Toripalimab combined with concurrent platinum-based Chemoradiotherapy in patients with locally advanced cervical Cancer: an open-label, single-arm, phase II trial.

BACKGROUND: Concurrent chemoradiotherapy is currently the standard of care for patients with locally advanced cervical cancer. However, even with the application of modern radiotherapy techniques, a considerable number of patients still develop distant metastases. PD-L1 inhibitors show good efficacy in cervical cancer. This single-arm phase II study aims to explore the efficacy and tolerability of combining PD-L1 inhibitor with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. METHODS/DESIGN: The primary endpoint of the study was the objective response rate assessed according to RECIST v1.1 criteria. The inclusion criteria were previously untreated patients aged 18-75 years with stage III-IVA (FIGO 2018 staging system) locally advanced cervical cancer. During concurrent chemoradiotherapy and consolidation chemotherapy, the enrolled patients will receive toripalimab (240 mg) every 3 weeks. After consolidation chemotherapy, the enrolled patients will be treated with toripalimab (240 mg) once every 6 weeks until the whole treatment cycle reaches 1 year. Intensity modulated radiotherapy was used for external beam radiation, and high-dose rate brachytherapy was delivered under image-guidance. Weekly DDP (40 mg/m2) was given concurrently with radiotherapy while 6 cycles of consolidated chemotherapy (paclitaxel plus DDP) were given after radiotherapy every three weeks. Secondary objectives included safety and tolerability, toxicity profile, progression-free survival, and overall survival. DISCUSSION: PD-L1 inhibitor has shown good efficacy in recurrent/metastatic cervical cancer. However, there is still a lack of evidence about its combination with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. The purpose of this study is to explore the efficacy and tolerance of this combination therapy, so as to lay the foundation for the future phase III randomized study. TRIAL REGISTRATION:  clinicaltrials.gov NCT05084677 . Retrospectively registered on Octorber 07, 2021.

Artificial Intelligence-Based Automated Treatment Planning of Postmastectomy Volumetric Modulated Arc Radiotherapy.

As a useful tool, artificial intelligence has surpassed human beings in many fields. Artificial intelligence-based automated radiotherapy planning strategies have been proposed in lots of cancer sites and are the future of treatment planning. Postmastectomy radiotherapy (PMRT) decreases local recurrence probability and improves overall survival, and volumetric modulated arc therapy (VMAT) has gradually become the mainstream technique of radiotherapy. However, there are few customized effective automated treatment planning schemes for postmastectomy VMAT so far. This study investigated an artificial intelligence based automated planning using the MD Anderson Cancer Center AutoPlan (MDAP) system and Pinnacle treatment planning system (TPS), to effectively generate high-quality postmastectomy VMAT plans. In this study, 20 patients treated with PMRT were retrospectively investigated, including 10 left- and 10 right-sided postmastectomy patients. Chest wall and the supraclavicular, subclavicular, and internal mammary regions were delineated as target volume by radiation oncologists, and 50 Gy in 25 fractions was prescribed. Organs at risk including heart, spinal cord, left lung, right lung, and lungs were also contoured. All patients were planned with VMAT using 2 arcs. An optimization objective template was summarized based on the dose of clinical plans and requirements from oncologists. Several treatment planning parameters were investigated using an artificial intelligence algorithm, including collimation angle, jaw collimator mode, gantry spacing resolution (GSR), and number of start optimization times. The treatment planning parameters with the best performance or that were most preferred were applied to the automated treatment planning method. Dosimetric indexes of automated treatment plans (autoplans) and manual clinical plans were compared by the paired t-test. The jaw tracking mode, 2-degree GSR, and 3 rounds of optimization were selected in all the PMRT autoplans. Additionally, the 350- and 10-degree collimation angles were selected in the left- and right-sided PMRT autoplans, respectively. The uniformity index and conformity index of the planning target volume, mean heart dose, spinal cord D0.03cc, mean lung dose, and V5Gy and V20Gy of the lung of autoplans were significantly better compared with the manual clinical plans. An artificial intelligence-based automated treatment planning method for postmastectomy VMAT has been developed to ensure plan quality and improve clinical efficiency.

A nomogram for predicting brain metastases of EGFR-mutated lung adenocarcinoma patients and estimating the efficacy of therapeutic strategies.

