionsCurrent HPD definitions had a better prognostic value when complemented with MNL. MNL should be integrated into the new definition of HPD.

Theranostic silk sericin/SPION nanoparticles for targeted delivery of ROR1 siRNA: Synthesis, characterization, diagnosis and anticancer effect on triple-negative breast cancer

Triple-negative breast cancer (TNBC) has the worst prognosis among all breast cancer subtypes. The lack of proper treatments prompted scientists to find a practical targeted therapy to treat this type of tumor. Based on previous studies, tyrosine kinase-like orphan receptor (ROR1) is overexpressed in TNBC cells. Here, we designed a system consisting of superparamagnetic iron oxide nanoparticles (SPIONs) decorated with silk sericin (SS NPs) for the targeted delivery of ROR1 siRNA, a gene silencer to knockdown the expression of human ROR1 gene. NPs exhibited spherical shape of about 193 nm with acceptable properties both in vitro and in vivo. The apoptosis study showed significant death of MDA-MB-231 cells after 24 h treatment with the prepared NPs. The real-time PCR study also demonstrated an almost complete shutdown of ROR1 expression. Guided by magnetic field, enhanced accumulation of NPs was observed in breast tumors induced by 4T1 cells in BALB/c mice. Histological evaluation of the tumor exhibited necrosis 14 days post-treatment with the siRNA-loaded NPs; whereas, the untreated tumor was proliferating. Also, the tumor growth rate was significantly decreased after treatment with siRNA-loaded NPs in vivo. In conclusion, the prepared delivery system could be considered as a potential therapeutic strategy for treating TNBC.

1224P Final analysis of clinical outcomes in the DELIVER trial: Observational study of nivolumab treatment in advanced gastric cancer (JACCRO GC-08)

We conducted a prospective observational study to evaluate the real-world effectiveness of nivolumab (Nivo) monotherapy in previously treated advanced gastric cancer (GC) (Gastric Cancer 2021). Pre-planned 2-year final analysis was performed to confirm survival and tumor behavior of Nivo treatment. The DELIVER trial enrolled 501 patients (pts) with advanced gastric or GEJ adenocarcinoma treated with Nivo alone from Mar 2018 to Aug 2019 (UMIN000030850). Primary endpoint was overall survival (OS), secondary endpoints were response rate (RR), disease control rate, progression-free survival (PFS), tumor regression rate (TRR) / tumor progression rate (TPR) at 1st evaluation, tumor growth rate (TGR) which was calculated as a percentage increase in tumor volume during 1 month, and safety. 487 pts were evaluable (median age 70y [26-90], 71% male, ECOG PS0/1/2 42/44/14%, No. of prior regimen 1/2/≥3 2/39/59%, 42% pts with ascites). Median OS was 5.8 months (m) (95%CI 5.3-6.9) with 1y-survival rate of 30% and 2y-survival rate of 14%, and median PFS was 1.8 m (95%CI 1.7-2.0). The RR was 14.5% in 282 pts with measurable lesions. The sub-group analysis of OS by clinical factors was the following: male/female; 6.5/5.1m (p=0.001), PS0/1/2; 8.7/5.6/2.5m(p<0.001), tub/por or sig; 8.1/5.2m (p<0.001), albumin<3.5/≥3.5; 4.2/8.8m (p<0.001), and with/without peritoneal metastases; 4.9/8.4m (p<0.001). Median OS and PFS by tumor response (CR or PR/SD/PD) were 32.8/11.4/4.2m and 13.9/11.7/3.8/1.5m, respectively. In 147 elderly pts aged ≥75-y, RR, PFS, and OS were 14.3%, 2.0m, and 6.5m, respectively, and the safety profile was comparable to pts aged <75-y. Median TRR and TPR were 20.0% and 26.7%, in 75 pts with tumor regression and 185 pts with tumor progression, respectively. The TGR decreased from 3.8 to 2.8 after Nivo introduction. There were no associations between PFS/OS and tumor burden or TGR at baseline before Nivo. The final analysis confirmed the efficacy of Nivo for advanced GC pts in clinical practice, with comparable outcomes in the elderly pts. Nivo was effective regardless of tumor burden or TGR at pre-treatment in advanced GC.

