Comparison of outcomes between early-stage cervical cancer patients without high-risk factors undergoing adjuvant concurrent chemoradiotherapy and radiotherapy alone after radical surgery.

PURPOSE: For patients with early-stage cervical cancer without high-risk factors, there is no consensus regarding the optimal postoperative treatment regimen and whether postoperative concurrent radiochemotherapy (CCRT) is superior to radiotherapy (RT) alone. PATIENTS AND METHODS: The medical records of patients with stage I-IIA cervical cancer, who underwent radical surgery and postoperative RT or CCRT between June 2012 and December 2017, were retrospectively reviewed. Patients with any high-risk factors, including positive pelvic lymph node(s), positive resection margin(s), and parametrial invasion, were excluded. Patients with large tumors (≥ 4 cm), deep stromal invasion (≥ 1/2), and lymphovascular space involvement were categorized as the intermediate-risk group. Patients without intermediate-risk factors were categorized as the low-risk group. RESULTS: A total of 403 patients were enrolled and divided into 2 groups according to postoperative treatment: RT alone (n = 105); and CCRT (n = 298). For risk stratification, patients were also divided into 2 groups: intermediate-risk (n = 350); and low-risk (n = 53). The median follow-up was 51.7 months. Patients in the intermediate-risk group and those with multiple intermediate-risk factors were more likely to undergo CCRT. For patients who underwent RT alone or CCRT in the intermediate-risk group, 5-year overall survival (OS) rates were 93.4% and 93.8% (p = 0.741), and 5-year disease-free survival (DFS) rates were 90.6% and 91.4%, respectively (p = 0.733). Similarly, for patients who underwent RT alone or CCRT in the low-risk group, the 5-year OS rates were 100.0% and 93.5% (p = 0.241), and 5-year DFS rates were 94.4% and 93.5%, respectively (p = 0.736). Adjuvant CCRT or RT were not independent risk factors for either OS or DFS. Patients who underwent CCRT appeared to develop a higher proportion of grade ≥ 3 acute hematological toxicities than those in the RT group (44.0% versus 11.4%, respectively; p < 0.001). There was no significant difference in grade ≥ 3 chronic toxicities of the urogenital and gastrointestinal systems between the CCRT and RT groups. CONCLUSION: There was no significant difference in 5-year OS and DFS rates between patients with early-stage cervical cancer without high-risk factors undergoing postoperative CCRT versus RT alone. Patients who underwent CCRT appeared to develop a higher proportion of grade ≥ 3 acute hematological toxicities than those who underwent RT alone.

Postoperative adjuvant radiotherapy for patients with upper tract urothelial carcinoma (UTUC) who underwent kidney-sparing surgery (KSS): a single-center study.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of postoperative adjuvant radiotherapy for patients with upper tract urothelial carcinoma (UTUC) who underwent kidney-sparing surgery (KSS). METHODS: We retrospectively reviewed the clinical records of 31 patients with primary UTUC who underwent kidney-sparing surgery (KSS) and who were treated with adjuvant radiotherapy at our center between October 1998 and May 2017. Statistical analyses were performed with SPSS 23.0. The primary endpoints of this study included overall survival (OS) and local recurrence-free survival (LRFS); the secondary endpoints were disease-free survival (DFS) and treatment-related toxicity. RESULTS: The median follow-up was 58.4 months (range, 12.7-185.3 months), and the median local recurrence time was 59.0 months (range, 7.0-185 months). All of the patients completed radiotherapy on schedule, and no grade 3-4 late-stage reaction was observed. The estimated 5-year and 10-year OS, DFS and LRFS rates of the patients were 64.0%, 61.1%, 69.6% and 48.0%, 40.9%, 64.6%, respectively. Univariate analysis showed that age (χ2 = 4.224, P = 0.040), R0 resection (χ2 = 3.949, P = 0.047), and early stage (I + II) (χ2 = 6.515, P = 0.011) were associated with good OS; DFS benefit in early stage patients (χ2 = 6.151, P = 0.013) and age<70 years old (χ2 = 5.091, P = 0.024). Patients with distal ureteral segments had better LRFS than patients with proximal ureteral cancer (χ2 = 5.248, P = 0.022). However, multivariate analysis showed that age was the only factor of OS (χ2 = 4.099, P = 0.043). CONCLUSION: Adjuvant radiotherapy is safe and tolerated, and LRFS was superior in middle and distal ureteral cancer than in proximal ureteral cancer.

