Background:The application and feasibility of minimally invasive liver resection(MILR)for huge liver tumours(≥10 cm)has not been well documented.Methods:Retrospective analysis of data on 6,617 patients who had MILR f...Background:The application and feasibility of minimally invasive liver resection(MILR)for huge liver tumours(≥10 cm)has not been well documented.Methods:Retrospective analysis of data on 6,617 patients who had MILR for liver tumours were gathered from 21 international centers between 2009-2019.Huge tumors and large tumors were defined as tumors with a size≥10.0 cm and 3.0-9.9 cm based on histology,respectively.1:1 coarsened exact-matching(CEM)and 1:2 Mahalanobis distance-matching(MDM)was performed according to clinically-selected variables.Regression discontinuity analyses were performed as an additional line of sensitivity analysis to estimate local treatment effects at the 10-cm tumor size cutoff.Results:Of 2,890 patients with tumours≥3 cm,there were 205 huge tumors.After 1:1 CEM,174 huge tumors were matched to 174 large tumors;and after 1:2 MDM,190 huge tumours were matched to 380 large tumours.There was significantly and consistently increased intraoperative blood loss,frequency in the application of Pringle maneuver,major morbidity and postoperative stay in the huge tumour group compared to the large tumour group after both 1:1 CEM and 1:2 MDM.These findings were reinforced in RD analyses.Intraoperative blood transfusion rate and open conversion rate were significantly higher in the huge tumor group after only 1:2 MDM but not 1:1 CEM.Conclusions:MILR for huge tumours can be safely performed in expert centers It is an operation with substantial complexity and high technical requirement,with worse perioperative outcomes compared to MILR for large tumors,therefore judicious patient selection is pivotal.展开更多
In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK ...In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies.Here,we report that roniciclib(BAY1000394),a potent pan-CDK inhibitor,displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma(NPC)models.Proliferation of the NPC cell lines HONE-1,CNE-2,C666-1,and HK-1 was effectively curbed by roniciclib treatment,with IC_(50)values between 11 and 38 nmol/L.These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1,2,3,and 4 and transcriptional CDKs 7 and 9,ultimately resulting in arrest at G1/S and G2/M,downregulation of the transcriptional apparatus,and repression of anti-apoptotic proteins.Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0μmol/L cisplatin;this combination therapy achieved a response over 250%greater than either drug alone.Although roniciclib chemosensitized NPC cells to cisplatin,it did not sensitize untransformed(NP69)cells.The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin,whereas combining these two agents produced far greater tumor suppression than either of the monotherapies.In summary,these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses,thus justifying further evaluation of this combinatorial approach in clinical settings.展开更多
文摘Background:The application and feasibility of minimally invasive liver resection(MILR)for huge liver tumours(≥10 cm)has not been well documented.Methods:Retrospective analysis of data on 6,617 patients who had MILR for liver tumours were gathered from 21 international centers between 2009-2019.Huge tumors and large tumors were defined as tumors with a size≥10.0 cm and 3.0-9.9 cm based on histology,respectively.1:1 coarsened exact-matching(CEM)and 1:2 Mahalanobis distance-matching(MDM)was performed according to clinically-selected variables.Regression discontinuity analyses were performed as an additional line of sensitivity analysis to estimate local treatment effects at the 10-cm tumor size cutoff.Results:Of 2,890 patients with tumours≥3 cm,there were 205 huge tumors.After 1:1 CEM,174 huge tumors were matched to 174 large tumors;and after 1:2 MDM,190 huge tumours were matched to 380 large tumours.There was significantly and consistently increased intraoperative blood loss,frequency in the application of Pringle maneuver,major morbidity and postoperative stay in the huge tumour group compared to the large tumour group after both 1:1 CEM and 1:2 MDM.These findings were reinforced in RD analyses.Intraoperative blood transfusion rate and open conversion rate were significantly higher in the huge tumor group after only 1:2 MDM but not 1:1 CEM.Conclusions:MILR for huge tumours can be safely performed in expert centers It is an operation with substantial complexity and high technical requirement,with worse perioperative outcomes compared to MILR for large tumors,therefore judicious patient selection is pivotal.
基金This work was supported by grants from the Singapore Ministry of Health’s National Medical Research Council(NMRC/CSA/021/2010 to B.C.Goh)the National Research Foundation Singapore and Singapore Ministry of Education under their Research Centres of Excellence(RCE)Initiative.
文摘In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies.Here,we report that roniciclib(BAY1000394),a potent pan-CDK inhibitor,displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma(NPC)models.Proliferation of the NPC cell lines HONE-1,CNE-2,C666-1,and HK-1 was effectively curbed by roniciclib treatment,with IC_(50)values between 11 and 38 nmol/L.These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1,2,3,and 4 and transcriptional CDKs 7 and 9,ultimately resulting in arrest at G1/S and G2/M,downregulation of the transcriptional apparatus,and repression of anti-apoptotic proteins.Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0μmol/L cisplatin;this combination therapy achieved a response over 250%greater than either drug alone.Although roniciclib chemosensitized NPC cells to cisplatin,it did not sensitize untransformed(NP69)cells.The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin,whereas combining these two agents produced far greater tumor suppression than either of the monotherapies.In summary,these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses,thus justifying further evaluation of this combinatorial approach in clinical settings.