Abstract PO025: GM-CSF neutralization enhances the efficacy of chemotherapy in an orthotopic murine model of cholangiocarcinoma

Abstract Introduction: With current effective treatments in cholangiocarcinoma (CCA) lacking, we expounded on our prior work highlighting the critical role of the granulocyte-macrophage-colony stimulating factor ligand/receptor (GM-CSF/GM-CSFRα) signaling pathway by evaluating GM-CSF neutralization combined with first-line chemotherapy in a novel murine model of CCA. Methods: Resected CCA specimens were used to construct a human tissue macro-array. Immunohistochemistry (IHC) staining for GM-CSFRα and digital quantification of staining intensity was performed. A novel syngeneic CCA cell line derived from spontaneous murine CCA from LSL-KrasG12D; Tp53Flox/Flox −; Alb-Cre (KPPC) mice was surgically injected into the left hepatic lobes of C57BL/6J mice. Disease onset and extent of progression was monitored over time using ultrasonography (US) in groups of mice enrolled into treatment with vehicle, gemcitabine, anti-GM-CSF, and gemcitabine plus anti-GM-CSF. Mice were sacrificed at predetermined endpoints for flow cytometry analysis. Results: IHC analysis and digital quantification of resected human tumors demonstrated that CCA expresses significantly higher levels of GM-CSFRα (p&amp;lt;0.01) compared to uninvolved normal liver. Mice injected with a novel syngeneic CCA cell line expressing high levels of GM-CSF protein uniformly developed tumors fourteen days after orthotopic implantation. Histopathological evaluation of orthotopic CCA tumors demonstrated faithful recapitulation of both spontaneous murine and human disease with marked development of malignant biliary ductal epithelium (CK7), desmoplastic stroma (Sirius red, trichrome), and prominent inflammatory leukocytic infiltrate (CD45). Flow cytometry analysis of end-stage orthotopically implanted tumors demonstrated a progressive expansion of myeloid cells (70.7% CD11b+) compared to CD8+ (0.8%) and CD4+ (2.0%) T cells, indicative of a highly immunosuppressive tumor immune microenvironment. Combination therapy with GM-CSF neutralization and chemotherapy significantly reduced tumor size as screened via US compared to vehicle (p&amp;lt;0.0001), anti-GM-CSF (p&amp;lt;0.01), and chemotherapy alone (p&amp;lt;0.01). In addition, combination therapy reduced the rate of tumor growth compared to each of the three other treatment groups (all p&amp;lt;0.0001). Finally, tumor weights were significantly reduced in the combination therapy group versus the vehicle (p&amp;lt;0.0001), anti-GM-CSF (p&amp;lt;0.001), and chemotherapy alone (p&amp;lt;0.05) cohorts. Conclusion: Human CCA demonstrates elevated levels of GM-CSFRα compared to normal liver. Neutralization of GM-CSF in combination with chemotherapy reduced tumor growth and weight in a novel murine model of CCA. Targeting the GM-CSF/GM-CSFRα pathway represents an innovative means of improving tumor control in CCA. Citation Format: Yatee A Dave, Paul R Burchard, Nicholas A Ullman, Mary Georger, Luis I Ruffolo, Brian A Belt, David C Linehan. GM-CSF neutralization enhances the efficacy of chemotherapy in an orthotopic murine model of cholangiocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO025.

Combination treatment with hENT1 and miR-143 reverses gemcitabine resistance in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and is susceptible to develop gemcitabine (GEM) resistance. Decreased expression of human equilibrative nucleoside transporter 1 (hENT1) accompanied by compensatory increase of glycolysis is strongly associated with GEM resistance in TNBC. In this study, we investigated the treatment feasibility of combined hENT1 upregulation and miR-143-mediated inhibition of glycolysis for reversing GEM resistance in TNBC.MethodsExperiments were performed in vitro and in vivo to compare the efficacy of GEM therapies. In this study, we established stable drug-resistant cell line, GEM-R cells, from parental cells (MDA-MB-231) through exposure to GEM following a stepwise incremental dosing strategy. Then GEM-R cells were transfected by lentiviral plasmids and GEM-R cells overexpressing hENT1 (GEM-R-hENT1) were established. The viability and apoptosis of wild-type (MDA-MB-231), GEM-R, and GEM-R-hENT1 cells treated with GEM or GEM + miR-143 were analyzed by CCK8 assay and flow cytometry. The RNA expression and protein expression were measured by RT-PCR and western blotting respectively. GEM uptake was determined by multiple reaction monitoring (MRM) analysis. Glycolysis was measured by glucose assay and 18F-FDG uptake. The antitumor effect was assessed in vivo in a tumor xenograft model by evaluating toxicity, tumor volume, and maximum standardized uptake value in 18F-FDG PET. Immunohistochemistry and fluorescence photography were taken in tumor samples. Pairwise comparisons were performed using Student’s t-test.ResultsOur results represented that overexpression of hENT1 reversed GEM resistance in GEM-R cells by showing lower IC50 and higher rate of apoptosis. MiR-143 suppressed glycolysis in GEM-R cells and enhanced the effect of reversing GEM resistance in GEM-R-hENT1 cells. The therapeutic efficacy was validated using a xenograft mouse model. Combination treatment decreased tumor growth rate and maximum standardized uptake value in 18F-FDG PET more effectively.ConclusionsCombined therapy of exogenous upregulation of hENT1 expression and miR-143 mimic administration was effective in reversing GEM resistance, providing a promising strategy for treating GEM-resistant TNBC.