Prophylactic Extended-Field Irradiation Versus Pelvic Irradiation in Patients With Cervical Cancer With 2018 FIGO Stage IIIC1 Disease.

PURPOSE: The aim of this study was to compare the survival rates and toxicities of prophylactic extended-field radiation therapy (EFRT) and pelvic radiation therapy (PRT) among patients with cervical cancer with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 disease. METHODS AND MATERIALS: We retrospectively analyzed patients with 2018 FIGO stage IIIC1 disease who were treated with definitive concurrent chemoradiotherapy at our institute between 2011 and 2015. A dose of 50.4 Gy in 28 fractions was delivered to the pelvic region (by PRT) or the pelvic plus para-aortic lymph node region (by EFRT) with intensity modulated radiation therapy. The first-line regimen of concurrent chemotherapy was weekly cisplatin. RESULTS: A total of 280 patients were included, with 161 patients treated with PRT and 119 patients treated with EFRT. After propensity score matching (1:1), 71 pairs of patients were selected. The respective 5-year rates of the patients treated with PRT and EFRT were 61.9% and 85.0% for overall survival (P = .025) and 53.0% and 77.9% for disease-free survival (DFS) (P = .004), respectively, after matching. In the subgroup analysis, patients were grouped into a high-risk group (122 patients) and a low-risk group (158 patients) based on 3 factors: positive common iliac lymph nodes, ≥3 pelvic lymph nodes, and 2014 FIGO stage IIIB disease. In both the high-risk and low-risk groups, EFRT significantly improved DFS compared with PRT. The rates of grade ≥3 chronic toxicities were 1.2% and 5.9% in the PRT and EFRT groups, respectively (P = .067). CONCLUSIONS: In comparison to PRT, prophylactic EFRT was associated with improved overall survival, DFS, and para-aortic lymph node control in patients with cervical cancer with FIGO stage IIIC1 disease. The incidence of grade ≥3 toxicities was higher in the EFRT group than in the PRT group, although the difference was not significant.

Expression of B7 family checkpoint proteins in cervical cancer.

The role of programmed cell death-ligand 1 (PD-L1) in cervical cancer has been widely investigated; however, the influences of other inhibitory B7 family members are poorly understood. We investigated the expression of PD-L1, B7 homolog 3 (B7-H3), B7-H4, and V-domain Ig suppressor of T-cell activation (VISTA) and their association with the clinicopathological features and outcomes of a large cohort of 673 patients with squamous cell carcinoma or adenocarcinoma of the uterine cervix. The positivity rates for PD-L1 (combined positive score ≥1), B7-H3 in tumor cells (TCs), B7-H4 (exclusively in TCs), VISTA in immune cells (ICs), and VISTA in TCs were 57.9%, 62.8%, 44.8%, 92.6%, and 4.8%, respectively, in 606 primary cervical cancer samples. Co-expression of PD-L1 with B7-H3 in TCs and with B7-H4 and VISTA in ICs was observed in 38.8%, 25.4%, and 57.9% of samples, respectively. B7-H3 in TCs and B7-H4 and VISTA in ICs were observed in 58.1%, 46.6%, and 83.1% of PD-L1-negative samples, respectively. These proteins were observed more frequently in squamous cell carcinomas and in moderately to poorly differentiated carcinomas. VISTA (in ICs) and B7-H4 were more frequent in primary tumors than in recurrent counterparts and correlated with improved survival; in contrast, B7-H3 positivity in TCs was less frequent in primary tumors and correlated with short disease-specific survival. Co-expression of B7-H4 and VISTA in ICs was an independent predictor of favorable outcomes overall and among patients with PD-L1-negative tumors. These data indicate that B7 family proteins exhibit differing expression patterns, distributions, and prognostic implications in cervical cancer. Furthermore, the co-expression of PD-L1 with other checkpoint proteins suggests that PD-1/PD-L1 blockade combined with modulating other immune checkpoints may present a novel therapeutic approach for cervical cancer. Future studies are needed to validate prognostic values of B7 family proteins and explore their biological roles in this malignancy.

