bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Babesia microti infection on the initiation and course of pregnancy in BALB/c mice
Authors: Tołkacz Katarzyna , Rodo Anna , Wdowiarska Agnieszka , Bajer Anna , Bednarska Małgorzata
Published: March 2021

Background

Protozoa in the genus Babesia are transmitted to humans through tick bites and cause babesiosis, a malaria-like illness. Vertical transmission of Babesia spp. has been reported in mammals; however, the exact timing and mechanisms involved are not currently known. The aims of this study were to evaluate the success of vertical transmission of B. microti in female mice infected before pregnancy (mated during the acute or chronic phases of Babesia infection) and that of pregnant mice infected during early and advanced pregnancy; to evaluate the possible influence of pregnancy on the course of parasite infections (parasitaemia); and to assess pathological changes induced by parasitic infection.

Methods

The first set of experiments involved two groups of female mice infected with B. microti before mating, and inseminated on the 7th day and after the 40th day post infection. A second set of experiments involved female mice infected with B. microti during pregnancy, on the 4th and 12th days of pregnancy. Blood smears and PCR targeting the 559 bp 18S rRNA gene fragment were used for the detection of B. microti. Pathology was assessed histologically.

Results

Successful development of pregnancy was recorded only in females mated during the chronic phase of infection. The success of vertical transmission of B. microti in this group was 63%. No evidence of pregnancy was found in females mated during the acute phase of infection or on the 4th day of pregnancy. In the group infected on the 12th day of pregnancy, numerous complications including loss of pregnancy and stillbirths were recorded. During the acute phase of infection, parasitaemia was lower in pregnant females in comparison to infected, non-pregnant control females.

Conclusions

Acute B. microti infection prevents the initiation of pregnancy and embryonic development if it occurs during the first trimester, and causes severe complications in foetal BALB/c mice in the second and third trimesters of pregnancy. Chronic B. microti infection has no detrimental impact on the initiation and development of pregnancy, but results in congenital infection of the offspring. Further study is required to determine the extent to which maternal anti-babesial immune responses contribute to compromise pregnancy in the murine model of congenital Babesia infection.

Graphical Abstract
Prevalence of schistosomiasis and its association with anemia among pregnant women: a systematic review and meta-analysis
Authors: Adam Ishag , ALhabardi Nadiah A. , Al-Wutayd Osama , Khamis Ammar H.
Published: March 2021

Background

Schistosomiasis is a highly prevalent parasitic disease that can lead to adverse maternal and perinatal outcomes. To our knowledge, there has been no systematic review and meta-analysis of schistosomiasis during pregnancy.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant published studies were searched in international databases (PubMed, Science Direct, Scopus, Web of Science, and Google Scholar), from their inception until May 31, 2020. The retrieved studies were assessed for quality using the Modified Newcastle-Ottawa Scale. OpenMeta Analyst software was used for the statistical analysis.

Results

Thirty-two studies enrolling 21024 pregnant women were included in this meta-analysis. All 32 of these studies were conducted in Africa. Of these studies, 19, 11, and 2 investigated S. mansoni, S. haematobium, and combined S. mansoni and S. haematobium infections, respectively. The pooled prevalence estimate of schistosomiasis during pregnancy was 13.2% (95 CI 11.0–15.4). A random model was used because of high heterogeneity (Q = 99.14; P < 0.001). In subgroup analyses, the pooled prevalence estimate of S. haematobium was significantly higher than the pooled prevalence estimates of S. mansoni [22.5% (95% CI 1.6–43.5) vs 8.7% (95% CI 6.0–11.3, P = 0.016), respectively]. The results of meta-regression analyses showed a non-significant difference in the prevalence of schistosomiasis during pregnancy according to the study sample sizes and year of publication. Only six studies evaluated the association between schistosomiasis during pregnancy and anemia. Schistosomiasis was associated with anemia in these six studies (OR = 3.02, 95% = 1.25‒7.28, P = 0.014).

Conclusion

The present meta-analysis suggests that schistosomiasis during pregnancy is an existing health problem. This meta-analysis also highlights the lack of data on the determinants and outcomes of schistosomiasis during pregnancy. Preventive measures are needed and could be part of antenatal care in areas endemic with schistosomiasis.

Graphical Abstract
Metabolomics study for exploring metabolic perturbations in soybean adventitious roots by fluorescent light irradiation
Authors: Yun Dae-Yong , Kang Young-Gyu , Lee Eun Jung , Kim Donghyun , Kim Eun-Hee , Hong Young-Shick
Published: March 2021

Soybeans are the most popular cultivated crops worldwide. They contain abundant functional components. As part of the research to enhance functional components in soybean plants, soybean adventitious roots were cultured under dark and fluorescent light irradiation conditions and difference in their metabolome was explored using 1H NMR-based metabolomics approach. Results revealed that fluorescent light irradiation increased the biomass of soybean adventitious roots and caused considerable metabolic perturbations. In particular, health-beneficial secondary metabolites such as soyasaponin (3.4-fold), isoflavones (3.9-fold), and coumestrol derivatives (1.3-fold) were accumulated more in soybean adventitious roots grown under fluorescent light irradiation than in those grown under a dark condition due to increased photosynthesis that was evidenced by increased levels of glucose. The present study provides useful information on global metabolite compositions of soybean adventitious roots and their quality improvement by controlling growth conditions to enhance functional potentials of soybeans.
Impact of the COVID-19 outbreak on the US equity sectors: Evidence from quantile return spillovers
Authors: Shahzad Syed Jawad Hussain , Bouri Elie , Kristoufek Ladislav , Saeed Tareq
Published: March 2021

