bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacteroides uniformis CECT 7771 requires adaptive immunity to improve glucose tolerance but not to prevent body weight gain in diet-induced obese mice
Authors: Romaní-Pérez Marina , López-Almela Inmaculada , Bullich-Vilarrubias Clara , Evtoski Zoran , Benítez-Páez Alfonso , Sanz Yolanda
Published: June 2024

Background

The metabolic disturbances of obesity can be mitigated by strategies modulating the gut microbiota. In this study, we sought to identify whether innate or adaptive immunity mediates the beneficial metabolic effects of the human intestinal bacterium Bacteroides uniformis CECT 7771 in obesity.

Methods

We evaluated the effects of orally administered B. uniformis on energy homeostasis, intestinal immunity, hormone levels, and gut microbiota in wild-type and Rag1-deficient mice with diet-induced obesity. We also assessed whether B. uniformis needed to be viable to exert its beneficial effects in obesity and to directly induce immunoregulatory effects.

Results

The administration of B. uniformis to obese mice improved glucose tolerance and insulin secretion, restored the caloric intake suppression after an oral glucose challenge, and reduced hyperglycemia. The pre- and post-prandial glucose-related benefits were associated with restoration of the anti-inflammatory tone mediated by type 2 macrophages and regulatory T cells (Tregs) in the lamina propria of the small intestine. Contrastingly, B. uniformis administration failed to improve glucose tolerance in obese Rag1-/- mice, but prevented the increased body weight gain and adiposity. Overall, the beneficial effects seemed to be independent of enteroendocrine effects and of major changes in gut microbiota composition. B. uniformis directly induced Tregs generation from naïve CD4+ T cells in vitro and was not required to be viable to improve glucose homeostasis but its viability was necessary to prevent body weight gain in diet-induced obese wild-type mice.

Conclusions

Here we demonstrate that B. uniformis modulates the energy homeostasis in diet-induced obese mice through different mechanisms. The bacterium improves oral glucose tolerance by adaptive immunity-dependent mechanisms that do not require cell viability and prevents body weight gain by adaptive immunity-independent mechanisms which require cell viability.
The relationship between unpredictability in childhood and depression among college students: the mediating roles of coping style and resilience
Authors: Ye Chengxiu , Ye Baojuan , Zhang Zheng
Published: June 2024

Background

According to previous studies, unpredictability in childhood could significantly increase the risk of depression in adulthood. Only a few studies have explored the relationship between these two variables in China. This paper aims to explore the relationship between unpredictability in childhood and depression and examine the mediating roles of coping styles and resilience.

Methods

We investigated 601 college students, who had an average age of 19.09 (SD = 2.78) years. Participants completed questionnaires regarding unpredictability in childhood, coping style, resilience, and depression. We analyzed survey data using the bias-corrected bootstrap method.

Results

The findings revealed a significant positive association between unpredictability in childhood and depression among college students. Mature coping style, immature coping style, and resilience were found to mediate this relationship independently. Furthermore, the study unveiled a serial mediation process, wherein both mature and immature coping styles, followed by resilience, sequentially mediate the relationship between unpredictability in childhood and depression, underscoring the complex interplay between these variables.

Conclusions

The results indicated that the risk of depression among college students who have experienced unpredictable childhood should be valued. Attention to coping styles and resilience should be paid to decrease depression among college students who have experienced unpredictable childhood.
Climate-induced shift of deep-sea benthic foraminifera at the onset of the mid-Brunhes dissolution interval in the northeast tropical Indian Ocean
Authors: Takata Hiroyuki , Ikehara Minoru , Seto Koji , Asahi Hirofumi , Lim Hyoun Soo , Hyun Sangmin , Khim Boo-Keun
Published: June 2024

The mid-Brunhes dissolution interval (MBDI; Marine Isotope Stage (MIS) 13 to 7; ~ 533–191 ka) is characterized by various paleoclimatic/paleoceanographic events in the world. We investigated fossil deep-sea benthic foraminifera and sediment geochemistry at the onset of the MBDI (~ 670–440 ka) using Ocean Drilling Program (ODP) Site 758 and core GPC03 in the northeast tropical Indian Ocean (TIO), primarily focusing on the relationship between the paleoceanographic conditions of the surface and deep oceans. Based on multi-dimensional scaling, MDS axis 1 is related to the specific depth habitats of benthic foraminiferal fauna, possibly at the trophic level. In MDS axis 1, the difference between the two core sites was smaller from ~ 610 to 560 ka, whereas it was larger from ~ 560 to 480 ka. In contrast, MDS axis 2 may be related to the low food supply at episodic food pulses/relatively stable and low food fluxes. MDS axis 2 showed generally similar stratigraphic variations between the two cores during ~ 610–560 ka, but was different during ~ 560–480 ka. The proportion of lithogenic matter to biogenic carbonate was relatively low from ~ 610 to 530 ka under the highstand when sediment transport to the study area was reduced. Thus, both the depth gradient in the distribution of benthic foraminiferal fauna and the lithogenic supply between the two cores changed coincidently across the MIS 15/14 (~ 570–540 ka) transition. Such paleoceanographic conditions across MIS 15/14 transition were attributed to the long-term weakening of the wind-driven mixing of surface waters, which might have been caused by the weakening of the Indian summer monsoon in the northeast TIO, possibly with the northward displacement of the InterTropical Convergence Zone in the Northern Hemisphere. In particular, the depth gradient in the distributions of benthic foraminiferal faunas represents the paleoceanographic linkage between the surface and deep oceans through particulate organic matter ballasting by calcareous plankton skeletons in addition to lithogenic matter, which changed transiently and significantly across MIS 15/14 transition close to the onset of the MBDI.
National chlorhexidine coverage and factors associated with newborn umbilical cord care in Bangladesh and Nepal: a cross-sectional analysis using household data
Authors: Singh Kavita , Simmons Elizabeth , Garriga Bliss , Hoover Grace , Ijdi Rashida E. , KC Ashish
Published: June 2024

Background

Preventable newborn deaths are a global tragedy with many of these deaths concentrated in the first week and day of life. A simple low-cost intervention, chlorhexidine cleansing of the umbilical cord, can prevent deaths from omphalitis, an infection of the umbilical cord. Bangladesh and Nepal have national policies promoting chlorhexidine use, as well as routinely collected household survey data, which allows for an assessment of coverage and predictors of the intervention.

