bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of trial-eligibility as factor for clinical outcome of patients with renal cell carcinoma treated with first-line pazopanib: Subgroup analysis from the prospective, non-interventional study PAZOREAL.
Authors: Schostak Martin , Boegemann Martin , Goebell Peter J. , Gruenwald Viktor , Welslau Manfred , Ehness Rainer , Degenkolbe Elisa , Witecy Stefanie , Doehn Christian
Published: June 2022

e16511

Background: In a real-world setting, a substantial number of patients (pts) with metastatic renal cell carcinoma (mRCC) do not meet all eligibility criteria for a clinical trial. Thus, data on effectiveness and safety of 1st-line (1L) treatment with pazopanib (PAZO) as well as quality of life (QoL) is underrepresented for those pts and data on treatment sequences implementing PAZO as 1L are sparse. Methods: PAZOREAL is a prospective, multi-center, non-interventional study to evaluate effectiveness, safety and QoL in pts with mRCC treated with 1L PAZO, and nivolumab (NIVO) or everolimus in second and third line. In this subgroup analysis, the clinical outcome of trial-eligible (TE) and trial-ineligible (TIE) pts with mRCC was assessed by means of overall survival (OS), time on drug (ToD), treatment-emergent adverse events (TEAE) and QoL evaluated by EQ-5D-5L. Pts were rated TIE if they met at least one of the following three ‘TIE criteria’: (i) Karnofsky Performance Status < 70%, (ii) hemoglobin below the lower limit of normal, and (iii) non-clear cell carcinoma1. Results: Of 398 pts treated between December 2015 and February 2021, 376 pts received 1L treatment with PAZO. The median age was 69.7 years. 146 pts were categorized TE and 184 pts TIE, for 46 pts assessment was not applicable. Most of all pts were initially treated with PAZO 800 mg (TE: 71.9% vs TIE: 63.0%). Median ToD for PAZO was 7.7 months (95% CI 6.1-9.0) for TE and 6.0 months (95% CI 4.5-8.1) for TIE. A similar fraction of TE and TIE pts were treated with 2L NIVO (43.8% vs 44.0%). Median OS was 53.2 months (95% CI 38.9-NA) for TE and 26.0 months (95% CI 17.3-35.9) for TIE. The 12-month OS rate was 77.9% for TE and 67.1% for TIE. In patient reported outcome (PRO) measures, baseline QoL was estimated higher for TE than TIE, i.e., 63.2% TE vs 49.2% TIE pts had no limitations for mobility and 82.9% TE vs 61.7% TIE pts were independent in self-care. Frequency of related TEAEs grade 3/4 were comparable for TE and TIE (26.7% vs 25.0%), while TE tended to have less related serious TEAEs (13.0% vs 16.3%). Treatment was discontinued due to related TEAEs in 19.2% of TE and 13.0% of TIE pts. Conclusions: PAZOREAL provides real-world data for mRCC pts usually not represented in clinical trials during the study period. As it was to be expected, median OS and PRO were more favorable for TE than for the TIE pts, reflecting the difference in general condition between these groups. But more importantly, these data underline the tolerability of 1L PAZO treatment even for TIE pts, which is supported by comparable ToD for 1L PAZO and the comparable safety profile in both subgroups.1 Marschner, N. et al. Clin Genitourin Cancer 2017; 15(2):e209-215. doi:10.1016/j.clgc.2016.08.022.
Socioeconomic factors associated with stages of bladder cancer at diagnosis: Analysis of the National Cancer Database.
Authors: Taylor Alexandra , Gallegos Jillian Marie , Verplancke Kiana , McMahon Kevin , Silberstein Peter T. , Dahl Mary Elizabeth
Published: June 2022

e16531

Background: The average 5-year survival rate of Bladder Cancer (BC) in the US is 77%, yet the 5-year survival for BC with metastatic disease is 5%. The extreme differences in survival rate based on stage and metastasis highlight the importance of determining the social factors at the time of diagnosis. The objective of this study is to identify the socioeconomic and demographic factors associated with receiving a delayed bladder cancer diagnosis (stage IV) vs an early (stage 0-I) diagnosis. Methods: Using the National Cancer Database, this study analyzed 511,177 patients diagnosed with stage 0-I and stage IV BC between 2004 and 2018. Patients were analyzed based on race, sex, insurance type, Charlson-Deyo comorbidity score, level of education, income, geographic location, and education. Socioeconomic factors of patients were analyzed using multivariate analysis, chi square analysis, and one-way ANOVA. Results: Significant (P < 0.05) associations were identified between certain socioeconomic factors and presentation of bladder cancer at an advanced stage (stage IV). African Americans were 66% more likely to be diagnosed with stage IV diagnosis compared to Caucasians (p < .001 and 95% CI = 1.598-1.724). Hispanics were 22% more likely than non-Hispanics to present with a stage IV diagnosis (p < .001 and 95% CI = 1.114-1.327). Females were 34% more likely than men to present with stage IV diagnosis (p < .001 and 95% CI = 1.307-1.367). Patients with private insurance were 53% less likely to be diagnosed with a stage IV diagnosis than those who were uninsured (p < .001 and 95% CI = 0.448-0.509). Patients with one or more co-morbidities (Charleson-Deyo score ≥1) were more likely to present with a stage IV diagnosis than those with no co-morbidities (p < .001). Patients whose median household income was ≥ $63,000 were 33% less likely to present with a stage IV diagnosis than those whose median household income was < $63,000 (p < .031). Conclusions: Factors associated with increased likelihood of bladder cancer presentation at advanced stage compared to early stage include race, ethnicity, sex, insurance status, one or more co-morbidities, and a median household income under $63,000.
Real-world, population-based study of treatments, survival and healthcare use in advanced urothelial carcinoma of the bladder.
Authors: Cheung Winson Y. , Batra Atul , Syed Iqra A. , Moldaver Daniel , Clouthier Derek L.
Published: June 2022

