bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of COVID-19 pandemic on the treatment of prostate cancer in the Brazilian public health system.
Authors: Carvalhal Gustavo , Morbeck Igor Alexandre Protzner , Herchenhorn Daniel , Sasse Andre Deeke , McKay Rana R. , Rose Brent Shane , Maluf Fernando Cotait , Monteiro Fernando Sabino Marques , Carrera Vinicius , Soares Andrey , Jardim Denis L. , Bastos Diogo Assed , Firminiano Elcio , Valverde Douglas Andreas , James Nick
Published: June 2023

e17106

Background: COVID-19 pandemic reached Brazil in the beginning of 2020 causing a profound impact in economic and social activities, up to the end of 2021. In Brazil, there is universal access to the public health system (BPHS-SUS); however, during the pandemic public resources were directed mainly to the management of COVID-19 infected patients. We evaluated the impact of the 2020/2021 pandemic on the treatment of prostate cancer in the BPHS-SUS. Methods: we compared data regarding the number of radical prostatectomies, radiotherapy treatments, and hormonal and chemotherapy treatments administered in the time frame from March 1st, 2020 (when lockdown measures were initially adopted in Brazil) to February 29th, 2022, with that of the two most recent pre-pandemic years (March 1st, 2018, to February 28th, 2020). A large proprietary healthcare data science platform offered by TECHTRIALSÒ was surveyed. Results: in the two pandemic years, 15,196 radical prostatectomies were performed in the BPHS, with a cost of U$ 14,271,297; there was a 23.3% reduction in the number of surgeries compared with the two pre-pandemic years (19,818 radical prostatectomies, with a cost of U$ 18,056,470). In the pandemic, 34,982 men were treated with radiation therapy, with a cost of U$ 39,616,736; this meant a 18.7% reduction in the number of patients treated with radiation therapy as compared with the two pre-pandemic years (43,013 men, with a cost of U$ 44,148,190). Regarding hormonal treatments, numbers were similar: 116,490 men were treated during the pandemic (cost of U$ 74,834,615); in the pre-pandemic timeframe, 115,949 patients received hormonal therapy (cost of U$ 75,179,674). As to chemotherapy for hormone-resistant disease, in the pandemic 14,946 men were treated (cost of U$ 23,402,947) compared with 12,695 men treated in the two pre-pandemic years (cost of U$ 19,239,099). Conclusions: there was a significant reduction in the number of radical prostatectomies and of radiation therapy treatments during the pandemic years in the BPHS-SUS. Abrupt reductions of potentially curative therapies will probably affect stage migration, costs to the public system and patients’ survival in the ensuing years. The number of systemic therapies (first- and second-line hormonal therapies, and chemotherapies) were slightly increased, probably reflecting the BPHS-SUS policy of maintaining systemic treatments active during the pandemic.
Deep learning-based histomorphological pattern profiles for effective risk stratification in prostate cancer.
Authors: Lee JaeHeon , Kwak Tae-Yeong , Cho Joonyoung , Kim Sun Woo , Chang Hyeyoon
Published: June 2023

e17107

Background: Prostate cancer affects millions of men globally and biochemical recurrence (BCR) is an important indicator of its progression. With the increasing use of computational techniques, there has been a growing interest in utilizing whole slide images (WSIs) of H&E stained prostate tissue to evaluate the patients’ clinical risks. Our study aimed to develop a novel method for predicting BCR by performing clustering on features extracted from deep learning models, thereby capturing morphological characteristics. Methods: The WSIs and clinical information were collected from The Cancer Genome Atlas (TCGA, from 2000 to 2013) dataset, for 321 patients (43 patients with BCR) who were not treated with any adjuvant therapies, with 2.5 years of median follow-up time. 356 collected WSIs were split into 1024 x 1024 patches at 5x magnification for the deep learning-based analysis. We used an ImageNet-pretrained deep learning-based clustering model (SwAV) to extract features from each patch and applied additional K-means clustering to assign the patches into one of 16 clusters. We tested both the cosine similarity and Euclidean distance as the clustering measure. After excluding the dissimilar patches under specific thresholds, the proportion of each cluster was calculated per slide to describe the distribution of morphological patterns as a 16-dimensional vector. To evaluate the predictability, we trained Cox models with the proportion vectors and assessed their performance via the concordance index (c-index). We repeated a stratified 5-fold cross-validation process 100 times to achieve robustness. As a reference, we conducted the same experiment with a BCR prediction nomogram published by MSKCC. Moreover, with the median proportion of each cluster, we separated two patient groups, drawed Kaplan-Meier curves, performed the log-rank test for significance, and we obtained the hazard ratio (HR) of each cluster from the trained Cox model of each fold. Results: We explored several thresholds to find ones yielding the best performance. When using the similarity, the best c-index was 0.704 with the threshold value of 0.25. With the distance value of 0.60, the c-index was 0.701. When using the MSKCC nomogram that incorporates clinical features, the average c-index was 0.717. The table contains the results of statistical analysis for selected clusterings that were significant in the log-rank test. Particularly in cluster B, the patches showed high-risk patterns including perineural invasion, high grade cancer, and necrosis in agreement with the high HR. Conclusions: Our results suggest that the histomorphological pattern profiles depicted by the deep learning model have the potential for effective risk stratification in prostate cancer. [Table: see text]
Perioperative safety and outcomes following radical prostatectomy in setting of locally advanced, node positive, and metastatic prostate cancer.
Authors: Wang Kerith Ruoyao , Simhal Rishabh , Shah Yash , Mark James Ryan , Shah Mihir S , Gomella Leonard G. , Lallas Costas D. , Chandrasekar Thenappan
Published: June 2023

