Prognostic nutritional index and neutrophil-lymphocyte ratio predict toxicities and prognosis in patients with cervical cancer treated with curative radiochemotherapy.

BACKGROUND: This study aimed to investigate the influence of immunonutritional factors on treatment-related toxicities and survival outcomes in patients with cervical cancer undergoing definitive radiochemotherapy. METHODS: Patients with cervical cancer who received curative radiochemotherapy between 2016 and 2021 were retrospectively investigated. Pretreatment prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) were measured. Survival outcomes, acute and late toxicities were evaluated. RESULTS: Among the 138 patients, those with larger tumor diameters had significantly lower pre-treatment PNI (p = 0.005). Pre-treatment immunonutritional factors were predictive of clinical survival, whereas post-treatment factors did not correlate with prognosis. Patients with low pre-treatment PNI (<49.5) or high NLR (>2.4) had shorter progression-free survival (PFS, HR: 1.86, p = 0.045 for PNI; HR: 3.15, p = 0.002 for NLR) and overall survival (OS, HR: 1.80, p = 0.048 for PNI; HR: 3.83, p = 0.015 for NLR). High pre-treatment NLR was associated with an increased risk of acute diarrhea (p = 0.049) and late severe toxicities (p = 0.046). Combined analysis revealed that pre-treatment good nutritional status and low systemic inflammation were linked to longer PFS (p = 0.007) and OS (p = 0.002), and poor nutritional status and substantial systemic inflammation were associated with higher rates of late severe toxicities (p = 0.036), with higher prognostic value in advanced stage patients. CONCLUSIONS: Pretreatment immunonutritional measures serve as quantitative biomarkers for predicting survivals and treatment toxicities in patients with cervical cancer treated with definitive radiochemotherapy.

Outcomes after fertility-sparing surgery of early-stage ovarian cancer: A nationwide population-based study.

BACKGROUND: Fertility-sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early-stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. METHODS: A total of 1297 patients aged between 20 and 44 years with newly diagnosed early-stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site-specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier method with log-rank test and Cox regression model. RESULTS: There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high-grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66-1.77, p = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06-0.82, p = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. CONCLUSION: FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.

Primary spontaneous inguinal endometriosis: Two cases with emphasis on the diagnostic approach.

OBJECTIVE: While endometriosis is common, inguinal endometriosis with hernia is rarely observed, making its preoperative diagnosis challenging. CASE REPORT: We report two cases of inguinal endometriosis with different presentations and focus on tailored surgical treatment. The two patients in our series presented with painful swelling in the right groin area. Surgery and pathological examination confirmed the diagnosis of endometriosis in both cases. Herniorrhaphy and excision of the extraperitoneal round ligament were performed in one patient with concomitant inguinal endometriosis and indirect inguinal hernia. CONCLUSION: We highlight the importance of the preoperative evaluation of concomitant pelvic endometriosis, round ligament involvement, and endometriosis within the inguinal hernia sac. Inguinal endometriosis with or without hernia should be considered even in reproductive-aged women without a previous medical and surgical history. Postoperative hormonal therapy, including dienogest, can be considered to prevent disease recurrence.

Nontuberculous mycobacterial infection mimicking gynecologic malignancy in a woman living with HIV.

The weakened immune system in people living with HIV (PLWH) can lead to infectious diseases occurring more aggressively and mimicking the clinical manifestations of malignancies. Mycobacterium sherrisii, a slow-growing nontuberculous mycobacterium, may cause opportunistic infections among PLWH. We present a case of a 41-year-old woman who initially presented with fever, vaginal spotting, and a bulky pelvic mass, raising suspicion of uterine malignancy. Following a surgical resection, she was pathologically diagnosed with leiomyoma and endometriosis. However, during an event of needlestick injury, she was unexpectedly found to be HIV-infected and the CD4 count was 157 cells/µL at diagnosis, which prompted a diagnostic work-up for opportunistic infections. The diagnosis of disseminated M. sherrisii infection was confirmed through cultures and special staining of specimens obtained from the pelvic tumor and blood. Subsequently, she was treated with a combination of ethambutol, azithromycin, and levofloxacin. Two months after treatment, abdominal and pelvic computed tomography revealed no evidence of recurrent tumor or abscess formation. Given the frequent association of pelvic masses with gynecologic malignancies in women living with HIV, it can be challenging to differentiate between a cancerous lesion and an infectious process, emphasizing the need for meticulous investigations to minimize the potential for misdiagnosis.

