Visible-Light-Promoted Regioselective Hydroborylation of Ketene Dithioacetals with NHC-Boranes.

NHC-boranes have been treated as a reliable source of boryl radicals. In this study, regioselective hydroborylation of ketene dithioacetals with NHC-borane was achieved under mild conditions via a visible-light-promoted radical chain process using thiophenol as a proton donor and hydrogen atom transfer. This protocol features a low-cost catalyst, good functional group tolerance, a relatively broad range of substrate scope, and good to excellent yields. Moreover, mechanism of this hydroborylation reaction was preliminarily studied.

Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements.

BACKGROUND: The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70-75% of infants, 5-6% of children and 10-15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. METHODS: A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. RESULTS: The 48 enrolled patients included 28 males and 20 females; 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 109/L was detected in 7 (14.58%) patients; testicular leukemia (TL) or central nervous system involvement was found in 5 (10.41%) or 3 (6.25%) patients, respectively. Statistical differences were not found in the age groups of sex or initial WBC count, whereas TL was more common in the infant group (P < 0.05). 11q23 was detected in 18 patients; KMT2Ar was detected in 46 (95.83%) or 45 (93.75%) patients by FISH or multiplex RT-PCR technology, respectively; RNA-seq data were obtained for 18 patients, and 3 patients with uncommon KMT2Ar were identified. KMT2A-AFF1, KMT2A-MLLT3 and KMT2A-MLLT1 were the most common transcripts. Statistical differences were not found in treatment response by age groups, including dexamethasone induction, bone marrow (BM) smear status and minimal residual disease (MRD) level at different time points (TP), treatment-related mortality (TRM), or complete remission (CR) rate (P > 0.05); MRD levels monitored by FCM or PCR were unequal at the same TP. Four patients died of treatment, and TRM was 8.33%; 40 patients achieved CR, and the CR rate for the cohort was 83.33%. Seven patients quit, 15 patients relapsed, and the 5 yr cumulative relapse rate was 59.16 ± 9.16%; the 5 yr prospective EFS (pEFS) for patients who were included or excluded from the TRM group was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively. Multivariate analysis for prognosis and hazard ratio was performed for 37 patients without TRM and revealed that an initial WBC count of > 300 × 109/L and a positive level of FCM-MRD were strongly related to a poor outcome for B-ALL patients with KMT2Ar (P < 0.05).

Dynamic multidisciplinary team discussions can improve the prognosis of metastatic castration-resistant prostate cancer patients.

BACKGROUND: Multidisciplinary team (MDT) management is a popular treatment paradigm in managing cancer patients, which provides fully-discussed, interdisciplinary treatment recommendations for patients. However, there has been a lack of data on its actual impact on the overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients. mCRPC is the end stage of prostate cancer, facing a treatment dilemma of overwhelming options; therefore, we hypothesize dynamic MDT discussions can be helpful in comprehensively managing these patients. METHODS: We retrospectively collected 422 mCRPC patients' clinical information from 2013 to 2020 from our institute. Patients can voluntarily choose whether to enroll in the dynamic MDT group, which includes discussions at CRPC diagnosis and subsequent disease progression. All patients were followed up regularly, and OS from CRPC diagnosis to death was set as the endpoint of this study. RESULTS: Participating in MDT discussions is a favorable independent indicator of longer overall survival (median OS: MDT (+): 39.7 months; MDT (-): 27.0 months, hazard ratio: 0.549, p = .001). Moreover, this survival benefit of MDT remained in subgroups with first-line therapy [median OS: MDT (+): not reached; MDT (-): 27.0 months, p = .001) and with multi-line therapy until the end of follow-up (median OS: MDT (+): 36.7 months; MDT (-): 25.6 months, p = .044). CONCLUSION: Therefore, regular MDT discussions are valuable in the management of mCRPC patients. Clinicians are encouraged to tailor MDT discussions dynamically to provide mCRPC patients with a better and more individualized treatment plan and more prolonged survival. Take-home messages ● The MDT model is defined as dynamic MDT discussions at the time of mCRPC diagnosis and each time they progressed later on throughout the disease management. ● Prostate cancer MDT usually includes specialists in urologic oncology, pathology, chemotherapy, radiotherapy, ultrasound, imaging and nuclear medicine. ● MDT model can benefit mCRPC patients in terms of overall survival.