e17108

Background: Historically, definitive surgical management with radical prostatectomy (RP) has only been considered an option for the treatment of localized prostate cancer (PCa). However, recent data may suggest a role for RP in advanced PCa treatment. Currently, there is limited data on the safety and perioperative outcomes of RP in this setting. Here, we aim to compare the perioperative outcomes of RP for locally advanced, node positive, and metastatic PCa using the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) new procedure targeted database. Methods: RP procedures performed between 2019-2020 were identified. Patients were stratified to compare the effect of locally advanced disease (T3-4), node-positivity (N+), and metastasis (M+) against patients with localized (T1-2 N0 M0) PCa. Baseline demographics and 30-day outcomes, including operative time, hospital length-of-stay, 30-day mortality, readmissions, reoperations, major complications, minor complications, and surgery-specific complications, were compared between groups. Results: Pathologic staging data was available for 9,276 RPs. Baseline demographics were comparable. There was a slightly higher rate of minor-complications in the locally-advanced cohort, but no significant difference in major-complications, 30-day-mortality, readmissions, or rectal injuries. In comparison, while node-positivity was associated with longer operative time, LOS, and incidence of 30-day renal failure, it was not associated with a higher rate of any major, minor or surgery-specific complication. Similarly, RP for metastatic cases appeared to be comparably safe to those with M0 disease, although they were associated with a slightly higher rate of bleeding, prolonged-NG-tube use, and ureteral obstruction. Conclusions: RP for patients with locally advanced, node positive, and metastatic prostate cancer appears to be safe, and is not associated with significantly higher rates of 30-day mortality or major complications compared to localized prostate cancer. Given the previously demonstrated survival benefit in treating the primary tumor in advanced disease with radiation therapy, there may be a role for the RP in treating advanced PCa. Further studies are needed to better characterize the risks and benefits of surgery in these patients.
Biochemical recurrence (BCR) among patients (pts) with prostate cancer (PC) after radiation therapy (RT).
Authors: Spratt Daniel Eidelberg , McKay Rana R. , Khan Nasreen , Constantinovici Niculae , Chen Guifang , Ortiz Jorge A. , Srinivasan Shankar , Vassilev Zdravko , Xu Julie , Shore Neal D.
Published: June 2023

e17111

Background: RT is a frequent primary treatment for pts with clinically localized PC. Despite its frequent success, 30-50% of pts eventually present with BCR, defined as rising prostate-specific antigen (PSA). BCR is associated with a higher risk of developing distant metastasis and ultimately death from PC. Understanding BCR occurrence and its impact on clinical outcomes is important for optimizing diagnostic and therapeutic strategies for recurrent disease. Methods: This is a retrospective cohort study using nationally representative Electronic Medical Records (EMR) data from Optum© from 1/2010-9/2021. Eligible pts were adults who underwent RT after PC diagnosis, had ≥ 3 available PSA values after initiating RT, and had EMR activity for at least 6 mo before and 12 mo after RT. Pts with a history of prior malignancy except nonmelanoma skin cancers and pts with metastatic PC (mPC) at baseline (BL) or within 3 months after RT were excluded. The BL period was 6 mo before RT initiation. Primary outcome was frequency of BCR, defined as rising PSA (PSA ≥ nadir + 2 ng/mL); secondary analyses included % of pts who progressed to mPC, castration-resistant PC (CRPC), and death after BCR and factors impacting time to BCR. Results: 9,292 RT pts were included in this analysis. Key pt characteristics/outcomes are shown in the Table. Median (range) age was 69.0 (40-88) y, 83.2% of pts were White, and 13.4% were Black. Median PSA nadir was 0.11 ng/mL, 32.5% of pts had received androgen deprivation therapy (ADT) during BL period, and median (Q1-Q3) follow-up from RT initiation was 3.8 (2.4-5.7) y. Overall, 10.2% of pts developed BCR. Among BCR pts (n = 949), 51.2% had a PSA doubling time (PSADT) < 6 mo and 16.9% had a PSADT between 6-10 mo; 35.0% developed mPC, 30.2% developed CRPC, and 23.4% died. In multivariate Cox regression models, the BL factor associated with the highest risk of developing BCR was PSA ≥ 20 ng/mL. Conversely, the risk of developing BCR was lower for pts who received ADT during BL. Conclusions: This real-world (RW) study evaluates BCR occurrence in pts who underwent RT with a curative intent from a large US database. The study confirms BL PSA as an important prognostic marker for BCR, while use of ADT before RT is associated with a lower risk of BCR. A considerable % of pts with BCR developed mPC (35%) or died (23%) during the study period. Novel treatment strategies are needed to delay BCR and further progression to advanced PC in pts with high-risk localized disease. [Table: see text]
Biochemical recurrence (BCR) and outcomes in patients (pts) with prostate cancer (PC) following radical prostatectomy (RP).
Authors: Khan Nasreen , McKay Rana R. , Spratt Daniel Eidelberg , Constantinovici Niculae , Chen Guifang , Ortiz Jorge A. , Srinivasan Shankar , Vassilev Zdravko , Xu Julie , Shore Neal D.
Published: June 2023