e16538

Background: Prior single institutional studies and case series suggest that management of urothelial carcinoma of the bladder (UCB) can be highly variable across different centers. To better contextualize emerging therapies and their place in management, we aimed to characterize current population-based treatment patterns, outcomes, and healthcare resource utilization. Methods: Using real-world registries and administrative data, we analyzed a contemporary cohort of patients diagnosed with advanced UCB from 2010 to 2017 in the large province of Alberta, Canada. The study time period was selected to allow for adequate follow-up. The Kaplan-Meier method was used to plot estimates of overall survival (OS) and Cox proportional hazards model was constructed to determine the associations of clinical characteristics with outcomes. Summary statistics were used to describe healthcare resource use. Results: We included 1,146 advanced UCB patients. Median age was 73 (IQR 65-81) years, majority (78%) were men, and most (69%) had a Charlson comorbidity index of 0 to 1. Only 363 (32%) were referred, consulted with oncologists, and received palliative systemic therapy. Common regimens consisted of platinum-based doublet in the first-line (1L) setting and single-agent chemotherapy or immunotherapy in the second-line (2L) setting. Only 116 (32%) of the 1L treated patients proceeded to 2L. Median OS was 9.8 months (10.2 and 5.3 months in treated and untreated patients, respectively). After adjusting for confounders, receipt of at least one line of systemic therapy was associated with improved OS (HR 0.79, 95% CI 0.65-0.95, P = 0.011) as was urban residence with more access to oncology care (HR 0.82, 95% CI 0.73-0.92, P = 0.001). Median number of emergency department visits was 4 (IQR 2-7) per patient. Median number of hospitalizations and duration of admissions were 3 (IQR 2-5) per patient and 10 (IQR 6-16) days, respectively. Conclusions: In our population-based sample, the poor prognosis of UCB may be largely attributed to the low receipt of systemic therapy rather than the burden of comorbidities or acute care encounters. Since treatment attrition is significant, efforts to streamline referral to and consultation with oncologists at the time of metastatic diagnosis may optimize the use of appropriate systemic therapies and improve survival. This is increasingly important as novel, more effective therapies for advanced UCB are introduced into the treatment armamentarium.
Activated protein kinase C-alpha as a simple test for urothelial cancer screening.
Authors: Inokuchi Junichi , Murata Masaharu , Kawano Takahito , Kang Jeong-Hun , Kinoshita Fumio , Matsumoto Takashi , Monji Keisuke , Kashiwagi Eiji , Takeuchi Ario , Shiota Masaki , Eto Masatoshi
Published: June 2022

e16552

Background: The development of a non-invasive, highly predictive diagnostic test for urothelial cancer (UC) would greatly benefit patients. Although numerous urine-based tests have been developed, it is not widely used, except for urine cytology, due to insufficient sensitivity, negative predictive value and high cost. Previously we reported that protein kinase C-alpha (PKCα) is overexpressed or activated in several cancer tissues but not in normal tissue, and we developed an activated PKCα-specific peptide substrate (FKKQGSFAKKK; Patent No. 5476559). The purpose of this study was to investigate the potential for UC screening of simple test detecting activated PKCα. Methods: This institutional review board-approved prospective study included patients with bladder cancer or upper urinary tract UC who underwent surgery at Kyushu University Hospital between September 2018 and December 2020. Patients with benign urologic disorders or healthy volunteers were included as a control group. Patients with prostate cancer (PC) or renal cell carcinoma (RCC) who underwent curative surgery were included as other genitourinary (GU) cancer group. Patients with other coexisting malignant tumors were excluded. Urine samples were collected prior to surgery, 20 mL of urine was centrifuged, and the pellet was lysed for analysis. We evaluated the phosphorylation status of the activated PKCα-specific peptide substrate by MALDI-TOF mass spectrometry. The utility of activated PKCα as a urinary biomarker was evaluated by its sensitivity and negative predictive value when compared to control group or other GU cancers group. Results: Urine samples were obtained from 226 individuals, which included 98 patients with UC, 51 with other GU caners, and 77 with control group. Of the 98 patients with UC, activated PKCα was detected in 75 patients, with sensitivity of 76.5%. The sensitivity in patients with high-grade and low-grade UC were 84% and 62%, respectively. The sensitivity in those with high-grade UC increased to 93% when combined with urine cytology. On the other hand, activated PKCα were rarely detected in non-UC patients which includes other GU cancers group and control group. The specificity among the non-UC patients was 74.2%. In the comparison between patients with UC and non-UC, the negative predictive value of activated PKCα was 80.5%. The area under the receiver operating characteristic curve (AUC) for detecting UC of activated PKCα was 0.80. Conclusions: This study demonstrates the utility of activated PKCα as a novel urine screening test for UC. (Patent Application No. PCT/JP2020/045257) Since this test is based on a single target, inexpensive detection devices can be developed.
Clinical and epidemiological features of penile squamous cell carcinoma according to pathological nodal stage in a Brazilian cancer reference hospital.
Authors: Preto Daniel D Almeida , Lordelo Bruno , Tavares Rosielly Melo , Gimenes Afonso Nathália , Araujo Hadson Silva , Neif Joao , Zucca Luis Eduardo Rosa , Carcano Flavio Mavignier
Published: June 2022