The aim of this study is to examine the extreme return spillovers among the US stock market sectors in the light of the COVID-19 outbreak. To this end, we extend the now-traditional Diebold-Yilmaz spillover index to the quantiles domain by building networks of generalized forecast error variance decomposition of a quantile vector autoregressive model specifically for extreme returns. Notably, we control for common movements by using the overall stock market index as a common factor for all sectors and uncover the effect of the COVID-19 outbreak on the dynamics of the network. The results show that the network structure and spillovers differ considerably with respect to the market state. During stable times, the network shows a nice sectoral clustering structure which, however, changes dramatically for both adverse and beneficial market conditions constituting a highly connected network structure. The pandemic period itself shows an interesting restructuring of the network as the dominant clusters become more tightly connected while the rest of the network remains well separated. The sectoral topology thus has not collapsed into a unified market during the pandemic.
Effect of copper sulfate on the external microbiota of adult common snook (Centropomus undecimalis)
Authors: Tarnecki Andrea M. , Levi Noah J. , Resley Matthew , Main Kevan
Published: March 2021

Background

The environment exerts a strong influence on the fish external microbiota, with lower diversity and increased abundances of opportunistic bacterial groups characterizing cultured fish compared to their wild counterparts. Deviation from a healthy external microbiota structure has been associated with increased susceptibility to bacterial pathogens. Treatment of wild-caught broodstock with copper sulfate for the removal of external parasites is a common aquaculture practice. Despite the microbiota’s importance to fish health, the effects of copper sulfate on mucosal bacterial communities and their ability to recover following this chemical treatment have not been examined. The skin microbiota of adult common snook was characterized from wild individuals (Wild), and wild-caught fish maintained in recirculating aquaculture systems (RAS) immediately following a month-long copper sulfate treatment (Captive-1), and then two-weeks (Captive-2) and 2 years (Captive-3) after cessation of copper treatment.

Results

The skin microbiota of wild fish were characterized by high diversity and taxa includingSynechocococcus, SAR11, and a member of theRoseobacterclade. Bacterial diversity decreased in Captive individuals during the 2-year sampling period. Captive fish harbored greater abundances ofFirmicutes, which may reflect glycan differences between aquaculture and natural feeds. Bacterial taxa with copper resistance mechanisms and indicative of metal contamination were enriched in Captive-1 and Captive-2 fish.Vibrionaceaewere dominant in Captive fish, particularly immediately and 2 weeks following copper treatment. Based on our observations and previous literature, our results suggest putatively beneficial taxa amass over time in captivity. Within 2 years, Captive individuals harboredBacilluswhich contains numerous probiotic candidates and the complex carbon degraders of the familySaprospiraceae. Predicted butanoate metabolism exceeded that of Wild fish, and its reported roles in immunity and energy provision suggest a prebiotic effect for fishes.

Conclusions

The mucosal microbiota contains bacterial taxa that may act as bioindicators of environmental pollution. Increases in mutualistic groups indicate a return to a beneficial skin microbiota following copper sulfate treatment. Our data also suggests that vastly different taxa, influenced by environmental conditions, can be associated with adult fish without noticeable health impairment, perhaps due to establishment of various mutualists to maintain fish mucosal health.
Effect of one-month treatment with methylphenidate on salivary cortisol level of attention deficit hyperactivity disorder children
Authors: Kholif Esraa Yahia , Awad Salwa Mohamed , Attia Nasr Mohamed , Tawhid Ziyad Essam , Elwasify Mahmoud
Published: March 2021

Background

Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychological disorders that affects children, adolescents, and adults. Dysfunction of the hypothalamic-pituitary-adrenal axis (HPA) has been implicated in its pathophysiology. So, this study aimed to compare the salivary cortisol level between ADHD children and healthy children. It also compared the salivary cortisol level of ADHD children before treatment and 1 month after treatment with methylphenidate.

Results

This study showed that there was a statistically significant decrease in salivary cortisol level of the ADHD group, specifically hyperactive/impulsive subtype compared to the control group. Furthermore, it showed a statistically significant increase of salivary cortisol level after treatment compared to before treatment in the ADHD group.

Conclusions

HPA axis dysfunction may be related to the pathophysiology of ADHD, specifically hyperactive/impulsive subtype. Methylphenidate positively affects the HPA axis of ADHD children.
Estimation of dose and cancer risk to newborn from chest X-ray in South-South Nigeria: a call for protocol optimization
Authors: Omojola Akintayo Daniel , Akpochafor Michael Onoriode , Adeneye Samuel Olaolu , Akala Isiaka Olusola , Agboje Azuka Anthonio
Published: March 2021

Background

The use of X-ray as a diagnostic tool for complication and anomaly in the neonatal patient has been helpful, but the effect of radiation on newborn stands to increase their cancer risk. This study aims to determine the mean, 50th percentile (quartile 2 (Q2)), and 75th percentile (quartile 3 (Q3)) entrance surface dose (ESD) from anteroposterior (AP) chest X-ray and to compare our findings with other relevant studies. The study used calibrated thermoluminescent dosimeters (TLDs), which was positioned on the central axis of the patient. The encapsulated TLD chips were held to the patients’ body using paper tape. The mean kilovoltage peak (kVp) and milliampere seconds (mAs) used was 56.63(52–60) and 5.7 (5–6.3). The mean background TLD counts were subtracted from the exposed TLD counts and a calibration factor was applied to determine ESD.