e17112

Background: RP is often the primary treatment option for pts with clinically localized PC. Despite its frequent success, more than 30% of pts eventually present with BCR, defined as detectable prostate-specific antigen (PSA) after RP. BCR is associated with a higher risk of developing distant metastasis and ultimately death. Current patterns of BCR and the impact of BCR on treatment choice and clinical outcomes are not well characterized. Methods: This retrospective cohort study uses nationally representative Optum© Electronic Medical Records (EMR) data from 1/2010 to 9/2021. Eligible pts were adults who underwent RP after PC diagnosis, had ≥ 3 available PSA values after RP, and had EMR activity for at least 6 mo before and 12 mo after RP. Pts with prior malignancy except nonmelanoma skin cancers and pts with metastatic PC at baseline (BL) or within 3 months after RP were excluded. The BL period was 6 mo before RP. Primary outcome was frequency of BCR (defined as PSA ≥ 0.2 ng/mL); secondary analyses included % of pts who progressed to metastasis, castration-resistant PC (CRPC), and death after BCR, and factors associated with time to BCR. Results: 15,198 pts who underwent RP were included in this analysis. Key pt characteristics/outcomes are shown in the Table. Median (range) age was 63.0 (36-88) y, 85.9% of pts were White, and 10.0% were African American. Median (Q1-Q3) follow-up was 3.9 (2.4-5.7) y, and 14.3% of pts had subsequent adjuvant/salvage radiation therapy (RT). Overall, 19.8% of all pts and 61.4% of the subgroup of 2,178 pts with subsequent RT developed BCR. Among pts with BCR (n = 3,016), 16.3% had a PSA doubling time ≤ 10 mo, 17.1% developed metastasis, 13.8% developed CRPC, and 9.7% died. In multivariate Cox regression models (Table), the BL factors associated with an increased risk of developing BCR were PSA 10- < 20 or ≥ 20 ng/mL, Charlson comorbidity index (CCI) > 0, age ≥ 65, African American race, public insurance, and living in the US South region. Conclusions: This real-world (RW) study evaluates the occurrence of BCR in pts who underwent RP with a curative intent from a large US database. This study confirms BL PSA as an important prognostic marker for BCR. A considerable % of pts with BCR developed metastatic PC (17%) or died (10%) during the study period. Novel treatment strategies are needed to delay BCR and further progression to advanced PC among pts with high-risk localized disease. [Table: see text]
Investigating the association (assoc) between mental health illness (MHI) and development of prostate cancer (PC) in a nationwide matched cohort of >5,000,000 US Veterans.
Authors: Klaassen Zachary , Janes Jessica , Parrish Joshua , Sayyid Rashid K. , McIntire Sydney , De Hoedt Amanda Marie , Satkunasivam Raj , Williams Stephen B. , Wallis Christopher J.D. , Terris Martha K. , Freedland Stephen J.
Published: June 2023

e17113

Background: Previous reports suggest that men with MHI who subsequently develop PC have worse outcomes. However, it has not been established whether a history of MHI is associated with a PC diagnosis (dx) or more aggressive PC. The objective of this study was to (i) investigate the assoc between MHI and development of PC, and (ii) in a subset of men with available Gleason Score (GS) data, assess the assoc between MHI and aggressive PC as measured by GS ≥7 PC at dx. Methods: This was a retrospective matched-cohort analysis to assess the assoc between MHI and time to PC dx in the Veterans Affairs (VA) Health Care System. Men with an ICD code for MHI dx between 2000-2020 were matched 1:1 to men with no MHI dx in the same time frame. The MHI dx date of the exposed (exp) male was assigned as the index date of the unexp male. Variables matched on included race, age at MHI exp (+/- 3 years), census region, and median household income. Uni- and multivariable competing risks models were used to test the assoc between MHI and time to PC using death from other causes as competing risk. In a subset of men with GS data available, logistic regression was used to test the assoc between MHI and GS ≥7 at PC dx. All multivariable models were adjusted for age, race, census region, income, Charlson Comorbidity Index, year of MHI index, and year of VA entry. Results: There were 2,597,810 MHI-exp men matched 1:1 to unexp men. During a median (Q1, Q3) follow up of 128 (65, 192) months, 390,977 PC diagnoses were observed (172,442 MHI-exp vs. 218,535 unexp). MHI-exp men were significantly less likely to be diagnosed with PC than unexp men in both uni- (HR: 0.798, 95% CI: 0.793-0.803) and multivariable (HR: 0.763, 95% CI: 0.758-0.768) analysis. Cumulative incidence estimates at 3, 5, 10, and 20 years were 2.1%, 3.1%, 5.2%, and 8.5%, respectively, for MHI-exp men vs 2.9%, 4.2%, 6.9%, and 11.7%, respectively, for unexp men. Among men with PC and available GS data (n = 51,404), 32,645 had GS ≥7 PC, of which 20,749 were MHI-exp vs 11,896 unexp. MHI-exp men had significantly higher odds of GS ≥7 PC in both uni- (OR: 2.38, 95% CI: 2.32-2.43) and multivariable (OR: 1.97, 95% CI: 1.92-2.02) analysis. Conclusions: Men with MHI are 20% less likely to be diagnosed with PC, however when diagnosed, are nearly 2 times more likely to have aggressive PC compared to non-MHI men. Although speculative based on the nature of the study, this may be due to poorer access to preventative health services resulting in delayed diagnoses.
Evaluating genetic screening/counseling for patients diagnosed with prostate cancer who meet hereditary risk assessment based on NCCN Guidelines.
Authors: Ruiz Vega Ruben , Abidoye Oluseyi , Adewunmi Comfort , Ghosh Aditya Kumar , Caton Andria P. , Johnson Andrew Thomas
Published: June 2023