e17017

Background: Penile cancer is a rare disease worldwide, but in the developing countries represent 2% of male cancers, and sociocultural issues are closely related to risk. Lymph node status is a key prognostic factor, and almost 60% of patients has lymph node disease at diagnosis. Perioperative treatment for patients with regional lymph node disease is essential for a better outcome. Methods: We retrospectively reviewed all penile cancer patients, with histological confirmation, between 2009 and 2019 at Barretos Cancer Hospital (Brazil). Only squamous cell carcinoma that performed lymphadenectomy were included. Univariable analysis were performed to explore association between clinical and pathological features. Cumulative survival probabilities were calculated using the Kaplan-Meier method and differences between survivals were tested using the log-rank test. Results: One hundred and thirteen patients were eligible for analyses. The mean age was 55.7 year. Most of the patients were declared white, in a stable relationship and had a lower education level, with more than 70% of patients attending only elementary school. Clinical-pathological staging concordance was 43%. Overall survival was related to pathologic lymph node staging (pN), ranging from 111 months for pN0 individuals to 46.9 months for pN3 (p < .001). Considering only pN2-3 stages, only 54% of patients were submitted to adjuvant treatment and those had significantly improved 5 years cumulative survival, almost 50% versus 20% (p = .027). Only one patient was submitted to neoadjuvant therapy. Conclusions: The epidemiological profile matches with the current literature, reaffirming this public health issue in low-income countries. Accurated lymph node staging is essential to define the prognosis and an agressive multi-modality approach could improve results in the perioperative nodal metastatatic setting. Further prospective controlled studies should be stimulated in this context.
Financial impact of generic therapeutic interchange of abiraterone in the oncology care model for the U.S. Oncology Network.
Authors: Indurlal Puneeth , Ives Hope , Garey Jody S. , McGuinness Margaret , Pacheco Alonso Victor , Wilfong Lalan S.
Published: June 2022

e17019

Background: Therapeutic interchange (TIC) to lower-cost generic products offers significant cost savings to payers and patients while maintaining equivalent quality of care. The Oncology Care Model (OCM) is a value-based care program from Medicare that rewards practices for decreasing the total cost of care (TCOC) compared to historical baseline prices that are adjusted by a trend factor to account for rising cost trends in oncology. One strategy for bending the cost curve is to utilize lower cost medications. A generic version of abiraterone acetate (FDA approved for treatment of Prostate Cancer) was first introduced into the market in late 2018. This led to a concerted approach to interchange the brand product with the generic equivalent in The US Oncology Network (The Network) as an opportunity to reduce TCOC. Here we describe utilization and the financial impact of abiraterone TIC in The Network during OCM performance period 8 (PP8) which enrolled patients from 1/2/2020 to 7/1/2020. Methods: Prescription drugs dispense data for the 14 US Oncology Network practices participating in the OCM were used to determine brand and generic abiraterone utilization. The impact of TIC on TCOC was measured by comparing the cost of the generic product vs. the estimated cost of the brand agents. Results: TIC resulted in an increase in generic abiraterone use from prior performance periods. Generic abiraterone increased from 0% in PP4 to 24% in PP5, 55% in PP6, 67% in PP7 and 80% in PP8 within the Network. We compared the actual cost of all abiraterone dispenses in PP8 vs. the calculated cost (based on Average Wholesale Price less 17.5%) of the brand product if the more expensive brand drugs were used instead. The difference in the actual cost vs estimated cost led to a savings of $4.37 million in PP6, $6.34 million in PP7 and $9.37 million in PP8 (about 1% of TCOC) by using generic versus brand abiraterone alone. Conclusions: TIC from brand to generic abiraterone in The Network generated significant savings for OCM. Continued shift towards lower cost generics will increase savings to CMS in the Oncology Care Model. We estimate that 100% Network adoption of the generic abiraterone could save nearly 1.25% of the TCOC compared to continued use of brand product.
Augmented alpha-beta PSMA radioligand therapy in metastatic prostate cancer: Analysis of prognostic factors for survival.
Authors: Kulkarni Harshad , Khushalani Jaya , Mancini Brandon Robert , Maupin Kevin , Robiller Franz Christoph , Baum Richard , Almaguel Frankis
Published: June 2022