Methods

We used data from the 2017–2018 Bangladesh Demographic and Health Survey and the 2016 Nepal Demographic and Health Survey, two large-scale nationally representative household surveys. We studied coverage of single application of chlorhexidine to the umbilical cord of newborns born in the past year using descriptive, bivariate and multivariable analyses. Key predictors of newborns receiving chlorhexidine cleansing, including socio-economic factors, healthcare related factors and the application of harmful and nonharmful substances, were explored in this study.

Results

Coverage of chlorhexidine cleansing was 15.0% in Bangladesh and 50.7% in Nepal, while the application of a harmful substance was 16.9% in Bangladesh and 22.6% in Nepal. Results from the multivariable analyses indicated that delivery in a health facility was strongly associated with a newborn’s receipt of chlorhexidine in both countries (Bangladesh: OR = 2.23, p = 0.002; Nepal: OR = 5.01, p = 0.000). In Bangladesh, delivery by Cesarean section and application of another non-harmful substance were significantly and positively associated with the receipt of chlorhexidine. In Nepal antenatal care was significantly and positively associated with chlorhexidine, while application of a harmful substance was significantly and negatively associated with receipt of chlorhexidine. Maternal education, urban/rural residence, religion and sex were not significant in the multivariable analysis. Wealth was not a significant factor in Bangladesh, but in Nepal newborns in the two highest wealth quintiles were significantly less likely to receive chlorhexidine than newborns in the lowest wealth quintile.

Conclusion

As Bangladesh and Nepal continue to scale-up chlorhexidine for newborn umbilical cord care, additional focus on newborns born in non-facility environments may be warranted. Chlorhexidine cleansing may have the potential to be an equitable intervention, as newborns from the poorest wealth quintiles and whose mothers had less education were not disadvantaged in receiving the intervention in these two settings.
Quantification of 11 metabolites in rat urine after exposure to organophosphates
Authors: Leninsky Michael A. , Sobolev Vladislav E. , Sokolova Margarita O. , Voitenko Natalya G. , Skvortsov Nikita V.
Published: June 2024

Background

The aim of the study was to develop a technique for quantitative determination of rat urine metabolites by HPLC–MS/MS, which can be used to search for biomarkers of acute intoxication with organophosphates (OPs).

Results

The content of metabolites in the urine of rats exposed to a single dose of paraoxon (POX1x); interval, twice daily administration of paraoxon (POX2x); exposure to 2-(o-cresyl)-4H-1, 3, 2-benzodioxaphosphorin-2-oxide and paraoxon (CBPOX) was investigated. New data were obtained on the content in the urine of intact rats as well as rats in 3 models of OP poisoning: 3-methylhistidine, threonine, creatine, creatinine, lactic acid, acetylcarnitine, inosine, hypoxanthine, adenine, 3-hydroxymethyl-butyrate and 2-hydroxymethyl-butyrate.

Conclusions

The proposed assay procedure is a simple and reliable tool for urine metabolomic studies. Within 1–3 days after OP exposure in all three models of acute intoxication, the concentration of metabolites in rat urine, with the exception of adenine, changes similarly and symmetrically, regardless of the method of poisoning modeling, in all three models of acute intoxication. Further studies are needed to determine the specificity and reliability of using urinary metabolite concentration changes as potential biomarkers of acute organophosphate intoxication.

Graphical Abstract
Editorial: Management of PJI/SSI after joint arthroplasty
Authors: Cao Li , Parvizi Javad , Zhang Xiaogang , Liu Xianzhe , Zijlstra Wierd P. , Tarabichi Saad
Published: June 2024

The management of periprosthetic joint infection (PJI) and surgical site infection (SSI) after joint arthroplasty poses a major challenge in orthopedic surgery. This Editorial provides an overview of the studies published in the special issue “Management of PJI/SSI after Joint Arthroplasty”, summarizing the key findings from these studies, which cover a wide range of topics, including stringent preventive strategies, comprehensive diagnostic methods, and personalized treatment modalities. The authors concluded the editorial with their perspectives regarding the status quo of research in this field and future directions for research, such as the development of novel antibiotics, biofilm research, patient-specific risk factors, and the integration of technological advancements (such as machine learning and artificial intelligence) into clinical practice. The authors emphasized the need for continued research, interdisciplinary collaboration, and the application of innovative technologies to enhance patient outcomes and mitigate the burden of these infections on healthcare systems.
Prevalence of Potentially Pathogenic Germline Variants Among Adult Patients in the Philippines With Solid Malignancies Who Underwent Tumor Genomic Profiling
Authors: Franco Paula Isabel , Andal Jose Jasper , Ang Daphne Chua , Que Frances Victoria
Published: June 2024

PURPOSE

In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for genetic testing on the basis of current guidelines. Our study determined the prevalence of potentially pathogenic germline variants (PPGVs) in TGP results of adult patients with solid malignancies in the Philippines.