Results

The mean ESDs of the newborn between 1 and 7, 8 and 14, 15 and 21, and 22 and 28 days were 1.09 ± 0.43, 1.15 ± 0.50, 1.19 ± 0.45, and 1.32 ± 0.47 mGy respectively. A one-way ANOVA test shows that there were no differences in the mean doses for the 4 age groups (P = 0.597). The 50th percentile for the 4 age groups was 1.07, 1.26, 1.09, and 1.29 mGy respectively, and 75th percentile were 1.41, 1.55, 1.55, and 1.69 mGy respectively. The mean effective dose (ED) in this study was 0.74 mSv, and the estimated cancer risk was 20.7 × 10−6.

Conclusion

ESD was primarily affected by the film-focus distance (FFD) and the patient field size. The ESD at 75th percentile and ED in this study was higher compared to other national and international studies. The estimated cancer risk to a newborn was below the International Commission on Radiological Protection (ICRP) limit for fatal childhood cancer (2.8 × 10−2Sv−1).
Differential activity of PARP inhibitors in BRCA1- versus BRCA2-altered metastatic castration-resistant prostate cancer (mCRPC).
Authors: Taza Fadi , Holler Albert E , Adra Nabil , Ashkar Ryan , Sokolova Alexandra , Kessel Adam , Nafissi Nellie , Barata Pedro C. , Bastos Diogo Assed , Smaletz Oren , Aggarwal Rahul Raj , Berchuck Jacob E , Vlachostergios Panagiotis J. , Su Christopher , Marshall Catherine Handy , Antonarakis Emmanuel S.
Published: March 2021

100

Background: Two PARP inhibitors (olaparib, rucaparib) are now FDA approved for mCRPC patients with mutations in BRCA1/2, but the relative efficacy of PARP inhibition in BRCA1- vs BRCA2-altered mCRPC is understudied. Methods: We conducted a multi-center retrospective analysis involving 11 academic sites. We collected genomic and clinical data from 123 BRCA1/2-altered mCRPC patients receiving PARP inhibitor treatment. The primary efficacy endpoint was PSA50 response rate (≥50% decline in PSA level). Secondary endpoints were PFS (clinical, radiographic or PSA progression, whichever occurred first) and overall survival (OS). We also captured information on other concurrent genomic alterations. We compared genomic characteristics and clinical outcomes among BRCA1- vs BRCA2-altered mCRPC. Results: A total of 123 patients (13 BRCA1, 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2) and veliparib (n = 2). All BRCA1 and 71% of BRCA2 patients had Gleason 8-10 disease. Compared to BRCA2 patients, BRCA1 patients were more likely to have received prior taxane chemotherapy (77% vs 62%). Age, baseline PSA, and prior enzalutamide/abiraterone treatment were similar between groups. PSA50 responses in BRCA1- vs BRCA2-altered patients were 38% vs 65% respectively ( P= 0.06). Median PFS in BRCA1 vs BRCA2 patients was 3.0 mo (95%CI, 0.9–5.1) vs 8.0 mo (95%CI, 5.3–10.6) respectively (HR 0.42, P= 0.01). Similarly, median OS in BRCA1 vs BRCA2 patients was 11.0 mo (95%CI, 9.9–12.1) vs 24.0 mo (95%CI, 18.2–29.8) respectively (HR 0.33, P= 0.005). There were roughly equal proportions of germline mutations (50% vs 45%) and biallelic mutations (31% vs 25%) in the BRCA2 and BRCA1 groups, respectively. There were numerically more TP53 mutations in the BRCA1 vs BRCA2 group (40% vs 29%, P= 0.45), but an equal number of mutations in other key genes ( PTEN, RB1 and AR). Conclusions: PARP inhibitor activity is diminished in BRCA1- vs BRCA2-altered mCRPC. In our cohort, this differential activity was not explained by mutation origin (germline vs somatic) or allelic status (mono- vs biallelic). These findings warrant validation.
UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castrate-sensitive prostate cancer.
Authors: Mahler Mary , Al-Ezzi Esmail Mutahar , Shani Shrem Noa , Winquist Eric , Canil Christina M. , Ong Michael , Hansen Aaron Richard , Emmenegger Urban
Published: March 2021