e17025

Background: PSMA-targeted radioligand therapy (PRLT) using the alpha-emitter Ac-225 PSMA-617 is effective in metastatic prostate cancer progressing after beta-emitter-based PRLT using Lu-177 PSMA-617, and in the presence of diffuse bone marrow metastases. Xerostomia is a dose-limiting factor in PRLT using Ac-225. Augmented Alpha-Beta PRLT is a concept of concomitantly administering Lu-177 and Ac-225 PSMA in lower activities, as a trade-off between efficacy and the dose-limiting toxicity, i.e., xerostomia. The objective of this study was to compare overall survival (OS), progression-free survival (PFS), and incidence of xerostomia among metastatic prostate cancer patients who received Ac-225 PSMA-617 augmentation in the initial phase of Lu-177 PSMA-617 RLT compared to those who received it in the late phase. Initial phase is defined as first two cycles of PSMA radioligand therapy (PRLT) vs late phase as after two cycles. We also examined prognostic factors associated with OS and PFS. Methods: Kaplan Meier method was used to examine survival curves and log-rank tests were conducted to examine differences in survival by groups. Cox Proportional Hazard (CPH) model was used to examine the impact of bone marrow and visceral metastasis and age on OS and PFS. Progression was defined as an increase of ≥ 25% in prostate-specific antigen (PSA) levels. Results: 68 patients who received Ac-225 PSMA-617 by itself, or Ac-225 PSMA-617 augmentation to Lu-PSMA-617 were included in the analysis. Out of these, 15 received early augmentation, 50 received late augmentation, and 3 received Ac-225 PSMA-617 alone. Of these, 48 experienced cancer progression and 21 died due to cancer progression. Median OS was 47 months and PFS was 11 months. Those who received early augmentation had significantly better PFS (median PFS not reached during study period) compared to those who received late augmentation (median PFS: 9 months) (p = 0.02). Early augmentation was associated with lower likelihood of xerostomia (p = 0.09). CPH model suggested that visceral or bone marrow metastasis were associated with significantly worse prognosis for PFS (p = 0.04). Conclusions: In patients progressing after Lu-177 PSMA radioligand therapy and those with diffuse bone-marrow metastases, an earlier augmentation with Ac-225 PSMA-617 is associated with better PFS and lower side effects such as xerostomia. Having visceral or bone marrow metastasis is a poor prognostic indicator for PFS in augmented alpha-beta PSMA radioligand therapy.
PTCH1 and AXIN2 modulation of AR copy number effects on AR gene overexpression in metastatic castration resistant prostate cancer (mCRPC).
Authors: Yan Raymond T. , Latourelle Jeanne , Khalid Omar , Parikh Ravi Bharat , Church Bruce W.
Published: June 2022

e17026

Background: Androgen receptor (AR) signaling is a critical pathway in prostate cancer progression. Reactivation of the AR pathway is a key driver in mCRPC. Patients with mCRPC often develop resistance to novel AR signaling inhibitors (ARSIs) such as enzalutamide. AR inhibitor resistance leads to shorter overall and progression-free survival and can be attributed to AR gene amplification with subsequent AR overexpression and androgen-sensitization in prostate tumors. Identifying novel modulators of AR amplification in patients progressing on ARSIs may lead towards potential targets in drug discovery. Methods: In this cross-sectional study, an in silico patient model was developed on prescribed drug therapies and failed therapies patient information, PSA measures, ̃100 mutation variables including somatic, germline, and gain/loss mutations, and ̃1K gene expressions data from 275 mCRPC patients obtained from the Tempus database using GNS Healthcare’s Causal artificial intelligence technology, REFS. A causal network model was reconstructed based on patient data with inferred effect estimates. The network model was topologically surveyed for biological interactions. Results: Causal analysis of this model uncovered two germline mutations, located in PTCH1 and AXIN2, which modify the effect of AR copy number gain ( ARgain+ : copy number 6, ARgain- : copy number < 6) on AR gene expression. For PTCH1-mutant group, there was a 2-fold increase in AR gene expression in ARgain+ patients compared to ARgain- patients (p = 2.1e-12), while only 1.4 fold increase in AR gene expression from the PTCH1 non-mutant group (p = 6.3e-08). Similarly, there was a 2-fold increase in AR gene expression in ARgain+ patients compared to ARgain- patients (p = 7.2e-16) for the AXIN2-mutant group, while only one-fold increase in AR gene expression with the AXIN2 non-mutant group (p = 0.001). The C to T missense mutation in codon 3746 in PTCH1 and codon 148 in AXIN2 have higher prevalences, 55% and 72%, respectively in this mCRPC cohort compared to their population allele frequencies, 38% and 47%, respectively. Conclusions: PTCH1 and AXIN2 mutations from our analyses is consistent with a literature reported role for Hedgehog signaling and Wnt/-catenin signaling pathways, respectively, influencing the disease progression in castration-resistant prostate cancer. Our findings suggest that the missense germline mutations in PTCH1 and AXIN2 predicts response to enzalutamide and other ARSIs in CRPC setting, and propose potential targets for combination therapy to overcome ARSI drug resistance in hormone-refractory prostate cancer. [Table: see text]
The effect of PARP inhibition on androgen receptor localization and activity in castration resistant prostate cancer.
Authors: Nizialek Emily , Haffner Michael , Bhamidipati Akshay , Yegnasubramanian Srinivasan
Published: June 2022

e17037

Background: The poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib and rucaparib have been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in the setting of homologous recombination deficiency (HRD). Additionally, PARPi have been shown to modulate androgen receptor (AR) signaling, with a recent report demonstrating mono-ADP-ribosylation of cysteine residues in AR by Parp7. Here, we further evaluated the effect of PARPi on AR activity and localization. Methods: The effect of PARPi on cell growth and survival of CRPC cell lines was evaluated in vitro and in vivo. AR ribosylation was assessed in CRPC cell lines by immunoprecipitation (IP) assays and proximity ligation assays (PLA). The subcellular localization of AR was determined by quantitative immunofluorescence microscopy in CRPC cell lines and xenograft models. Changes in AR activity with PARPi treatment were evaluated by a luciferase reporter assay and AR target gene expression in a PDX model. Finally, PARPi mediated alteration in the AR protein interactome was evaluated by liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics. Results: The PARPi olaparib and talazoparib, and to a lesser extent veliparib, inhibited CRPC cell growth. Evidence of AR ribosylation was seen by IP and PLA. PARPi treatment of multiple in vitro and in vivo prostate cancer models resulted in a shift of AR subcellular localization, from predominantly nuclear to cytoplasmic compartments. In luciferase reporter assays, AR transactivation activity was decreased after PARPi treatment in a dose dependent manner. In vivo, in prostate cancer xenograft models, decreased AR target gene expression was seen upon PARPi treatment. LC-MS/MS proteomic studies revealed that PARP inhibition resulted in significant changes in the composition of AR interaction partners, in particular of proteins related to intracellular trafficking and nuclear transport. This suggests a potential link between altered AR complex assembly and the observed changes in AR subcellular localization in the context of PARPi treatment. Conclusions: We describe a novel sequela of PARPi therapy to alter AR localization and activity in CRPC. Single agent PARP inhibition can alter prostate cancer cell growth in vitro and in vivo. With PARPi treatment, AR localization is shifted to the cytoplasm, the AR interactome is altered, and AR transcriptional activity decreased. These findings implicate a collateral mechanism of PARPi in preventing prostate cancer cell growth/survival that may augment previously described mechanisms related to HDR and synthetic lethality. It is essential to understand the role of PARPi beyond synthetic lethality in the context of HRD in order to better define the spectrum of response to PARPi across patients, and for development of biology-informed combination therapies.
Changes of immune microenvironment before and after chemoradiotherapy in cervical cancer.
Authors: Liu Sihan , He Qianru , Xing Xiaodan , Sun Tingting , Qi Chuang
Published: June 2022