METHODS

Annotated reports of patients with solid cancers who underwent TGP using FoundationOne or FoundationOne Heme between January 2021 and July 2023 were reviewed. PPGV criteria include having a variant allele frequency of >30% and were categorized as (1) high penetrance gene (HP), founder variant (FV), or variant associated with clinical presentation (VA). Pathogenicity was crosschecked through the ClinVar database.

RESULTS

Of 446 patients, 13 PPGV variants were found in 50 (11.2%) patients at a median age of 60.5 years. Of them, 28 (56%) had HP ( BRCA1, BRCA2, MSH2, MSH6, MLH1, RAD51C, RAD51D), 25 (50%) patients had VA ( APC, SMAD4, CDH1, CDKN2A, PTEN), and two patients with lung cancer had a FV ( EGFR p.Thr790Met). Six patients had more than one PPGV. PPGVs were primarily found in patients with colorectal (42% of 50 patients with PPGVs), breast (16%), ovarian (6%), and lung (6%) cancer ( P < .001). HP genes were mostly found in female patients (71.4%; P = .03).

CONCLUSION

With a PPGV prevalence of 11% in this study, it is important to recognize PPGVs as it can prompt genetic counseling and confirmatory germline testing.
Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection.
Authors: Albiges Laurence , Bex Axel , Suárez Cristina , Uzzo Robert , Tang Xiaobin , Assaf Zoe June , Dubey Sarita , Goluboff Erik T. , Carter Corey , Banchereau Romain , Huseni Mahrukh A , Pal Sumanta Kumar , Rini Brian I.
Published: June 2024

4506

Background: In IMmotion010, adj atezo did not prolong investigator-assessed disease-free survival (DFS; primary endpoint) vs pbo after resection in pts with RCC (HR: 0.93, 95% CI: 0.75, 1.15; P=0.50; Pal Lancet 2023). This exploratory analysis of circulating protein biomarkers was performed to identify high-risk pts with minimal residual disease (MRD) who may show differential benefit from treatment (tx) with atezo. Methods: Pts with RCC with clear-cell or sarcomatoid component and increased recurrence risk post nephrectomy were randomized 1:1 to atezo 1200 mg or pbo IV q3w for 16 cycles or 1 year. A retrospective proteomics analysis was done with an affinity-based proximity extension assay (PEA) panel of ≈3000 analytes to identify circulating proteins with differential abundance patterns in matched serum samples (baseline vs at recurrence). A high sensitivity electrochemiluminescence (ECL) assay was then used to evaluate levels of KIM-1, a membrane glycoprotein overexpressed in clear-cell and papillary RCC, in all available baseline and post-tx serum samples. Outcomes in pts with KIM-1 high (≥86 pg/mL) vs low status at baseline were analyzed. Results: In pts with matched PEA samples (n=73), circulating KIM-1 was identified as the most significantly enriched protein at recurrence vs baseline. Of 778 pts enrolled in IMmotion010, 752 (97%) had baseline KIM-1 data (high: 300 [40%]; low: 452 [60%]). KIM-1–high status was associated with reduced DFS, and pts with KIM-1 high had better DFS with atezo vs pbo (Table). Longitudinal analysis of matched samples showed that in KIM-1–high pts, 9% (12/138) and 26% (36/141) of pts had a ≥30% increase from baseline in KIM-1 levels at Cycle 4 Day 1 with atezo vs pbo, compared with 16% (34/213) and 12% (25/207) in KIM-1-low pts, respectively. A ≥30% KIM-1 increase was associated with worse DFS in both KIM-1–high (atezo HR: 1.68, 95% CI: 0.77, 3.69; pbo HR: 3.53, 95% CI: 2.24, 5.58) and KIM-1–low (atezo HR: 3.56, 95% CI 2.21, 5.75; pbo HR: 3.22, 95% CI: 1.81, 5.70) subgroups. In pts with matched ECL samples (n=103), median KIM-1 levels were higher ( P<0.001) at recurrence (172 pg/mL) than at baseline (79 pg/mL). Conclusions: In IMmotion010, high baseline serum KIM-1 levels were associated with poorer prognosis but improved clinical outcomes with atezo vs pbo. Increased post-tx KIM-1 was associated with worse DFS. These data suggest that circulating KIM-1 may be a non-invasive marker of MRD and disease recurrence and be associated with benefit from atezo in adj RCC. Further investigation of KIM-1 in adj RCC is warranted. Clinical trial information: NCT03024996 . [Table: see text]
Long term cardiovascular adverse outcomes in testicular cancer survivors: Real-world U.S. population-based study.
Authors: Alkhatib Khalid Y. , Pluta John , Lee Daniel , Nathanson Katherine L. , Jacobs Linda A. , Guzzo Thomas J. , Adra Nabil , Gietema Jourik A. , Vaughn David J. , Pierorazio Phillip M.
Published: June 2024