Bevacizumab Combined with S-1 and Raltitrexed for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies: A Phase II Study.

LESSONS LEARNED: Bevacizumab combined with S-1 and raltitrexed demonstrated positive antitumor efficacy and acceptable toxicity. This combination might represent a treatment option for refractory metastatic colorectal cancer. BACKGROUND: In patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, S-1 plus raltitrexed showed a good objective response rate (ORR) and significant survival benefit in our previous study. In the present study, we assessed the activity and safety of bevacizumab combined with S-1 and raltitrexed. METHODS: This investigator-initiated, open-label, single-arm, phase II trial was performed at West China Hospital in China. Patients with mCRC who had disease progression after fluoropyrimidine, irinotecan, and oxaliplatin and had at least one measurable lesion were eligible for this trial. Anti-epidermal growth factor receptor (EGFR) (for tumors with wild-type RAS) and anti-vascular endothelial growth factor (VEGF) therapy in the first or second line was allowed, but patients who had been treated with bevacizumab across two consecutive chemotherapy regimens were excluded. Patients received bevacizumab (7.5 mg/kg on day 1), oral S-1 (80-120 mg per day for 14 days), and raltitrexed (3 mg/m2 on day 1) every 3 weeks. The primary endpoint was ORR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: From September 2015 to November 2019, 44 patients were enrolled. Tumor response evaluation was available in 44 patients at the time of the analysis. There were no complete responses; the ORR was 15.9%, and the disease control rate was 54.5%. Median PFS and OS were 110 days (95% confidence interval [CI], 65.0-155.0) and 367 days (95% CI, 310.4-423.6), respectively. The combination was well tolerated. CONCLUSION: Bevacizumab combined with S-1 and raltitrexed showed promising antitumor activity and safety in refractory mCRC.

Cisplatin/capecitabine with intensity-modulated radiation therapy in anal squamous cell carcinoma: a preliminary study.

OBJECTIVE: Mitomycin (MMC)/5-fluoroural (5-FU) with concurrent radiation is the standard treatment of anal squamous cell carcinoma (ASCC). The aim of this study is to evaluate the efficacy and safety of cisplatin/capecitabine (XP) as an alternative with intensity-modulated radiation therapy (IMRT) in ASCC setting. METHODS: We retrospectively screened all patients with stage I-IV ASCC from January 2010 to June 2019. The records of patients who received definitive chemoradiation with cisplatin/capecitabine (XP) and IMRT were collected and analyzed. RESULTS: The first patient was treated with XP in 2017, so totally 11 patients were included in our study from January 2017 to June 2019. All patients have experienced clinical complete response (cCR). After a median follow-up of 30 months (range, 18-39 months), no patient had local recurrence or distant metastasis. Two-year colostomy-free survival (CFS) and two-year disease-free survival (DFS) were both 100%. The median overall survival (OS) has not reached. Grade 3 acute toxicities included leukopenia (1, 9.1%), neutropenia (2, 18.2%) and thrombocytopenia (2, 18.2%). No grade 4 acute adverse events occurred. CONCLUSION: In our study, cisplatin/capecitabine combined with IMRT was safe in ASCC patients, with favorable efficacy as an alternative, and is expected to be explored in study with larger sample.

Clinical features and prognosis of children with acute leukemias of ambiguous lineage under different diagnostic criteria. / ä¸åŒè¯Šæ–­æ ‡å‡†ä¸‹å„¿ç«¥æ€¥æ€§ä¸æ˜Žè°±ç³»ç™½è¡€ç— çš„ä¸´åºŠç‰¹ç‚¹å’Œé¢„åŽåˆ†æž.

