Is cryoablation still suitable for advanced non-small cell lung cancer after failure of first-line chemotherapy? A multicenter, prospective, randomized-controlled trial of eighty-seven patients.

The aim of this study was to investigate the therapeutic effect of cryoablation treatment in advanced NSCLC patients who had failed first-line chemotherapy. Eighty-seven patients from ten hospitals in China were enrolled into the study, forty-four patients received cryoablation treatment plus basic treatment (experimental group), and forty-three patients had basic treatment alone (control group). Follow-up was performed once every three months until the end of the study or the death of the patient. The primary endpoints were overall and post-intervention survival; secondary endpoints included tumor markers, solid tumor efficacy, and symptom changes before and after treatment. There was no significant difference in median OS between the two groups of patients (9.0 months vs 11.2 months, P = 0.583). The disease control rate (DCR) and living quality of the experimental group was higher than that of the control group. In terms of OS, indiscriminate use of cryoablation for such patients was not beneficial, though it could improve symptoms of patients. Cryoablation had a significant effect on selected advanced NSCLC patients after the failure of first-line chemotherapy.

Exceptional Response of Cryoablation Followed by Pembrolizumab in a Patient with Metastatic Cervical Carcinosarcoma with High Tumor Mutational Burden: A Case Report.

Cervical carcinosarcoma is an extremely rare type of neoplasm that lacks standard of care. Preclinical and clinical evidence has suggested that cryoablation in combination with immunotherapy may result in a synergistic effect, generating a more robust immune response to distant lesions. A few clinical trials have evaluated the efficacy of such combination treatment in a variety of solid tumors, but with conflicting results. This report describes the first clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden (TMB)-high metastatic cervical carcinosarcoma that was negative for programmed cell death protein 1 expression, microsatellite instability stable, and had mutations in DNA polymerase epsilon (POLE). She had achieved complete response (CR) after 3 months of pembrolizumab treatment and had maintained CR as of the time of submission of this manuscript, with a progression-free survival of 11 months and counting. The case exhibited an exceptional response to cryoablation followed by pembrolizumab, potentially attributed to mutations in POLE, which lead to an extremely high TMB. This report paves the avenue for establishing treatment regimens for patients with TMB-high cervical carcinosarcoma. KEY POINTS: Owing to its rarity, cervical carcinosarcoma has not been well characterized, and currently, there is no standard of care for this disease. This report describes the first case of clinical efficacy of cryoablation followed by pembrolizumab observed in a patient with tumor mutational burden-high metastatic cervical carcinosarcoma. The case exhibited an exceptional response (maintained CR as of the time of submission of this article: 11 months) to cryoablation followed by pembrolizumab. This is the first POLE-mutated cervical carcinosarcoma case.

The efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis. METHODS: Designed as a retrospective study, a total of 105 metastatic osteosarcoma patients who progressed after standard therapy were included in this study. The metastatic osteosarcoma patients received 500-750 mg Apatinib mesylate according to body surface area until disease progression or unacceptable toxicity with 28 days one cycle. Overall response was evaluated after two cycles Apatinib treatment, then progression-free survival (PFS) and overall survival (OS) were evaluated, and safety data were recorded. Additionally. peripheral blood and peripheral blood mononuclear cell (PBMC) specimens in the osteosarcoma patients were collected for the genotyping of VEGFR2 genetic variation and mRNA expression, respectively. Analysis on the association between genotype and baseline characteristics and VEGFR2 gene mRNA expression was analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis was adjusted by Cox regression analysis. RESULTS: The objective response rate (ORR) of the 105 metastatic osteosarcoma patients was 37.14%, disease control rate (DCR) was 77.14%, median PFS was 4.1 months, and median OS was 9.0 months. Regarding the VEGFR2 gene polymorphisms analysis, only - 906 T > C was of clinical significance. The prevalence of - 906 T > C in VEGFR2 among the study population was as follows: TT genotype 62 cases (59.05%), TC genotype 36 cases (34.29%) and CC genotype 7 cases (6.66%), minor allele frequency of - 906 T > C was 0.24. Compared with patients with TC/CC genotype, patients with TT genotype showed longer median PFS (5.0 versus 3.1 months, P = 0.011) and median OS (9.8 versus 7.6 months, P = 0.032). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression in 69 randomly selected sample indicated that the mRNA expression of VEGFR2 of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P < 0.001). CONCLUSION: Apatinib was safe and effective in the treatment of metastatic osteosarcoma patients who progressed after standard therapy. The clinical outcomes of Apatinib may be influenced by the polymorphism - 906 T > C of VEGFR2 through mediating the mRNA expression of VEGFR2.

