Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

[Research progress in preparations of Panax ginseng].

Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits, among which the roots are the most commonly used. The main active components of this medicinal plant include triterpenoid saponins, polysaccharides, peptides, and volatile oils. The chemical components and active metabolites endow this herb with a variety of pharmacological effects, and thus this herb is used to treat various diseases and play healthcare roles. Currently, a wide range of preparations of P. ginseng have been officially registered and marketed, including tablets, oral liquids, and injections, which demonstrate good clinical efficacy in regulating immunity, adjuvant treatment of tumors, alleviating fatigue, delaying the aging process, improving glucose and lipid metabolism, treating cardiovascular diseases, and relieving inflammation and pain. The production process and quality standards of these drugs are of great significance to ensure their efficacy. According to the theory that Ginseng Radix et Rhizoma can greatly replenish original Qi, tonify the spleen and lung, promote fluid production to quench thirst, tranquilize mind and enrich the intelligence, this paper systematically summarized the clinical application progress of P. ginseng and rela-ted preparations on the market and prospected the further development of preparations from P. ginseng, providing a reference for further exploring the medicinal value and healthcare function of this herb. The above contents, as an important basis for the in-depth development of P. ginseng and related drugs, increase the possibilities for the application of P. ginseng.

Renin-angiotensin system inhibitors improve the survival of cholangiocarcinoma: a propensity score-matched cohort study.

BACKGROUND: Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. METHODS: This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. RESULTS: Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32-0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20-0.79), respectively. Calcium channel blockers, diuretics, and ß-blockers didn't show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2-34.4); OS, 24.8 months (16.5-42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1-24.1); OS, 14.6 months (10.6-28.4)). The 1 year, 2 years, and 3 years' survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). CONCLUSIONS: RASis usage improves the survival of patients with CCA and hypertension concurrently.

Phytochemistry, data mining, pharmacology, toxicology and the analytical methods of Cyperus rotundus L. (Cyperaceae): a comprehensive review.

Cyperus rotundus L. has been widely used in the treatment and prevention of numerous diseases in traditional systems of medicine around the world, such as nervous, gastrointestinal systems diseases and inflammation. In traditional Chinese medicine (TCM), its rhizomes are frequently used to treat liver disease, stomach pain, breast tenderness, dysmenorrheal and menstrual irregularities. The review is conducted to summarize comprehensively the plant's vernacular names, distribution, phytochemistry, pharmacology, toxicology and analytical methods, along with the data mining for TCM prescriptions containing C. rotundus. Herein, 552 compounds isolated or identified from C. rotundus were systematically collated and classified, concerning monoterpenoids, sesquiterpenoids, flavonoids, phenylpropanoids, phenolics and phenolic glycosides, triterpenoids and steroids, diterpenoids, quinonoids, alkaloids, saccharides and others. Their pharmacological effects on the digestive system, nervous system, gynecological diseases, and other bioactivities like antioxidant, anti-inflammatory, anti-cancer, insect repellent, anti-microbial activity, etc. were summarized accordingly. Moreover, except for the data mining on the compatibility of C. rotundus in TCM, the separation, identification and analytical methods of C. rotundus compositions were also systematically summarized, and constituents of the essential oils from different regions were re-analyzed using multivariate statistical analysis. In addition, the toxicological study progresses on C. rotundus revealed the safety property of this herb. This review is designed to serve as a scientific basis and theoretical reference for further exploration into the clinical use and scientific research of C. rotundus. Supplementary Information: The online version contains supplementary materials available at 10.1007/s11101-023-09870-3.

Ebselen inhibits enterovirus A71-induced apoptosis through reactive oxygen species-mediated signaling pathway.

BACKGROUND: Enterovirus A71 (EV-A71)is a prevalent infection in severe hand, foot and mouth disease HFMD and can induce acute central nervous system seizures. The three EV-A71 vaccines now circulating in the market are produced for a single subtype. While EV-A71 is constantly evolving and the vaccine's efficacy is gradually reducing, no specialized anti-EV-A71 medication has yet been developed. Therefore, it is crucial to consistently develop new anti-EV-A71 medications. METHOD: Ebselen, an organoselenium molecule with glutathione oxidase-like activity, is resistant to a range of viruses. In this investigation, we used the Cell counting kit-8 (CCK-8 kit) assay in a Vero cell model to confirm the effectiveness of ebselen against EV-A71 infection. Later, to examine ebselen's anti-EV-A71 mechanism, we measured the apoptosis level of cells in different treatment groups through Annexin V, JC-1, and cell cycle assays, as well as the intracellular reactive oxygen species (ROS) concentration. Ebselen may have an impact on the apoptotic signaling pathway caused by EV-A71 infection, according to the results of a caspase-3 activity experiment. RESULT: The results showed that Ebselen protected cell damage from ROS generation, decreased the frequency of EV-A71-induced apoptosis, and inhibited caspase-3-mediated apoptosis by lowering caspase-3 activity. CONCLUSION: To summarize, ebselen is a promising anti-EV-A71 medication.