e17117

Background: Prostate cancer is most common cancer among men and is the second leading cause of cancer deaths in American men. Genetic predisposition to cancer is increasingly noted as a cause in many cancers including prostate cancer. Genetic testing and counseling are recommended in certain groups of men; Men with or without a personal history of prostate cancer who have a family history of prostate, breast, colon, ovarian, or pancreatic cancers, especially if any of these were diagnosed under age 50 and those with metastatic prostate cancer. A recent study of 3,600 men with prostate cancer found that 17% had inherited genetic mutations that may have contributed to their cancer. Of those men, 31% of the mutations were in the BRCA genes. Because of this, familiarity and understanding of the most current clinical guidelines for genetic risk assessment are of great importance in the survivorship care of men with prostate cancer. The National Comprehensive Cancer Network (NCCN) guidelines recommends genetic assessment/counseling for genetic/familial high-risk individuals diagnosed with prostate cancer. This retrospective study reports on adherence to genetic screening based on NCCN guidelines for newly diagnosed Prostate cancer patients who were receiving treatment at Northeast Georgia Medical Center (NGMC). Methods: We obtained data using EPIC database from NGMC electronic medical records to identify patients who were diagnosed between 1/1/20-12/31/20. Data included patients who were high risk and fit the criteria for genetic testing based on NCCN as well as identifying patients who were sent for genetic testing/counsellng. The dataset was de-identified and analyzed using appropriate descriptive statistical testing. Results: A total of 42 cases for prostate cancer were reviewed. All 42 of the cases were under the age of 60 at diagnosis. A total of 13 of the cases meet the genetic/familial high-risk assessment based on NCCN guidelines. Of the 13 of the cases, only 1 case was referred for genetic counseling which was 7.6% compliance with NCCN guidelines for genetic counseling/referral. In terms of high-penetrance prostate cancer risk screening, none of the 13 cases (0%) meeting genetic/familial high-risk were screened. Based on our findings, there was poor adherence in genetic testing/counseling in high risk patients with prostate cancer at NGMC. Conclusions: This study points out poor adherence to NCCN guideline directed genetic counseling/testing in high risk patients with prostate cancer. Based on findings, it is clear that high importance should be placed on awareness on the current guidelines in relation to gene testing for patients who are high risk as this would play an important role in identifying family members who at risk and ensure early screening.
Bone health practices in metastatic prostate cancer (mPCA).
Authors: Eule Corbin Jeffrey , Hu Junxiao , Gilbert Danielle , Eskandar Joy , Lam Elaine T.
Published: June 2023

e17119

Background: Patients (pts) with mPCA and bone metastases (BM) are at risk for skeletal-related events (SREs), which include pathologic fracture, bone irradiation or surgery, spinal cord compression, and hypercalcemia. This study examined the evaluation, prevention, and treatment of osteopenia/-porosis (OP/P) and BM in pts with mPCA at the UCCC and affiliated sites. Methods: Pts diagnosed with mPCA and BM between 2011-2021 and treated with ADT were included. Demographic, clinical, treatment, and outcomes data were retrospectively collected. The primary endpoint was time from mPCA diagnosis to first SRE. Secondary endpoints included rates of DEXA scans, rates of vitamin D and calcium supplementation, and bone agent toxicity. The log-rank test was conducted to compare the primary endpoint by use of a bone strengthening agent. The Kruskal Wallis non-parametric test was used for continuous variables and Fisher’s exact test for categorical variables. Results: Of the 369 pts with mPCA, 247 (66.9%) were treated with a bone agent. Median age at metastatic diagnosis (mDx) was 69.6 years. Pts were predominately white (315, 85.4%) with hormone-sensitive mPCA (mHSPC) (327, 88.6%) at mDx. There were no significant differences in race, ethnicity, PSA, Gleason score, or time on ADT between patients who did and did not receive a bone agent. 222 pts (60.2%) were former or current smokers, 5 (1.4%) had pre-existing low testosterone ( < 150 ng/dL), 8 (2.2%) had prolonged glucocorticoid use (equivalent > 10 mg prednisone for 30 days), and 17 (4.6%) had known OP/P prior to mDx. 130 pts (35.3%) had a DEXA scan (27 pre-ADT, 103 post-ADT). 325 pts (88.1%) and 286 pts (77.5%) were recommended vitamin D and calcium supplementation, respectively. Bone agent use and toxicity are presented in table 1. 110 of 247 pts (44.5%) treated with a bone agent were started in the mHSPC setting without OP/P. Time from mPCA diagnosis to first SRE was a median of 32.8 months (IQR 13.5 to 66.8) for pts who received a bone agent vs. 28.2 months (IQR 8.7 to 59.1) who did not (Chi-squared = 7.089, p = 0.008). Among SREs, 102 pts (27.6%) had a pathologic fracture, 1 (0.3%) severe hypercalcemia > 14 mg/dL, 23 (6.2%) bone surgery, 142 (38.5%) bone irradiation, and 4 (1.1%) spinal cord compression. Conclusions: Bone agent use was associated with an expected improvement in time to first SRE. Pts with mPCA had high rates of vitamin D and calcium supplementation for OP/P prevention. Denosumab was the most used bone agent in concordance with guidelines for mPCA. DEXA scan rates were low, and nearly half of patients received a bone agent prior to castrate resistance. [Table: see text]
Treatment trends and prognostic factors related to histology of squamous cell carcinoma of the prostate: A SEER review.
Authors: Siripurapu Vaishnavi , Pasli Melisa , Bhatt Arjun , Ashley Lucas W. , Gordon Julian , Peach Matthew Sean
Published: June 2023