1150P Progression of advanced non-small cell lung cancer after durable clinical benefit on anti-PD-1/PD-L1 monotherapy: Prolonged post-progression survival and interest of tumor growth rate

Immunotherapy blocking the PD-1/PD-L1 axis has been used as monotherapy for barely a decade in advanced non-small cell lung cancers (aNSCLC). Tumor progression can occur even after durable clinical benefit (DCB), defined as a minimum of 6 month of responsive/stable disease (per RECIST 1.1). It is qualified as oligo-progression (OPD) if occurring in ≤3 lesions. Clinical and radiological data in this situation is still scarce and heterogeneous, but needed to optimize care and understand the underlying biological processes.

Preventive cancer stem cell-based vaccination modulates tumor development in syngeneic colon adenocarcinoma murine model.

Cancer stem cells (CSCs), a rare sub-fraction of tumor cells, with the capability of self-renewal and strong oncogenicity are tightly responsible for chemo and radio resistance and tumor metastasis in colorectal cancer. Hence, CSCs targeting would improve the efficacy of therapeutic strategies and clinical outcomes. Here, using three-dimensional CSC spheroids and syngeneic mice model, we evaluated the cancer preventive impact of CSCs-based vaccination. CSCs enrichment was performed via colonosphere formation from CT-26 cell line and CT-26-derived tumor biopsy and characterized by confirming high expression of key stemness genes (OCT4, SOX2, and NANOG) and CSC-related surface biomarkers (CD166, DCLK1, and CD133) via real-time PCR and flow cytometry, respectively. Then, the stemness phenotype and self-renewal in CSC-enriched spheroids were further confirmed by showing serial sphere formation capacity, clonogenicity potential, and enhanced in vivo tumorigenic capacity compared to their parental counterparts. CSCs lysates were used as vaccines in prophylactic settings compared to the parental cell lysate and PBS groups. Immunization of syngeneic mice with CSCs lysates was effective in the prevention of tumor establishment and significantly decreased tumor growth rate accompanied by an improvement in survival rate in tumor-bearing mice compared to groups subjected to parental cells lysate and PBS. These results, for the first time, showed that mice immunized with cell lysate from tumor biopsy-derived spheroids are resistant to tumor induction. Immunofluorescence staining indicated that only the serum antibodies from CSC-vaccinated mice reacted with colonospheres. These findings represent CSCs lysate-based vaccination as a potential approach to hampering immunotherapy failure of colorectal cancer which along with other traditional therapies may effectively apply to prevent the establishment of aggressive tumors harboring stemness features.

A unifying framework for continuous tumour growth modelling of breast cancer screening data

The aim of the current article is to present theory that can help unify continuous growth approaches for modelling breast cancer tumour growth based on human data. We present a framework that has three main features: a general likelihood function to account for patient specific screening regiments; stable disease assumptions describing tumour population dynamics; and mathematical models describing tumour growth, individual variation in tumour growth, a hazard for symptomatic detection, and screening test sensitivity. The framework is able to incorporate any random effects distributions for the tumour growth rate parameter, any hazard functions for symptomatic tumour detection, as well as any monotonously increasing function for the tumour growth model.Based on a sample of 1902 incident breast cancer cases with data on mammography screening, we show how the framework can be used to estimate tumour growth based on different growth functions.

The Effects of Placental Mesenchymal Stem Cells Labeled With Ultrasmall Superparamagnetic Iron Oxides on the Growth of Colorectal Cancer Cells.