5042

Background: The focus of Testicular Cancer (TC) has shifted towards survivorship due to the high cure rates. With the increase in TC survivors population, long-term cardiovascular disease (CVD) have been suggested to be strongly linked with earlier treatment for TC by various hospital based small studies. As it is crucial to investigate this relationship at a population level to develop early prevention strategies to improve TC survivors' overall quality of life (QoL), we analyzed the U.S. The Behavioral Risk Factor Surveillance System (BRFSS) to describe the long-term outcomes of TC survivors in a real-world random population sample. Methods: Using BRFSS cycles between 2014 and 2022, we pulled all patients who reported having a history of TC and compared them to the rest of the men's population sample who had no history of cancer diagnosis. Using national complex weights, we estimated each group outcomes proportions. Further, we evaluated several complex-weighted logistic regression models adjusted for different covariates to describe the association of high blood pressure, high cholesterol, diabetes, BMI of >25, angina, myocardial infarction (MI), and coronary heart disease (CHD). Results: Out of 3,077,806 participants, we identified 308 with a history of TC and 1,169,061 men with no history of cancer. After calculating descriptive demographics, our modeling analysis showed a consistent significant association in reporting history of Angina (OR range from 3.84 to 4.27), CHD or MI (OR range from 2.92 to 3.14). see table. Conclusions: Real-world data indicate alarming results of high prevalence CVD in TC survivors; our results confirm previously reported results from hospital-based cohorts. Our findings support immediate actions to develop and implement preventative strategies in TC survivors. [Table: see text]
Site versus central read discrepancy rates in PCWG3 evaluation for progression.
Authors: Phillippi Danielle , Marini Matthew , Bowman Erin
Published: June 2024

5067

Background: Prostate Cancer Working Group-3 Criteria (PCWG3) is the standard for determining radiographic response assessments in Prostate Cancer (PC) Clinical Trials. PCWG3 accounts for soft tissue and bone responses by following RECIST and evaluation of metastatic bone disease, respectively. In PC, the determination of progressive disease (PD) by bone metastases is often challenging due to increased osteoblastic activity during drug treatment known as flare phenomenon. To account for this, PCWG3 uses the 2+2 rule during the flare window and requires persistence of bone lesions over a specified period. Protocols often require blinded independent central review (BICR) verification of PD (VOP) where sites request BICR confirm site suspected radiographic PD (rPD). This is often a challenge as BICR radiologists are required to follow the strict PCWG3 requirements for PD. Previous studies have shown a 32% site vs. central discordance in RECIST trials, yet there is limited data for PCWG3. Due to the complexity of PCWG3, we hypothesized that site vs central discordance is greater than that of RECIST. Thus, we aimed to examine site vs central discordance for PD by PCWG3 by analyzing archived data on site requested radiographic VOP. Methods: Aggregate data from metastatic PC trials requiring BICR VOP by PCWG3 was collected and retrospectively analyzed. Of the 6537 patient data reviewed, 3685 patients had at least one site requested VOP. For these patients with site suspected progression, a comparison between site submitted VOP requests and the BICR outcome of PD or non-PD was used for determination of discordance. The data was further categorized based on the number of times the site submitted a request and when BICR verified PD. Results: Analyses showed 50.91% of patients had BICR verified PD at the time of initial site request. The remaining 49.09% of patients had at least one instance of non-PD before PD was determined by BICR. For 33.3% of patients, central PD was never verified by BICR. In the remaining patients with VOP requests, 11.78% had verified PD following one Non-PD result, 4.03% had verified PD following two or more non-PD results. Conclusions: BICR verified rPD serves as an important endpoint in PC trials yet our analysis shows almost half of initial patient VOP requests from the site were not verified centrally. This is greater than the established discordance in RECIST trials and warrants further investigation. For over 15% of patients who did not have verified PD by BICR on the first request, PD was verified in a subsequent request. We postulate that these discrepancies are due site misinterpretation of PCWG3 or sites requesting VOP when insufficient time has passed to meet the persistence requirements. In addition, PCWG3s requirement for lesion persistence may differ from clinical practice in the assessment of PD. This preliminary analysis provides vital insight into site vs central discordance in BICR confirmation of PD in PC trials.
Dynamic androgen receptor alterations (ARa) ctDNA profiles and clinical outcomes in metastatic prostate cancer (mPC).
Authors: Jani Chinmay , Tran Eli , Zhang Nicole , Tsai Jill , Bucheit Leslie A , Pan Elizabeth , Panian Justine , McKay Rana R.
Published: June 2024

5069

Background: The AR plays a pivotal role in PC pathogenesis and ARa, including ligand binding domain mutations and amplifications, can evolve under the selective pressure of androgen deprivation therapy and androgen receptor signaling inhibitors (ARSi). Next-generation sequencing of circulating tumor DNA (ctDNA) enables non-invasive, longitudinal monitoring of AR dynamics in patients (pts) undergoing systemic therapies. This study aims to explore the dynamic changes in ctDNA profiles, particularly focusing on the AR gene and its association with clinical outcomes. Methods: We utilized GuardantINFORM, a clinical-genomics database containing de-identified ctDNA test results and commercial payer-claims data. Eligible pts had a diagnosis of mPC and underwent ctDNA testing pre (within 3 months prior to initiation) and post (within 3 months of discontinuation prior to initiating subsequent treatment) ARSi, poly ADP‐ribose polymerase inhibitors (PARPi), and taxane chemotherapy. The primary endpoint was to characterize changes in molecular alterations pre- and post-therapy. Secondary endpoints included overall survival (OS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) for pts receiving with ctDNA testing within 3 months prior to 1L ARSI for mCRPC. Results: From a database of 21,682 pts with PC, 145 had ctDNA collected pre/post ARSI, 54 pre/post PARPi, and 115 pre/post taxane chemotherapy. We observed increased ARa across the three treatment groups (%pre/%post): ARSi (17/35), PARPi (39/43), and taxanes (44/58) (Table). In the ARSi group, most common (%pre/%post) ARa included AR amplifications (11/23), AR T878A (5/9), AR L702H (2/6) and AR H875Y (0.7/1.4). In the PARPi group, the most prevalent (%pre/%post) ARa comprised AR amplifications (24/32), AR L720H (15/15), AR T878A (11/9) and AR F877L (2/6). In the taxane group, notable (%pre/%post) ARa consisted of AR amplifications (33/44), AR L702H (4/10), AR H875Y (3/9) and AR T878A (7/8). 1294 pts had ctDNA testing prior to 1L ARSi for mCRPC and were included in the outcomes analysis. Pts with ARa showed worse TTD (2.8 vs 4.3, p<0.0001), TTNT (6.9 vs 4.8, p<0.0001) and (OS (15.3 vs 49.3, p<0.0001). Conclusions: Our study elucidates evolving changes in AR in mPC using ctDNA profiling. We observed an increase in ARa following ARSi, PARPi, and taxane treatment in mPC. Furthermore, our findings highlight associations between ARa and clinical outcomes, emphasizing the potential for personalized treatment strategies in mPC pts based on molecular profiling. [Table: see text]
Abiraterone with discontinuation of gonadotropin-releasing hormone (GnRH) analogues in patients (pts) with metastatic prostate cancer (PC): A single arm, phase II study.
Authors: Makrakis Dimitrios , Goel Sanjay , O'Sullivan Darciann , White Monique , Gartrell Benjamin Adam
Published: June 2024