SGLT-2 inhibitors may increase ultrafiltration in incident peritoneal dialysis patients: a case report.

BACKGROUND: Adequate fluid removal to achieve euvolemic status can be difficult in patients with incident peritoneal dialysis (PD). Limited treatments such as increased high dextrose PD solutions and icodextrin are currently available. We reported four incident PD patients whose' ultrafiltration volume was increased after sodium-glucose cotransporter-2 inhibitors. CASE PRESENTATION: The four reported cases were diabetic kidney disease stage 5 (cases 1-3) and IgA nephritis (case 4) patients whostartedt PD because of acute pulmonary edema (case 1 and 3), nausea vomiting (case 2), and hyperkalemia (case 4). They had an ultrafiltration volume of 700-1000 ml per day but hpersistentted peripheral pitting edema or pulmonary edema. Their ultrafiltration volincreased after dapagliflozin 5 mg daily, and the fluid overload symptoms ere improved. No hypotension, or hypoglycemia was found, and the urine was not increased during dapagliflozin treatment. CONCLUSIONS: SGLT-2 inhibitors may increase ultrafiltration in incident PD patients. More studies are needed to support the safety of SGLT-2 inhibitors in PD patients.

Furfural Derivatives and Phenolic Constituents in Stemona tuberosa Lour.

Chemical investigation on the water-soluble constituents of Stemona tuberosa Lour. resulted in the isolation of a previously undescribed furfural derivative namely (S)-5-((R)-hydroxy(5-(hydroxymethyl)furan-2-yl)methyl)-5-methylfuran-2(5H)-one and twenty-five known compounds from the water decoction of the dried root tubers. Their structures were determined by analysis of the extensive spectroscopic data, including 1D/2D NMR, HR-ESI-MS, and ORD, as well as the ECD simulation and comparison. Most of them were phenolic and among them, four compounds were isolated from Stemona plants for the first time. This study uncovers diverse constituents from water decoction of S. tuberosa dedicated for its quality control and allows for the exploitation of chemical markers with potential significance for discrimination of Stemona plants.

Steroidal Saponins from Solanum lyratum Thunb.

Four undescribed steroidal compounds along with twenty known compounds were isolated from n-butanol extracted fraction of the whole plants of Solanum lyratum Thunb (SLNF). Their structures were assigned based on analyses of the extensive spectroscopic data (including MS, 1D/2D NMR, and ECD) or comparisons of the NMR data with those reported. Among the knowns, three compounds were isolated from Solanum plants for the first time, while one compound was isolated from S. lyratum for the first time. In addition, the cytotoxicities of these isolates against human colon SW480 and hepatoma Hep3B cells were evaluated by a MTT assay. And, nine of them and SLNF exhibited significant activities against both SW480 and Hep3B cells, while twelve of them significantly inhibited the activities of SW480 cells. This study allows for the exploitation of chemical markers with potential significance in discrimination of Solanum plants, and uncovers the diverse steroidal constituents from S. lyratum dedicated for its future application in cancer treatment.

Multiphonon Process in Mn-Doped ZnO Nanowires.

The multiphonon process plays an essential role in understanding electron-phonon coupling, which significantly influences the optical and transport properties of solids. Multiphonon processes have been observed in many materials, but how to distinguish them directly by their spectral characteristics remains controversial. Here, we report high-order Raman scattering up to 10 orders and hot luminescence involving 11 orders of phonons in Mn-doped ZnO nanowires by selecting the excitation energy. Our results show that the intensity distribution of high-order Raman scattering obeys an exponential decrease as the order number increases, while hot luminescence is fitted with a Poisson distribution with a resonance factor. Their linewidth and frequency can be well explained by two different transition models. Our work provides a paradigm for understanding the multiphonon-involved decay process of an excited state and may inspire studies of the statistical characteristics of excited state decay.

Laser Cooling of a Lattice Vibration in van der Waals Semiconductor.