OBJECTIVES: To study the clinical features and prognosis of children with acute leukemias of ambiguous lineage (ALAL) under different diagnostic criteria. METHODS: A retrospective analysis was performed on the medical data of 39 children with ALAL who were diagnosed and treated from December 2015 to December 2019. Among the 39 children, 34 received treatment. According to the diagnostic criteria for ALAL by World Health Organization and European Group for the Immunological Characterization of Leukemias, the 39 children were divided into two groups: ALAL group (n=28) and myeloid expression group (n=11). The clinical features, treatment, and prognosis were compared between the two groups. RESULTS: The 34 children receiving treatment had a 3-year event-free survival (EFS) rate of 75%±9% and an overall survival rate of 88%±6%. The children treated with acute myeloid leukemia (AML) protocol had a 3-year EFS rate of 33%±27%, those treated with acute lymphoblastic leukemia (ALL) protocol had a 3-year EFS rate of 78%±10%, and those who had no remission after induction with AML protocol and then received ALL protocol had a 3-year EFS rate of 100%±0% (P<0.05). The children with negative minimal residual disease (MRD) after induction therapy had a significantly higher 3-year EFS rate than those with positive MRD (96%±4% vs 38%±28%, P<0.05). Positive ETV6-RUNX1 was observed in the myeloid expression group, and positive BCR-ABL1, positive MLL-r, and hyperleukocytosis (white blood cell count ≥50×109/L) were observed in the ALAL group. There was no significant difference in the 3-year EFS rate between the myeloid expression and ALAL groups (100%±0% vs 66%±11%, P>0.05). CONCLUSIONS: ALL protocol has a better clinical effect than AML protocol in children with ALAL, and positive MRD after induction therapy suggests poor prognosis. Hyperleukocytosis and adverse genetic changes are not observed in children with myeloid expression, and such children tend to have a good prognosis, suggesting that we should be cautious to take it as ALAL in diagnosis and treatment.

Prognostic significance of measurable residual disease based on multiparameter flow cytometry in childhood acute myeloid leukemia. / åŸºäºŽæµå¼ç»†èƒžæœ¯çš„å¯æµ‹é‡æ®‹ç•™ç— å¯¹å„¿ç«¥æ€¥æ€§é«“ç³»ç™½è¡€ç— é¢„åŽæ„ä¹‰çš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To study the prognostic value of measurable residual disease (MRD) for childhood acute myeloid leukemia (AML) by analyzing MRD-guided risk stratification therapy. METHODS: A total of 93 children with AML were prospectively enrolled in this study. Chemotherapy with the 2015-AML-03 regimen was completed according to the risk stratification determined by genetic abnormality at initial diagnosis and MRD and bone marrow cytology after induction therapy I. Multiparameter flow cytometry was used to dynamically monitor MRD and analyze the prognostic effect of MRD on 3-year cumulative incidence of recurrence (CIR) rate, event-free survival (EFS) rate, and overall survival (OS) rate. RESULTS: The 93 children with AML had a 3-year CIR rate of 48%±6%, a median time to recurrence of 11 months (range 2-32 months), a 3-year OS rate of 65%±6%, and a 3-year EFS rate of 50%±5%. After induction therapy I and intensive therapy I, the MRD-positive children had a significantly higher 3-year CIR rate and significantly lower 3-year EFS and OS rates than the MRD-negative children (P<0.05). There were no significant differences in 3-year CIR, EFS, and OS rates between the MRD-positive children with a low risk at initial diagnosis and the MRD-negative children after adjustment of chemotherapy intensity (P>0.05). The multivariate analysis showed that positive MRD after intensive treatment I was a risk factor for 3-year OS rate in children with AML (P<0.05). CONCLUSIONS: MRD has predictive value for the prognosis of children with AML. Based on the MRD-guided risk stratification therapy, reasonable application of chemotherapy may improve the overall prognosis of children with AML.

Alter between gut bacteria and blood metabolites and the anti-tumor effects of Faecalibacterium prausnitzii in breast cancer.