Age-specific trend and birth cohort effect on different histologic types of uterine corpus cancers.

To evaluate the uterine corpus cancer incidence rates, age-specific trends, and birth cohort patterns by different histologic types. We conducted a retrospective cohort study of uterine cancer patients (n = 28,769) of all ages from the National Cancer Registry of Taiwan between 1998 and 2017. We estimated the incidence trends, average annual percent changes (AAPCs), and cancer-specific survival (CSS) rate for the two main subtypes (endometrioid and nonendometrioid) of uterine cancer in Taiwan. During the study period, uterine corpus cancer incidence rates increased over time from 5.3 to 15.21 per 100,000 women. Incidence trends for endometrioid carcinoma increased in all age groups (positive AAPCs > 5% for each age group), and the rise was steeper among women aged 50 years and younger. For nonendometrioid carcinomas, incidence rates increased among women over 50 years. The CSS rate improved among women with stage I (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49-0.81) and stage III (HR 0.72, 95% CI 0.58-0.90) endometrioid carcinomas after 2013 compared with those during 2009-2012. However, the CSS rate remained unchanged for nonendometrioid carcinomas. Age, diagnostic period, stage and histologic types were significant factors associated with the 5-year CSS rate. We found that the incidences of both endometrioid and nonendometrioid carcinomas continued to increase among contemporary birth cohorts. Etiologic research is needed to explain the causes of these trends.

Outcome and prognostic factors of unexpected ovarian carcinomas.

BACKGROUND: We investigated risk factors influencing the outcome of unexpected ovarian carcinomas. METHODS: We reviewed the ovarian carcinoma patients treated at atertiary medical institution between 2000 and 2017 and analyze the clinico-pathological characteristics, treatment strategies, recurrence status, and outcome. RESULTS: A total of 112 women (65 primary laparoscopic surgery [LSC] and 47 laparotomic surgery [LAPA]) were included in the analysis. The LSC group had smaller ovarian tumors (10.5 ± 7.3 cm vs. 16.6 ± 8.7 cm, p = 0.031) and higher incidence of subsequent staging surgery (56.9% vs. 25.5%, p = 0.0001) compared to the LAPA group. There were 98/112 (86.6%) of early stages (I/II) diseases. The difference between the recurrent rate (27.7% vs. 31.9%), disease-free survival (DFS), and overall survival (OS) were not significant among surgical groups. In the multivariate analysis, FIGO stage (stage II hazard ratio [HR] 6.61, p = 0.007; stage III HR 8.40, p = 0.002) was the only prognostic factor for DFS. FIGO stage (stage II HR 20.78, p = 0.0001; stage III HR 7.99, p = 0.017), histological type (mucinous HR 12.49, p = 0.036), and tumor grade (grade 3 HR 35.01, p = 0.003) were independent prognostic factors for OS, while women with latency >28 days from primary to staging surgery had significantly poorer OS (p = 0.008). Women with latency >28 days between primary surgery and adjuvant chemotherapy had similar DFS (p = 0.31) and a trend of poorer OS (p = 0.064). CONCLUSIONS: The prognosis of unexpected ovarian cancer is independent from the primary surgical procedure and comprehensive staging surgery should be performed at close proximity after the diagnosis of unexpected ovarian malignancy.

Overexpression of transmembrane protein 102 implicates poor prognosis and chemoresistance in epithelial ovarian carcinoma patients.