BACKGROUND: To establish a nomogram for predicting the outcome of EGFR-mutated lung adenocarcinoma patients with brain metastases (BMs) and to estimate the efficacy of different therapeutic strategies. METHODS: The data of 129 cases with BM from the period between January 1st 2011 and December 31st 2014 were collected, and all of the cases were pathologically confirmed to be lung adenocarcinoma, stages I-IV and with 19 and/or 21 exon mutations of EGFR. Cox regression analysis and log-rank test were used for data analysis. The nomogram was used to establish the progression models. RESULTS: In the univariate analysis, the stage, ECOG score, interval between the diagnosis of lung cancer and BM, the number of brain metastatic lesions, and the diameter of the maximal brain metastatic lesion correlated well with overall survival (OS). In multivariate Cox proportional hazard analysis, the ECOG score, interval between the diagnosis of lung cancer and BM, and the number of brain metastatic lesions correlated well with the OS. Patients were divided into the poor prognostic group and the good prognostic group based on the nomogram prognostic model score. Subgroup analysis showed that in the poor prognostic group, the OS of patients who received radiotherapy was better than that of the patients who did not receive radiotherapy as the first-line treatment (30 vs. 19 months, P<0.05). The OS was 30 months in the TKI subgroup and 21 months in the no TKI subgroup, but no statistical difference was found (P>0.05). Patients in the good prognostic group who received radiotherapy had a better 3-y OS rate than the patients who received no radiotherapy as the first-line treatment (91.2% vs. 58.1%, P<0.05). The 3-y OS rate was 87.6% in the TKI subgroup and 67.8% in the no TKI group (P<0.05). CONCLUSIONS: We established an effective nomogram model to predict the progression of EGFR-mutated lung adenocarcinoma patients with BM and the therapeutic effect of the individual treatments. Radiotherapy was beneficial for the patients of both the poor and good prognostic groups, but TKI may be better suited for treating the patients with good prognosis.

Dosimetry comparison between a 3D printed minimally invasive guidance template and free implantation in the brachytherapy treatment of postoperative recurrent cervical carcinoma.

Objective: This study aimed to investigate the dosimetry difference between a 3D printed minimally invasive guidance template and conventional free implantation in brachytherapy of postoperative recurrent cervical carcinoma under the guidance of computed tomography (CT). Methods: A total of 21 cases of patients with recurrent cervical cancer after operation were enrolled from January 2017 to June 2018. After external irradiation treatment in 1.8-Gy fractions to 45 Gy, patients were randomly divided into two groups to receive brachytherapy: 11 cases were assisted by a 3D-printed minimally invasive guidance template, and the other 10 cases were free implantation. In the template group, needles were inserted according to the main guide channel of the template commissioned in medical photosensitive resin, while patients in the other group were treated with bare hands under the guidance of CT, which was used in both groups to adjust the position and depth of the implant needles. After transmission of the CT images into the Oncentra® Brachy TPS system, the target organs and organs at risk were delineated for further treatment. Results: The D90 value of the high-risk clinical target volume in the template group was 6.30±0.21 Gy while that in the other group was 6.07±0.32 Gy (P<0.05). In addition, the D2cm3 (illuminated dose of 2 cm3 of organ at risk) value of the bladder, rectum, sigmoid colon, and bowel was significantly decreased in the template group as compared to the free group (P<0.05). The number of needles used for each treatment in the template group was 5.71±1.82, while that for the free injection group was 7.78±2.35 (P<0.05). Conclusion: Compared with conventional free implantation, the 3D printed minimally invasive guidance template-assisted treatment has an obvious dosimetry advantage in the treatment of postoperative recurrent cervical carcinoma, with shorter time of implantation and better repeatability.

Moderate hypofractionated radiotherapy vs conventional fractionated radiotherapy in localized prostate cancer: a systemic review and meta-analysis from Phase III randomized trials.