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Background: Since docetaxel has been advanced to the metastatic castrate-sensitive prostate cancer (mCSPC) setting, there is a lack of evidence guiding its re-introduction upon castrate-resistant (CR) progression. We sought to identify clinical characteristics and outcomes of patients subjected to docetaxel rechallenge (DR) following prior docetaxel exposure in the mCSPC realm. Methods: Patients rechallenged with docetaxel following treatment in the mCSPC setting were identified from three academic centres in Ontario, Canada. Retrospective chart reviews were performed to identify clinical, treatment and outcome variables. Results: Of the 45 patients with DR initiated between 06/2015 and 07/2020, the median age was 65, 60% had a Gleason score of ≥8, and 64% had an ECOG of ≤1. 56% had bone only metastasis, 4% lymph node only metastasis, 29% bone and lymph node metastasis, and 11% had visceral metastasis. In the mCSPC setting, 98% of patients received 6 cycles of docetaxel with 13% requiring dose delays. Of 43 informative patients, all had a PSA response to chemohormonal therapy. 91% achieved at least a 50% PSA response (PSA50), of which 40% had a 50-89% PSA reduction and 51% had a ≥90% PSA reduction. 29% of patients obtained a PSA nadir of < 0.2 ng/mL. 16% had CR progression in < 6 months, 56% in 6-12 months, and 28% in > 12 months. DR was initiated after a median of 20.8 months (range 6.0-40.4) following the last dose of docetaxel for mCSPC, and was given as first line treatment for CR disease to 7%, second line to 51%, third line to 40%, and fourth line or beyond to 2% of patients. 69% of patients had received an androgen-receptor axis targeted therapy prior to DR, 18% radium 223, and 7% had received a trial drug. Notably, no patients had received cabazitaxel prior to DR. The median number of cycles of docetaxel received at rechallenge was 5 (range 1-11) with 18% of patients requiring treatment delays. 64% of patients stopped treatment due to progression, 16% due to side effects, 7% at the patient’s request, 7% due to completion of the planned number of cycles, and 6% due to death or other causes. Among 44 informative patients, 23% achieved at least a PSA50, with 18% having a 50-90% PSA reduction, and 5% having a ≥90% PSA reduction. The median time to progression (biochemical, radiographic, or death) was 2.3 months (95%CI 1.7-4.4) and the median overall survival was 11.0 months (95%CI 8.5-14.3). Conclusions: DR following exposure to docetaxel in the mCSPC setting resulted in a PSA50 in only around one quarter of patients. Both the median time to progression and overall survival were found to be short. With future investigations, we hope to identify clinical variables that will help predict which patients might benefit most from DR.
Association of the clinical cell-cycle risk score with metastasis after radiation therapy and identification of men with prostate cancer who can forgo combined androgen deprivation therapy.
Authors: Tward Jonathan David , Mantz Constantine , Shore Neal D. , Nguyen Paul , Garraway Isla , Olsson Carl A , Lee Steve Pai-hsun , Hung Arthur , Henderson R Jonathan , Liauw Stanley L. , Raben David , Fabrizio Michael D. , Saltzstein Daniel R. , Yonover Paul , Gay Hiram Alberto , Albertson Daniel Joseph , Antic Tatjana , Lenz Lauren , Stone Steven , Cohen Todd
Published: March 2021

195

Background: This study evaluated the ability of the combined clinical cell-cycle risk score (CCR) to prognosticate the risk of prostate cancer metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). Methods: The CCR score is a validated model that combines the cell cycle progression score (CCP) with the UCSF Cancer of the Prostate Risk Assessment score (CAPRA). The CCR score and a CCR-based multimodality threshold score (2.112) were evaluated in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Center (NCCN) intermediate- or high-risk localized disease (N = 741) who received single (RT) or multimodality therapy (ADT with RT). Effects of prognostic variables were analyzed using Kaplan-Meier and Cox regression methods. Results: Median follow-up was 5.9 years. CCR predicted metastasis [hazard ratio (HR) 2.21, 95% Confidence Interval (CI) 1.70-2.87, p < 0.001]. The CCR score was a better prognosticator of metastasis (C-index 0.78) than either NCCN-risk group (C-index 0.70), CAPRA score (C-index 0.71), or CCP score (C-index 0.69) alone. In bivariate analyses, the CCR score remained highly prognostic for metastasis when comparing any ADT vs none (HR 2.19, 95% CI 1.62 to 2.97, p < 0.001), ADT duration as a continuous variable (HR 2.05, 95% CI 1.54-2.72, p < 0.001), or ADT use given as less than or at the recommended duration for each NCCN risk group (HR 2.22, 95% CI 1.71-2.88, p < 0.001). Men with CCR scores either below or above the threshold (2.112) had a 10-year risk of metastasis of 4.2% and 25.3%, respectively. For men below the threshold receiving RT alone versus RT+ADT, the 10-year risk of metastasis was 4.2% and 3.9%, respectively. Conclusions: CCR is a highly precise and accurate predictor of metastasis in men undergoing dose-escalated RT, with or without ADT. CCR adds clinically actionable information relative to guideline recommended therapies that are based on NCCN risk groups or CAPRA alone. Men with scores below the multimodality threshold may not significantly reduce their 10-year risk of metastasis with the addition of ADT.
Association between percentage of positive biopsy cores and risk of pelvic lymph node involvement in prostate cancer.
Authors: Yang David Dewei , Dee Edward Christopher , Arega Melaku A , Nguyen Paul L. , Orio Peter F. , King Martin T. , Kann Benjamin Harris , Yu James B. , Cook Kiri , Ma Ting Martin , Kishan Amar Upadhyaya , Muralidhar Vinayak
Published: March 2021