Laser cooling atoms and molecules to ultralow temperatures has produced plenty of opportunities in fundamental physics, precision metrology, and quantum science. Although theoretically proposed over 40 years, the laser cooling of certain lattice vibrations (i.e., phonon) remains a challenge owing to the complexity of solid structures. Here, we demonstrate Raman cooling of a longitudinal optical phonon in two-dimensional semiconductor WS2 by red-detuning excitation at the sideband of the exciton (bound electron-hole pair). Strong coupling between the phonon and exciton and appreciable optomechanical coupling rates provide access to cooling high-frequency phonons that are robust against thermal decoherence even at room temperature. Our experiment opens possibilities of laser cooling and control of individual optical phonon and, eventually, possible cooling of matter in van der Waals semiconductor.

Donor-Acceptor Pair Quantum Emitters in Hexagonal Boron Nitride.

Quantum emitters are needed for a myriad of applications ranging from quantum sensing to quantum computing. Hexagonal boron nitride (hBN) quantum emitters are one of the most promising solid-state platforms to date due to their high brightness and stability and the possibility of a spin-photon interface. However, the understanding of the physical origins of the single-photon emitters (SPEs) is still limited. Here we report dense SPEs in hBN across the entire visible spectrum and present evidence that most of these SPEs can be well explained by donor-acceptor pairs (DAPs). On the basis of the DAP transition generation mechanism, we calculated their wavelength fingerprint, matching well with the experimentally observed photoluminescence spectrum. Our work serves as a step forward for the physical understanding of SPEs in hBN and their applications in quantum technologies.

The Application of Ethnomedicine in Modulating Megakaryocyte Differentiation and Platelet Counts.

Megakaryocytes (MKs), a kind of functional hematopoietic stem cell, form platelets to maintain platelet balance through cell differentiation and maturation. In recent years, the incidence of blood diseases such as thrombocytopenia has increased, but these diseases cannot be fundamentally solved. The platelets produced by MKs can treat thrombocytopenia-associated diseases in the body, and myeloid differentiation induced by MKs has the potential to improve myelosuppression and erythroleukemia. Currently, ethnomedicine is extensively used in the clinical treatment of blood diseases, and the recent literature has reported that many phytomedicines can improve the disease status through MK differentiation. This paper reviewed the effects of botanical drugs on megakaryocytic differentiation covering the period 1994-2022, and information was obtained from PubMed, Web of Science and Google Scholar. In conclusions, we summarized the role and molecular mechanism of many typical botanical drugs in promoting megakaryocyte differentiation in vivo, providing evidence as much as possible for botanical drugs treating thrombocytopenia and other related diseases in the future.

Selenium Nanoparticles Control H1N1 Virus by Inhibiting Inflammatory Response and Cell Apoptosis.

The treatment of influenza caused by H1N1 has been the focus of much attention. Selenium nanoparticles (SeNPs) have been used in many aspects of research in the last two decades. They have shown excellent performance in antiviral, anti-inflammatory, and antioxidant functions. Previous anti-H1N1 cell experiments using SeNPs have shown that they have evident antiviral effects and low toxicities. This study focuses on the mechanism of selenium nanoparticles against an H1N1 influenza virus infection in vivo. The results showed that the selenium levels in the body decreased after an H1N1 virus infection, and inflammatory factors in the lung tissues increased abnormally, leading to the onset and aggravation of an inflammatory response. The H1N1 virus infection also led to the excessive activation of apoptotic pathways in the body and induced the apoptosis of tissue cells. In addition, this study found that SeNPs can alleviate this phenomenon. All results showed that SeNPs are promising inhibitors for controlling influenza H1N1 virus infections.

Naringenin Induces HepG2 Cell Apoptosis via ROS-Mediated JAK-2/STAT-3 Signaling Pathways.

Hepatocarcinoma is one of the most prevalent digestive system tumors worldwide and lacks effective therapy. Recently, naringenin has been isolated from some citrus fruits, and its anticancer effects have been tested. However, the molecular mechanisms of naringenin and the potential implications of oxidative stress in naringenin-induced cytotoxicity in HepG2 cells remain elusive. Based on the above, the present study examined the effect of naringenin on the cytotoxic and anticancer mechanisms of HepG2 cells. Naringenin-induced HepG2 cell apoptosis was confirmed via the accumulation of the sub-G1 cell population, phosphatidylserine exposure, mitochondrial transmembrane potential loss, DNA fragmentation, caspase-3 activation, and caspase-9 activation. Furthermore, naringenin enhanced cytotoxic effects on HepG2 cells and triggered intracellular reactive oxygen species; the signaling pathways of JAK-2/STAT-3 were inhibited, and caspase-3 was activated to advance cell apoptosis. These results suggest that naringenin plays an important role in inducing apoptosis in HepG2 cells and that naringenin may be a promising candidate for cancer therapy.