5086

Background: Abiraterone acetate (AA) is approved in metastatic PC. AA inhibits CYP17, required for androgen biosynthesis. A first in human trial suggested that AA monotherapy was inadequate to maintain castrate testosterone (T) in non-castrate men and AA development required continued GnRH analogues. However, T recovery is often delayed post GnRH analogue cessation; the need for their ongoing use to maintain castrate T with AA use is unclear and studies are limited. We present a single arm, phase II trial of pts with metastatic PC treated with AA+Prednisone (AAP) after GnRH discontinuation. Methods: We conducted a single arm, phase II study for pts with metastatic PC treated with AAP with GnRH analogue discontinuation. Entry criteria required metastatic PC treated with AAP and GnRH analogue & baseline T of <50 ng/dl without previous orchiectomy. After enrollment AAP was continued with GnRH analogue discontinuation. Primary endpoint was the pt proportion with castrate T (<50 ng/dl) at 6 months. Secondary endpoints included time to LH normalization, PSA response, radiographic progression-free survival (rPFS) and overall survival (OS). T, PSA & LH levels were monitored at 12-week intervals. We used descriptive statistics to assess the time to non-castrate testosterone levels, LH normalization time & mean T, LH & PSA levels at each monitoring timepoint. Results: We enrolled 31 pts; 27 were evaluable at 6 months. Median age was 69 years. Race/Ethnicity included 21 (68%) non-Hispanic black (68%) and 10 (32%) Hispanic pts. Sixteen (52%) had castration-resistant disease as AAP indication. Mean duration of ADT and AAP prior to enrollment were 29.1 (3-204) and 9.2 (1-38) months, respectively. Median follow up was 28 months. At 6 months, 25/27 (92%) patients had castrate T as did 22/26 (85%) at 12 months, 18/23 (78%) at 18 months, 16/22 (73%) at 24 months and 11/17 (65%) at 30 months. There were no treatment discontinuations due to toxicity Mean T, LH and PSA values at timepoints are reported. rPFS and OS will be reported later. Conclusions: Pts with metastatic PC treated with AAP after GnRH analogue discontinuation often remain castrate with AAP monotherapy even 30 months after GnRH analogue cessation. Phase III trials showing benefit of AAP required continued GnRH analogue; this small phase II study does not change standard of care but does suggest that further evaluation of AAP monotherapy may be warranted; AAP without use of GnRH inhibitors successfully suppressed T levels. Further randomized clinical trials are needed to assess the role of AAP monotherapy without GnRH analogues in metastatic PC. Clinical trial information: NCT03565835 . [Table: see text]
Germline gene-specific associations in a large prostate cancer cohort.
Authors: Khan Hiba M , Nielsen Young Sarah M. , Russell Emily M. , Esplin Ed , Korn W. Michael , Cheng Heather H.
Published: June 2024

5102

Background: Identification of pathogenic germline variants (PGV) in patients (pts) with prostate cancer (PC) enables precision therapy and cascade testing. Equitable advances in precision PC management require more detailed understanding of gene-level associations. Herein we describe PC gene-specific demography in a large cohort of PC pts. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare Map) data were linked for PC pts from 2015-2023. ICD/CPT codes were used to define PC personal and family history and disease stage (early-stage = codes for active surveillance or definitive local treatment; advanced = remaining pts). PC genes analyzed were those in NCCN PC guidelines with >100 PGV+ pts: ATM, BRCA1, BRCA2, CHEK2, HOXB13 and mismatch repair (MMR) genes ( EPCAM, MLH1, MSH2, MSH6, PMS2). Two sample t-tests were used for age and chi-square tests were used for other variables, with a Bonferroni correction for post hoc analysis. Results: 14,979 pts had GGT: 68% with advanced disease (enriched for BRCA2) and 32% with early-stage. Mean diagnosis age was 64, and significantly younger for ATM/ BRCA2/ HOXB13+ pts (p<0.04) (Table). BRCA2was the most common PGV but was not enriched in any clinician-reported race/ethnicity. CHEK2/MMR+ pts were more likely to be White ( post hoc p<0.001). The Midwest had the highest frequency of PGV (12%). A lower proportion of CHEK2+ pts resided in the South ( post hoc p<0.001). 26% of PGV+ pts had documented PC family history, which was significantly associated with BRCA2/HOXB13, and negatively correlated with MMR (p<0.02 for both). Conclusions: In this cohort of ~15,000 PC pts, gene-specific associations were detected that warrant further study. Three-quarters of pts with PGV had no claims for family PC history, highlighting the importance of GGT in all pts meeting criteria, independent of family history. Further analysis of linked data will assess real-world treatment decisions and outcomes by GGT result. [Table: see text]
Willingness of patients with biochemically recurrent prostate cancer (BCR) with positive 18F-dcfpyl PET/CT PSMA to monitor without treatment.
Authors: Williams Monique , Hankin Amy , Hausler Megan , Mena Gonzalez Esther , Lindenberg Liza , Aragon-Ching Jeanny B. , Sena Laura , Arlen Philip M. , Karzai Fatima , Choyke Peter L , Madan Ravi Amrit
Published: June 2024