e17503

Background: Cervical cancer is the fourth most common cancer in women worldwide. Metastasis and invasion of cervical cancer are closely related to the tumor microenvironment. As an effective treatment, chemoradiotherapy plays a vital role in immune-related cells and factors. However, little is known about the effect of chemoradiotherapy on the immune microenvironment in cervical cancers. Therefore, we studied the immune microenvironment alterations before and after chemoradiotherapy and analyzed their prognostic significance in cervical cancer patients. Methods: We recruited 15 patients with stage IB1-IVA cervical squamous cell carcinoma. Pelvic intensity-modulated radiotherapy (IMRT) was performed with conventional segmentation of 2Gy per irradiation (IB3 stage was treated with synchronous cisplatin for weeks), FFPE samples pre-treatment, and one-week after-chemoradiotherapy were conducted an exploratory biomarker analysis based on gene expression profiling (GEP). The panel of 289 genes was customized based on critical genes and pathways during tumor immunoregulation (e.g., tumor antigen release, T cell activation, and immune metabolism). The differential expressed genes between these two groups were then assessed. Results: Forty-two genes were found to be differentially expressed, with 21 genes having > 1.5-fold mean expression difference after chemoradiotherapy. Analysis of important GO terms and KEGG pathways indicated that the pathways enriched by different genes are located in immune-related pathways, specifically, T cell activation (GO-BP), cytokine activity (GO-MF), and cytokine-cytokine receptor interaction (KEGG). After-chemoradiotherapy, the enrichment of tumor-infiltrating lymphocytes (TILs) varied greatly, especially the macrophages. Conclusions: This study preliminarily demonstrated that chemoradiotherapy caused the release of pro-inflammatory like CCR7 and CD69 and immune cell (macrophages) infiltration alterations after chemoradiotherapy in cervical cancer patients.
Low doses of visible electromagnetic radiation activating endogenous nonspecific antitumor resistance in patients with cervical cancer.
Authors: Rodionova Olga G. , Sakun Pavel G. , Sheiko Elena A. , Karnaukhova Elena A. , Pustovalova Alla V. , Chalabova Tatiana G. , Savchenko Dmitriy A. , Kabanov Sergey N. , Adamyan Meri L. , Kruze Polina A. , Poryvaev Yuriy A. , Chernikova Natalia V. , Voshedskiy Vitaliy I. , Tolmacheva Ekaterina A. , Vasilieva Ekaterina O. , Solntseva Anna A. , Zhenilo Oksana E. , Cherkasova Anna A. , Krokhmal Julia N.
Published: June 2022

e17506

Background: Ionizing radiation inhibits the immunological reactivity of the body and the system of nonspecific antitumor resistance in patients with cervical cancer (CC). The purpose of this study was to activate the system of nonspecific antitumor resistance using visible electromagnetic radiation in CC patients receiving chemoradiotherapy. Methods: The study included 30 patients, mean age 61 years, with stage IIIb CC (T3bNxM0). The main group (n = 15) received standard chemoradiotherapy (CRT): irradiation of the primary focus 80 Gy, lymphatic paths 55 Gy, with radiomodification with cisplatin 40mg/m2; the patients were additionally exposed to visible electromagnetic radiation: the red spectrum λ = 640 nm on the cubital vein projection (exposure time 5 minutes, dose 6.86 J/cm2), twice a week (the total of 14 sessions). The method is based on the ability of monochrome red light to induce photobioadaptive processes in the body, leading to the formation of non-specific antistress reactions, activation of reparative and regenerative tissue reactions with an increase in the synthetic, phagocytic activity of neutrophils and the growth of the immunity lymphoid indicators. The control group included 12 patients receiving only standard CRT. Parameters of nonspecific antitumor adaptation reactions were evaluated. Results: Lower abdominal pain and discomfort were managed in 20% of patients of the main group on day 8, in 30% on day 10, and in 50% on day 14. In the control group, the symptoms were managed in 40% of patients only on day 22. More rapid regression of the cervical tumor was registered in patients of the main group, as well as decreased infiltration of the parametrium and vaginal fornices, disappearance of bloody discharge, management of intoxication syndrome. Gastrointestinal toxicity (nausea, diarrhea, flatulence) was noted in 10% of patients in the main group and in 100% controls. 7 patients in the control group developed leukopenia; in the main group, it was not observed. MRI-confirmed complete tumor regression amounted to 88% in the main group and 65% in the control group. CRT was completed within 7 weeks in the main group and 8.5 weeks in the control group. Conclusions: Low doses of electromagnetic radiation of the red spectrum activate endogenous nonspecific antitumor resistance of the body by forming nonspecific antistress reactions of activation and increasing the immunity lymphoid indicators, which improves the efficacy of CRT.
Opportunistic cervical cancer screening for elderly women without standardized screening.
Authors: Li Kemin , Yin Rutie
Published: June 2022