Implication of VEGFR2 Polymorphism on the Prognosis of Anlotinib Monotherapy for Patients With Treatment-Refractory Advanced NSCLC: An Exploratory Study.

Background: This study aimed to investigate the implication of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) polymorphism on the prognosis of anlotinib monotherapy among patients with treatment-refractory advanced nonsmall cell lung cancer (NSCLC). Methods: Designed as a retrospective study, this study included a total of 129 patients with treatment-refractory advanced NSCLC who were administered with anlotinib monotherapy. The efficacy of the patients was assessed regularly. The prognosis was performed and adverse reactions during anlotinib administration were collected. Available and appropriate biological specimens of the 129 patients were collected to perform VEGFR2 polymorphism analysis and VEGFR2 gene mRNA expression analysis accordingly. Association analysis between genotype status of VEGFR2 polymorphism and other variables was implemented in univariate and multivariate analysis. Results: Efficacy data indicated that the objective response rate (ORR) and disease control rate (DCR) of the 129 patients with NSCLC who received anlotinib monotherapy was 9.3% (95% CI: 4.9%-15.7%) and 78.3% (95%CI: 70.2%-85.1%), respectively. Additionally, prognostic data suggested that the median progression-free survival (PFS) and overall survival (OS) of the 129 patients with NSCLC were 4.1 months (95%CI: 2.84-5.36) and 10.1 months (95%CI: 8.58-11.62), respectively. Furthermore, polymorphism analysis indicated that polymorphism of 4397T>C in VEGFR2 was of clinical significance in the exploratory analysis, which exhibited that the median PFS of patients with TC/CC and TT genotype of 4397T>C polymorphism were 2.8 and 5.0 months, respectively (P = .009). Additionally, patients with TT genotype conferred a superior OS compared with those with TC/CC genotype (median OS: 11.5 vs 7.3 months, P = .016). Interestingly, mRNA expression of the VEGFR2 gene suggested that mRNA expression of VEGFR2 in PBMC specimens of patients with TC/CC genotype was significantly higher than that of patients with TT genotype (P < .001). Conclusion: Anlotinib monotherapy exhibited potential efficacy for patients with treatment-refractory advanced NSCLC. VEGFR2 polymorphism 4397T>C might be used as a promising biomarker to predict the survival of patients with NSCLC who received anlotinib administration.

Hepatic Artery Injection of 131I-Metuximab Combined with Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Prospective Nonrandomized, Multicenter Clinical Trial.

This prospective nonrandomized, multicenter clinical trial was performed to investigate the efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 mo in the TACE + 131I-metuximab group (n = 160) and 3 mo in the TACE group (n = 160) (hazard ratio, 0.55; 95% CI, 0.43-0.70; P < 0.001). The median overall survival was 28 mo in the TACE + 131I-metuximab group and 19 mo in the TACE group (hazard ratio, 0.62; 95% CI, 0.47-0.82; P = 0.001). Conclusion: TACE + 131I-metuximab showed a greater antirecurrence benefit, significantly improved the 5-y survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

Co-ablation versus cryoablation for the treatment of stage III-IV non-small cell lung cancer: A prospective, noninferiority, randomized, controlled trial (RCT).

