Novel-fosfamide monotherapy or in combination with doxorubicin versus doxorubicin alone in patients with advanced soft tissue sarcoma: A pooled analysis of randomized clinical trials.

BACKGROUND: Novel-fosfamides (NFOs) belong to active metabolites of ifosfamide that bypass the generation of toxic byproducts. In this analysis, we aimed to comprehensively assess the benefits and risks of NFO monotherapy or in combination with doxorubicin (DOX) versus single-drug DOX in previously untreated patients with advanced soft-tissue sarcoma (ASTS). METHODS: Online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases were systematically searched on April 26, 2022. Objective response rate and disease control rate were primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events were secondary outcomes. RESULTS: In all, 3 randomized clinical trials with a total of 1207 ASTS patients were eligible. DOX plus NFO combination therapy showed higher risk ratios of objective response rate (1.50, 95% CI 1.20-1.68, P = .0003) and disease control rate (1.15, 95% CI 1.05-1.27, P = .0030) compared with DOX monotherapy. Nevertheless, NFO-based monotherapy and combination therapy were found no improvements on OS (hazard ratio 0.93, 95% CI 0.52-1.65, P = .8050) and PFS (hazard ratio 0.88, 95% CI 0.54-1.43, P = .6088) against DOX. More incidences of grade 3 or worse anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia were observed in NFO-based treatments. CONCLUSION: Adding NFO to DOX as first-line therapy improved the responses in ASTS patients but did not prolong OS and PFS. Grade 3 or worse treatment-related adverse events should be treated with caution during the NFO-based therapies.

A Bayesian network analysis of immunotherapy and taxane chemotherapy as second- or later-line treatments in non-small cell lung cancer.

BACKGROUND: Taxane chemotherapy represents the standard of care in the second-line setting for non-small cell lung cancer (NSCLC) patients, but immunotherapy agents pose great challenges. Whether immunotherapy/chemotherapy alone or combination therapy has more benefits remains controversial. In this study, we provided comparisons to integrate the efficacy of immunotherapy and taxane chemotherapy as second- or later-line treatments in advanced NSCLC. METHODS: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to September 1, 2020. Randomized controlled trials comparing immunotherapy and taxane chemotherapy were enrolled in the Bayesian network analysis. Overall survival (OS) and progression-free survival (PFS) with hazard ratios (HRs) were investigated. RESULTS: Eight trials in 13 studies with 4398 patients comparing seven treatments were identified. Pembrolizumab 10 mg/kg was associated with the best improved OS, with significant differences versus docetaxel (HR 0.81, 95% credible interval [CrI] 0.74-0.88), avelumab (HR 0.84, 95% CrI 0.75-0.95), and pembrolizumab 200 mg plus docetaxel (HR 0.75, 95% CrI 0.56-1.00). Although pembrolizumab 200 mg plus docetaxel ranked the last in terms of OS, the combination therapy showed the most favorable PFS. Additionally, the anti-programmed death-ligand 1 (PD-L1) agent, avelumab, was associated with the least improvement in PFS. CONCLUSION: As second- or later-line therapeutic strategies, pembrolizumab 10 mg/kg provided the largest OS benefits and pembrolizumab 200 mg plus docetaxel improved PFS to the greatest extent. Considering that immunotherapy has been recommended to the first-line setting of NSCLC, advanced patients who have not received immunotherapy previously might be the suitable population for our findings.

Poziotinib in non-small-cell lung cancer patients with HER2 exon 20 mutations: A pooled analysis of randomized clinical trials.

BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) exon 20 mutant occurs in 3% of NSCLCs. Targeted agents for this population remain an unmet need. In this analysis, we pooled-analyzed the efficacy and safety of poziotinib, a novel tyrosine kinase inhibitor, in HER2 exon 20 mutant NSCLC. METHODS: PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were systematically searched on March 9, 2022. The primary endpoints were objective response rate (ORR) and disease control rate. The secondary endpoint was treatment-related adverse events. RESULTS: Three prospective clinical trials, involving 126 patients, were identified. The pooled ORR and disease control rate of poziotinib in HER2 exon 20 mutant NSCLC were 27% (95% CI, 19-35) and 72% (95% CI, 64-80), respectively. Patients with G778_P780dupGSP had the highest ORR (88%; 95% CI, 33-100; n = 12), followed by Y772_A775dupYVMA (20%; 95% CI, 12-30; n = 88) and G776delinsVC (19%; 95% CI, 0-50; n = 13). The most common grade 3 to 4 treatment-related adverse events were skin rash (36%), diarrhea (23%), and oral mucositis (13%). CONCLUSION: Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies.

Induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: A systematic review and meta-analysis.

Background: Adding induction chemotherapy to concurrent platinum-based chemoradiotherapy has significantly prolonged the survival time of patients with locoregionally advanced nasopharyngeal carcinoma. In this study, we intend to evaluate the survival outcomes, responses, and incidences of toxicities of induction chemotherapy and the differences between different strategies. Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, and Cochrane CENTRAL on August 10, 2021. Single-arm or multi-arm prospective clinical trials on induction chemotherapy without targeted therapies or immune checkpoint inhibitors were included. Primary outcomes included survival outcomes, objective response rate, and disease control rate, and the secondary outcome was the rates of grade 3 or higher treatment-related adverse events. Results: The 39 studies included in the systematic review and meta-analysis comprised 36 clinical trials and 5389 patients. The estimates for 3-year overall and fail-free survival rates were 87% and 77%. The estimates for 5-year rates of overall and fail-free survival were 81% and 73%. Gemcitabine plus platinum and docetaxel combined with 5-fluorouracil plus platinum strategies were associated with the highest rates of 3-year and 5-year overall survival. The objective response and disease control rates were 85% and 98% after the completion of induction chemotherapy. Neutropenia (27%) and nausea/vomiting (7%) were the most common grade 3 or higher treatment-related hematological and non-hematological adverse events during the induction phase. Conclusions: Different induction chemotherapeutic strategies appear to have varying effects and risks; a comprehensive summary of the survival outcomes, responses, and toxicities in clinical trials may provide a crucial guide for clinicians.

Differences in the therapeutic effects of high-intensity focused ultrasound (HIFU) ablation on uterine fibroids with different shear wave velocity (SWV): a study of histopathological characteristics.

OBJECTIVE: To explore correlations between the therapeutic effect of high intensity focused ultrasound (HIFU) and histopathological characteristics of uterine fibroids with different Shear Wave Velocity (SWV) values. METHODS: A retrospective study was conducted on 36 women (43 fibroids) who had undergone high intensity focused ultrasound (HIFU) uterine fibroids ablation between January 2019 and January 2020. Preoperative fibroids tissue sections were obtained for histopathological examination. The pathological sections were stained with Masson-trichrome, and were observed and imaged under a Low-power microscope (4 × 10), while the smooth muscle cell (SMC) and collagen fiber content were semi-quantitatively measured. Preoperative fibroid SWV was measured using the Virtual Touch tissue quantification (VTQ) technique. Within one month after HIFU ablation, all patients had undergone a pelvic cavity MRI examination, which measured the size, volume, and non-perfused volume (NPV) of the fibroids. The formula: the ablation rate = NPV/target fibroid volume × 100% was used to calculate the ablation rate of the uterine fibroids. Correlation analysis of SWV values, HIFU ablation rate, along with the smooth muscle cell (SMC) and collagen fiber content, were conducted using the Spearman's correlation test. RESULTS: The collagen fiber and SMC content of the preoperative fibroids were 32.09 ± 15.90%/view and 37.61 ± 15.32%/view, respectively. Preoperative fibroid SWV value was 3.56 ± 0.71 m/s. Preoperative fibroid SWV was negatively correlated with SMC content (r = -0.445, p = 0.003), but positively correlated with collagen fiber content (r = 0.454, p = 0.002). The ablation rate was negatively correlated with collagen fiber content (r = -0.377, p = 0.013), but positively correlated with SMC content (r = 0.402, p = 0.007). CONCLUSION: Differences in histopathological characteristics may be important factors that induce differences in the therapeutic effects of HIFU ablation on uterine fibroids with different SWV values.

The value of acoustic radiation force impulse imaging in preoperative prediction for efficacy of high-Intensity focused ultrasound uterine fibroids ablation.