e17511

Background: To explore the important of the opportunistic cervical cancer screening for elderly women without standardized screening and the best opportunistic screening strategy. Methods: The participants were elderly women over the age of 65 without being undergone standardized cervical cancer screening from June 2017 to June 2021. All participants were undergone an opportunistic cervical cancer screening. High-risk HPV distribution was analyzed, and we would analysis the accuracy of different screening methods (only cytology, only HPV, HPV +cytology triage, and non-HPV 16/18 +cytology triage or HPV 16/18) for CINII+. Results: A total of 848 elderly women with high-risk HPV infection were included. There were 325 (38.3%) CINII+ patients and 145 (17.1%) invasive cancer patients. The top five HPV subtypes are HPV16, HPV52, HPV58, HPV53 and HPV56, and the infection rates are 31.4%, 21.9%, 19.7%, 11.6%, and 11.6%, respectively. The area under the ROC curve of five screening strategies was 0.715(0.681, 0.750) (ASCUS+), 0.498(0.458, 0.538), 0.623(0.584, 0.663), 0.714(0.680, 0.748) (ASCUS+), and 0.698(0.664, 0.733) (ASCUS+). Conclusions: Elderly women without being undergone standardized cervical cancer screening should be given a chance to be screened for cervical cancer, and the standardized screening program is suitable for elderly women.
Characteristics of expression of cancer stem cell markers in various approaches to cervical cancer treatment.
Authors: Menshenina Anna P. , Ulianova Elena P. , Nepomnyashchaya Evgeniya M. , Sagakyants Aleksandr B. , Verenikina Ekaterina V. , Moiseenko Tatiana I. , Frantsiyants Elena M. , Cherkasova Anna A. , Selezneva Olga G. , Rogozin Mark A.
Published: June 2022

e17516

Background: Cancer stem cells (CSCs) are being actively studied as a possible origin of malignant neoplasms. Research of the properties of CSCs and mechanisms of their regulation holds the promise of the development of new approaches to antitumor therapy. The most frequently detected CSC markers in different tumors are CD44 and CD133. In this regard, the aim of our study was to identify characteristics of expression of CSC markers in cervical cancer treatment and their possible predictive value. Methods: The study included 237 patients with locally advanced cervical cancer T2a-2bNx-1M0. Patients were divided depending on the treatment: neoadjuvant chemotherapy with cisplatin and bleomycin (NACT, n = 84); plasmapheresis (PA) in combination with NACT (PA+NACT, n = 60); PA+NACT with nonspecific immunotherapy with an interferon inducer (PA+NACT+IT, n = 93). Immunohistochemical study was performed on sections from paraffin blocks of tumors using anti-CD44 monoclonal mouse antibodies (156-3C11, Thermo Scientific) at a dilution of 1:2500 and anti-CD133 polyclonal rabbit antibodies (AF5120, Affinity Biosciences) at a dilution of 1:400 (Thermo autostainer Scientific 480S). Membrane staining and staining intensity were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong staining. Protein expression was defined as positive when staining was detected in ≥10% of all tumor cells with a staining intensity ≥2. Statistical analysis of the results was performed with the STATISTICA 13.0 program (StatSoftInc., USA) using the Mann-Whitney U-test. Results: Tumors with positive CD133 and CD44 expression were observed in all groups of patients. However, only PA+NACT+IT patients had CD133- (57%) and CD44- (43%) tumors. Median expression of CD133: in NACT - 70 [60;80]; PA+NACT - 60 [37;70], PA+NACT+IT - 25 [5;60]. Median expression of CD44: in NACT - 30 [10;40]; PA+NACT - 30 [13;65], PA+NACT+IT - 20 [2; 40]. CD133 expression in PA+NACT+IT patients was significantly lower than in PA+NACT and NACT patients by 2.4 times (*p = 0.009) and 2.8 times (*p = 0.002), respectively. CD44 expression in tumors of patients with PA+NACT+IT was 1.5 times lower (statistically non-significant). Differences in tumors of NACT and PA+NACT patients were not found. Conclusions: The immunohistochemical study revealed a decline in the expression of CSC markers (CD133 and CD44) in tumors of patients who received PA+NAPCT+IT. The results obtained for the CD133 marker show its possible value as a predictive factor in the treatment of cervical cancer.
Tumor-stroma interaction in cervical cancer: The prognostic importance of desmoplasia.
Authors: Wolf Benjamin , Horn Lars-Christian , Höckel Michael , Aktas Bahriye
Published: June 2022