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, with effective intervention and treatment being essential for CRC management. This study investigated the effects of human placental mesenchymal stem cells (PMSCs) labeled with ultrasmall superparamagnetic iron oxides (USPIOs) on the growth of CRC cells and the feasibility of 3.0-T magnetic resonance (MR) imaging as an in vivo tracer. Twenty subcutaneous CRC HT-29 xenograft model in immunodeficient mice was established. Mice injected with labeled PMSCs were considered as the experimental group. Thereafter, the growth and MR signal changes of xenograft tumors of every nude mouse were measured. Then, growth curve was plotted, and the MR image quality in different sequences was analyzed. Pathological staining was performed after MR scan. Ultrasmall superparamagnetic iron oxides-labeled PMSCs had no significant influence on biological characteristics ( P > 0.05). The growth of tumors in mice in the experimental group before the injection of PMSCs was similar to that of the control group. Contrarily, the tumor growth rate in the experimental group on day 5 post-PMSCs injection was slightly lower than that of the control group. Moreover, the tumor volume on day 14 was noticeably smaller than in the control group. The tracing ability of T2* mapping sequences for USPIOs-labeled cells was significantly more effective than T2-weighted image and T2 mapping sequences. Ultrasmall superparamagnetic iron oxides-labeled PMSCs injected into CRC transplanted tumors can be studied for a long period of time. Furthermore, 3.0-T MRI in vivo molecular imaging was demonstrated to be effective for CRC intervention.

HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer.

Simple SummaryThe high incidence and death rates of breast cancer make the development of new therapies an urgent need. The introduction into the clinic of the anti-HER2 monoclonal antibody trastuzumab considerably improved the overall survival and time-to-disease progression of patients with HER2-positive breast cancer. However, many patients do not benefit from it because of resistance to therapy. Cancer vaccines, by inducing into the patient an anti-cancer specific immunity, might represent an alternative immunotherapeutic approach, but despite promises, so far no anti-HER2 cancer vaccine has been approved for human use. In this study, we propose therapeutic phage-based vaccines, against HER2 and its aggressive isoform Δ16HER2, able to elicit a protective immunity and potentially capable of preventing relapse in HER2-positive breast cancer patients, even in those who develop trastuzumab resistance.The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient’s immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment.

Natural History of Cystic Vestibular Schwannomas.

To determine the natural history of cystic vestibular schwannomas (VS). Retrospective cohort. Single tertiary academic hospital. Adults diagnosed with cystic VS who had at least 2 MRIs performed at least 6 months apart between 2008 and 2016 with no intervening treatment. Volumetric growth rates of both the entire tumor and individual cystic and solid components were measured. Linear growth rate of the entire tumor was assessed using the largest diameter parallel to the petrous face at the cerebellopontine angle (CPA). Twenty-one patients met inclusion criteria. The average volumetric growth rate of the tumor was 1.1 ± 2 (range: -1.2 to 7.8), while the average growth rate of the cystic component was 0.8 ± 1.6 (range: -0.5 to 5.3) cm3/year. The CPA diameter of the tumor demonstrated an average linear growth rate of was 1.2 ± 4.4 (range: -8to 13.5) mm/year. With regards to tumor diameter, 9/21 (42.9%) remained stable, 3/21 (14.2%) decreased in size, while 9/21 (42.9%) increased in size. Cystic tumors demonstrate a wide variability in growth rate. Larger, multi-center studies will be required to further compare this relationship to solid tumors.

Microwave ablation combined with anti-PD-1/CTLA-4 therapy induces an antitumor immune response to renal cell carcinoma in a murine model

ABSTRACT The study was designed to evaluate the efficiency of microwave ablation (MWA) in combination with anti-programmed death receptor 1 (anti-PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in renal cell carcinoma (RCC) treatment. After tumors were established on C57/BL6 mice, MWA treatment and/or immune checkpoint inhibitor (ICI) treatment to the mice were performed. Tumor volume was recorded every 7 days. A rechallenge test was conducted on mice with tumors in the left kidney to explore the systemic establishment of antitumor immunity on day 7. In this study, during the 21-day observation period, tumors were continued to grow in all groups. However, compared with the tumor growth rate in MWA or control group, the rate in the ICI or MWA+ICI groups was decreased. Moreover, the population of CD8+T-cells was increased only in the MWA+ICI group, while that of regulatory T cells was decreased in the MWA, ICI, and MWA+ICI groups. Additionally, the MWA+ICI group had the highest interferon-γ level among all groups. Furthermore, histopathological examination revealed that CTLA-4 expression in distant tumors was reduced in the ICI and MWA + ICI groups. MWA treatment increased PD-L1/PD-1 expression; however, after the combination treatment with ICI, PD-L1/PD-1 expression was decreased. According to the rechallenge test, mice (16.7%) in the MWA group, ICI group (50%), and MWA+ICI group (66.7%) exhibited successful tumor rejection, whereas no mice in the control group exhibited the capability of tumor rejection. Overall, the systemic antitumor immunity induced by MWA was boosted when combined with anti-PD-1/CTLA-4 treatment in an RCC murine model.