Degradation Profiling of Nardosinone at High Temperature and in Simulated Gastric and Intestinal Fluids.

Nardosinone, a predominant bioactive product from Nardostachys jatamansi DC, is well-known for its promising therapeutic applications, such as being used as a drug on anti-inflammatory, antidepressant, cardioprotective, anti-neuroinflammatory, anti-arrhythmic, anti-periodontitis, etc. However, its stability under varying environmental conditions and its degradation products remain unclear. In this study, four main degradation products, including two previously undescribed compounds [2-deoxokanshone M (64.23%) and 2-deoxokanshone L (1.10%)] and two known compounds [desoxo-narchinol A (2.17%) and isonardosinone (3.44%)], were firstly afforded from the refluxed products of nardosinone in boiling water; their structures were identified using an analysis of the extensive NMR and X-ray diffraction data and the simulation and comparison of electronic circular dichroism spectra. Compared with nardosinone, 2-deoxokanshone M exhibited potent vasodilatory activity without any of the significant anti-neuroinflammatory activity that nardosinone contains. Secondly, UPLC-PDA and UHPLC-DAD/Q-TOF MS analyses on the degradation patterns of nardosinone revealed that nardosinone degraded more easily under high temperatures and in simulated gastric fluid compared with the simulated intestinal fluid. A plausible degradation pathway of nardosinone was finally proposed using nardosinonediol as the initial intermediate and involved multiple chemical reactions, including peroxy ring-opening, keto-enol tautomerization, oxidation, isopropyl cleavage, and pinacol rearrangement. Our findings may supply certain guidance and scientific evidence for the quality control and reasonable application of nardosinone-related products.

A novel fluorescence ratio probe based on dual-emission carbon dots for highly selective and sensitive detection of chlortetracycline and cell imaging.

The novel dual-emission carbon dots (DECDs) for highly selective and sensitive recognition of chlortetracycline (CTC) and cell imaging were synthesized successfully by one-step synthesis. The obtained DECDs possessed two fluorescence peaks (345 nm and 450 nm) and showed specific response to CTC, resulting in a decrease in fluorescence intensity at 345 nm, a blue shift, and an increase in fluorescence intensity at 450 nm. The obtained DECDs exhibited highly selective response to CTC and not to its analogues, such as tetracycline, doxycycline, and oxytetracycline. Thus, an excellent ratiometric probe for the detection of CTC was fabricated successfully and used for the detection of CTC in real samples with the detection limit (LOD) of 16.45 nM. More importantly, the DECDs were used for quantitative detection of CTC in living cells, which demonstrated excellent biocompatibility and broad prospects in biomedicine application. Finally, the excellent selectivity of DECDs toward CTC was attributed to the FRET mechanism and the formation of complexes.

Macrophage cell membrane-based nanoparticles: a new promising biomimetic platform for targeted delivery and treatment.

Synthetic nanoparticles with surface bioconjugation are promising platforms for targeted therapy, but their simple biological functionalization is still a challenging task against the complex intercellular environment. Once synthetic nanoparticles enter the body, they are phagocytosed by immune cells by the immune system. Recently, the cell membrane camouflage strategy has emerged as a novel therapeutic tactic to overcome these issues by utilizing the fundamental properties of natural cells. Macrophage, a type of immune system cells, plays critical roles in various diseases, including cancer, atherosclerosis, rheumatoid arthritis, infection and inflammation, due to the recognition and engulfment function of removing substances and pathogens. Macrophage membranes inherit the surface protein profiles and biointerfacing properties of source cells. Therefore, the macrophage membrane cloaking can protect synthetic nanoparticles from phagocytosis by the immune cells. Meanwhile, the macrophage membrane can make use of the natural correspondence to accurately recognize antigens and target inflamed tissue or tumor sites. In this review, we have summarized the advances in the fabrication, characterization and homing capacity of macrophage membrane cloaking nanoparticles in various diseases, including cancers, immune diseases, cardiovascular diseases, central nervous system diseases, and microbial infections. Although macrophage membrane-camouflaged nanoparticles are currently in the fetal stage of development, there is huge potential and challenge to explore the conversion mode in the clinic.

Methyl Gallate Alleviates Acute Ulcerative Colitis by Modulating Gut Microbiota and Inhibiting TLR4/NF-κB Pathway.