205

Background: Commonly used tools for predicting the risk of pelvic lymph node involvement (LNI) in prostate cancer often do not incorporate information on the percentage of positive biopsy cores (PPB). To better inform the use of elective nodal irradiation in the definitive treatment of prostate cancer, we examined the association between PPB and risk of pathologic pelvic LNI in men with prostate cancer who underwent radical prostatectomy (RP). Methods: We identified 109,577 men from the National Cancer Database who were diagnosed in 2010-2015 with cN0M0 prostate cancer, had 6-24 cores sampled at biopsy, and underwent RP with pathologic nodal evaluation. Multivariable logistic regression was used to examine the association between PPB and the likelihood of having ≥1 positive pelvic lymph node, adjusting for other known clinicopathologic prognostic variables. Results: Overall, 4.0% (4,340) of the cohort was found to have pelvic LNI at the time of RP. Higher PPB was associated with an increased risk of pelvic LNI (adjusted odds ratio [AOR] 1.75 for 25.1-50.0% PPB, 2.63 for 50.1-75.0% PPB, and 4.49 for 75.1-100.0% PPB vs. ≤25.0% PPB, all P<0.001). Notably, men with Gleason 8 disease and ≤25.0% PPB only had a 3.6% risk of pelvic LNI, whereas men with Gleason 9-10 disease and 75.1-100.0% PPB had a 32.6% risk (Table). Other factors associated with the likelihood of pelvic LNI included a higher biopsy Gleason score (AOR 1.43 for Gleason 8 and 2.84 for Gleason 9-10 vs. Gleason 4+3, both P<0.001), more advanced clinical tumor stage (AOR 1.48 for cT2, 1.97 for cT3, and 3.87 for cT4 vs. cT1, all P<0.001), and a higher PSA (AOR 1.90 for 10.0-19.9 ng/mL, 2.40 for 20.0-39.9 ng/mL, and 2.60 for ≥40.0 ng/mL vs. <10.0 ng/mL, all P<0.001), but not more advanced age (AOR 0.98 for >62 years [median] vs. ≤62 years, P=0.59) or black vs. white race (AOR 0.99, P=0.92). Conclusions: There was a statistically significant and clinically relevant association between increasing PPB and a higher risk of pelvic LNI. As the ongoing RTOG 0924 randomized trial matures, clinicians should consider incorporating information on PPB in determining which patients with prostate cancer may benefit from receiving radiation therapy to the pelvic lymph nodes. [Table: see text]
Treatment decisions and outcomes for NCCN favorable intermediate-risk prostate cancer patients after receiving the 17-gene genomic prostate cancer score result.
Authors: Margolis Eric , Bennett John , Pavlova Marina , Wong Kenny , Pieczonka Christopher Michael , Lowentritt Benjamin H. , Uchio Edward M. , Stoppler Melissa Conrad
Published: March 2021

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Background: Molecular assays are used to improve risk stratification in prostate cancer. This study determined how the 17-gene Genomic Prostate Score (GPS) assay guides treatment decisions in patients with NCCN favorable intermediate-risk prostate cancer. Methods: This retrospective study included 324 patients from 7 urology practices in the United States. All patients had NCCN favorable intermediate-risk prostate cancer, defined as <50% positive biopsy cores and only one of the following risk factors: grade group 2 (Gleason Score 3+4), clinical stage T2b-T2c, or PSA 10-20 ng/mL. All patients also had a GPS assay report dated May 2017 to April 2019. The GPS assay allows risk stratification into post-GPS very low-, low-, favorable intermediate-, unfavorable intermediate-, and high-risk groups, with higher GPS scores representing increased risk. Data were collected from patients' charts/electronic health records. The proportion of patients who selected active surveillance (AS) over immediate definitive treatment and AS, monotherapy, or multimodal therapy was calculated with 95% confidence intervals (CI) using the Clopper-Pearson method. Results: Patients comprised 79% with Gleason Score 3+4, 19% with PSA 10-20 ng/mL, and 2% with clinical stage T2b; median GPS result was 26. Post-GPS risk groups were 0%, 16%, 11%, 57%, and 16% very low-, low-, favorable intermediate-, unfavorable intermediate-, and high-risk groups respectively. Overall, 31% (95% CI 26%, 36%) of patients selected active surveillance (AS), with rate declining as post-GPS risk increased: 57% (95% CI 42%, 71%) selected AS in the post-GPS low-risk, 51% (95% CI 34%, 69%) in the post-GPS favorable intermediate-risk, 26% (95% CI 20%, 33%) in the post-GPS unfavorable intermediate-risk, and 6% (95% CI 1%, 16%) in the post-GPS high-risk group. Post-GPS unfavorable intermediate/high risk-patients were more likely to receive monotherapy than low/favorable intermediate-risk patients (high, 72%; unfavorable intermediate, 64%; favorable intermediate, 37%; and low, 37%); high-risk patients were more likely to receive multimodal therapy (high, 23%; unfavorable intermediate, 10%; favorable intermediate, 11%; and low, 6%). Median follow-up time was 18 months, and one prostate cancer-related metastasis and 2 deaths (neither prostate cancer-related) were reported. Complications (erectile dysfunction, urinary/bowel incontinence) were more common in treated than AS patients. AS persistence was 91% (95% CI 82%, 95%) at 12 months; patients discontinued AS due to disease progression (61%) or patient preference/unknown reasons (39%). Conclusions: The GPS result is associated with selection of AS and treatment intensity in this first examination of genomic classifiers in a cohort of prostate cancer patients with NCCN favorable intermediate-risk.
Adverse pathology as a predictor of distant metastasis and prostate cancer mortality with 20-year follow up.
Authors: Brooks Michael Austin , Thomas Lewis , Magi-Galluzi Cristina , Li Jianbo , Crager Michael , Lu Ruixiao , Abran John , Aboushwareb Tamer , Klein Eric A.
Published: March 2021