Most ovarian cancer patients experience disease recurrence and chemotherapeutic resistance, and the underlying mechanisms are unclear. Identifying relevant pathways could reveal new therapeutic targets. Here we examined expression of transmembrane protein 102 (TMEM102), a biomarker of prognosis and chemoresistance, in epithelial ovarian cancer (EOC), and assessed its role in inhibiting tumor cell apoptosis. We performed qRT-PCR to investigate the association of TMEM102 expression with clinical outcomes in 226 EOC patients. We also conducted in vitro studies to explore possible mechanisms through which TMEM102 may influence chemoresistance, including the effects of downregulating TMEM102 expression with small interfering RNA. Serous and high-grade carcinomas expressed significantly higher TMEM102 than normal ovarian tissues. TMEM102 was also overexpressed in patients with advanced-stage disease and chemoresistance. Reduction of TMEM102 expression by small interfering RNA induced ovarian cancer cell apoptosis after cytotoxic treatment. TMEM102 overexpression enhanced chemoresistance via upregulation of heat shock proteins 27, 60, and 70; and survivin, resulting in decreased cytochrome c in the mitochondria and decreased caspase 9 expression. Our results indicate that TMEM102 overexpression may promote chemoresistance via inhibition of a mitochondria-associated apoptotic pathway.

Preoperative magnetic resonance imaging predicts clinicopathological parameters and stages of endometrial carcinomas.

BACKGROUND: We investigated the agreement and accuracy of preoperative magnetic resonance imaging (MRI) with postoperative pathological characteristics and stages of endometrial endometrioid carcinoma (EEC). METHODS: We recruited 527 women with EEC who underwent staging surgery at a single medical institution. The preoperative MRI, stages, and clinical and pathological parameters, including myometrial invasion (MI), cervical invasion (CI), adnexal metastasis (AM), intra-abdominal metastasis, and pelvic and/or para-aortic nodal metastasis, were recorded and analyzed. The agreement and accuracy between the preoperative MRI findings and these parameters and stages were assessed. RESULTS: The rate of the preoperative MRI-based clinical stage matching the postoperative surgical stage was 85.2% in International Federation of Gynecology and Obstetrics stage IA, 51.9% in stage IB, 35.5% in stage II, 5.3% in stage IIIA, 33.3% in stage IIIB, 28.6% in stage IIIC1, 64.3% in stage IIIC2, and 93.8% in stage IVB. The consistency between radiologists and pathologists was 80.5% for deep MI, 91.5% for cervical invasion, 92.2% for adnexal metastasis, 98.9% for intra-abdominal metastasis, and 87.5% and 92.2% for pelvic and para-aortic nodal metastases, respectively. The negative predictive value of intra-abdominal metastasis was the highest with 99.8%. CONCLUSIONS: Preoperative MRI could be an excellent tool for routine preoperative assessment to predict pathological parameters and stages of EEC, especially in excluding intra-abdominal metastatic disease.

Ovarian cancer risk score predicts chemo-response and outcome in epithelial ovarian carcinoma patients.

OBJECTIVE: Cytoreductive surgery followed by adjuvant chemotherapy is a standard frontline treatment for epithelial ovarian cancer (EOC). We aimed to develop an ovarian cancer risk score (OVRS) based on the expression of 10 ovarian-cancer-related genes to predict the chemoresistance, and outcomes of EOC patients. METHODS: We designed a case-control study with total 149 EOC women including 75 chemosensitives and 74 chemoresistants. Gene expression was measured using the quantitative real-time polymerase chain reaction. We tested for correlation between the OVRS and chemosensitivity or chemoresistance, disease-free survival (DFS), and overall survival (OS), and validated the OVRS by analyzing patients from the TCGA database. RESULTS: The chemosensitive group had lower OVRS than the chemoresistant group (5 vs. 15, p≤0.001, Mann-Whitney U test). Patients with disease relapse (13 vs. 5, p<0.001, Mann-Whitney U test) or disease-related death (13.5 vs. 6, p<0.001) had higher OVRS than those without. OVRS ≥10 (hazard ratio=3.29; 95% confidence interval=1.94-5.58; p<0.001) was the only predictor for chemoresistance in multivariate analysis. The median DFS (5 months vs. 24 months) and OS (39 months vs. >60 months) of patients with OVRS ≥10 were significantly shorter than those of patients with OVRS <10). The high OVRS group also had significantly shorter median OS than the low OVRS group in 255 patients in the TCGA database (39 vs. 49 months, p=0.046). CONCLUSIONS: Specific genes panel can be clinically applied in predicting the chemoresistance and outcome, and decision-making of epithelial ovarian cancer.

Factors Influencing the Discordancy Between Intraoperative Frozen Sections and Final Paraffin Pathologies in Ovarian Tumors.