Ulcerative colitis (UC) is a complex immune-mediated inflammatory disease. In recent years, the incidence of UC has increased rapidly, however, its exact etiology and mechanism are still unclear. Based on the definite anti-inflammatory and antibacterial activities of Sanguisorba officinalis L., we studied its monomer, methyl gallate (MG). In this study, we employed flow cytometry and detected nitric oxide production, finding MG regulated macrophage polarization and inhibited the expression of proinflammatory cytokines in vitro. MG also exhibited anti-inflammatory activity accompanying with ameliorating body weight loss, improving colon length and histological damage in dextran sulfate sodium-induced UC mice. Meanwhile, transcription sequencing and 16S rRNA sequencing analyzed the key signaling pathways and changes in the gut microbiota of MG for UC treatment, proving that MG could alleviate inflammation by regulating the TLR4/NF-κB pathway in vivo and in vitro. Additionally, MG altered the diversity and composition of the gut microbiota and changed the abundance of metabolic products. In conclusion, our results are the first to demonstrate that MG has obvious therapeutic effects against acute UC, which is related to macrophage polarization, improved intestinal flora dysbiosis and inhibition of TLR4/NF-κB signaling pathway, and MG may be a promising therapeutic agent for UC treatment.

The presence of microvascular invasion guides treatment strategy in recurrent HBV-related HCC.

OBJECTIVES: We used the status of microvascular invasion (MVI) at primary resection to help treatment selection for hepatitis B virus-positive (HBV+) recurrent hepatocellular carcinoma (rHCC) patients in Barcelona Clinic Liver Cancer (BCLC) stage B-C. METHODS: From 2009 to 2017, we enrolled 221 consecutive HBV+ rHCC patients at BCLC stage B-C who underwent re-resection (RR), radiofrequency ablation (RFA), or transarterial chemoembolization (TACE). Post recurrence survival (PRS) and overall survival (OS) were compared between RR/RFA and TACE according to MVI status. A one-to-one propensity score matching analysis was performed. RESULTS: For MVI(-) patients, the median PRS was 62.3 months for the RR/RFA group and 21.1 months for the TACE group (p = 0.039). The corresponding OS was 71.4 months and 26.6 months, respectively (p = 0.010). For MVI(+) patients, the median PRS in the RR/RFA group and TACE group was 14.7 months and 10.1 months (p = 0.115). The corresponding OS was 23.4 months and 16.4 months, respectively (p = 0.067). After matching, the dominance of RR/RFA over TACE remained in MVI(-) patients for both PRS (62.3 months vs 15.3 months, p = 0.019) and OS (98.1 months vs 33.4 months, p = 0.046). No significant difference was found in MVI(+) patients for either PRS (14.7 months vs 11.8 months, p = 0.593) or OS (23.4 months vs 28.1 months, p = 0.662). CONCLUSIONS: MVI status definitely helps select treatment options in HBV+ rHCC patients. For MVI(-) patients, RR/RFA provided better survival than TACE while for MVI(+) patients, TACE shared similar survival outcomes. KEY POINTS: • This study aimed at the determination of the optimal treatment options (ablation /resection vs TACE) in case of recurrent HBV-related HCC. • It showed that MVI status, established at primary resection of HCC, was a powerful marker for selecting the best treatment option in these patients. • In MVI(-) patients, RR/RFA achieved a better survival than TACE. In MVI(+) patients, TACE shared similar survival.

Association between number of dissected lymph nodes and survival in stage IA non-small cell lung cancer: a propensity score matching analysis.

BACKGROUND: For patients with stage IA non-small cell lung cancer (NSCLC) with tumor size ≤ 2 cm, the prognostic significance of the number of removed lymph nodes (NLNs) through different surgical methods remains unclear. To determine the association of NLNs with cancer-specific survival (CSS) and overall survival (OS) in patients with stage IA NSCLC with tumor size ≤ 2 cm who underwent different lung surgeries. METHODS: We retrospectively enrolled 7293 patients from the Surveillance, Epidemiology and End Results database. Median NLNs was used to classify the patients into two groups: group A with NLNs ≤ 5 and group B with NLNs > 5. Propensity score matching (PSM) was performed to decrease selection bias. Kaplan-Meier analysis and Cox regression analysis were performed to identify the association between NLNs and survival outcomes. RESULTS: Group B had better survival than group A in the unmatched cohort and matched cohort (all P < 0.05). Multivariable analyses revealed that the NLNs significantly affected CSS and OS of eligible cases in the unmatched cohort and matched cohort. Additionally, we found that the NLNs was a protective prognostic predictor of OS for patients who underwent wedge resection, segmental resection, or lobectomy. CONCLUSION: The NLNs was a protective prognostic factor in NSCLC patients with tumor size ≤ 2 cm. We demonstrated that patients with > 5 NLNs in the cohort of wedge resection, segmental resection, or lobectomy exhibited a significantly better OS.