Comparison of Outcomes and Prognostic Factors Between Early-Stage Cervical Adenocarcinoma and Adenosquamous Carcinoma Patients After Radical Surgery and Postoperative Adjuvant Radiotherapy.

PURPOSE: No consensus has been reached regarding the survival difference between cervical adenocarcinoma (ADC) and adenosquamous carcinoma (ASC) patients. The purpose of this study was to compare survival outcomes and prognostic factors between early-stage ADC and ASC patients. PATIENTS AND METHODS: We retrospectively reviewed stage IB-IIA patients with ADC and ASC who underwent radical hysterectomy and postoperative radiotherapy between June 2012 and December 2017. RESULTS: A total of 125 patients were enrolled in our study (97 with ADC and 28 with ASC). The median follow-up period was 53.4 months. Compared with ASC patients, patients with ADC tended to have a higher proportion of positive pelvic lymph nodes (7.1% and 26.8%, respectively; p = 0.028). The most common site of distant metastasis was the lung, followed by the intestine and colon. The 5-year overall survival (OS), disease-free survival (DFS), pelvic control, and distant control rates for ADC and ASC patients were 83.6% and 92.0% (p = 0.349), 77.5% and 87.7% (p = 0.279), 81.8% and 96.2% (p = 0.121), and 88.3% and 87.7% (p = 0.948), respectively. Parametrial invasion was a prognostic factor for OS. Lymphovascular space involvement was a prognostic factor for DFS. CONCLUSION: ADC patients were more likely to have positive pelvic lymph nodes than those with ASC. There was no significant difference in survival outcomes between patients with ADC and ASC.

The 100 Most Cited Papers in Radiotherapy or Chemoradiotherapy for Cervical Cancer: 1990-2020.

OBJECTIVE: This work aims to analyze the 100 most cited papers in radiotherapy or chemoradiotherapy for cervical cancer. METHODS: The 100 most cited papers in radiotherapy or chemoradiotherapy between 1990 and 2020 were identified with Thompson Reuters Web of Science citation indexing on August 24, 2020. The publication years, source titles, countries/regions, total citations, and average citations per year were extracted from the Web of Science. The research type and research domain were classified by the authors. RESULTS: These 100 papers were cited a total of 28,714 times, and the median number of citations was 169.5 (ranging from 116 to 1,700 times). The most cited paper was "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer" by Rose et al., with a total citation of 1,700 times. The International Journal of Radiation Oncology Biology Physics (40 papers), Radiotherapy and Oncology (14 papers), and the Journal of Clinical Oncology (12 papers) published the largest number of papers. USA (47 papers), Austria (18 papers), Canada (13 papers), and England (13 papers) contributed the largest number of papers. Image-guided adaptive brachytherapy (IGABT) had the largest number of papers (25 papers). Concurrent chemotherapy was the most cited research domain, with 10,663 total citations and 592.4 citations per paper. CONCLUSION: In the present study, we conducted a bibliometric analysis of the 100 most cited papers in radiotherapy or concurrent chemoradiotherapy for cervical cancer in the past 30 years. IGABT and concurrent chemotherapy were the most cited research domains.