AIM: To retrospectively investigate the pre-operative clinical factors and ultrasonographic features that influence the accuracy of the intraoperative frozen section (IFS) of ovarian tumors. PATIENTS AND METHODS: Women with ovarian tumors that underwent IFS in one tertiary medical center were recruited from January 2010 to December 2018. Demographic and clinical data of these women were retrieved from medical records in the hospital's centralized database. RESULTS: A total of 903 ovarian tumors were enrolled, including 237 (26.2%) benign, 150 (16.6%) borderline tumor, and 516 (57.2%) malignant. The overall accuracy of IFS among all specimens was 89.9%. The sensitivities of IFS in diagnosing borderline tumors (82.0%) and malignant tumors (88.2%) were lower than in diagnosing benign tumors (98.7%, p <0.001, Z-test). The specificity of diagnosing malignant tumors (99.7%) was significantly higher than that of diagnosing benign tumors (94.7%, p <0.001, Z-test). The group with discordant IFS and final paraffin pathology (FPP) had younger age (47.2 ± 14.0 vs. 51.5 ± 11.8 years, p = 0.013, Mann-Whitney U test), and higher percentage of early-stage disease (85.2% vs. 65.1%, p = 0.001, chi-square test) and mucinous (39.3% vs. 3.3%) and endometrioid histologic types (34.4% vs. 20.2%) than the concordant group (all by chi-square test). Menopause (OR 0.34, 95% CI 0.15-0.76, p = 0.009), multicystic tumor in ultrasound (OR 2.14, 95% CI 1.14-4.01, p = 0.018), and ascites existence (OR 0.33, 95% CI 0.14-0.82, p = 0.016) were factors related to the discordant IFS by multivariate analysis. CONCLUSIONS: IFS has good accuracy in the diagnosis of ovarian tumors. We recommend more frozen tissue sampling for sonographic multicystic tumors in premenopausal women to improve the accuracy of IFS.

A DNA Damage Response Gene Panel for Different Histologic Types of Epithelial Ovarian Carcinomas and Their Outcomes.

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.

Increased risk of second primary malignancies among endometrial cancer survivors receiving surgery alone: A population-based analysis.

BACKGROUND: Women with endometrial cancer (EC) have favorable prognoses, leaving them vulnerable to the development of second primary cancers (SPCs). We investigated the SPC risk and survival outcomes among EC patients treated with surgery alone in order to exclude the impact of adjuvant treatment on the results. METHODS: Data from the Taiwan Cancer Registry from 1995 to 2013 were analyzed. Standardized incidence ratios (SIRs) of SPCs among EC survivors were calculated. RESULTS: Among 7725 women enrolled, 478 developed an SPC. The overall SIR for SPCs in EC survivors was 2.84 (95% confidence interval [CI] 2.59-3.10) compared with the general female population. Women diagnosed with EC at age <50 years had a higher SIR for an SPC than those diagnosed at age ≥50 years (SIR = 4.38 vs. 1.28). The most frequent site of an SPC was the small intestine (SIR = 8.39, 95% CI 2.72-19.58), followed by the kidney (SIR = 4.84, 95% CI 1.78-10.54), and oral cavity (SIR = 4.52, 95% CI 2.17-8.31). Women, regardless of age at EC diagnosis, had significantly higher SIRs for subsequent breast, colorectal, lung, and thyroid cancer, and lymphoma. Women with an SPC had shorter overall survival than those without (5-year: 88.9 vs. 94.2%, 10-year: 71.3 vs. 89.8%, 15-year: 62.3 vs. 86.1%, and 20-year: 47.6 vs. 81.1%, all ps<0.001). CONCLUSIONS: Even women treated for EC with surgery alone, especially young EC survivors, had an increased risk of SPCs. Genetic counseling/testing is recommended for young EC patients, and all are recommended to receive regular surveillance and screening for breast, colorectal, and lung cancers.

Outcome and Subsequent Pregnancy after Fertility-Sparing Surgery of Early-Stage Cervical Cancers.