e17120

Background: Excluding skin cancers, prostate cancer is the most common malignancy in males. Over 93% of prostate cancers are adenocarcinomas, and as such, an abundance of literature exists with regards to its screening, treatment, and prognosis. Often overlooked, however, data is lacking with regards to squamous cell carcinoma (SCC) of the prostate, a rare alternative form of prostatic cancer comprising fewer than 1% of malignancies. Given the rarity of SCC of the prostate there are neither accepted treatment guidelines nor consistent characterizations of the disease’s histogenesis and histopathology. This study seeks to improve existing guidelines on the treatment of prostate SCC by supplementing current literature with a novel method of longitudinal data collection in the form of the SEER database. Methods: This was a retrospective cohort study utilizing the Surveillance, Epidemiology and End Results (SEER) database sponsored by the National Cancer Institute (NCI). Investigated variables entailed patient demographics such as race and age, tumor characteristics including grade, tumor type, and histopathologic characteristics. Treatment modalities (surgical resection, radiation therapy, and systemic therapy) as well as disease characteristics were considered in generating Kaplan Meier overall survival (OS) curves compared using log rank test. Results: The most abundantly utilized treatment was surgery (58.6%), either alone or in conjunction with systemic and radiotherapy. Surgery alone was utilized for 24 patients and chemotherapy alone was utilized for 7 patients. Interestingly, only 14% of patients received multimodality treatment. Prostatic squamous cell carcinoma was the ultimate cause of death in 63.8% of cases. Kaplan Meier analysis demonstrated a median OS of 13 months. When stratifying by histopathologic characteristics, our results showed a significant difference in overall survival between patients with papillary carcinoma, with the median survival time of four years, and non-keratinizing squamous cell carcinoma, with a median survival time of one year (p = 0.005). Conclusions: Further studies are warranted regarding this exceedingly rare and understudied malignancy. The current analysis suggests subclassification of SSC of the prostate into papillary versus non-keratinizing squamous cell carcinoma may yield valuable prognostic information. Further research may emphasize this distinction as well as the role of multimodal treatment which appears to be underrepresented in SSC of the prostate when compared to other similar malignancies.
Update on the outcome of patients with metastatic prostate cancer in Kentucky: A Kentucky Cancer Registry (KCR) study.
Authors: Pandey Deepali , Chen Quan , Huang Bin , Myint Zin , Wang Peng
Published: June 2023

e17121

Background: Overall survival (OS) of metastatic Prostate Cancer (mPC) in USA has improved by 3.6% during 2011–2016 compared to 2001–2005 (CDC, Oct 2020). Improvements in OS for mPC might reflect changes in clinical management, with approval of several new treatments. We aim to analyze if there is an improvement in OS of mPC in Kentucky between 2004-2011(T1) and 2012-2019(T2) and also analyze the impact of socioeconomic status as defined by Area Deprivation Index (ADI) on survival of mPC. Methods: All Kentucky male patients diagnosed between 2004 and 2019 who were > 20 years old at diagnosis with first primary of metastatic prostate adenocarcinoma were extracted from the Kentucky Cancer Registry (KCR) data. Basic demographics and survival outcomes were compared between two time periods - T1 vs T2 and by Appalachian status. Kaplan Meir (KM) and Multivariate Cox Regression (MCR) were used to examine OS. ADI is divided into three groups – bottom tertile (low deprivation-ADI 1-3, Gr 1), middle tertile (ADI 4-6, Gr 2), and top tertile (high deprivation-ADI 7-10, Gr 3). Results: A total of 2619 patients with mPC were included in this retrospective analysis, of which 69.3% were Non-Appalachian (Non-AP) and 30.7% were Appalachian (AP). Caucasians predominated in both time periods (89.2% vs 90%). T2 had a higher proportion of patients aged 50-74 years (72.5% vs 64.2%), and private insurance (31.4% vs 27.1%) compared to T1. T1 had more patients who were > 75 years (31.6% vs 24.8%), smokers (51.2% vs 47.4%), had medicare (59.6% vs 56.8%) and no insurance (4.2% vs 1.5%) compared to T2. KM showed improved OS in T2 (p < 0.0001). Non-AP had better OS compared to AP and improved more between T1 & T2. Median OS in months(95% CI) in T1 vs T2 for Non-AP was - 30(27-38) vs 58(53-69), p < 0.0001 & for AP was -34 (27-39) vs 44 (37-51), p = 0.0163. MCR showed that younger age, private insurance, being a nonsmoker, and receiving treatment, contributed to better OS. Gr 3 had higher proportion of African Americans (10.7% vs 6.5%), less private insurance (23.9% vs 39.7%) and more patients receiving no treatment (10.9% vs 7.5%) compared to Gr 1. AP Kentucky had more patients in Gr 3 (60.5% vs 39.5%) compared to Non-AP. KM showed OS had improved for all ADI groups in T2 vs T1. Within ADI groups, Gr 3 had significantly lower OS compared to Gr 1 & Gr 2 (p = 0.04) in T2. In T1, OS was not different within ADI groups. In MCR, race and ADI did not impact OS. Conclusions: OS has improved in mPC patients in Kentucky during 2012-2019, likely due to new treatments being available. There is improvement in OS in Appalachian Kentucky but numerically lower than Non-Appalachian, and worse OS in Gr 3 during 2012-2019 which could be partially due to differences in access to new treatments (or quality of care). Interestingly, race did not impact survival.
The insights of mutations of gynecological oncology by liquid biopsy for Chinese patients.
Authors: Huang Yan , Yin Yan , Peng Bo , Hu Bo , Chen Shifu , Zhang Meiqin
Published: June 2023