High VISTA Expression Correlates With a Favorable Prognosis in Patients With Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. The novel immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) has emerged as a promising target for cancer treatment; however, the prognostic significance of its expression in CRC remains unknown. In this study, immunohistochemical staining was used to investigate VISTA expression in tissue microarrays from 1434 patients with stage I-III CRC (816 in the exploratory cohort and 618 in the validation cohort). VISTA protein was evaluated separately in tumor cells and tumor-infiltrating immune cells (ICs). The associations between VISTA expression, mismatch repair (MMR) status, and clinicopathologic parameters were analyzed, as was the effect of VISTA on survival. High VISTA expression on ICs (ie, ≥5% staining) was more frequent in patients with N0 stage, T1-2 stage, low tumor grade, high CD8 density, and MMR-deficient tumors, and was positively associated with prolonged survival in patients with CRC. High VISTA expression was a significant predictor of prolonged survival independent of clinicopathologic parameters and MMR status. Overall, our results indicate that high VISTA expression on tumor-infiltrating ICs correlates with early tumor stage, MMR deficiency, and a favorable prognosis in patients with CRC. This ought to be considered in future trials of VISTA-modulating immunotherapy for patients with CRC.

Prophylactic Extended-Field Irradiation in Patients With Cervical Cancer: A Literature Review.

Currently, the standard radiation field for locally advanced cervical cancer patients without evidence of para-aortic lymph node (PALN) metastasis is the pelvis. Due to the low accuracy of imaging in the diagnosis of PALN metastasis and the high incidence of PALN failure after pelvic radiotherapy, prophylactic pelvic and para-aortic irradiation, also called extended-field irradiation (EFI), is performed for patients with cervical cancer. In the era of concurrent chemoradiotherapy, randomized controlled trials are limited, and whether patients with cervical cancer can benefit from prophylactic EFI is still controversial. With conformal or intensity-modulated radiation therapy, patients tolerate prophylactic EFI very well. The severe toxicities of prophylactic EFI are not significantly higher than those of pelvic radiotherapy. We recommend delivering prophylactic EFI to cervical cancer patients with common iliac lymph nodes metastasis. Clinical trials are needed to investigate whether patients with ≥3 positive pelvic lymph nodes and FIGO stage IIIB disease can benefit from prophylactic EFI. According to the distribution of PALNs, it is reasonable to use the renal vein as the upper border of the radiation therapy field for patients treated with prophylactic EFI. The clinical target volume expansion of the node from the vessel should be smaller in the right para-caval region than in the left lateral para-aortic region. The right para-caval region above L2 or L3 may be omitted from the PALN target volume to reduce the dose to the duodenum. More clinical trials on prophylactic EFI in cervical cancer are needed.

Risk factors associated with Para-Aortic Lymph Node Failure after pelvic irradiation in patients with Cervical Cancer.

Objective: Previous studies have shown that prophylactic extended-field irradiation can reduce para-aortic lymph node failure (PALNF) rates in patients with cervical cancer. As such, this type of irradiation may particularly benefit patients with a high risk of PALNF. In the present study, we analyzed the risk factors for PALNF in patients with cervical cancer treated with pelvic irradiation in order to identify potential indications of prophylactic extended-field irradiation. Methods: We evaluated patients with 2018 FIGO stage IB3-IIIC1 cervical cancer who were treated with definitive pelvic radiotherapy or concurrent chemoradiotherapy at our institution between 2011 and 2014. Univariate and multivariate analyses were performed to identify risk factors for PALNF. Results: We included 572 patients in the study. The median follow-up period was 37.9 months. Eighteen patients (3.1%) first site of tumor relapse was the para-aortic lymph nodes, and thus showed PALNF. Using multivariate Cox regression analysis, we identified two significant risk factors for PALNF: tumor extension to the pelvic wall (hazard ratio, HR 3.60, p=0.026) and ≥ 2 pelvic MLNs (HR 5.30, p=0.005). For patients with and without risk factors, the 3-year overall survival, disease-free survival, and PALNF rates were 77.3% and 90.1% (p<0.001), 56.4% and 83.1% (p<0.001), and 12.0% and 2.3% (p<0.001), respectively. Conclusion: Tumor extension to the pelvic wall and ≥ 2 pelvic MLNs are positively associated with PALNF after pelvic irradiation in patients with cervical cancer. Further trials will be required to validate whether patients with these two risk factors may benefit from prophylactic extended-field irradiation.