We aimed to investigate the outcomes and subsequent pregnancies of early-stage cervical cancer patients who received conservative fertility-sparing surgery. Women with early-stage cervical cancer who underwent conservative or fertility-sparing surgery in a tertiary medical center were reviewed from 2004 to 2017. Each patient's clinicopathologic characteristics, adjuvant therapy, subsequent pregnancy, and outcome were recorded. There were 32 women recruited, including 12 stage IA1 patients and 20 stage IB1 patients. Twenty-two patients received conization/LEEP and the other 10 patients received radical trachelectomy. Two patients did not complete the definite treatment after fertility-sparing surgery. There were 11 women who had subsequent pregnancies and nine had at least one live birth. The live birth rate was 73.3% (11/15). We conclude that patients with early-stage cervical cancer who undergo fertility-sparing surgery can have a successful pregnancy and delivery. However, patients must receive a detailed consultation before surgery and undergo definitive treatment, if indicated, and regular postoperative surveillance.

Impact of Adjuvant Modalities on Survival in Patients with Advanced Stage Endometrial Carcinoma: A Retrospective Analysis from a Tertiary Medical Center.

Adjuvant treatment in advanced-stage (stages III /IV) endometrial carcinomas in terms of tumor grades has not yet been explored. We retrospectively analyzed 194 patients with advanced-stage endometrioid endometrial carcinoma who received surgery, followed by adjuvant therapy, at National Taiwan University Hospital between January 1, 2000 and August 31, 2017. Adjuvant therapies included radiation (RT), chemotherapy alone (CT), and combined modality treatment (CMT: radiation and chemotherapy). The prognostic factors were determined from multivariate survival analyses using Cox regression models. Progression-free survival (PFS) and overall survival (OS) times were estimated with the Kaplan-Meier method. The median follow-up was 45.5 months (range: 6.2-207.9). In grade 1/2 endometrioid carcinoma, neither adjuvant CT nor CMT could prolong PFS significantly compared to RT (CT: HR 1.59, 95% CI 0.64-3.97; CMT: HR 2.03, 95% CI 0.72-5.74). Notably, maximal cytoreduction independently improved PFS (HR 0.31, 95% CI 0.10-0.90). No particular adjuvant treatment provided an OS advantage over the others for grade 1/2 endometrioid carcinomas. However, for grade 3 endometrioid carcinoma, CMT showed OS benefits (HR 0.15, 95% CI 0.03-0.89) compared to RT and CT. In conclusion, maximal cytoreduction should be the goal in patients with grade 1/2 advanced-stage endometrioid carcinomas. Based on our results, patients with grade 3 endometrioid carcinomas might benefit from adjuvant CMT.

CHI3L1 results in poor outcome of ovarian cancer by promoting properties of stem-like cells.

The role of chitinase-3-like protein 1 (CHI3L1) in ovarian cancer and the possible mechanisms were elucidated. CHI3L1 is a secreted glycoprotein and associated with inflammation, fibrosis, asthma, extracellular tissue remodeling and solid tumors. Our previous study showed CHI3L1 could be a potential prognostic biomarker for epithelial ovarian cancer and could protect cancer cells from apoptosis. Therefore, clinical data and quantitation of CHI3L1 of ovarian cancer patients, tumor spheroid formation, side-population assays, Aldefluor and apoptotic assays, ELISA, RT-PCR, immunoblotting and animal experiments were performed in two ovarian cancer cells lines, OVCAR3 and CA5171, and their CHI3L1-overexpressing and -knockdown transfectants. High expression of CHI3L1 was associated with poor outcome and chemoresistance in ovarian cancer patients. The mRNA expression of CHI3L1 in CA5171 ovarian cancer stem-like cells was 3-fold higher than in CA5171 parental cells. CHI3L1 promoted the properties of ovarian cancer stem-like cells including generating more and larger tumor spheroids and a higher percentage of ALDH+ in tumor cells and promoting resistance to cytotoxic drug-induced apoptosis. CHI3L1 could induce both the Akt (essential) and Erk signaling pathways, and then enhance expression of ß-catenin followed by SOX2, and finally promote tumor spheroid formation and other properties of ovarian cancer stem-like cells. OVCAR3 CHI3L1-overexpressing transfectants were more tumorigenic in vivo, whereas CA5171 CHI3L1-knockdown transfectants were not tumorigenic in vivo. CHI3L1 critically enhances the properties of ovarian cancer stem-like cells. CHI3L1 or CHI3L1-regulated signaling pathways and molecules could be potential therapeutic targets in ovarian cancer.