PURPOSE: To determine the efficacy and late toxicities of moderate (2.5-4 Gy) hypofractionated radiotherapy (H-RT) in localized prostate cancer, a meta-analysis of published randomized clinical trials comparing moderate H-RT with conventional fractionated RT (C-RT) was performed. MATERIALS AND METHODS: Systematic search on published randomized clinical trials in English according to Cochrane review guidelines in databases of Pubmed, Embase, Cochrane, web of science, and Wiley Online Library was carried out. Outcomes of interests were biochemical and clinical disease failure (BCDF), biochemical failure (BF), overall survival (OS), and late toxicities. RESULTS: Seven of the 365 studies fulfilled inclusion criteria with 8,156 participants. Compared with C-RT, moderate H-RT showed a lower BF rate (risk ratio [RR] =0.80, 95% CI: 0.68-0.95, P=0.009), while did not improve OS (RR =0.68, 95% CI: 0.78-1.02, P=0.10). There was no significant difference in BCDF rates between H-RT and C-RT (RR =0.92, 95% CI: 0.82-1.02, P=0.12). The H-RT was deeply grouped into dose-escalated H-RT (with a higher biologically effective dose [BED1.5] than C-RT) and no dose-escalated H-RT; dose-escalated H-RT significantly decreased BCDF rate compared with C-RT (RR =0.84, 95% CI: 0.73-0.96, P=0.01). Regarding late toxicities, there is no significant difference in late gastrointestinal (GI; RR =0.97, 95% CI: 0.71-1.33, P=0.85) and genitourinary (GU) toxicities (RR =1.04, 95% CI: 0.87-1.24, P=0.69). When subgrouped into dose-escalated H-RT (with a higher BED5 compared with C-RT) and no dose-escalated H-RT, dose-escalated H-RT increased GI toxicity (RR =1.62, 95% CI: 1.26-2.09, P=0.0002) and GU toxicity (RR =1.28, 95% CI: 1.05-1.55, P=0.01), while no dose-escalated H-RT significantly lowered GI toxicity (RR =0.81, 95% CI: 0.70-0.94, P=0.005) and placed no influence on GU toxicity (RR =1.02, 95% CI: 0.88-1.20, P=0.77). CONCLUSION: This meta-analysis provides reliable evidence that moderate H-RT decreases BF rate, while does not improve OS. Compared with C-RT, H-RT with an increase in BED1.5 improved BCDF rates significantly, and accordingly, an increase in BED5 will result in elevated late GI and GU toxicities.

Diffuse large B-cell lymphoma of the breast: prognostic factors and treatment outcomes.

BACKGROUND: The breast is a rare site of extranodal involvement of diffuse large B-cell lymphoma (DLBCL). We aimed to assess the clinical characteristics, prognostic factors, and treatment outcomes of breast DLBCL. PATIENTS AND METHODS: We retrospectively analyzed 113 patients (from our institution and the literature) between 1973 and 2014. The primary end point was overall survival (OS). Kaplan-Meier OS curves were compared with the log-rank test. Cox regression analysis was applied to determine the prognostic factors for OS, progression-free survival (PFS), local control (LC), and cause-specific survival (CSS). RESULTS: A total of 113 patients were included in the study: 42 cases from our hospital and 71 cases from 12 publications. The median age at diagnosis was 58 years. With a median follow-up time of 39.2 months, the estimated 5-year OS, PFS, LC, and CSS were 71.4%, 58.8%, 75.6%, and 74.9%, respectively. In multivariate analysis, more than four cycles of chemotherapy, having localized cancer, lumpectomy with or without axillary lymph node (ALN) dissection, and low to low-to-intermediate International Prognostic Index were favorable factors for OS. For PFS, significant prognostic factors were rituximab use, B symptoms, and tumor size. As for the local group, lumpectomy with or without ALN dissection and more than four cycles of chemotherapy were favorable factors for OS. Tumor size >4 cm and nonuse of rituximab were adverse factors for PFS. Twenty-one patients (18.6%) developed local relapse and 33 (29.2%) developed systemic relapse. Eight patients had central nervous system relapse (7.3%). CONCLUSION: Our results reveal that local and extended staging criteria can reflect the different prognosis and treatment outcomes of breast DLBCL. Rituximab use, lumpectomy, and more than four cycles of chemotherapy are recommended as a treatment regimen. However, further study is warranted to validate our data.

MiR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4.

miR-99a is frequently downregulated in various types of human malignancies including lung adenocarcinoma. Recent studies have reported that miR-99a regulates cell growth and cell cycle progression by targeting mTOR, AKT1 and FGFR3. However, the underlying mechanisms involved in the modulation of invasion and migration by miR-99a remain elusive. In this study, we analyzed the relationship between the expression of miR-99a and clinical stage or metastasis in 90 matched lung adenocarcinoma and adjacent non-tumor lung tissues. Downregulation of miR-99a was significantly associated with advanced stage and tumor metastasis in lung adenocarcinoma patients, and it was found to be a poor prognostic factor in lung adenocarcinoma. Furthermore, functional experiments found that overexpression of miR-99a inhibited the proliferation, migration and invasion of lung adenocarcinoma A549 and Calu3 cells in vitro. We then identified NOX4 as a target gene of miR-99a and NOX4 mediated the inhibition of invasion and migration of lung adenocarcinoma cells by miR-99a. By targeting NOX4-mediated ROS production, miR-99a regulated the invasion and migration of lung adenocarcinoma cells. Moreover, overexpression of miR-99a significantly inhibited tumor growth in vivo. Immunohistochemical staining analysis of the mouse tumor tissues revealed that NOX4 levels were downregulated in the miR-99a treatment group, confirming the in vitro data of NOX4 as a direct target gene of miR-99a. Taken together, these data indicate for the first time that miR-99a directly regulates the invasion and migration in lung adenocarcinoma by targeting NOX4 and that overexpression of miR-99a may become a therapeutic strategy for lung adenocarcinoma.