e17501

Background: Liquid biopsy drew dramatic attention in the field of cancer research because of its attribution of nontraumatic, easy to obtain, providing overall state of tumor, allowing for real-time monitoring and so on. However, the transformation from research to application of liquid biopsy technique in clinical gynecological oncology management require more evidence and further investigation. Methods: Blood samples of 104 patients were collected, of whom 33 were diagnosed as cervical cancer, 20 were diagnosed as endometrial cancer, and 51 were diagnosed as ovarian cancer. cfDNA were extracted from blood and examined by next-generation sequencing technique with Haplox HapOnco panel. cfDNA mutations were analyzed and compared with genomic mutations in tumor tissues in publications. Results: In cfDNA, there were 120 genes mutated in cervical cancer patients, 150 genes mutated in endometrial cancer patients, and 58 genes mutated in ovarian cancer patients. Detecting by cfDNA, the average number of mutations was 6 (4.1 to 7.9, 95% CI) for each cervical cancer patient, 8.1 (2.1 to 14.1, 95% CI) for each endometrial cancer patient, and 5.1 (3.7 to 6.5, 95% CI) for each ovarian cancer patient. As the mutations in cfDNA compared with those in tumor tissues, the results revealed that there was no significant difference in mutation rate for 94.2% genes in blood and tumor tissues for cervical cancer patients, 93.3% for endometrial cancer patients, and 98.3% for ovarian cancer patients. Besides, there were no significant differences in microsatellite instability rates in blood and tumor tissues for cervical cancer patients and endometrial cancer patients. Conclusions: Most mutated genes in tumor tissues were detected in blood for gynecological oncology patients. The mutation rate for most genes and microsatellite instability rate had no significant difference in blood and tumor tissues, which suggested that liquid biopsy using cfDNA is helpful in gynecological oncology management.
AXL pathway as a target to overcome resistance to PARP inhibitors in high-grade serous ovarian (HGSOC) and triple-negative breast cancer (TNBC) cell lines.
Authors: Perez-Fidalgo Jose Alejandro , Martinez Pretel Juan Jose , Sanchez Serrano Paloma , Heredia Victoria , Hochstadt Jan , Mendiola Marta , Redondo Andres , Gonzalez Villena Lidia , Ruiz Linuesa Miriam , Pineda Begona
Published: June 2023

e17502

Background: PARP inhibitors (PARPi) as olaparib (OLA) have become the new standard in maintenance treatment in high grade serous ovarian carcinoma (HGSOC) and triple negative breast cancer (TNBC). Thus there is an important need to identify the mechanisms for PARPi resistance and the strategies to overcome it. Our aim is to intervene in vitro AXL, a receptor tyrosine kinase, linking its function to the OLA-resistance mechanism and assess its suitability as a therapeutical target to overcome PARPi-resistance. Methods: Three cell lines, 2 from HGSOC (PEO1-S and Kuramochi-S) and 1 from TNBC (MDA-MB-231-S) were selected, isogenic resistant pairs generated in vitro by pulsed exposure to OLA (PEO1-R) or by exposure to growing concentrations of OLA (Kuramochi-R and MDA-MB-231-R) were obtained. Resistance was confirm by the comparison of IC50 of OLA in -S vs -R lines. AXL expression was assessed by western blot (WB). Cells were treated with OLA before and after the downregulation of AXL expression by a specific siRNA. Cell viability was assessed by MTT assay and DNA damage by the evaluation of markers by western blot (WB). Results: AXL expression was maintained upon OLA treatment in all 3 resistant cell lines. However, AXL expression was reduced upon OLA exposure in 3 sensible parental cell lines. AXL silencing (Si) lead to a significantly decrease of OLA IC50 in all 3 sensitive and resistant cell lines. For sensitive cell lines, IC50 of OLA was in 1) PEO1S with control (scramble) was 5.79 mM vs 2.24 mM after silencing with siRNA, p < 0.0001; 2) Kuramochi-S scramble OLA IC50 was 481.8 mM vs 199.7 mM with siRNA, p < 0.0001 and 3) MDA-MB-231-S with control of scramble the OLA IC50 was 61.62 mM vs 26.21 mM with siRNA, p = 0.001. For resistant cell lines, 4) PEO1R control with scramble 91.49 mM vs siRNA 45.72 mM, p < 0.0001; 5) Kuramochi-R scramble OLA IC50 579.8 mM vs 219.8 mM with siRNA, p = 0.0008 and 6) 231-R scramble OLA IC50 68.22 mM vs 9.247 mM with siRNA, p < 0.0001. These results suggest that AXL downregulation increases sensitivity to OLA in both sensitive and resistant cell lines. Histone γ-H2AX was analysed pre and post silencing and both increased when treating with OLA, especially when AXL was downregulated in alll three resistant cell lines. Conclusions: This in vitro study suggest a potential role of AXL in OLA resistance and AXL downregulation migh represent a potential mechanism to overcome resistance to OLA in ovarian and TNBC cell lines.
Incidence of low volume metastases after retrospective ultrastaging of patients with early stage, node negative cervical cancer and receipt of post-operative adjuvant therapy.
Authors: Welp Annalyn , Crawford Michael , O'Brien Rachel , Sullivan Stephanie , Duska Linda R.
Published: June 2023

e17506

Background: Nodal positivity directs receipt of adjuvant post-operative therapy in early stage cervical cancer; the significance of low-volume metastases (LVM) is unclear. We hypothesized patients with early stage cervical cancer with high risk factors on pathology and negative nodes would have a higher incidence of LVM on retrospective ultrastaging. Methods: This retrospective cohort study collected clinicopathologic data via chart review on early stage cervical cancer patients treated at our institution from January 2011 - June 2021. The study was approved by the IRB. Inclusion criteria included patients >18 years old who underwent a radical hysterectomy/trachelectomy with pathology-proven negative nodes who went on to be recommended for post-operative adjuvant therapy, due to factors defined under Sedlis or Peters criteria. Patients were excluded for rare histology or prior pelvic radiation. Resected nodes were ultrastaged, performed by 4 re-cuts at 20 microns on each lymph node staging, stained with H&E and one level with CK AE1/AE3 to identify presence of any LVM. Analysis was performed via descriptive statistics with Microsoft Excel. Results: 199 patients were treated with radical hysterectomy between 2011-2021; 20 met study criteria. The average age at diagnosis was 51 years: 65% Caucasian, 25% Black, 10% Latino. 75% had Squamous cell carcinoma, 85% (n=17) of the cohort were a 2009 FIGO pathologic Stage 1B. 35% of the cohort underwent a minimally invasive hysterectomy. Tumor size varied: 25% (n=5) of tumors were less than 2 cm, 35% (n=7) of tumors measured greater than or equal to 2 cm, 30% (n=6) measured greater than or equal to 3 cm, and 10% (n=2) measured greater than or equal to 4 cm. Lymphovascular space invasion was noted in 75% (n=15) of samples. Superficial stromal invasion was noted in 5% (n=1), deep stromal invasion was noted in 65% (n=13). 5% (n=1) of patients had parametrial invasion, and 5% (n=1) had positive margins. A full bilateral pelvic lymphadenectomy was performed on every patient, with 245 nodal blocks ultrastaged. 80% (n=16) received adjuvant therapy: 3 chemoradiation, 13 radiation, 4 declined. LVM was identified in 5% (n=1) patients; a macrometastases was identified as missed in the initial pathologic evaluation of another. 10% (n=2) patients developed recurrence, one at the pelvic brim and one distant (lung). The patient with the newly identified LVM received adjuvant radiation, and developed recurrence at the pelvic brim. Conclusions: The results of this small study suggest traditional “high risk” factors in surgically managed cervical cancer is associated with positive ultrastaged nodes in 5% of cases. This finding suggests that utilization of sentinel node identification with associated ultrastaging will accurately identify patients who will benefit from adjuvant therapy.
18F-FDG PET/CT parameters in precision treatment planning for locally advanced squamous cell carcinoma of the uterine cervix.
Authors: Lai Chyong-Huey , Liu Feng-yuan , Chen Wei-Chun , Yang Lan-Yan , Wang Chun-Chieh , Chao Angel
Published: June 2023