BACKGROUND: This study compared a co-ablation (CA) system, which is a novel ablation device, with an argon-helium cryoablation (AHC) system. We aimed to compare the efficacy and safety of CA and AHC for the treatment of stage III-IV non-small cell lung cancer (NSCLC). METHODS: We conducted a multicenter randomized controlled trial (RCT) to determine whether CA was noninferior to AHC. The primary efficacy endpoints were the iceball coverage rate (ICR) and the disease control rate (DCR) one month after treatment. Noninferiority was declared if the lower limit of two-sided 95% confidence interval (CI) was less than 10%. The ICR and DCR were identified by logistic regression. Treatment safety was assessed. RESULTS: A total of 81 patients underwent randomization (41 assigned to the CA and 40 assigned to the AHC groups)and transthoracic ablation. The ICRs in the CA and AHC groups were 99.24% ± 2.18% and 98.66% ± 3.79%, respectively. Central lesions were associated with an increased risk of an incomplete ICR. The DCRs in the CA and AHC groups were 97.6% and 95%, respectively. A smaller lesion area in the CA group was significantly correlated with a better DCR. The rate of complications was 29.26% in the CA group and 30% in the AHC group. (P = 0.943). There was less probe usage per patient in the CA group. CONCLUSIONS: We determined that CA is noninferior to AHC in terms of efficacy and safety for the treatment of stage III-IV NSCLC. A smaller lesion area in the CA group was significantly correlated with a better DCR. KEY POINTS: CA was noninferior to AHC for stage III-IV NSCLC.

[Analysis of complications of high intensity focused ultrasound in treatment of uterine leiomyoma].

OBJECTIVE: To analysis complications and its associated risk factors of high intensity focused ultrasound (HIFU) in treatment of uterine leiomyoma for selecting rationale indicated patients and reducing complications. METHODS: Medical documents of 171 patients with 231 leiomyomas in total treated by HIFU were studied retrospectively. Common complications were categorized and analyzed, the relationship between risk factors and complications were studied. RESULTS: Common complications in treatment of uterine leiomyomas by HIFU were 71.9% (123/171) of abdominal pain, 17.5% (30/171) of vaginal bloody discharge, 8.2% (14/171) of sacroiliac or buttock pain, 7.6% (13/171) of skin blister, 4.7% (8/171) of leg pain, 2.9% (5/171) of hematuria and 1.8% (3/171) of febrile. By logistic regression analysis, the factor correlated with abdominal pain included diameter of uterine leiomyomas, sonication time and average power (P < 0.05). The factor correlated with sacroiliac or buttock pain was uterine leiomyomas located in posteriors of uterine wall (P < 0.05); the factors correlated with vaginal bloody discharge were sonication time and type of uterine leiomyomas (submucous > intramural > subserous, P < 0.05); the factors correlated with skin blister was sonication time (P < 0.05). There were no statistical relationship between multiple factors and leg pain, hematuria, febrile (P > 0.05). CONCLUSION: The modality of high-power and short-term treatment might reduce complications of HIFU ablation.

[Study on the efficacy and safety of ultrasound ablation in treatment of uterine fibroids].