Correction to: Expression of the immune checkpoint VISTA in breast cancer.

The original version of this article unfortunately contained a mistake. The correct information is given below.

Expression and Significance of Immune Checkpoints in Clear Cell Carcinoma of the Uterine Cervix.

The purpose of this study was to investigate the expression levels of the immune checkpoint proteins, programmed cell death-ligand 1 (PD-L1), B7-H3, B7-H4, and V-domain Ig suppressor of T cell activation (VISTA), as well as the significance thereof, in clear cell carcinoma (CCC) of the cervix (a rare histological subtype of cervical cancer). We also compared the expression statuses of these biomarkers in cervical CCCs with those in cervical squamous cell carcinomas (SCCs). We evaluated the expression of PD-L1, B7-H3, B7-H4, and VISTA in 50 cervical CCCs and 100 SCCs using immunohistochemical staining and investigated the associations between these markers, clinicopathologic features, and survival in patients with CCCs. Of the cervical CCC samples examined, 22%, 16%, 32%, and 34% were positive for PD-L1, B7-H3, B7-H4, and VISTA, respectively. Nineteen samples (38%) were negative for all 4 of these markers, whereas 31 (62%) expressed at least 1 marker. None of these markers was associated with the investigated clinicopathologic variables or patient survival. PD-L1, B7-H3, and VISTA were observed significantly more frequently in SCCs than in CCCs of the cervix. Our study confirmed the expression of immune checkpoint proteins in cervical CCCs and indicated their nonredundant and complementary roles. As such, our data suggest that monotherapeutic immune checkpoint blockade may not be sufficiently effective in patients with cervical CCC.

Expression of the immune checkpoint VISTA in breast cancer.

V-domain Ig suppressor of T cell activation (VISTA) is a novel immune checkpoint that is an emerging target for cancer immunotherapy. This study aimed to investigate the expression of VISTA and its association with clinicopathologic parameters as well as with the key immune markers including programmed cell death-1 (PD-1) and PD-1 ligand-1 (PD-L1) in invasive ductal carcinoma (IDC) of the breast [corrected]. Immunohistochemistry was used to detect VISTA, PD-1, PD-L1, and CD8 in tissue microarrays from 919 patients with IDC (N = 341 in the exploratory cohort and = 578 in the validation cohort). VISTA was expressed on the immune cells of 29.1% (267/919) of the samples and on the tumor cells of 8.2% (75/919). VISTA was more frequently expressed in samples that were estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor 2-positive, poorly differentiated, human epidermal growth factor receptor 2-enriched, and consisting of basal-like tumors. VISTA on immune cells correlated with PD-1, PD-L1, stromal CD8, and tumor-infiltrating lymphocyte expression and was an independent prognostic factor for improved relapse-free and disease-specific survival in patients with estrogen receptor-negative, progesterone receptor-negative, and basal-like IDC. These findings support therapeutic strategies that modulate VISTA expression, perhaps in combination with PD-1/PD-L1 blockade, in human breast cancer immunotherapy.

VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer.