e17508

Background: Concurrent chemoradiotherapy (CCRT) is the standard of care for locally advanced cervical cancer. We aimed to analyze pretreatment 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters and clinicopathological characteristics in patients with locally advanced cervical squamous cell carcinoma (SCC) to establish a scoring system for prognostic stratification. Methods: Cohort 1 consisted of patients with cervical SCC with FIGO (2009) stage III-IVA or stage I-II with positive nodes on PET/CT recruited in AGOG09-001 trial. Cohort 2 consisted of institutional patients treated in 2016-2020 with similar inclusion criteria. Pretreatment clinical characteristics and PET/CT parameters including maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of cervical tumor and nodal SUVmax were assessed for outcomes using the stepwise multivariable Cox regression. Results: With two cohorts combined (Cohort 1, n= 55, Cohort 2, n= 120), the median follow-up for 175 patients was 55 months (range, 2-164). Age (≥66 years old), MTV (≥87.1 mL) of cervical tumor and PET/CT-defined para-aortic lymph node (PALN) metastasis were independent significant adverse predictors for cancer-specific survival (CSS) ( P<0.001, P=0.002, and P=0.033, respectively). Counting each risk predictor as score one, patients with risk score sum 0, 1, 2, 3 had a 5-year CSS of 85.8%, 68.5%, 29.7%, and 0%, respectively ( P<0.001). Conclusions: Age, cervical tumor MTV and PET/CT-defined PALN metastasis are independent risk predictors in locally advanced cervical SCC. Patients with risk score sum 0 may receive CCRT with single-agent cisplatin, while patients with risk score sum ≥1 may consider receiving novel combination therapies or entering clinical trials.
Penpulimab plus platinum-based chemotherapy combined with anlotinib in first-line treatment for persistent, recurrent, or metastatic cervical cancer: A single-arm, open-label phase Ⅱ study (ALTN-AK105-II-06).
Authors: Xu Qin , Liu Jing , Li Li , Lin Yibin , Chen Ying , Song Yanwen , Luo Lan
Published: June 2023

e17512

Background: Penpulimab is a novel human immunoglobulin G1 (IgG1) anti-programmed cell death-1 (PD-1) antibody. Anlotinib is a novel oral multi-target tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. ALTN-AK105-II-06 (ChiCTR2200062897) is a single-arm, open phase Ⅱ clinical trial aimed to assess the effiacy and safety of penpulimab plus chemotherapy combined with anlotinib as fist-line therapy for persistent, recurrent, or metastatic cervical cancer. Methods: Eligible adults with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy and not amenable curative treatment, with CPS more than 1% PD-L1 expression, and ECOG 0-1 were considered eligible for enrolment. Patients received 2 cycles of penpulimab 200mg Q3W + chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) + anlotinib 10mg, following with penpulimab and anlotinib for maintenance therapy. Patients were treated on continuous 3 weeks of penpulimab for up to 2 years, until disease progression, or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS), 6-month PFS, safety and quality of life. Results: From Sep 2022 to Feb 2023, 9 patients were recruited with a median age of 56.4 years (range: 45-66), FIGO histopathological stage IIB (33.3%), III (44.5%) and IV (22.2%) were enrolled. 22.2% patients had ECOG PS 0. At data cutoff date (Feb 02, 2023), 8 patients had at least one post treatment anti-tumor assessment. 1 (12.5%) patient achieved CR, 6 (75%) patients achieved PR and 1 (12.5%) patient NE. The ORR was 87.5%. Median PFS and OS were not reached. Grade ≥3 TRAEs incidence was 44.44%. The most common grade ≥3 TRAEs were hypertension (22.22%), leukopenia (11.11%), neutropenia (11.11%) and hypertriglyceridemia (11.11%). Conclusions: This chemo-less therapy of only 2 cycles of chemotherapy combined with penpulimab + anlotinib in first-line treatment, maintaining with penpulimab and anlotinib showed promising efficacy with a favourable toxicity profile for patients with persistent, recurrent, or metastatic cervical cancer. We will report more data in the future. Clinical trial information: ChiCTR2200062897 .
Circulating exosomal PD-L1 to predict response with immunotherapy in patients with advanced cervical cancer.
Authors: Tang Wenjie , Guo Qiufen , Chen Jinlong , Wu Qian , Zhang Tingting , Wang Qian , Zhang Xueliang , Xie Peng
Published: June 2023