Tumor Growth Rate as a Predictive Marker for Recurrence and Survival After Liver Resection in Patients with Liver Metastases of Uveal Melanoma.

Surgical management of liver metastases of uveal melanoma (LMUM) is associated with the best survival rates, especially for patients with a low tumor burden in the liver. The aim was to determine whether the tumor growth rate (TGR0) before liver resection helps predict survival in patients with resectable LMUM. This retrospective study included 99 patients with LMUM treated with liver resection between November 2007 and November 2020. TGR0 was expressed as the percentage change in tumor volume over 1 month according to two pretreatment imaging scans. Multivariate Cox analyses identified independent predictors of disease-free survival (DFS) and overall survival (OS). DFS and OS had a statistically significant positive linear relationship (Spearman correlation r = 0.68, p < 0.001). A disease-free interval (DFI) > 24 months and a TGR0 ≤ 50%/month were independent factors associated with better DFS and OS. The 2-component model including TGR0 and DFI had a mean time-dependent area under the curve (AUC) of 0.81 (95% CI, 0.75-0.86) and 0.77 (95% CI, 0.67-0.87), respectively, for predicting DFS and OS. DFI with TGR0 defined three kinetic risk groups that had distinct DFS and OS outcomes (p < 0.001). Cytogenetic alterations at baseline were partially predictive factors of the kinetic risk score based on TGR0 and DFI. The assessment of TGR0 improves prognostic stratification by identifying patients at high risk of recurrence and poor survival after liver resection. TGR0 and DFI, reflecting tumor aggressivity, have the potential to be important markers for systemic adjuvant decisions.

CPNE1 silencing inhibits cell proliferation and accelerates apoptosis in human gastric cancer

Gastric cancer is a heterogeneous disease accompanied by the alteration of various causative genes. The discovery of molecular targets and potential mechanisms of gastric cancer is valuable. Here we explored the biological function of CPNE1 and its molecular mechanisms in gastric cancer. Immunohistochemistry and Kaplan–Meier plotter database were used to identify that CPNE1 was upregulated in human gastric cancer and high expression of CPNE1 suggested a worse prognosis. Silencing CPNE1 could effectively suppress tumor proliferation, accelerate cell apoptosis and arrest cell cycle in vitro. CPNE1 knockdown mediating apoptosis by PARP-1 cleavage via caspase-3 and -7 activation through cytochrome c release from mitochondria in gastric cancer cells. Xenograft mouse model showed that targeted inhibition of CPNE1 slowed down the rate of tumor growth in vivo. We also verified that CPNE1 knockdown inhibited the activation of MAPK pathway mediated by DDIT3-FOS-MKNK2 axis. Specific inhibitor of DDIT3-FOS-MKNK2 axis could suppress gastric cancer cell proliferation, concomitant with knockdown of CPNE1. In conclusion, CPNE1 silencing inhibited gastric cancer growth via deactivating DDIT3-FOS-MKNK2 axis, which indicated that CPNE1 might serve as a therapeutic target for gastric cancer.

Influence of copper nanoparticles on the growth characteristics of tumors in white outbreed rats

Purpose of the study. To study the effect of copper nanoparticles on the characteristics of the transplanted tumors of rats, as well as to assess the dependence of the effect on the method of administration of nanoparticles.Materials and methods. In experiments on 163 white outbred male rats, 160–200 g, the size and growth rate of transplanted sarcoma 45 and Pliss' lymphosarcoma were determined in dynamics when a suspension of copper nanoparticles in physiological saline was injected intratumorally or intraperitoneally in a total dose of 10 mg/kg. Nanoparticles had a "core-shell" structure with variable diameter in the range of 30–75 nm. Contrary to other researches, we started the exposure to metal nanoparticles only when the tumors had become visible and had grown up to the sizes at which their spontaneous regression was unlikely.Results. In most animals (up to 89 %), significant antitumor effects of copper nanoparticles were obtained up to complete regression of tumors with large volumes. The effects of nanodispersed copper differed in tumors with different histological structures and growth patterns. Experiments on a transplantable, slowly growing sarcoma 45 showed a decrease in the specific tumor growth rate after a single injection of nanoparticles (1.25 mg/kg), a decrease in tumor size could be observed after 4 injections (a total dose of 5 mg/kg). In the case of a rapidly growing tumor model (Pliss' lymphosarcoma), a decrease in tumor growth rates caused by copper nanoparticles occurred at later stages of exposure, after the animals received nanoparticles at a total dose of 5–10 mg/kg. The efficiency depended on the approach of nanoparticles injection.Conclusion. In case of sarcoma 45, intraperitoneal injection of copper nanoparticles was more effective than intratumoral one, while in rats with Pliss' lymphosarcoma intratumoral injection of the nanoparticles had some advantages. The results indicate that nanodispersed copper is a promising antitumor factor. The mechanisms of regression of large transplanted tumors under the influence of copper nanoparticles are discussed.