5104

Background: For patients that have a rising PSA and negative CT and bone scan after surgery or radiation, there are no therapies that have been shown to improve survival. This fact has not been changed by the approval of DCFPyL PET/CT PSMA, which can now define subclinical disease in patients with bone and CT scans that are otherwise negative. Treatment and outcome data in BCR is not equivalent to metastatic castration sensitive prostate cancer (mCSPC). Despite the lack of data for the optimal management for prostate cancer that is PSMA positive (ppBCR), many providers feel they must treat patients because patients are unwilling to monitor ppBCR over time. Methods: The NCI is currently accruing to a study (NCT05588128; goal n=250) designed to monitor patients with BCR to understand the evolution of PSMA imaging over time. Eligible patients have BCR and underwent definitive treatment (surgery and/or radiation therapy) > 6 months prior to enrollment. Required PSA minimum 0.5 ng/mL; Testosterone minimum 100 ng/dL. Baseline CT and Tc-99m bone scans must be negative. Initial PSMA assessments occur within 8 weeks of confirmed eligibility. Positive PSMAs will be repeated every 6 months and negative PSMAs are repeated every 12 months for up to 5 years. PSAs are collected every 3 months. Following each PSMA scan, patients are counseled on the results. Radiation and intermittent systemic therapies (for 6 months or less) are allowed on this trial. Results: 57 patients have enrolled on the study and have been evaluated with PSMA PET thus far. Median PSA value at enrollment is 3.65 ng/mL (range, 0.5-71.6 ng/mL). Median PSA doubling time is 11.3 months (range, 1.2-132.4 months). Median patient age is 71 years (range, 54-92 years old). Self-reported race/ethnicity as follows: 75% White, non-Hispanic, 12% Black, non-Hispanic, 3.5% White, Hispanic, 3.5% Other, Hispanic, 2% Asian, 4% Unknown. Of the first 57 patients enrolled who have had PSMA PET scans, 52 patients (91%) were found to have positive findings. Among these, 49 patients (94%) with ppBCR elected to monitor their disease until the next scan. Conclusions: This study (NCT05588128) is the first prospective trial to monitor ppBCR patients to better define the natural history of BCR in the PSMA era. This preliminary data from the ongoing study thus far suggests that with appropriate counseling and a follow-up plan, the majority of patients are willing to monitor ppBCR. Given that no data has demonstrated a survival advantage for BCR or ppBCR, it is important for providers to have balanced conversations with patients about the implications of ppBCR, which often results in an indolent disease course. Clinical trial information: NCT05588128 .
Trends in phase 3 gynecological clinical trials of targeted therapies: Study oversight and pharmaceutical involvement in the past 12 years.
Authors: Ruan Qiao , Johnson Caitlin Ruth , Kapp Daniel Stuart , Chan John K
Published: June 2024

5503

Background: To determine the trends, progress, and pharmaceutical sponsorship of clinical trials in targeted therapy treatments for gynecologic cancers. Methods: From January 1st, 2011, to May 31st, 2023, all phase III gynecological clinical trials in targeted therapy treatment were identified from clinicaltrials.gov and reviewed using peer review publications. Characteristics of demographics and authorship were analyzed for comparison using Chi-square analyses and Fisher’s exact tests. P-values <0.05 were considered statistically significant. Results: Over the 12-year period, we identified 18,424 patients enrolled across 30 clinical trials studying targeted therapy treatments for gynecologic cancers. Of these trials, 86.7%, 10.0%, and 3.3% involved ovarian, cervical, and endometrial cancers, respectively. Of patients enrolled in these trials, 77.0% identified as White, 13.3% as Asian, and 2.4% as Black; only 3.0% identified as Hispanic. Approximately 46.7% of first authors of publications for these trials were from the U.S. and 43.3% were from Europe. Furthermore, 23.4% of co-authors served or consulted on a committee board, 15.2% received grants/honoraria, and 10.0% were pharmaceutical employees. 73.3% of dedicated medical writers were funded by pharmaceutical groups. Additionally, 83.3% of trials were led by the pharmaceutical industry while 16.7% mainly funded by cooperative groups. 70.0% of clinical trials employed pharmaceutical group funding for study design, and 66.7% of trials had data analyzed by pharmaceutical groups. Clinical trials were then divided into three time periods based on time of publication (2011-2015, 2016-2019, and 2020-2023). Over these periods, diverse patient enrollment increased. There were statistically significant decreases in the proportion of White (80.7% vs. 82.6% vs. 70.3%; p<0.0001) and Black (2.8% vs. 2.5% vs. 2.1%; p<0.0001) patients while increases were found among Asians (6.4% vs. 10.3% vs. 20.5%; p<0.0001) and Hispanics (2.3% vs. 0.7% vs. 12.3%; p<0.0001). The proportion of authors receiving grants/honoraria support increased from 8.0% to 14.2% to 18.2% (p<0.0001). Authors serving as industrial employees rose from 6.3% to 7.1% to 13.1% (p=0.02). Conversely, the proportion of authors acting as pharmaceutical advisory board members or consultants changed from 31.3% to 30.1% to 16.5% (p<0.0001). However, authors without pharmaceutical affiliation remained stable at 49.1% to 53.6% to 48.9% (p=0.004). Conclusions: The number of trials over the last 12 years sponsored by industry increased, as well as pharmaceutical employee participation and grant support. Additionally, Asian and Hispanic participant enrollment significantly increased. Balancing the benefits of pharmaceutical partnership with study oversight and disclosure is important in protecting the interests of our patients.
Efficacy and safety of sintilimab plus paclitaxel and cisplatin as neoadjuvant therapy for locally advanced cervical cancer: A phase II trial.
Authors: Wan Ting , Huang He , Feng Yanling , Li Jundong , Zheng Min , Meng Yifan , Liu Jihong
Published: June 2024