BACKGROUND: The aim was to evaluate the changes of 16S rDNA sequencing and LC-MS metabolomics in breast cancer and explore the growth inhibition of breast cancer cells by Faecalibacterium prausnitzii. RESULTS: Total 49 significantly different flora and 26 different metabolites were screened between two groups, and the correlation was calculated. Relative abudance of Firmicutes and Bacteroidetes were decreased, while relative abundance of verrucomicrobla, proteobacteria and actinobacteria was increased in breast cancer group. Differentially expressed metabolites were mainly enriched in pathways such as linoleic acid metabolism, retrograde endocannabinoid signaling, biosynthesis of unsaturated fatty acids, choline metabolism in cancer and arachidonic acid metabolism. Lipid upregulation was found in breast cancer patients, especially phosphorocholine. The abundance of Faecalibacterium was reduced in breast cancer patients, which was negatively correlated with various phosphorylcholines. Moreover, Faecalibacterium prausnitzii, the most well-known species in Faecalibacterium genus, could inhibit the secretion of interleukin-6 (IL-6) and the phosphorylation of Janus kinases 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) in breast cancer cells. Faecalibacterium prausnitzii also suppressed the proliferation and invasion and promoted the apoptosis of breast cancer cells, while these effects disappeared after adding recombinant human IL-6. CONCLUSIONS: Flora-metabolites combined with the flora-bacteria (such as Faecalibacterium combined with phosphorocholine) might a new detection method for breast cancer. Faecalibacterium may be helpful for prevention of breast cancer. Faecalibacterium prausnitzii suppresses the growth of breast cancer cells through inhibition of IL-6/STAT3 pathway.

[Serious adverse events associated with chemotherapy in children with acute lymphoblastic leukemia].

OBJECTIVE: To study the occurrence of serious adverse events (SAEs) related to chemotherapy with CCCG-ALL-2015 regimen in children with acute lymphoblastic leukemia (ALL) and the risk factors for death after the SAEs. METHODS: A retrospective analysis was performed on the medical data of 734 children with ALL. They were treated with CCCG-ALL-2015 regimen from January 2015 to June 2019. The occurrence of SAEs during the treatment was investigated. The children with SAEs were divided into a death group with 25 children and a survival group with 31 children. A multivariate logistic regression analysis was used to analyze the risk factors for death after the SAEs. RESULTS: Among the 734 children with ALL, 56 (7.6%) experienced SAEs (66 cases) after chemotherapy, among which 41 cases occurred in the stage of remission induction therapy. Of all 66 cases of SAEs, 46 (70%) were infection-related SAEs, including 25 cases of septic shock (38%), 20 cases of severe pneumonia (30%), and 1 case of severe chickenpox (2%), and 87% of the children with infection-related SAEs had neutrophil deficiency. The most common infection sites were blood and the lungs. The most common pathogens were Gram-negative bacteria, viruses, fungi, and Gram-positive bacteria. There were 16 cases (24%) of hemorrhage-related SAEs, with 11 cases of gastrointestinal bleeding (17%), 4 cases of pulmonary bleeding (6%), and 1 case of intracranial bleeding (2%). Of all 734 children with ALL, 66 (9.0%) died, among whom 25 died due to SAEs. The treatment-related mortality rate was 3.4%, and infection (72%) and bleeding (24%) were the main causes of death. Severe pneumonia was an independent risk factor for treatment-related death in ALL children (OR=4.087, 95%CI: 1.161-14.384, P=0.028). CONCLUSIONS: SAEs often occur in the stage of remission induction therapy, and infection-related SAEs are more common in ALL children accepting chemotherapy with CCCG-ALL-2015 regimen. The development of severe pneumonia suggests an increased risk for death in these children.

S-1 plus Raltitrexed for Refractory Metastatic Colorectal Cancer: A Phase II Trial.

LESSONS LEARNED: The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU.S-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC. BACKGROUND: 5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted. METHODS: Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80-120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m2 on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population (n = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3-117.7) and 373 days (95% CI, 226.2-519.8), respectively. Most of the adverse effects were mild to moderate. CONCLUSION: S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.

BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Clinical Significance of Antinuclear and Antiextractable Nuclear Antigen Antibody in Childhood Immune Thrombocytopenia.

This study aims to determine the clinical significance of positive antinuclear/antiextractable nuclear antigen (ANA/A-ENA) antibody on manifestation and therapeutic response of childhood immune thrombocytopenia (ITP). Overall, 1,330 patients aged between 1 and 15.6 years diagnosed with primary ITP were retrospectively analyzed, excluding those with secondary ITP. Bleeding manifestations were recorded. All patients underwent autoantibody testing and follow-up for 32 months on average (range: 23-54 months). Steroid response was also assessed. Response rates were compared between ANA/A-ENA-positive and ANA/A-ENA-negative patients. Of all the patients enrolled, 84 tested positive only for ANA, 102 tested positive for A-ENA, 54 tested positive for both ANA and A-ENA, and 1,090 tested negative for both. Patients who were ANA/A-ENA positive were more likely to be female and older than 10 years. Patients who were A-ENA positive were more likely to have either persistent or chronic disease and suffer from life-threatening bleeding as well as poor short-term therapeutic response. We conclude that autoantibody testing is important to determine the short-term prognosis of ITP patients. Females, patients older than 10 years of age, and patients with either mixed positivity or A-ENA positivity should be more closely monitored.