OBJECTIVE: To investigate the safety and efficacy of ultrasound ablation in treatment of uterine fibroids. METHODS: Ninety-nine patients with 117 leiomyomas in total treated by Haifu JC focused ultrasound tumor therapeutic system were enrolled in prospective and non-randomized clinical trial in First Affiliated Hospital of Chongqing Medical University and Academy of Military Medical Sciences. Ultrasound ablation was performed guided by real-time ultrasonography under conscious sedation for single session. All patients were followed up at 6 months after treatment. On the day of treatment and after 1 month, patients were given by magnetic resonance imaging (MRI) exam to evaluate the effect of fibroids ablation. At 3 and 6 months after treatment, the ratio of ablated area and volume reduction of fibroids more than 50% were evaluated by MRI exam again. The symptoms improvements were evaluated by uterine fibroid symptom (UFS) and complications were analyzed by guideline of society of international radiation (SIR). RESULTS: The average ablated area ratio of the target fibroid was (76 ± 24)%. The average reduction in fibroid volume determined by MRI at 3 and 6 months after treatment was (45 ± 21)% and (59 ± 26)%. Which were significantly decreased than those before treatment (P < 0.05). At 6 months after treatment, 84.6% (99/117) of patients showed more than 50% volume reduction, the rate of improved symptom score was 92% (66/72). All patients could resume normal daily activities at 2 hours after treatment. The adverse reactions of SIR C-D included delayed hospitalization, repeat treatment and increased level of nursing. E-F included permanent sequelae and death. In this study, no adverse reactions of C-F were recorded. Common complications (SIR A-B, only observation or simple management without sequelae) were 35% (35/99). Four cases with adverse reactions B of SIR were found, including 2 cases with skin burning of degree II and 2 cases with febrile, they were administered by symptomatic therapy and changing dressing. The other adverse reaction A of SIR included sorness of buttock, vaginal discharge, dysuria and painful urination, they were only suggested by follow-up. CONCLUSION: It was efficacy and safe that ultrasound ablation as a single strategy were used in treatment of uterine fibroids.

High-intensity focused ultrasound ablation for advanced pancreatic cancer.

AIMS: The aim of this study was to evaluate the efficacy, safety, and survival factors of high-intensity focused ultrasound (HIFU) ablation in the treatment of advanced pancreatic cancer. SUBJECTS AND METHODS: A retrospective analysis was conducted between September 2010 and March 2016. Advanced pancreatic cancer patients with HIFU treatment were enrolled in the analysis to evaluate the efficacy of local ablation, pain relief, and relative complications of HIFU therapy. The main factors that affected Overall survival rate (OSR) and median survival time (MST) were also analyzed. RESULTS: Eighty-six patients received HIFU treatment, with a total of 93 treatments performed, and 83 cases were evaluated. Complete response rate (RR) was 3.6% (3/83) and partial RR was 79.5% (66/83). After HIFU treatment, pain reduction was observed in 74 patients, and the total remission rate was 97.6% (74/76). The total MST was 9.9 months (2-58.7 months), the total OSR in 1 and 2 years was 41.5% and 9.6%, respectively. Minor complications occurred in 97.7% (42/43) patients, including transient fever, abdominal pain, skin burn, and amylase elevation. The univariate analysis showed that the clinical stage, treatment method, ablation efficacy, and combined treatment were significant prognostic factors. CONCLUSION: HIFU can significantly alleviate cancer-related pain and prolong the survival time of patients with pancreatic cancer.

Efficacy and safety of apatinib monotherapy in advanced bone and soft tissue sarcoma: An observational study.

Sarcomas are rare but malignant tumors with high risks of local recurrence and distant metastasis. Anti-angiogenic therapy is a potential strategy against un-controlled and not-organized tumor angiogenesis. We aimed to assess the safety and efficacy of apatinib, an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, in patients with advanced sarcoma. Thirty-one patients who received initial apatinib between September 2015 and August 2016 were retrospectively reviewed. Among them, 19 (61.3%) patients were heavily pretreated with two or more lines of cytotoxic chemotherapy. Apatinib was given at a start-dose of 425 mg qd. During therapy, 9 (29.0%) patients required dose interruption and 7 (22.6%) needed dose reduction, and the mean dosage of apatinib was 372.9 ± 68.4 mg/day. In the study cohort, one patient was treated as adjunctive therapy and 6 patients stopped treatment before radiographic response assessment. Thus, 24 patients were eligible for tumor response evaluation. The objective response rate was 33.3% and clinical benefit rate was as high as 75.0%. The progression free survival was 4.25 (95% confidence interval [CI], 2.22-5.11) months, whereas the overall survival was 9.43 (95% CI, 6.64-18.72) months. Compared with other histological subtypes, leiomyosarcoma did not show significant survival benefits. Most of the adverse events (AEs) were at grade 1 or 2. The main grade 3 AEs were hypertension (6.5%), hand foot skin reaction (6.5%), and diarrhea (3.2%). In conclusion, apatinib showed promising efficacy and acceptable safety profile in metastatic or recurrent sarcoma, giving rationale clinical evidence to conduct clinical trials.