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Background: Adverse pathology (AP) at radical prostatectomy (RP) is often used as a proxy for long-term prostate cancer outcomes. The goal of this study was to assess the association of AP at RP, defined as high-grade (> Grade Group 3) and/or non-organ confined disease (pT3), with distant metastasis and prostate cancer death. Methods: A stratified cohort sample of 428 patients was used to evaluate the association of adverse pathology with the risk of distant metastases and prostate cancer-specific mortality over 20 years after prostatectomy in 2641 patients treated between 1987-2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both endpoints, with death from other causes treated as a competing risk. Subgroup analysis in patients with low/intermediate risk disease potentially eligible for active surveillance was performed. Results: Among the 428 patients, 343 had AUA Low or Intermediate risk disease and 85 had High risk disease. Median follow-up time was 15.5 years (IQR 14.6–16.6 years). Using the cohort sampling weights for estimation, at RP 29.8% of patients had high-grade disease, 42.3 % had non-organ confined disease, 19.3% had both, and thus 52.8% had AP. Adverse pathology was highly associated with metastasis and prostate cancer mortality in the overall cohort (HR 12.30, 95% CI 5.30-28.55, and 10.03, 95% CI 3.42-29.47, respectively, both p<0.001), and in the low/intermediate risk subgroup potentially eligible for active surveillance (HR 10.48, 95% CI 4.18-26.28, and 8.60, 95% CI 2.40-30.84, respectively, both p≤0.001). Conclusions: Adverse pathology at radical prostatectomy is highly associated with future development of metastasis and prostate cancer mortality and may be used as a short-term predictor of outcomes. [Table: see text]
Effectiveness of early diagnosis for prostate cancer based on PSA and multiparametric MRI: A simulation study.
Authors: Timsit Marc-Olivier , Baciarello Giulia , Hennequin Christophe , Kleinclauss Francois , Bazil Marie Laure , Bonnard Philippe , Pettre Segolene , Martin Blachier , Leleu Henri
Published: March 2021

224

Background: Multiparametric magnetic resonance imaging (mpMRI) detects ISUP grade≥ 2 prostate cancer (PC) with a sensitivity over 90%. mpMRI can be used for early detection in patients with a risk of clinically significant PC (csPC) either in combination with systematic biopsy (SB) to increase the detection rate of csPC, or to reduce the number of biopsy procedures by performing biopsies only in positive mpMRI patients. Methods: We estimated the numbers of PC diagnosed, PC deaths averted, and biopsy procedures performed with early diagnosis in a simulated population of men beginning at age 50 using a microsimulation model. The model simulates the natural history of PC and the impact of early diagnosis using epidemiological data from a systematic review of literature. Early diagnosis started at age 55 years, with a PSA threshold of 4 ng/mL. The strategies included (S1) SB alone, (S2) SB combined with mpMRI-targeted biopsy (SB/mpMRI-TB), and (S3) SB/mpMRI-TB following selection of patients based on positive mpMRI (PIRAD3-5) or PSA density (PSAd) < 0.15. A sensitivity of 0.92 and specificity of 0.48 for detecting ISUP grade ≥ 2 PC was used for mpMRI. Results: Compared to no early diagnosis, early diagnosis with SB alone (S1) was estimated to avoid 647 PC-related deaths per 100,000 men over their lifetimes. Using mpMRI was estimated to result in an additional 126 and 118 fewer deaths per 100,000 if mpMRI was used in conjunction with SB (S2) or with SB following patient selection for biopsy by mpMRI or PSAd (S3). To avoid a PC-related death was estimated to require screening of 145 men with SB alone, 121 with SB/mpMRI-TB, and 122 with mpMRI or PSAd followed by SB/mpMRI-TB. Adding mpMRI to SB was also found to reduce the predicted number of biopsies performed (21,821 for SB alone versus 16,510 for SB/mpMRI-TB and 15,385 for SB/mpMRI-TB following selection with mpMRI or PSAd). Conclusions: The results indicate that using mpMRI as a detection method will improve the effectiveness of early diagnosis. Compared to SB alone, using mpMRI through the SB/mpMRI-TB approach, with or without prior patient selection based on mpMRI or PSAd assessments, would result in a reduction in PC-related mortality and in the number of biopsies performed. [Table: see text]
Impact of 5-ALPHA reductase inhibitor use on prostate cancer risk at the time of urology referral.
Authors: Kearns James T , Matulay Justin T. , Anderson William E. , Hetherington Timothy C. , Grigg Claud , Zhu Jason , Gaston Kris E. , Riggs Stephen Boyd , Burgess Earle F , Clark Peter E
Published: March 2021

226

Background: 5-alpha reductase inhibitors (5-ARIs) are commonly used medications for the treatment of lower urinary tract symptoms caused by benign prostatic hyperplasia. One of the consequences of 5-ARI use is a 50% drop in serum PSA without a concomitant reduction in prostate cancer (PCa) risk. Previous work has suggested that 5-ARI use is associated with worse PCa-specific outcomes. The objective of this study was to evaluate the impact of 5-ARI use on patients’ PCa risk at the time of referral from primary care to urology. Methods: This retrospective cohort study included all men ≥ 40 years who had a PSA resulted between 2018-2019 and were seen in an ambulatory setting. PSA testing was determined through laboratory data in the electronic health record (EHR). Clinical and demographic data were collected for all men. 5-ARI use was determined through orders in the EHR. Men were assigned PCa risk according to both the Prostate Biopsy Collaborative Group (PBCG) and Prostate Cancer Prevention Trial (PCPT) risk calculators. PSA values were doubled for 5-ARI users prior to calculating risk. Referral to urology for PCa risk was determined using the narrative reason for referral associated with the referral order. Results: Between 2018-2019, 91,368 men had a PSA test, including 2,939 5-ARI users, and 88,429 non-users. Uncorrected median PSA and the proportion of men referred to urology for PCa risk were similar between the two groups (p = 0.60 and p = 0.17, respectively). Of men referred to urology for PCa risk, 5-ARI users had similar uncorrected PSA to non-users (p=0.86) but higher risk for high grade PCa once PSA correction was performed, median (IQR) 48% (24%) vs 28% (18%) using the PBCG and 21% (17%) vs 10% (10%) using the PCPT (p < 0.01 for both) (Table). Conclusions: Men taking 5-ARIs have significantly higher risk for high-grade PCa at time of referral to urology than non-users in this cohort. As the unadjusted PSA at referral to urology for PCa risk was the same between 5-ARI users and non-users, this indicates that the effect of 5-ARI use on serum PSA levels is not routinely accounted for when assessing PCa risk. Further study on interventions to account for 5-ARI use when screening for PCa are warranted. [Table: see text]
Real-world prevalence of homologous recombination repair gene (BRCA1/2 and ATM) mutations (HRRm) in patients (pts) with advanced prostate cancer (aPC) as detected by comprehensive genomic profiling (CGP) of circulating cell-free DNA (cfDNA).
Authors: Sayegh Nicolas , Swami Umang , Barata Pedro C. , Lilly Michael B. , Nussenzveig Roberto , Hensel Chuck , Bryce Alan Haruo , Bilen Mehmet Asim , Heath Elisabeth I. , Nandagopal Lakshminarayanan , Garje Rohan , Saylor Philip James , Babiker Hani M. , Vaena Daniel A. , Kohli Manish , Pal Sumanta K. , Sartor A. Oliver , Agarwal Neeraj
Published: March 2021