Bevacizumab Dose Affects the Severity of Adverse Events in Gynecologic Malignancies.

In this retrospective study, we investigated adverse events and outcomes in patients treated with bevacizumab for ovarian, fallopian tube, or primary peritoneal cancers at a single hospital. We determined the cumulative incidences of various bevacizumab-related adverse events and the correlation between dose and adverse event incidences. We analyzed data from 154 patients that received 251 rounds of bevacizumab as first-line, first salvage, >2 salvage treatments. Adverse events of any grade were observed in 121 (78.6%) patients; at least one grade 3 or 4 adverse event occurred in 32 (20.8%) patients. The two most common events were proteinuria (38.3%) and hypertension (33.8%). The first-line treatment group displayed significantly higher frequencies of hypertension (52.7% vs. 18.9% vs. 15.5%, p < 0.001), wound complications (9.1% vs. 0% vs. 1.2%, p = 0.010), arthralgia (29.1% vs. 11.3% vs. 8.3%, p = 0.003), and reduced range of joint motion (14.5% vs. 5.7% vs. 3.6%, p = 0.046), compared to those in the first and >2 lines salvage groups, respectively (Kruskal-Wallis test). The cumulative incidences of all grades and grades 3/4 of hypertension cumulative incidence plateaued at around 30% for all grades and 10% for grades 3 and 4, at bevacizumab doses above 8080 and 3510 mg, respectively. The proteinuria cumulative incidence plateaued at around 35% for all grades and 3% for grades 3 and 4, at bevacizumab doses above 11,190 and 4530 mg, respectively. We concluded that, in this realistic clinical population, different kinds and higher cumulative incidences of adverse events were observed compared to those reported in previous clinical trials. Moreover, bevacizumab doses showed cumulative toxicity and plateau effects on hypertension and proteinuria.

Immune checkpoint Ab enhances the antigen-specific anti-tumor effects by modulating both dendritic cells and regulatory T lymphocytes.

We determined the anti-tumor effects and possible mechanisms of an antigen-specific DNA vaccine combined with PD-1 or CTLA-4 blockade. Using the HPV16 E6/E7+ syngeneic mouse tumor model, we investigated whether anti-CTLA-4 antibody (Ab) or anti-PD-1 Ab increases the antigen-specific anti-tumor effects and immune response induced by CTGF/E7 chimeric DNA vaccine and the possible mechanisms. Anti-PD-1 Ab or anti-CTLA-4 Ab combined with E7-specific DNA vaccine generated more potent antigen-specific immunity, including anti-E7 Abs and the number and cytotoxic activity of E7-specific cytotoxic CD8+ T lymphocytes, and anti-tumor effects than E7-specific DNA vaccine alone. In addition, the number of systemic and intratumoral Tregs was lower with the anti-PD-1 or anti-CTLA-4 Ab and E7-specific DNA vaccine. Furthermore, anti-PD-1 and anti-CTLA-4 Abs could enhance the maturation and abilities of intratumoral DCs to activate E7-specific cytotoxic CD8+ T cells. Immune checkpoint blockade overcomes the immunosuppressive status of the tumor-microenvironment to enhance the antigen-specific immunity and anti-tumor effects generated by an antigen-specific DNA vaccine. Antigen-specific immunotherapy combined with immune checkpoint blockade can be a novel strategy in clinical cancer therapy.

Blockade of PD-L1 Enhances Cancer Immunotherapy by Regulating Dendritic Cell Maturation and Macrophage Polarization.