Immunomodulation characteristics by thermal ablation therapy in cancer patients.

AIM: Thermal ablation therapy has recently emerged as a promising noninvasive treatment modality for localized solid malignancies. Except its direct tumor-cell-killing effect on local tumor tissues, the immunomodulatory effect has also long been noticed which too has substantial effect on clinical outcome, but it is complicated. Though much has been investigated and rich evidences have been achieved, the fundamental state and profile of immunomodulation by thermal ablation in cancer patients, its exact mechanism, especially the systematic mechanism, and its effect on antitumor immunity remain unclear. METHODS: In this study, we dynamically monitored the immunomodulation by thermal ablation through combined analysis of peripheral lymphocyte populations, functional T cell subtype Th1 (CD3+CD4+IFN-r+), Th2 (CD3+CD4+IL-4+), Tc1 (CD3+CD8+IFN-r+), Tc2 (CD3+CD8+IL-4+) and mRNA expression of several immune-active and -suppressive molecules including CD25, CD28, cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, Foxp3, transforming growth factor beta (TGF-ß) and interleukin (IL-10) in 16 cancer patients. RESULTS: The results show that local cancer thermal ablation modulated the cellular immunity characterized by obviously downregulation of regulatory T cells (Treg) and cytotoxicity T cells followed by CD4, CD8 and suppressor T cells (Ts), but upregulation of natural killer (NK) cells and mRNA expression of TGF-ß and IL-10, suggesting a slight inhibition of the cellular immunity which may affect antitumor immunity. CONCLUSIONS: We suggest a further immunomodulation therapy after thermal therapy for recovering a Th1- and Tc1-dominant immune response for pursuing a better long-term antitumor immunity.

[Effects of STAT3 antisense oligonucleotide on proliferation and apoptosis of non-small cell lung cancer cell line A549].

BACKGROUND & OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is highly expressed in various human tumor tissues and tumor cell lines, and may be involved in tumor genesis and development. This study was to design effective antisense oligonucleotide targeting STAT3 mRNA, and explore its effect on the proliferation and apoptosis of human non-small cell lung cancer cell line A549. METHODS: Ten sets of antisense sequences targeting STAT3 were designed with RNAstructure4.2 software and STAT3 mRNA total sequences, and transfected respectively into A549 cells (AS group). Cell proliferation inhibition was measured by Cell Count Kit (CCK-8) assay. Cell proliferation and apoptosis were observed under inverted phase contrast microscope. Cell apoptosis was determined by flow cytometry (FCM) with Hoechst33258 staining and Annexin V/PI double staining. The expression of STAT3, p-STAT3, and Bcl-x(L) were detected by Western blot. Cell cycle was detected by FCM. RESULTS: The 10 sets of designed sequences inhibited the proliferation of A549 cells. The inhibition rate of A549 cell proliferation reached 75.46% after transfection of AS10; the higher the concentration of the antisense oligonucleotide was, the heavier the inhibitory effect was displayed (P<0.01). Apoptotic cells were increased after transfection of antisense oligonucleotide. Antisense oligonucleotide induced early apoptosis in A549 cells: the early apoptosis rate was significantly higher in AS group than in control group (11.51% vs. 5.18%, P<0.01). The expression of STAT3, p-STAT3, and Bcl-x(L) were down-regulated after transfection of antisense oligonucleotide. The G1 phase proportion of A549 cells was significantly higher in AS group than in control group (63.96% vs. 44.47%, P<0.01). CONCLUSION: The antisense oligonucleotide sequences targeting STAT3 designed with computer could inhibit the proliferation and induce the apoptosis of A549 cells.