5512

Background: The KEYNOTE 826 study has demonstrated significant survival benefits with first-line pembrolizumab (anti PD-1) plus chemotherapy for recurrent/metastatic cervical cancer (CC). This phase II study aims to evaluate the efficacy and safety of Sintilimab (anti PD-1) plus paclitaxel and cisplatin as neoadjuvant therapy for locally advanced CC. Methods: Patients with newly confirmed locally advanced CC (stage IB3 or IIA2) received neoadjuvant chemotherapy with paclitaxel (150mg/m2, iv) and cisplatin (70mg/m2, iv) plus Sintilimab (200mg, iv) Q3W for 3 cycles, followed by radical surgery. The patients evaluated PD without distant metastases after 2 cycles of neoadjuvant therapy underwent surgery immediately. The primary endpoint was pathological complete remission rate (pCR). Secondary endpoints included ORR, PFS, 2-years PFS rate and adverse events (CTCAE 5.0) and biomarker exploration. Results: As of data cutoff on Feb 1st, 2024, 47 eligible patients were enrolled, 44 patients received 3 cycles of neoadjuvant therapy, 43 patients then underwent radical surgery and were evaluable. The primary endpoint of pCR rate was 32.6% (14/43), optimal remission rate (residual tumor cells with a depth of less than 3mm) was 51.2% (22/43). Except for one patient with SD, 42 had objective responses (97.7%). At the date cutoff, the median follow-up time was 17 months (range 1-35), two patients who evaluated as PR after neoadjuvant therapy were recurred, one with distant lymph node recurrence, and the other with lung metastasis. In terms of hematological toxicity, 15 patients presented with grade 3-4 neutropenia and no other grade 3-4 adverse events. Possible immune-related side effects included skin rash (17/47, G1-2), alanine aminotransferase increased (8/47, G1), hypothyroidism (6/47, G1-2), creatinine increased (5/47, G1), and hyperlipidemia (1/47, G1). Conclusions: Sintilimab plus paclitaxel and cisplatin as neoadjuvant therapy showed encouraging antitumor activity with 32.6% pCR rate and manageable toxicities in patients with locally advanced CC. Clinical trial information: NCT04799639 .
Combination of cemiplimab and ISA101b vaccine for the treatment of recurrent/metastatic HPV16 cervical cancer.
Authors: Lorusso Domenica , Oaknin Ana , Santos Borges Giuliano , Damian Fernanda , Ottevanger P. B. , Van Gorp Toon , Paiva Carlos Eduardo , Kroep Judith R. , Kim Yong Man , Kim Hee Seung , Lee Jae-Kwan , Melief Cornelis JM , Hooftman Leon , Jamil Shaheda Jamil , Yoo Suk-Young , Seebach Frank A. , Lowy Israel , Fury Matthew G. , Mathias Melissa Divya , Colombo Nicoletta
Published: June 2024

5522

Background: Cemiplimab + ISA101b vaccine is being studied in HPV16-positive cancers in several phase 2 clinical trials. Here, we present the clinical efficacy and safety results of a phase 2 study of cemiplimab + ISA101b vaccine in patients with recurrent HPV16 cervical cancer who had disease progression after first-line chemotherapy (NCT04646005). Methods: Patients received cemiplimab 350 mg administered intravenously every 3 weeks + 3 doses of ISA101b vaccine 100 µg/peptide administered by subcutaneous injection on Days 1, 29, and 50. The primary endpoint was objective response rate (ORR) as measured by RECIST version 1.1. Secondary endpoints included duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety. Efficacy and safety endpoints were assessed in the full analysis set (patients who received ≥1 dose). Baseline PD-L1 expression was assessed by immunohistochemistry using anti–PD-L1 clone SP263. Results: This single arm study included 113 patients (Table). Median duration of follow-up was 4.9 months (interquartile range [IQR]: 3.0–7.5); median duration of treatment exposure was 10.0 weeks (IQR: 9.7–10.3) for ISA101b and 18.2 weeks (IQR: 9.0–27.6) for cemiplimab. At data cutoff (May 22, 2023), 90 patients discontinued treatment for reasons including disease progression (66.4%), death (7.1%), and an adverse event (AE; 3.5%) and 20.4% of patients were still on treatment. ORR (95% CI) was 16.8% (9.9–23.7). ORR by PD-L1 expression in tumor cells was 12.5% for patients with PD-L1 <1% and 22.4% for patients with PD-L1 ≥1%, per investigator assessment. Median (95% CI) DOR was 5.6 (3.5–not estimable) months. Median (95% CI) OS and PFS were 13.3 (10.8–16.3) months and 3.0 (1.7–4.0) months, respectively. At 6 and 12 months, the estimated survival probabilities (95% CI) were 80.5% (71.7–86.9) and 54.5% (42.1–65.3), respectively, for OS, and 20.5% (13.4–28.6) and 7.8% (3.3–15.0), respectively, for PFS. Treatment-emergent AEs occurred in 92.9% of patients, with the most common being injection-site reaction (38.9%), anemia (25.7%) and nausea (22.1%). Six (5.3%) patients died due to a treatment-emergent AE. Conclusions: Results from this phase 2 study of cemiplimab + ISA101b in patients with recurrent HPV16 cervical cancer show clinical benefit, especially in patients with high PD-L1 expression, and no unexpected safety signals, supporting further research. Clinical trial information: NCT04646005 . [Table: see text]
Specific vaginal and gut microbiome and the anti-tumor effect of butyrate in women with cervical cancer.
Authors: Han Mengzhen , Feng Yun , Zhou Yuhang , Han Li , Liu Xiaolin , Sun Tao , Xu Junnan
Published: June 2024