Objective: To investigate the application value of acoustic radiation force impulse imaging in preoperative prediction for efficacy of High-Intensity Focused Ultrasound uterine fibroids ablationMethods: A prospective study was conducted on 32 women (41 fibroids) undergoing HIFU uterine fibroids ablation between January 2019 and September 2019. The virtual touch tissue quantification (VTQ) technique was used for the preoperative determination of uterine fibroids shear wave velocity (SWV). The stiffness of the preoperative uterine fibroids was graded on a virtual touch tissue image (VTI). All uterine fibroids were ablated with a single point ablation acoustic power of 400 W. All patients underwent pelvic cavity MRI examination for the measurement of the size, volume and non-perfused volume (NPV) of fibroids within the first month after HIFU ablation. The ablation rate of uterine fibroids was calculated according to the formula: ablation rate = NPV × 100/target fibroid volume. The patients were divided into two groups based on the postoperative ablation rate: ≥70% ablation rate group, and＜70% ablation rate group. The preoperative SWV and VTI grade of uterine fibroids were compared between the two groups. The correlation of preoperative uterine fibroids' SWV and VTI grade with HIFU ablation rate were analyzed using the Spearman's correlation coefficient. The optimal cutoff points in preoperative uterine fibroids SWV of 70% ablation rate were determined by receiver operating curve (ROC) analysis.Results: A total of 30 patients (73.17%, 30/41) showed ablation rate ≥70%, with preoperative uterine fibroids' SWV values of (3.42 ± 0.71) m/s. Of these, 24 patients (80%, 24/30) had VTI grades II-III. On the other hand, 26.83% (11/41) showed ablation rate <70%, with preoperative uterine fibroids' SWV values of (4.02 ± 0.69) m/s; of these, 63.6% (7/11) had VTI grade IV. The SWV values and VTI grades of preoperative uterine fibroids were significantly different in the two groups (p < 0.05). Interestingly, postoperative ablation rate was negatively correlated with preoperative uterine fibroids' SWV values (r= -0.536, p = 0.0003) and VTI grades (r= -0.511, p = 0.001). The area under the ROC curve of preoperative uterine fibroids' SWV values with ablation rate <70% was 0.75 at a cutoff value of 3.915 m/s (p < 0.05). Specificity was 72.7% and sensitivity was 80.1%; the positive predictive value was 72.7%, and the negative predictive value was 80%.Conclusion: ARFI technique is an effective and feasible noninvasive ultrasound technique for the preoperative prediction of the efficacy of HIFU uterine fibroids ablation.

Single-nucleotide Polymorphism rs2275294 in ZNF512B is not Associated with Susceptibility to Amyotrophic Lateral Sclerosis in a Large Chinese Cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons and has no effective treatment. Recently, Iida et al. identified a single-nucleotide polymorphism (SNP) rs2275294 in the ZNF512B gene that is significantly associated with susceptibility to ALS in the Japanese population. Here, we performed a case-control study examining the possible association of rs2275294 with risk of sporadic ALS (SALS) in a large Chinese cohort. METHODS: To assess this association, we performed a replication study in 953 SALS patients and 1039 age- and gender-matched healthy control subjects, who were recruited from Peking University Third Hospital and the First Affiliated Hospital of Anhui Medical University from January 2004 to December 2013 throughout China. We genotyped the rs2275294 SNP using polymerase chain reaction and direct sequencing. RESULTS: The allele frequency of rs2275294 in ZNF512B was different between Japanese and Chinese. The association in Chinese between ALS patients and controls did not reach statistical significance (P = 0.54; odds ratio = 0.94; 95% confidence interval = 0.76-1.15). CONCLUSIONS: The SNP rs2275294 in ZNF512B is not considered to be associated with ALS susceptibility in the Chinese population. Our study highlights genetic heterogeneity in ALS susceptibility in different population. Given our negative results, further replication study involving larger and more homogeneous samples in different ethnicities should be performed in the future.

Similar PDK1-AKT-mTOR pathway activation in balloon cells and dysmorphic neurons of type II focal cortical dysplasia with refractory epilepsy.

Dysmorphic neurons and balloon cells constitute the neuropathological hallmarks of type II focal cortical dysplasias (FCDs) with refractory epilepsy. The genesis of these cells may be critical to the histological findings in type II FCD. Recent work has shown enhanced activation of the mTOR cascade in both balloon cells and dysmorphic neurons, suggesting a common pathogenesis for these two neuropathological hallmarks. A direct comparative analysis of balloon cells and dysmorphic neurons might identify a molecular link between balloon cells and dysmorphic neurons. Here, we addressed whether PDK1-AKT-mTOR activation differentiates balloon cells from dysmorphic neurons. We used immunohistochemistry with antibodies against phosphorylated (p)-PDK1 (Ser241), p-AKT (Thr308), p-AKT (Ser473), p-mTOR (Ser2448), p-P70S6K (Thr229), and p-p70S6 kinase (Thr389) in balloon cells compared with dysmorphic neurons. Strong or moderate staining for components of the PDK1-AKT-mTOR signaling pathway was observed in both balloon cells and dysmorphic neurons. However, only a few pyramidal neurons displayed weak staining in control group (perilesional neocortex and histologically normal neocortex). Additionally, p-PDK1 (Ser241) and p-AKT (Thr308) staining in balloon cells were stronger than in dysmorphic neurons, whereas p-P70S6K (Thr229) and p-p70S6 kinase (Thr389) staining in balloon cells was weaker than in dysmorphic neurons. In balloon cells, p-AKT (Ser473) and p-mTOR (Ser2448) staining was comparable with the staining in dysmorphic neurons. Our data support the previously suggested pathogenic relationship between balloon cells and dysmorphic neurons concerning activation of the PDK1-AKT-mTOR, which may play important roles in the pathogenesis of type II FCD. Differential expression of some components of the PDK1-AKT-mTOR pathway between balloon cells and dysmorphic neurons may result from cell-specific gene expression.