Demographic and pathologic factor regression to a growth rate model of p16-negative oral cavity squamous cell carcinoma.

ObjectivesThe current study aims to quantify the growth rate of p16‐negative oral cavity squamous cell carcinoma, characterize causative relationships between demographic risk factors and tumor growth, and examine pathologic findings associated with the tumor growth rate at a tertiary care institution. It is hypothesized that causative relationships will be drawn between the individual sociodemographic and pathologic factors and oral cavity p16‐negative squamous cell carcinoma growth rate.MethodsProspectively recruited participants, receiving surgical intervention only, were followed from initial staging CT scan to surgical resection. Interval growth was calculated in cm3/week. Demographic information including age, sex, smoking history, alcohol consumption history, previous all‐type malignancy, previous chemotherapy treatment, previous head or neck radiation exposure, and time interval elapsed between diagnosis and surgery was collected from each participant, and regression analysis was applied to determine causality.ResultsSummary statistics revealed a mean growth rate for the study sample of 1.385cm3/week. Statistically significant regression correlations were detected between tumor growth and alcohol consumption, origination at the retromolar trigone, and clinical nodal stage.ConclusionsThrough a small prospective cohort sample, the current study suggests clinical associations between alcohol consumption, origination at the retromolar trigone, and clinical nodal stage with rate of tumor growth. Future work will validate these relationships in a larger patient cohort, and against stronger modeling techniques.Level of EvidenceProspective non‐random cohort design.

HER3 PET Imaging Predicts Response to Pan Receptor Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

New generation of receptor tyrosine kinase inhibitors (RTKIs) have shown to improve survival in many solid tumors. However, an imaging biomarker is needed for patient selection and prediction of treatment response. This study evaluates the use of quantitative changes of HER3 on 68Ga-NOTA-HER3P1 PET/MRI for prediction of early response to pan-RTKIs in gastric cancer (GCa). GCa cell lines were evaluated for expression of RTKs, and downstream signaling pathways (AKT and MAPK). Cell viability was assessed following 24-72h of treatment with 0.01-1µmol/L of afatinib, a pan-RTKI. HER3-expressing afatinib-sensitive (NCI-N87) and resistant cells (SNU16) were selected for evaluation of changes in RTKs expression and downstream pathways, with 24-72h of 0.1µmol/L afatinib treatment. 68Ga-NOTA-HER3P1 PET/MRI was performed in subcutaneous NCI-N87 and SNU16 xenografts (nu:nu, n = 12/group) at baseline and 4days after afatinib treatment (10mg/kg, PO, daily). Temporal changes in PET measures were correlated to HER3 expression in tumors, tumor growth rate, and treatment response. With afatinib therapy, NCI-N87 cells showed increased total HER3 expression, and reduction of other RTKs and downstream nodes within 72h, while SNU16 cells showed no significant change in total HER3 and downstream nodes. 68Ga-HER3P1 PET/MRI showed increased uptake in NCI-N87 and no significant change in SNU16 tumors (day 4 vs. baseline SUVmean: 3.8 ± 0.7 vs. 1.6 ± 0.6, p < 0.05 in NCI-N87, and 1.5 ± 0.7 vs. 1.7 ± 0.7, p > 0.05 in SNU16). These findings were in concordance with HER3 expression in histopathological analyses and tumor growth over 3weeks of treatment (mean tumor volume in treated vs. control: 11 ± 17 mm3 vs. 293 ± 79 mm3, p < 0.001 in NCI-N87, and 238 ± 91 mm3 vs. 282 ± 35 mm3, p > 0.05 in SNU16). Quantitative changes in HER3 PET could be used to predict response to pan-RTKI within few days after initiation of treatment and can help with personalizing GCa management.