5529

Background: To investigate the vaginal and gut microbes changes during the carcinogenesis of cervical and the auxiliary diagnostic value of microbial markers. To investigate the effect of microbiome-specific metabolites butyric on cervical cancer cells. Methods: We studied 416 vaginal 16S rRNA sequencing data and 116 gut data. Reads were processed using VSEARCH. We used Shannon index, Chao1 index, Simpson diversity index, Beta diversity index, LEfSe analysis, co-abundance network analysis and KEGG enrichment analysis to explore microbiome differences between groups. We constructed random forest models based on genus and validated the models to test their diagnostic effectiveness. Finally, we used the cell counting kit-8 (CCK-8) method to detect cell proliferation capacity and flow cytometry to detect apoptosis and induction of cell cycle progression. Results: Compared to the non-cancerous population, patients with cervical cancer had unique microbial community characteristics in both vaginal and gut ecological niches. Our predictive model based on genus in two ecological regions achieved high accuracy in the diagnosis of cervical cancer (vaginal model AUC=91.58%; gut model AUC=99.95%). Potential functional pathways analysis indicated significant differences between the normal women microbiomes and cervical cancer women microbiomes. Butyric inhibited cervical cancer cell proliferation in a concentration-dependent manner and promoted apoptosis of cancer cells. Conclusions: Significant differences were found in vaginal and gut microbes in patients with cervical cancer compared to the non-cancerous population, and the microflora is involved in cervical carcinogenesis. The prediction models constructed at the genus level in both ecological sites have good diagnostic value for cervical cancer. Microorganisms may be involved in cervical cancer progression in a metabolite-dependent way, and targeting butyric may provide therapeutic options for cervical cancer.
The efficacy of recombinant human adenovirus type 5 (H101) intra-tumor therapy in persistent/recurrent/metastatic gynecological cancer and the exploration of changes in tumor microenvironment.
Authors: Zhang Qiying , Liu Zi , Zhang Jing , Wang Fei , Fan Shi , Wang Juan , Wang Tao , Su Jin
Published: June 2024

5536

Background: Previous small sample retrospective study has showed that H101 has promising efficacy and favorable safety in patients with persistent /recurrent/metastatic (P/R/M) gynecological cancer. To further assess the effecacy and safety of H101 in P/R/M gynecological cancer, we conducted this prospective Phase II study and further explore the tumor microenvironment (TME) through Cell DIVE multiplexed imaging solution. Methods: This was a prospective, open-label, single-arm study (clinicaltrials.gov number NCT05051696). P/R/M gynecological cancer patients who had at least one injectable lesion and had received at least one line of systemic therapy or could not tolerate chemotherapy were eligible. H101 (0.5-1.5×1012 viral particles) was injected into the target lesion once a day for 5 consecutive days, with a cycle of 3 weeks and a maximum of 4 cycles. Whether added other medications was at the physician’s discretion. Cell DIVE multiplexing of 15 immune cell markers were performed in 6 paired pre- and post-H101 injected tumors. Results: From September 2021 to February 2024, 116 P/R/M patients received H101 intro-tumor injection, of which 16 patients did not evaluate for the efficacy endpoint. At the data cut-off of February 2024 for the primary analysis, overall median follow-up time was 10 months. The best complete response was achieved in 30 patients, 34 patients achieved partial response and 15 patients had stable disease, yielding an objective response rate of 64%. The disease control rate was 79% by RECIST1.1, and the median duration of time was 7.1 months. The median progression-free survival was 8.7 months, and the median overall survival was currently not reached. Furthermore, 83% of the patients experienced treatment-related adverse events and the major adverse events were fever (64%), fatigue (31%) and pain at the injection site (25%). Compared with baseline, the number of B cells, T regulatory cells and Ki 67+ tumor cells decreased in the injected lesions, while the number of M1 macrophage, monocytes, CD4 and CD8 T cells were increased. Additionally, B cells and CD68+CD163- tumor associated macrophage (M1 TAM) were higher in response patients. Conclusions: This was the first reported large sample size prospective study regarding H101 in gynecological cancer. These results indicated that H101 as second line or later therapy for P/R/M gynecological cancer patients was efficacious and safe. Cell DIVE multiplexing of immune cell markers suggested that the H101 efficiently reshaped the TME and the response of H101 oncolytic virotherapy may associated with increased B cells and M1 TAM in the TME. Clinical trial information: NCT05051696 .