Pharmacokinetics of dimemorfan phosphate tablets in healthy Chinese volunteers.

OBJECTIVE: Investigate the pharmacokinetic properties of the antitussive dimemorfan phosphate tablets in healthy male and female Chinese volunteers after single and multiple-dose administration; and to evaluate the food-effect on pharmacokinetics of dimemorfan. METHODS: 12 subjects received a single dose of 10 mg and 40 mg dimemorfan phosphate tablets, respectively in study stage 1. Another 12 subjects received a single dose of 20 mg dimemorfan phosphate tablets under fed conditions, a single dose of 20 mg dimemorfan phosphate tablets under fasting conditions and multiple-dosing of 20 mg dimemorfan phosphate tablets 3 times per day, respectively in study stage 2. The washout between each treatment was 1 week. Plasma dimemorfan was quantified by a high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. RESULTS: After single-dosing of 10 mg, 20 mg and 40 mg dimemorfan phosphate tablets, Cmax, AUC0-t and AUC0-∞ were dose proportional, which achievd 6.19 ± 7.61 ng·mL-1, 101 ± 171 and 117 ± 210 ng·mL-1·h, respectively after single-dosing of 40 mg dimemorfan phosphate tablets. Tmax ranged from 2.75 to 3.96 h and t1/2 ranged from 10.6 to 11.4 h. After multiple-dosing of 20 mg dimemorfan phosphate tablets, the Accumulation Index (AI) was 2.65 ± 1.11. The pharmacokinetic parameters after single-dosing of 20 mg dimemorfan phosphate tablets under fed conditions were similar with those under fasting conditions. Sex did not affect the pharmacokinetics of dimemorfan phosphate tablets. CONCLUSIONS: Single-dosing of dimemorfan phosphate tablets exhibited linear kinetic characteristics. Multiple-dosing of 20 mg dimemorfan phosphate tablets 3 times per day caused obvious accumulation. No food effect or sex effect on the pharmacokinetics of dimemorfan phosphate tablets was observed. Chictr.org identifier: ChiCTR-ONC-14004851.

A phase II trial of concurrent 3D-CRT/IMRT and oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) in gastric cancer patients with R0 gastrectomy and D2 lymph node dissection.

BACKGROUND: To evaluate the safety and efficacy of a concurrent three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) plus oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) regimen in completely resected gastric cancer patients with D2 lymph node dissection. MATERIALS AND METHODS: Patients with stage IB-IIIC gastric cancer (per the AJCC, 7th edition) who had undergone R0 and D2 gastrectomy were recruited. Two cycles of FOLFOX with concurrent 3D-CRT or IMRT (50.4 Gy/28f) were administered. One and an additional five cycles of FOLFOX were delivered before and after concurrent chemoradiotherapy, respectively. Primary endpoints were relapse-free survival (RFS) and overall survival (OS), with adverse events as secondary endpoints. RESULTS: From 2008 to 2011, 110 patients were evaluable. The 1-, 2- and 3-year RFS and OS were 86.2, 72.2, 67.8 and 94.7, 87.2, 77.6%, respectively. On multivariate analysis, stage (≤ IIIA vs. >IIIA) was a statistically significant factor affecting both RFS and OS. Additionally, the T-category (≤ T4a vs. = T4b) was a statistically significant factor affecting only the RFS. The most commonly observed grade 3 or 4 adverse events were nausea and vomiting, decreased appetite, leukopenia/neutropenia and fatigue, each of which occurred in 14.5, 11.8, 9.1 and 6.4% patients, respectively. CONCLUSIONS: Adjuvant 3D-CRT/IMRT to a dose of 50.4 Gy/28f with concurrent FOLFOX is safe and effective in patients following radical gastrectomy with D2 lymph node dissection.

Long-term follow-up results of simultaneous integrated or late course accelerated boost with external beam radiotherapy to vaginal cuff for high risk cervical cancer patients after radical hysterectomy.