e17519

Background: During tumor growth, cancer cells can induce the formation of new extracellular matrix, mainly by activating peritumoral fibroblasts. This stromal reconfiguration has been termed desmoplasia. In pancreatic and ovarian cancer models, targeting desmoplasia therapeutically to normalize the microenvironment has recently shown promising results. We investigated the frequency and prognostic relevance of peritumoral desmoplasia, as well as its association with other prognostic factors such as lymph node involvement and parametrial tumor extension in cervical cancer patients. Methods: A retrospective cohort study based on data from the prospective monocentric observational Leipzig School Mesometrial Resection study was conducted. Cervical cancer patients staged IB1 to IVA according to the Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) who underwent primary surgery between 1999 and 2017 were included. Information regarding desmoplastic tumor reaction was retrospectively retrieved from the pathology reports. All other data had been collected prospectively during the trial period. Using non-parametric tests, we calculated the association of peritumoral desmoplasia with other common risk factors. To determine the prognostic significance of desmoplasia, we used the Kaplan-Meier estimator and performed multivariable Cox-regression modelling. Results: Overall, 355 patients were included. Desmoplasia was present in 298 cases and was associated with a significantly higher likelihood of lymphovascular space involvement (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.4 – 5.1, p = 0.001) and venous infiltration (OR 5.1, 95%-CI 1.3 – 44.9, p = 0.01). Lymph node metastasis was more common in patients with desmoplasia (OR 2.4, 95%-CI 1.2 – 5.0, p = 0.01), as was parametrial involvement (OR 3.5, 95%-CI 1.7 – 7.9, p = 0.0002). Interestingly, the presence of desmoplasia was not associated with larger tumor size. Patients with desmoplastic tissue reaction were significantly older than those without desmoplasia (median 41 years [inter quartile range 34 – 51] vs. 47 years [IQR 39-56], p = 0.009). These prognostically negative parameters in patients with desmoplastic disease translated into inferior overall (94.5% vs 80.5%, OR 3.9 [95%-CI 1.2 – 12.5], p = 0.02) and recurrence-free survival (86.8% vs. 74.2%, OR 2.3 [95%-CI 1.0 – 4.9], p = 0.04). A multivariable Cox-regression model including tumor size, patient age, and nodal status indicated that desmoplasia was an independent risk factor for overall death (OR 4.2, 95%-CI 1.03 – 17.5, p = 0.04). Conclusions: Desmoplastic stromal remodeling is associated with a more aggressive phenotype of cervical cancer and inferior survival. Targeting desmoplasia, especially in advanced disease when surgical treatment is not feasible, might be a promising treatment approach in the future.
A novel predictor for the use of concurrent chemotherapy in early-stage cervical cancer with intermediate-risk factors.
Authors: Zhang Guangyu , Fu Chunli , Ma Changdong , Zhang Youzhong , Miao Li , Wang Cong
Published: June 2022

e17521

Background: For early-stage cervical cancer patients experiencing radical surgery, postoperative radiotherapy was recommended for patients with a combination of intermediate-risk factors. However, there was no consensus on whether to administer concurrent chemotherapy. The aim of the study was to confirm the clinical value of the controlling nutritional status (COUNT) score in guiding the use of concurrent chemotherapy in patients with early-stage cervical cancers during postoperative radiotherapy. Methods: A total of 945 patients with FIGO stage IB-IIA (2009) cervical cancer were retrospectively analyzed in the study from 2009 to 2018. There were 503 patents receiving concurrent chemoradiotherapy, while another 442 patents undergone radiotherapy lonely. Radiotherapy was performed by conformal radiotherapy or intensity-modulated radiotherapy. The concurrent chemotherapy regimen included either cisplatin or paclitaxel. Pre-treatment CONUT score were calculated within 1 weeks before curative resection. Low CONUT group and high CONUT group were defined based on the cutoff value of CONUT score which was determined by the receiver operating characteristic analysis. Kaplan-Meier survival analysis was performed to compare disease-free survival (DFS) and cancer-specific survival (CSS) rates between different group. A Cox proportional hazards regression test was used to conduct multivariate analyses of DFS, local recurrence-free survival and distant metastasis-free survival (DMFS). Results: The median follow-up was 54.6 months (range: 4.8-147.5 months). The optimal cutoff value of CONUT was 3 in the study. For the patients included in the high CONUT group (≥3), the addition of concurrent chemotherapy significantly improved treatment outcomes, and had better 5-year DFS (90.37% vs 70.69%, P < 0.001) and CSS (95.02% vs 78.74%, P = 0.005) than those without it. Meanwhile, the patients with concurrent chemotherapy had less rate of distant metastasis (6.5% vs 28.1%, P < 0.001). For the patients included in low CONUT group (< 3), there was no difference in prognosis between patients receiving concurrent chemotherapy and not receiving. In the high CONUT group, the multivariate analysis showed that concurrent chemotherapy was detected to be a factor significantly associated with DFS (HR 3.077; 95% CI: 1.295-6.679, P = 0.011) and DMFS (HR 3.435; 95% CI: 1.506-7.014, P = 0.006). Conclusions: Pre-treatment CONUT score may be a predictive factor for the use of concurrent chemotherapy in early-stage cervical cancer patients with intermediate-risk factors during postoperative radiotherapy, and it can be helpful to determine the adjuvant treatment scheme.
Photodynamic therapy for early cervical cancer.
Authors: Ivanova Viktoria A. , Nikitina Vera P. , Verenikina Ekaterina V. , Zhenilo Oksana E. , Ardzha Anna Yu
Published: June 2022