256

Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, & from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]
Lower risk of prostate cancer in patients with sedentary occupations presenting for a prostate biopsy: Analysis of a Veterans Affairs cohort.
Authors: Khadir Rimaz M. , Sayyid Rashid K. , Terris Martha K.
Published: March 2021

257

Background: Sedentary behavior has been associated with increased serum prostate-specific antigen (PSA) levels. It is currently unknown whether this correlates with an increased risk of underlying prostate cancer (PCa). Our objective was to determine whether patients with sedentary occupations presenting for a prostate biopsy were at increased risk of PCa diagnosis. Methods: A prospectively collected registry of patients undergoing a prostate biopsy between July 1995 and June 2016 at the Veterans Affairs Medical Center in Augusta, GA was utilized. The occupation was classified as sedentary if it was associated with prolonged periods of sitting (i.e. >50% work hours). This was determined via patient reported history at time of biopsy. The associations between a sedentary lifestyle and risk of a positive prostate biopsy, high grade cancer (i.e. Gleason score 8 or higher), and high volume cancer (i.e. at least 50% of total cores were positive) were evaluated using multivariable logistic regression analyses, controlling for age, race, body mass index, PSA level, free PSA ratio, clinical stage, prostate volume, and family history of prostate cancer. Statistical significance was set at p<0.05. All statistical analyses were performed using R version 3.6.1. Results: Our cohort included 1,914 patients. 271 (14.2%) patients had sedentary jobs. Median patient age was 61.0 years (Interquartile range [IQR] 57.0 – 66.0). Median PSA at time of biopsy was 5.7 ng/ml (IQR 4.4 – 8.2). Of the 1,914 initial biopsies performed, 974 (50.9%) were positive for malignancy. Of patients diagnosed with PCa, 229 (23.5%) had high-grade disease and 316 (32.4%) had high volume disease. On multivariable analysis, patients with a sedentary job had a significantly decreased risk of PCa diagnosis (Odds ratio [OR] 0.43, 95% confidence interval [CI] 0.18-1.03, p= 0.058), but no difference in odds of high grade (OR 0.63, 95% CI 0.089-2.99, p= 0.60) or high volume disease (OR 1.07, 95% CI 0.93-1.21, p= 0.89). Conclusions: Patients with sedentary occupations presenting for a prostate biopsy are at a lower apparent risk for a positive prostate biopsy. These results suggest that the serum PSA levels in such patients may be artificially elevated secondary to increased recumbence with no corresponding increase in risk of malignancy. [Table: see text]
Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma (ccRCC).
Authors: Graham Jeffrey , Wells Connor , Dudani Shaan , Gan Chun Loo , Donskov Frede , Lee Jae-Lyun , Kollmannsberger Christian K. , Pal Sumanta K. , Beuselinck Benoit , Hansen Aaron Richard , North Scott A. , Bjarnason Georg A. , Agarwal Neeraj , Kanesvaran Ravindran , Wood Lori , Hotte Sebastien J. , McKay Rana R. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: March 2021

316

Background: Immune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options in this setting. Data supporting the effectiveness of ICI based therapy in non-clear cell RCC (nccRCC) is more limited. Methods: We performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC). Patients with nccRCC were classified into 3 groups based on first-line therapy: ICI based therapy (in monotherapy or in combination), vascular endothelial growth factor targeted therapy (VEGF-TT) monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. Primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used Kaplan-Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. Results: We identified 1181 patients with nccRCC. In first-line, 78.2% received VEGF-TT, 15.8% mTOR inhibitors, and 5.5% ICI based therapy, of which 41.5% in monotherapy, 30.8% doublet-ICIs and 27.7% an ICI combined with VEGF-TT. Median OS in the ICI group was 28.6 months, compared to 19.2 and 12.6 in the VEGF-TT and mTOR groups, respectively. Median TTF was 6.9 months vs. 5.1 and 3.9 and ORR was 25% vs. 17.8% and 5.8% in the ICI, VEGF-TT and mTOR groups, respectively. After adjusting for IMDC risk group, histological subtype, and age, the hazard ratio (HR) for OS was 0.58 (95% CI 0.35-0.94, p=0.03) for ICI vs. VEGF-TT and 0.48 (95% CI 0.29-0.80, p=0.005) for ICI vs. mTOR. Conclusions: In advanced nccRCC, first-line ICI based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results need to be confirmed in prospective randomized trials. [Table: see text]
68Ga-PSMA expression changes on PET/CT for response assessment during taxane-based chemotherapy in metastatic prostate cancer patients.
Authors: Shagera Qaid , Artigas Carlos , Flamen Patrick
Published: March 2021