BACKGROUND: To assess the safety and efficacy of simultaneous integrated boost (SIB) or late course accelerated boost (LCAB) with external beam radiotherapy (EBRT) to the vaginal cuff for high risk cervical cancer patients after radical hysterectomy. METHODS: Between October 2009 and January 2012, patients with high risk cervical cancer who had undergone radical surgery followed by EBRT to the vaginal cuff were enrolled. Patients were treated with either intensity modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) with SIB (arm A) or IMRT/VMAT to the pelvis followed by LCAB (arm B) to vaginal cuff. In arm A, the pelvic and boost doses were 50.4 Gy and 60.2 Gy in 28 fractions, respectively. In arm B, pelvic irradiation to 50 Gy in 25 fractions followed by a boost of 9 Gy in 3 fractions were delivered. Chemotherapy was given concurrently. RESULTS: Overall, 80 patients were analyzed in this study (42 in arm A, 38 in arm B). In arm A and B, median follow-up was 37 and 32 months, respectively. The 3-year disease-free survival and overall survival in arms A vs B were 88.7% vs. 93.4% (p = 0.89), and 91.8% vs.100% (p = 0.21), respectively. The 3-year local-regional control and distant failure were 97.6% vs. 100% (p = 0.34), and 4.8% vs. 5.3% (p = 0.92), respectively. Grade 3-4 acute leukopenia and dermatitis were seen in 11 (26.2%) and 8 (19.0%) patients in Arm A, vs. 7 (17.8%) and 6 (15.8%) patients in Arm B, respectively (p > 0.05). Only Grade 1-2 chronic gastrointestinal (GI) and genitourinary (GU) toxicities were observed. CONCLUSIONS: Our results indicate that both SIB and LCAB to vaginal cuff for high risk cervical cancer patients after radical hysterectomy are associated with excellent survival, local control and low toxicity.

Determination of SUMO1 and ATP affinity for the SUMO E1by quantitative FRET technology.

SUMOylation plays important roles in many key physiological and pathological processes. The SUMOylation cascade involves a heterodimer of activating enzyme, E1 (Aos1/Uba2); a conjugating enzyme, E2 (Ubc9); and many ligase enzymes, E3. Focusing on the activation step of the SUMOylation process, we examined the interaction of E1 with its substrates. Previous studies reported the Km of E1 enzymes in ubiquitin and other ubiquitin-like pathways, but the Km of the SUMO paralogs (SUMO2 and SUMO3) is unknown. Here, by using quantitative FRET to measure the SUMO E1 enzyme kinetics of SUMO1, 2, and 3 and ATP under steady state conditions, we found that the enzyme kinetics from the quantitative FRET method are comparable to those from conventional radioactive assays. Additionally, the kinetic constants, Km , of SUMO2 (3.418 ± 0.9131 µM) and SUMO3 (2.764 ± 0.75 µM) [FW1] are approximately four to five times higher than that of SUMO1 Km (0.7458 ± 0.1105 µM). These results demonstrate the advantages of FRET technology for determining Km , including the ability to monitor reaction progress in real-time with high-throughput and high-sensitivity in an environmentally friendly manner. The processes discussed here extend the utility of quantitative FRET in characterizing protein-protein interactions and enzyme kinetics.

Combination therapy analysis of ezetimibe and statins in Chinese patients with acute coronary syndrome and type 2 diabetes.