Similar Outcomes of Standard Radiotherapy and Hypofractionated Radiotherapy Following Breast-Conserving Surgery.

BACKGROUND: Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. MATERIAL AND METHODS: Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. RESULTS: The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. CONCLUSIONS: A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.

Brain metastasis treated with Cyberknife.

BACKGROUND: Cyberknife can greatly raise the fractional dose of stereotactic radiosurgery, thus improving its clinical efficacy. We retrospectively analyzed clinical outcomes of brain metastasis treated with Cyberknife. METHODS: We analyzed 40 cases of brain metastases treated with Cyberknife in the Tianjin Cancer Hospital from August 1, 2006 to August 1, 2007, for a total of 68 lesions with maximal diameter of 0.4 - 7.5 cm (average 1.88 cm). Total hypofractional radiated dosage was 18 - 36 Gy (5 - 25 Gy/F, 1 - 5 F) by Cyberknife. We evaluated the remission rate of clinical symptoms, correlation factors to new foci, 3-month local control rates, and 3-month and 1-year survival rates. All patients were followed up for more than 14 months. RESULTS: After 1 week, clinical remission was 90.0% (36/40). After 3 months, the local control rate and therapeutic effective rate were 77.9% (53/68) and 94.1% (64/68), respectively, as observed by cranium augmentation CT or MRI. The three-month, six-month and 1-year survival rates were 97.5% (39/40), 82.5% (33/40) and 67.5% (27/40), respectively. Fourteen patients had neopathy outside the original lesion after 3 months. Neopathy was not correlated with age, whole-brain radiotherapy, number of original lesions, maximum diameter of the original lesion, therapeutic dose per fraction, therapeutic frequency or total therapeutic dose. CONCLUSIONS: Cyberknife got perfect clinical outcomes by higher dosage per fraction. It is an appropriate and valid treatment shortcut for brain metastasis.

[Protein expression of p53, bcl-2, and bax in adenoid cystic carcinoma of lacrimal gland].

OBJECTIVE: To investigate the expression of p53, bcl-2, and hax, apoptosis regulating genes, in adenoid cystic carcinoma of larcrimal gland and the roles thereof in clinical prognosis. METHODS: 56 patients of adenoid cystic carcinoma of larcrimal gland were divided into two groups according to the prognosis: poor prognosis group with recurrence or metastasis within 5 years (n=32) and better prognosis group (n=24) surviving tumor free within 5 years. The protein expression levels of p53, tumor suppressor gene, bax, apoptosis promoting gene, and bcl-2, anti-apoptosis gene, were analyzed by strepavidin peroxidase method. 8 cases of normal lacrimal gland tissues were used as controls. RESULTS: (1) The overall positive rate of p53 of the patients with adenoid cystic carcinoma of larcrimal gland was 73.2%, significantly higher than that of the normal controls (0, P < 0.05). The p53 positive rate of better prognosis group was 62.5%, significantly higher than that of the poor prognosis group (81.3%, P < 0.05). The protein expression of p53 in adenoid cystic carcinoma of larcrimal gland was negatively correlated with clinical prognosis. (2) The overall expression rate of bcl-2 of the patients with adenoid cystic carcinoma of larcrimal gland was 69.6%, significantly lower than that of the control group (P < 0.05). The expression bcl-2 protein was correlated with better clinical prognosis. (3) The bax positive rate of the patients with adenoid cystic carcinoma of larcrimal gland group was 60.7%, not significantly lower than the control group. The bar positive rate of the better prognosis group was 91.7%, significantly higher than that of the poor prognosis group (65.6%, P < 0.05). CONCLUSION: Some apoptosis regulating genes, such as mutation-type (mt) p53 play an important role in the gene ration and development of adenoid cystic carcinoma of larcrimal gland. p53, bax, and bcl-2 proteins may act as valuable signals for clinical prognosis. The patients with over expression of bcl-2 and bax and low expression of p53 may have better prognosis than the contrary ones.