The immuno-inhibitory checkpoint PD-L1, regulated by tumor cells and antigen-presenting cells (APCs), dampened the activation of T cells from the PD-1/PD-L1 axis. PD-L1-expressing APCs rather than tumor cells demonstrated the essential anti-tumor effects of anti-PD-L1 monotherapy in preclinical tumor models. Using the murine tumor model, we investigated whether anti-PD-L1 antibody increased the antigen-specific immune response and anti-tumor effects induced by the antigen-specific protein vaccine, as well as the possible mechanisms regarding activation of APCs. Anti-PD-L1 antibody combined with the PEK protein vaccine generated more potent E7-specific immunity (including the number and cytotoxic activity of E7-specific cytotoxic CD8+ T lymphocytes) and anti-tumor effects than protein vaccine alone. Anti-PD-L1 antibody enhanced the maturation of dendritic cells and the proportion of M1-like macrophages in tumor-draining lymph nodes and tumors in tumor-bearing mice treated with combinatorial therapy. PD-L1 blockade overturned the immunosuppressive status of the tumor microenvironment and then enhanced the E7 tumor-specific antigen-specific immunity and anti-tumor effects generated by an E7-specific protein vaccine through modulation of APCs in an E7-expressing small tumor model. Tumor-specific antigen (like HPV E7 antigen)-specific immunotherapy combined with APC-targeting modality by PD-L1 blockade has a high translational potential in E7-specific cancer therapy.

Factors predicting parametrial invasion in patients with early-stage cervical carcinomas.

We aimed to identify factors predicting parametrial invasion in early-stage cervical cancer patients undergoing radical hysterectomy. We recruited women with invasive cervical cancer who underwent radical hysterectomy at a single medical institute from 2000-2011. The clinical and pathological characteristics and outcomes were retrospectively recorded, and the risk factors for parametrial invasion were analyzed. We enrolled 339 patients, including 7 with stage IA1 carcinomas, 10 with stage IA2, 266 with stage IB1, 39 with stage IB2, 14 with stage IIA1, and 3 with stage IIA2. The majority (237/339, 69.9%) had squamous cell carcinoma, while 32 (12.4%) had parametrial invasion. The 16 patients with stage IB1 tumors and parametrial invasion were older (55.9±9.5vs. 49.0±9.9 years, p = 0.005, Mann-Whitney U test), and had deeper cervical stromal invasion (9.59±4.87 vs. 7.47±5.48 mm, p = 0.048, Mann-Whitney U test), larger tumor size (2.32±1.15 vs. 1.74±1.14cm, p = 0.043, Mann-Whitney U test), higher incidences of lymphovascular space invasion (87.5% vs. 28.8%, p<0.001, chi-square test), and greater lymph node metastasis (68.8% vs. 10.8%, p<0.001, chi-square test) than the 260 patients without parametrial invasion. Among the patients with stage IB1 tumor size >2 cm,10% had parametrial invasion and 24.2% had lymph node metastasis compared with only 4% and 9.4% of stage IB1 patients with a tumor size <2 cm, respectively. Only one (0.9%) of the 109 patients aged less than 50 years had parametrial invasion compared with 6 (9.7%) of the 62 patients aged over 50 years. Patients with stage IA2 and IB1 tumors <2 cm may not need radical hysterectomy owing to the low incidence of parametrial invasion.

Risks of cervical intraepithelial neoplasia grade 3 or invasive cancers in ASCUS women with different management: a population-based cohort study.

OBJECTIVE: To investigate the progression risk of atypical squamous cells of undetermined significance (ASCUS) with different clinical managements. METHODS: Women with their first diagnosis of ASCUS cytology were retrieved from the national cervical cancer screening database and linked to the national health insurance research database to identify the management of these women. The incidences of developing cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+) were calculated, and the hazard ratios (HRs) were estimated using a Cox proportional hazards model. This study was approved by the Research Ethics Committee of the National Taiwan University Hospital and is registered at ClinicalTrials.gov (Identifier: NCT02063152). RESULTS: There were total 69,741 women included. Various management strategies including colposcopy, cervical biopsies and/or endocervical curettage, and cryotherapy, failed to reduce the risk of subsequent CIN3+ compared with repeat cervical smears. Loop electrosurgical excision procedure/conization significantly decreased risk of subsequent CIN3+ lesions (HR=0.22; 95% confidence interval [CI]=0.07-0.68; p=0.010). Women in their 40s-50s had an approximately 30% risk reduction compared to other age groups. Women with a previous screening history >5 years from the present ASCUS diagnosis were at increased risk for CIN3+ (HR=1.24; 95% CI=1.03-1.49; p=0.020). CONCLUSION: In women of first-time ASCUS cytology, a program of repeat cytology can be an acceptable clinical option in low-resource settings. Caution should be taken especially in women with remote cervical screening history more than 5 years.