35

Background: Imaging-based response to systemic therapies in metastatic prostate cancer is still challenging. The aim of this study was to retrospectively investigate the association between Prostate-Specific Membrane Antigen (PSMA) expression changes on 68Ga PSMA PET/CT and the response to treatment following the start of taxane-based chemotherapies (docetaxel or cabazitaxel) in both metastatic hormonosensitive (mHSPC) and castration-resistant prostate cancer (mCRPC) patients. Methods: We retrospectively reviewed all 68Ga-PSMA-11 PET/CT scans performed at our institution from November 2014 to June 2020. We included mHSPC and mCRPC patients with a baseline 68Ga-PSMA PET/CT performed < 2 months before, and a second 68Ga-PSMA PET/CT performed < 3 months after docetaxel or cabazitaxel (with no modification in therapy between scans). The biological data was used to distinguish PSA-non-responders (increasing PSA or decreasing PSA by < 50% from pretherapy level) and PSA-responders (decreasing PSA > 50% following the start of therapy or the peak thereafter). The PSMA PET/CT response was assessed visually by two independent nuclear medicine physicians blinded to clinical data and patient outcomes. Patients were classified as PSMA-non-responders (≥1 new PSMA-expressing metastases, majority of PSMA-expressing metastases increasing in intensity, or stable PSMA-expression of the disease) or PSMA-responders (complete disappearance of pathologic PSMA uptake, or majority of PSMA-expressing metastases decreasing in intensity). Majority of lesions was defined as > 50% of registered lesions. Descriptive statistics and measures of associations (two-sided Fisher’s exact test and Phi coefficient) were calculated. Results: A total of 37 patients were included (8 mHSPC and 29 mCRPC), 21 patients under docetaxel and 16 cabazitaxel. All patients received at least 3 cycles [median 6 (range 3-10)]. The mean time (±standard deviation) between the first 68Ga-PSMA PET/CT and the start of therapy was 22±16 days. The mean time between the the last cycleand the second 68Ga-PSMA PET/CT was 36±27 days. PSA-response and PSMA-response were concordant in 95% of cases with 18 patients PSA/PSMA-non-responders and 17 PSA/PSMA-responders (Phi = 0.90, p = 0.0001). Two discordant patients presented with PSMA-response but PSA-non-response. No isolated PSMA flare was observed, as PSA-response was always associated with a decrease in PSMA-expression on the second PET/CT. Conclusions: This retrospective study suggests PSMA expression changes on PET/CT at least after 3 cycles of chemotherapy (docetaxel or cabazitaxel) are strongly associated with PSA response. No flare phenomenon was found at this evaluation. Prospective studies are needed to better define the potential role of PSMA-PET/CT in response assessment.
Prognostic value of simple blood biomarkers of systemic inflammation for metastatic renal cell carcinoma (mRCC) patients who undergo cytoreductive nephrectomy (CNx).
Authors: Moudgil-Joshi Jigi , Stares Mark , Laird Alex , Leung Steve , Malik Jahangeer , Sundaramurthy Aravindhan , Symeonides Stefan N.
Published: March 2021

350

Background: The role of cytoreductive nephrectomy (CNx) in patients with metastatic renal cell carcinoma (mRCC) is currently in question. Assessing the benefits and risks of CNx is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response have prognostic utility in mRCC and are included in the IMDC score used to predict survival in patients with mRCC treated with systemic therapy. We sought to investigate their role in patients with mRCC who had undergone CNx. Methods: A cohort of 68 patients, suitable for first-line VEGFR inhibitor (VEGFRi) systemic therapy, who had undergone CNx for mRCC, were identified from a clinical database of patients referred to a regional mRCC service. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and overall survival and time to VEGFRi (tVEGFRi) was examined using Kaplan-Meier and Cox-regression methods. Results: Data were available for 68 patients. Median survival was 33.7 months. On multivariate analysis, albumin ( < 35g g/dL v ≥35 g/dL) and CRP (≤ 10 mg/L v > 10 mg/L) were independently associated with overall survival (p = 0.027 and p = 0.034 respectively). Albumin stratified survival from 24.7 to 87.2 months (p < 0.0001) and CRP from 29.4 to 82.3 months (p = 0.004). 40 (59%) patients subsequently commenced VEGFRi therapy. Median tVEGFRi was 18.1 months, with only 5 (7%) patients commencing treatment within 3 months. 16 (24%) patients yet to receive systemic therapy remain alive after a median 54.0 months follow-up. On multivariate analysis, albumin was also predictive of tVEGFRi (p = 0.037), stratifying tVEGFRi from 6.07 to 45.7 months (p = 0.002). Conclusions: These results highlight that biomarkers of the systemic inflammatory response are strong prognostic factors in mRCC patients who have undergone CNx. Albumin and CRP, but not IMDC, predict survival in this patient group. Significantly, the population investigated here differ from those included in the CARMENA and SURTIME studies, with a majority undergoing surveillance prior to VEGFRi therapy. Our results support a role for CNx in patients where deferred systemic therapy strategies may be employed. Albumin may assist in clinical decision making when considering when to start systemic therapy. We advocate further studies to investigate the prognostic role of these simple, routine clinical tests in patients with mRCC undergoing CNx.