e17514

Background: Programmed death ligand 1 (PD-L1) expression was wildly used to predict immune Check-Point Inhibitors (ICIs) efficiency. However, emerging results showed that PD-L1 was of great heterogeneity in sampling time and site. Recently, some studies found that exosomal PD-L1(ExoPD-L1) was related to ICIs response. In this study, we aimed to explore the predictive value of ExoPD-L1 in ICIs treatment of cervical cancer (CC) for the first time. Methods: 40 primarily diagnosed CC patients who accepted radical radiotherapy (RT) were included. The consecutive tumor sample were collected before and during RT. Another 37 advanced CC patients who accepted ICIs combination therapy were collected. Blood samples were collected from each participant before and during treatment. Exosomes were derived by differential centrifugation, which was further identified by Western blot (CD9/TSG101/Calnexin), transmission electron microscope analysis and nanoparticle tracking analysis. ExoPD-L1 detection was conducted by enzyme-linked immuno-sorbent assay (ELISA). The knockout of PD-L1 was conducted via CRISPR/Cas9 assay and the overexpress of PD-L1 was conducted by lentiviral transfection. CD8+ T cells were extracted from murine spleen by CD8+ T Cell Isolation Kit. Immune cells and cytokines markers were detected by multicolor flow cytometry. Results: The consecutive detection of PD-L1 showed a dynamic change during RT. Compared with the level before RT, PD-L1 expression elevated in most patients (87.5%, 35/40) after RT. And the responders (n = 18) had elevated ExoPD-L1 level at the first two circles in the ICIs combination therapy (P < 0.001). Whereas the level of pre-treatment ExoPD-L1 couldn’t stratified clinical responders and non-responders (P = 0.181). The median follow-up time was 14.13 months. The mPFS in increased group vs. decreased group: not reach vs.11.02 months (P = 0.025, HR: 0.218, 0.052-0.913). Continuous blood sampling of mice models also found that effective therapeutic intervention could increase ExoPD-L1 in the early stage. The combination of exosome inhibitor GW4869 and anti-PD-1 further inhibited tumor growth. Mice were injected with external ExoPD-L1OE and ExoPD-L1KO. The results showed that ExoPD-L1OE suppressed body immunity and promoted tumor growth. The results of flow cytometry showed that ExoPD-L1OE inhibited CD8+ T cells from releasing interferon-γand granzyme B. And ExoPD-L1OE also suppressed the CD8+ T cells proliferation in murine spleen. The coculture of CD8+ T cells and exosomes in vitro also confirmed the above conclusion. Conclusions: Compared with unstable and impressionable tumoral PD-L1, ExoPD-L1 seems to be better predictor for the efficacy of immunotherapy in CC, which was with easy accessibility and continuation. Exosome PD-L1 played an immunosuppressive role by inhibiting the proliferation and functional factor release of CD8+ T cell.
The safety and efficacy of cadonilimab in the treatment of advanced and metastatic cervical cancer: A retrospective, real-world study.
Authors: Fan Shi , Wang Tao , Zhang Qiying , Wang Juan , Su Jin , Zhang Jing , Wang Fei , Liu Zi
Published: June 2023

e17515

Background: Recurrent/metastatic cervical cancer (r/m CC) patients have limited treatment options. Cadonilimab, a PD-1/CTLA-4 bi-specific antibody, was approved in China on 29 June 2022 for the treatment of patients with r/m CC who have progressed on or after platinum-based chemotherapy. As monotherapy provides encouraging safety and efficacy, it may be better combined with another therapy including chemotherapy, radiotherapy, targeted therapy, or immunotherapy. The objective of this retrospective study was to evaluate the safety and efficacy of Cadonilimab monotherapy/combination therapy in patients with advanced r/m CC. Methods: Patients with FIGO stage IIIc2r-IVb CC treated with Cadonilimab containing therapy were enrolled. All patients received at least one dose of Cadonilimab (10mg/kg, Q3W), among them, 5 patients received Cadonilimab monotherapy, 11 patients received concurrent radiotherapy, 19 patients received concurrent chemotherapy, 12 patients received targeted therapy, and 4 patients received local injection s of oncolytic virus. Treatment-related toxicity (TRAEs), objective response rate (ORR) and disease control rate (DCR) were evaluated. Results: 26 patients with a median age of 54 years (40-73 years) were evaluated up to 20 January 2023. As shown in the table, 21 patients were still on treatment, 5 patients were discontinued due to death. In the efficacy-evaluable population(n=24), the ORR was 70.8% (17/24,95% CI:51.2%-90.4%) with 3 (12.5%) CR,14 PR, 2 SD, and the DCR was 79.2%(19/24,95% CI:61.6%-96.7%). Immune-related AEs (irAEs) were all G1-2, and occurred in 4 (16.7%) patients. Main irAEs included hypothyroidism (n=3, 12.5%), fatigue (n=1, 4.2%), loss of appetite (n=1, 4.2%), hematologic toxicity (thrombocytopenia) (n=1, 4.2%), mucositis (n=1, 4.2%), and rash (n=1, 4.2%). Rashes and loss of appetite typically developed after the first cycle of Cadonilimab treatment, while hypothyroidism usually developed after the second or third cycle. 2 (8.3%) patients experienced G3-5 TRAEs, which were thought to be primarily related to chemotherapy. All the 5 deaths were heavily pretreated (≥3 lines) patients who received Cadonilimab monotherapy. Among the 24 patients, only 1 patient delayed treatment after the 1st cycle due to economic reasons. There were no toxic deaths reported. Conclusions: In the real world, Cadonilimab showed a manageable safety profile. Patients with advanced r/m CC tend to benefit from first-line/second-line Cadonilimab containing combination therapies due to the excellent response rates. [Table: see text]