Blockading programmed death ligand 1 (PD-L1) shows promising results in patients with some cancers, but not in those with ovarian cancer. V-domain Ig suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint protein that suppresses T cell activation. This study aimed to investigate the expression and clinical significance of VISTA in ovarian cancer as well as its relationship with PD-L1. VISTA and PD-L1 levels in 146 ovarian cancer samples were assessed using immunohistochemistry. We investigated the association between VISTA and other clinicopathological variables, including survival. The associations between the VISTA-encoding C10orf54 gene, other immune checkpoints, and survival were analyzed. VISTA was detected in 51.4% of all samples and 46.6% of PD-L1-negative samples; it was expressed in 28.8%, 35.6%, and 4.1% of tumor cells (TCs), immune cells (ICs), and endothelial cells, respectively. Furthermore, VISTA expression was associated with pathologic type and PD-L1 expression. Moreover, VISTA expression in TCs, but not in ICs, was associated with prolonged progression-free and overall survival in patients with high-grade serous ovarian cancer. The expression of C10orf54 mRNA was associated with prolonged overall survival and immune escape-modulating genes. These results showed that VISTA expression in ovarian tumor cells was associated with a favorable prognosis in patients with high-grade serous ovarian cancer; however, additional studies are required to better understand the expression and role of VISTA in ovarian cancer.

The tumor-stroma ratio is an independent predictor of survival in patients with 2018 FIGO stage IIIC squamous cell carcinoma of the cervix following primary radical surgery.

OBJECTIVE: To determine the value of the tumor-stroma ratio (TSR) while identifying prognostic factors in patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IIIC squamous cell carcinoma of the cervix following primary radical surgery. METHODS: Three hundred eighty-four patients with node-positive squamous cell carcinoma of the cervix (2018 FIGO stage IIIC) who underwent radical surgery between January 2005 and December 2016 were included in this retrospective study. The TSRs were assessed on hematoxylin and eosin-stained tumor slides and classified as stroma-low (<50% stroma) or stroma-high (≥50% stroma). RESULTS: Sixty-seven patients were categorized as stroma-high; they had shorter disease-free survival (DFS) and overall survival (OS) periods than did their stroma-low counterparts. On multivariate analysis, a tumor size ≥4 cm, ≥3 metastatic lymph nodes, and stroma-high status were independent predictors of shorter DFS and OS. These factors were incorporated into a prognostic scoring system in which patients were categorized into low- (score 0), intermediate- (score 1), and high-risk (scores 2-3) groups. The scoring system differentiated DFS and OS well (C-index = 0.65, 95% confidence interval, 0.59-0.72; and C-index = 0.65, 95% confidence interval, 0.59-0.72, respectively). CONCLUSIONS: The TSR is an independent prognostic factor, and our prognostic scoring system that incorporates this parameter exhibits good discriminative ability for both recurrence and survival in patients with 2018 FIGO stage IIIC cervical cancer after radical surgery. The TSR is a potentially novel clinicopathological variable for predicting the prognoses of these patients contingent on the validation of our findings.

Extralobar pulmonary sequestration with absence of pericardium and atrial septal defect in a woman.

BACKGROUND: Extralobar sequestration is a rare congenital malformation of lung tissue, which can be combined with other foregut and cardiac abnormalities. Our case is the first to report extralobar sequestration, absence of pericardium and atrial septal defect in the same patient. CASE PRESENTATION: A 22-year-old female with atrial septal defect came for her recent atypical symptom of intermittent palpitation and shortness of breath. Her computed tomography showed a cystic mass located in left superior anterior mediastinum near the pulmonary trunk. With specious of cystic teratoma prior to video-assisted thoracoscopic surgery, she finally was diagnosed as extralobar sequestration, while incidentally found with congenital absence of pericardium during surgery. CONCLUSIONS: Extralobar sequestration, absence of pericardium and atrial septal defect can occur in the same patient. The preoperative diagnostic rate of extralobar sequestration and asymptomatic absence of pericardium remains low attributed to atypical imaging features. A cardiac magnetic resonance imaging is highly recommended if necessary. Regular follow-up is essential to asymptomatic absence of pericardium and atrial septal defect patients. To patients with extralobar sequestration, an operation could be performed.