e17528

Background: Photodynamic therapy (PDT), with its high efficiency and selective impact on tumor cells without damaging healthy tissues, is an organ-sparing treatment preserving the anatomy and function of the cervix. Preservation of the reproductive function is the most significant criterion for the efficacy of an organ-sparing treatment. The purpose of this study was to evaluate the efficacy of PDT for early cervical cancer. Methods: PDT results were studied in 74 patients aged 18-40 years with early cervical cancer. The patients were divided into 3 groups depending on the type of transformation zone (TZ), the degree of invasion and the tumor site: group 1 - 36 patients with preinvasive cancer in the exocervix (TZ type I-II); group 2 - 34 patients with preinvasive cancer in the endocervix (TZ type III); group 3 - 4 patients with microinvasive cancer T1a1N0M0 with invasion of no more than 1 mm as an alternative to surgical intervention. Infection with high-risk genotypes of HPV (16, 18, 31, 33, 35, 45, 56) was detected with PCR in 62 (84%) women. All patients received PDT with the semiconductor Latus laser up to 3 W, a single-use diffusing fiber for the exocervix irradiation and a single-use cylindrical diffusing fiber for tumors in the cervical canal. Chlorin e6 was used as a photosensitizer. The efficiency criteria included the normalization of the colposcopic and morphological picture, and the HPV elimination confirmed by the PCR test. 4 to 8 procedures were required to restore the normal layer of stratified squamous epithelium. Results: PDT was followed by direct photocoagulation necrosis caused by the destruction of cellular structures, and ischemic necrosis as a result of damage and destruction of the microvasculature of the initial tumor changes in the cervical epithelium. Epithelialization of the cervix was completed by days 35-40. Normal morphological picture was observed in 96% of patients in group 1 and in 95% of patients in group 2; all patients in group 3 had a pronounced positive response. PCR 3 months after PDT showed a positive HPV reaction in 5.1% of patients. No negative changes in the cytogram were detected 6 and 12 months after PDT. The maximum follow-up period has lasted for 5.1 years. No relapses of the disease have been registered. During the follow-up period, four patients with preinvasive cancer and one patient with microinvasive cancer successfully gave birth to healthy children. Conclusions: PDT is an alternative treatment for precancerous and early malignant tumors of the cervix; it preserves the anatomical and functional integrity of the organ, which is important for the female reproductive function. The results of the study allow recommending PDT in the treatment of early cervical cancer.
BRCA variants and the risk of adverse reactions in patients with ovarian cancer: A single-center real-world study.
Authors: Li Kemin , Yin Rutie
Published: June 2022

e17530

Background: To study the correlation between BRCA mutation status and the risk of adverse reactions in patients with ovarian cancer. Methods: A real-world study was conducted at the largest gynecological oncology center in western China, the West China Second University Hospital of Sichuan University. The research subjects were patients diagnosed with ovarian cancer who were initially treated in our hospital from January 2016 to January 2020 and had their BRCA gene status evaluated. Multivariate Cox analysis was conducted to investigate the correlation between the BRCA mutation status and adverse reactions in ovarian cancer patients during initial treatment. Results: A total of 349 ovarian cancer patients were enrolled, including 79 patients with pathogenic BRCA variants, resulting in a pathogenic mutation rate of 22.6%. Among these 79 patients, 57 had BRCA1 variants and 22 had BRCA2 variants, yielding a pathogenic mutation rate of 16.3% and 6.3%, respectively. Multivariate COX analysis revealed that pathogenic BRCA variants were not related to the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, during the initial treatment of ovarian cancer. Conclusions: BRCA variants did not increase the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, in ovarian cancer patients during initial treatment.
CCND1 and PTEN gene copy number variations as markers of vulvar cancer progression.
Authors: Petrusenko Natalia A. , Kutilin Denis S. , Busarova Angelina V. , Porkhanova Natalya V. , Kit Oleg I.
Published: June 2022

e17531

Background: More than 90% of malignant vulvar tumors and almost 5% of all gynecological cancers are squamous cell carcinoma. 1/3 of patients with vulvar cancer relapse after initial treatment, and the 2-year overall survival is less than 15%. Development of more effective treatments requires understanding of the molecular pathogenesis of vulvar cancer. The aim of this study was the screening of potential prognostic tumor markers in vulvar cancer based on relative copy number analysis (CNV) of MYC, PTEN, CCND1, PIK3CA, TP53, CDKN2A, MDM2, MCL1, AEPX1, NFKBIA, MTAP, BIRC2, SYNE1, KMT2C genes. Methods: The study was performed on 300 patients aged 29-80 years diagnosed with vulvar squamous cell carcinoma with lymph nodes metastases (n = 150) and without metastases (n = 150). The material for the study was DNA from FFPE-blocks of tumor and non-tumor vulvar tissues. The RT-qPCR method was used to evaluate the relative copy number of MYC, PTEN, CCND1, PIK3CA, TP53, CDKN2A, MDM2, MCL1, AEPX1, NFKBIA, MTAP, BIRC2, SYNE1, KMT2C, GAPDH and B2M genes (the last two were reference genes). Differences were assessed using the Mann-Whitney test (Bonferroni correction was used). Results: All genes showed a change in the dose in vulva tumor cells relative to normal ones: amplifications for the MYC, MCL1, AEPX1, NFKBIA, CCND1, PIK3CA, TP53, MDM2, BIRC2, SYNE1, KMT2C genes, respectively, in 46%, 36%, 28%, 40%, 56%, 43%, 62%, 39%, 57%, 35%, 44% of cases, and a decrease in copy number for PTEN, MTAP, CDKN2A genes, respectively, in 34%, 28%, 35% of cases. At the same time, a statistically significant increase in the CNV of the CCND1 gene (p < 0.05) by 1.7 times and a decrease in the PTEN gene (p < 0.05) by 1.9 times were observed in the group of vulvar squamous cell carcinoma patients with lymph nodes metastases. No statistically significant change in the CNV of other genes was found. Conclusions: Thus, the identified aberrant copy numbers of CCND1 and PTEN genes can serve as prognostic markers for vulvar cancer patients.