[Fetoscopic guided laser occlusion for twin-to-twin transfusion syndrome in 33 cases].

OBJECTIVE: To evaluate the clinical effect of fetoscopic laser occlusion of chorioangiopagous vessels (FLOC) for monochorionic diamniotic twins (MCDA) pregnancies complicated with twin-to-twin transfusion syndrome(TTTS). METHODS: The clinical data of 33 consecutive cases of TTTS from Mainland China, who had FLOC in the Department of Obstetrics and Gynaecology of Prince of Wales Hospital (The Chinese University of Hong Kong) from November 2003 to December 2010, were reviewed and analyzed for peri-operative complications, perinatal outcomes and fetal survival rate. Clinical stage of TTTS was according to the Quintero staging system. RESULTS: (1) Pregnancy characteristics: the mean maternal age was 30; the median gestational age at FLOC was 23(+4) weeks; according to the Quintero staging system, 3 cases were Quintero staging I, 14 cases were Quintero staging II, 7 cases were Quintero staging III and 9 cases were Quintero staging IV. For the 3 stage I cases, FLOC was performed for severe maternal symptoms of polyhyramnios or severe fetal cardiac dysfunction. (2) COMPLICATIONS: intraoperative complications occurred in 5 patients including four uterine bleedings at the puncture site, one placental vascular anastomosis bleeding. Postoperative complications occurred in 6 patients including 2 abortions and 1 intrauterine death within one week after operation, 2 abortions and 1 amniotic band syndrome occurred from two to four weeks after operation. (3) Perinatal outcome and fetal survival rate: the median interval of 33 patients between FLOC and delivery was 9(+4) weeks; the median gestational age at delivery was 31(+6) weeks; the gestation at delivery was less than 24 weeks in 6% (2/33), 24 to 28 weeks in 21% (7/33), 28 to 32 weeks in 18% (6/33), 32 to 37 weeks in 55% (18/33). The mean birth weight of the donor was 1600 g (350 - 2520 g); the mean birth weight of the recipiert was 1930 g (400 - 3040 g). The overall survival rate, the double infant survival rate, the single survival rate and survival rate for at least one twin was 59% (39/66), 52% (17/33), 15% (5/33) and 67% (22/33), respectively. The overall survival rate dropped from 61% (17/28) in Quintero staging II to 9/18 in Quintero staging IV. CONCLUSIONS: FLOC for MCDA complicated with TTTS is associated with an overall survival of about 60%. Major complications are rare. The outcome is not only related to Quintero staging but also the close monitoring and timely termination of pregnancy.

Sonographic evaluation of the development of the fetal rectum and anal canal.

PURPOSE: To describe the sonographic (US) appearance of fetal anal canal and rectum and establish nomograms of their normal measurements. METHODS: This was a prospective, cross-sectional study of 524 healthy women (mean age, 27 years; range, 21-37 years) with normal singleton pregnancy between 18 and 40 weeks of gestational age (GA). High-resolution transabdominal US was used to visualize and measure the normal fetal anal canal and rectum. RESULTS: Satisfactory images and measurements of the fetal anal canal and rectum were obtained in 496 normal fetuses. The diameters of the normal anal canal and rectum were plotted as a function of GA in a sigmoid curve. The curve estimations were expressed by the following cubic regression equations with R(2) of 0.87 and 0.88, respectively (p < 0.001): anal canal diameter (mm) = 18.272 - 2.151 × GA + 0.0095 × GA(2) - 0.0011 × GA(3) , and rectal diameter (mm) = 18.545 - 2.543 × GA + 0.1237 × GA(2) - 0.0016 × GA(3) . CONCLUSIONS: The fetal anal canal and rectum are visible sonographically between 18 and 40 weeks of GA. The knowledge of their normal US appearance and size from the second trimester of pregnancy onwards may help identify developmental anomalies.