BACKGROUND: Dyslipidemia management situation in Chinese patients with high risk and very high risk has been demonstrated very low, despite the wide use of statins. The effects and safety of the combined treatment of ezetimibe (EZ) and statins in Chinese patients with acute coronary syndrome (ACS) and type 2 diabetes mellitus (T2DM) remain unknown. METHODS: Chinese Patients with ACS and T2DM were divided into the statins group (n=40) and the combination group of EZ and statins (n=44). In order to evaluate the clinical effects on lipids-lowering, systemic inflammation response and clinical safety, the follow-up of all patients was carried out at day 7th and 30th after treatment. RESULTS: The level of low-density lipoprotein cholesterol (LDL-C) in combination group and statins group was 1.87±0.42 and 2.18±0.58 mmol/L at day 7th, 1.51±0.29 and 1.94±0.49 mmol/L at day 30th, respectively. The control rates of LDL-C level in the combination group and the statins group were 77% and 45% at day 30(th), respectively. There was no significant improvement on high-density lipoprotein cholesterol (HDL-C) level during follow-up. The triglyceride (TG) levels were significantly reduced in both groups, while no obvious difference was observed between two groups. No significant difference on serum high-sensitivity C-reactive protein (hs-CRP) level between two groups was observed. Moreover, we did not observe any significant correlation between serum lipids levels and serum hs-CRP level during follow-up. The liver dysfunction and muscle related side effects (MRSE), creatine kinase (CK) and myopathy were not observed in both groups. CONCLUSION: Our study demonstrated that it is feasible to initiate combination therapy during acute phase for Chinese patients with ACS and T2DM, which can bring more significant effect on LDL-C-lowering and improve the control rate of LDL-C level with good safety.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

PURPOSE: To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). METHOD AND MATERIALS: All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. RESULTS: ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. CONCLUSION: The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

Bladder sparing by short-course radiotherapy combined with toripalimab in high-risk/extremely high-risk non-muscle invasive bladder cancer (HOPE-04): study protocol for a single-arm, prospective, phase II trial.

INTRODUCTION: Radical cystectomy remains the standard treatment for intravesical Bacille Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) because potential bladder-preserving therapies are not well established. Combination of radiotherapy with programmed death-1 (PD-1) antibody may offer an optional bladder preservation treatment for high-risk/extremely high risk NMIBC. Hence, the current study aims to investigate the safety and efficacy of short-course radiotherapy (5×5 Gy) and toripalimab (PD-1 antibody) as a novel bladder sparing treatment in this population. METHODS AND ANALYSIS: HOPE-04 is an open-label, single-arm, phase II study, designed to evaluate the safety and efficacy of short-course radiotherapy and toripalimab in patients with high-risk/extremely high risk NMIBC. Fifty-five patients with pathological and imaging diagnosed NMIBC with or without BCG treatment will be recruited. Radiotherapy of 5×5 Gy will be given to the whole bladder followed by a focal tumour bed boost and concomitant administration of toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about 1 year). The primary endpoints are disease-free survival and safety. The secondary endpoint is overall survival. Additional indicators include implementation rate of salvage surgery and quality of life. ETHICS AND DISSEMINATION: This trial has been approved by the Ethics Committee of West China Hospital, Sichuan University. Trial findings will be disseminated via peer reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: Chinese Ethics Committee of Registering Clinical Trials (ChiCTR2200059970).

Energy-guided diffusion model for CBCT-to-CT synthesis.

Cone Beam Computed Tomography (CBCT) plays a crucial role in Image-Guided Radiation Therapy (IGRT), providing essential assurance of accuracy in radiation treatment by monitoring changes in anatomical structures during the treatment process. However, CBCT images often face interference from scatter noise and artifacts, posing a significant challenge when relying solely on CBCT for precise dose calculation and accurate tissue localization. There is an urgent need to enhance the quality of CBCT images, enabling a more practical application in IGRT. This study introduces EGDiff, a novel framework based on the diffusion model, designed to address the challenges posed by scatter noise and artifacts in CBCT images. In our approach, we employ a forward diffusion process by adding Gaussian noise to CT images, followed by a reverse denoising process using ResUNet with an attention mechanism to predict noise intensity, ultimately synthesizing CBCT-to-CT images. Additionally, we design an energy-guided function to retain domain-independent features and discard domain-specific features during the denoising process, enhancing the effectiveness of CBCT-CT generation. We conduct numerous experiments on the thorax dataset and pancreas dataset. The results demonstrate that EGDiff performs better on the thoracic tumor dataset with SSIM of 0.850, MAE of 26.87 HU, PSNR of 19.83 dB, and NCC of 0.874. EGDiff outperforms SoTA CBCT-to-CT synthesis methods on the pancreas dataset with SSIM of 0.754, MAE of 32.19 HU, PSNR of 19.35 dB, and NCC of 0.846. By improving the accuracy and reliability of CBCT images, EGDiff can enhance the precision of radiation therapy, minimize radiation exposure to healthy tissues, and ultimately contribute to more effective and personalized cancer treatment strategies.