bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of cumulative exposure to anticholinergic and sedative drugs on cognition in older adults: a memory clinic cohort study
Authors: Reallon Elsa , Gervais Frédéric , Moutet Claire , Dauphinot Virginie , Desnavailles Pauline , Novais Teddy , Krolak-Salmon Pierre , Garnier-Crussard Antoine , Mouchoux Christelle ,   MEMORA group, Makaroff Zaza , Coste Marie-Hélène , Dautricourt Sophie , Rouch Isabelle , Danaila Keren , Waissi Aziza , Dorey Jean-Michel , Sarciron Alain , Guilhermet Yves , Gaujard Sylvain , Grosmaître Pierre , Gilbert Thomas , Vernaudon Julien , Desestret Virginie , Grangé Clémence , Gervais Frederic , Teillac Achille , Verdurand Mathieu , Delphin-Combe Floriane , Bathsavanis Anthony , Bachelet Romain , Temedda Mohamed-Nour
Published: July 2024

Background

Long-term exposure to anticholinergic and sedative drugs could be a modifiable risk factor for cognitive decline. The objective of this study was to measure the association between previous cumulative anticholinergic and sedative drug exposure (Drug Burden Index) and cognitive decline.

Methods

A cohort study (MEMORA cohort) was conducted in a French memory clinic for patients attending a consultation between November 2014 and December 2020, with at least 2 Mini-Mental State Examination (MMSE) measurements (≥ 6 months apart) and available medication data from the local Primary Health Insurance Fund database (n = 1,970). Drug Burden Index was linearly cumulated until each MMSE measurement and was used to categorise patients according to their level of exposure (no exposure, moderate, or high). The longitudinal association between Drug Burden Index and MMSE was assessed using a multivariate linear mixed model, adjusted for age, education level, anxiety disorders, depressive disorders, functional autonomy, and behavioural disorders.

Results

Overall, 1,970 patients were included with a mean follow-up duration of 2.78 years (± 1.54) and 2.99 visits per patients (5,900 MMSE + Drug Burden Index measurements collected). At baseline, 68.0% of patients had moderate cumulative anticholinergic and sedative drug exposure and a mean MMSE of 21.1. MMSE decrease was steeper in patients with moderate and high Drug Burden Index ( -1.74 and -1.70/year, respectively) than in patients with no exposure (-1.26/year) after adjusting for age, education, anxiety and depressive disorders, functional autonomy, and behavioural disorders (p < 0.01).

Conclusions

Long-term exposure to anticholinergic and sedative drugs is associated with steeper cognitive decline. Medication review focusing on de-prescribing these drugs could be implemented early to reduce cognitive impairment.
A systematic review and meta-analysis of thoracic epidural analgesia versus other analgesic techniques in patients post-oesophagectomy
Authors: Macrosson Duncan , Beebeejaun Adam , Odor Peter M.
Published: July 2024

Background

Oesophageal cancer surgery represents a high perioperative risk of complications to patients, such as postoperative pulmonary complications (PPCs). Postoperative analgesia may influence these risks, but the most favourable analgesic technique is debated. This review aims to provide an updated evaluation of whether thoracic epidural analgesia (TEA) has benefits compared to other analgesic techniques in patients undergoing oesophagectomy surgery. Our hypothesis is that TEA reduces pain scores and PPCs compared to intravenous opioid analgesia in patients post-oesophagectomy.

Methods

Electronic databases PubMed, Excerpta Medica Database (EMBASE) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomised trials of analgesic interventions in patients undergoing oesophagectomy surgery. Only trials including thoracic epidural analgesia compared with other analgesic techniques were included. The primary outcome was a composite of respiratory infection, atelectasis and respiratory failure (PPCs), with pain scores at rest and on movement as secondary outcomes. Data was pooled using random effect models and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs).

Results

Data from a total of 741 patients in 10 randomised controlled trials (RCTs) from 1993 to 2023 were included. Nine trials were open surgery, and one trial was laparoscopic. Relative to intravenous opioids, TEA significantly reduced a composite of PPCs (risk ratio (RR) 3.88; 95% confidence interval (CI) 1.98–7.61; n = 222; 3 RCTs) and pain scores (0–100-mm visual analogue scale or VAS) at rest at 24 h (MD 9.02; 95% CI 5.88–12.17; n = 685; 10 RCTs) and 48 h (MD 8.64; 95% CI 5.91–11.37; n = 685; 10 RCTs) and pain scores on movement at 24 h (MD 14.96; 95% CI 5.46–24.46; n = 275; 4 RCTs) and 48 h (MD 16.60; 95% CI 8.72–24.47; n = 275; 4 RCTs).

Conclusions

Recent trials of analgesic technique in oesophagectomy surgery are restricted by small sample size and variation of outcome measurement. Despite these limitations, current evidence indicates that thoracic epidural analgesia reduces the risk of PPCs and severe pain, compared to intravenous opioids in patients following oesophageal cancer surgery. Future research should include minimally invasive surgery, non-epidural regional techniques and record morbidity, using core outcome measures with standardised endpoints.

Trial registration

Prospectively registered on PROSPERO (CRD42023484720).
Altitude-dependent agro-ecologies impact the microbiome diversity of scavenging indigenous chicken in Ethiopia
Authors: Glendinning Laura , Jia Xinzheng , Kebede Adebabay , Oyola Samuel O. , Park Jong-Eun , Park Woncheoul , Assiri Abdulwahab , Holm Jacob Bak , Kristiansen Karsten , Han Jianlin , Hanotte Olivier
Published: July 2024

Background

Scavenging indigenous village chickens play a vital role in sub-Saharan Africa, sustaining the livelihood of millions of farmers. These chickens are exposed to vastly different environments and feeds compared to commercial chickens. In this study, we analysed the caecal microbiota of 243 Ethiopian village chickens living in different altitude-dependent agro-ecologies.

Results

Differences in bacterial diversity were significantly correlated with differences in specific climate factors, topsoil characteristics, and supplemental diets provided by farmers. Microbiota clustered into three enterotypes, with one particularly enriched at high altitudes. We assembled 9977 taxonomically and functionally diverse metagenome-assembled genomes. The vast majority of these were not found in a dataset of previously published chicken microbes or in the Genome Taxonomy Database.

Conclusions

The wide functional and taxonomic diversity of these microbes highlights their importance in the local adaptation of indigenous poultry, and the significant impacts of environmental factors on the microbiota argue for further discoveries in other agro-ecologies.
“Just as expensive as sending him to college:” barriers and perceptions of treatment in justice-involved youth
Authors: McBrayer Corey , Turner Annie , Whitener Mackenzie , Adams Zachary W. , Hulvershorn Leslie , Zapolski Tamika C. B. , Aalsma Matthew C.
Published: July 2024

Background

Justice-involved youth have higher rates of substance use disorders (SUDs) than the general population. Many do not connect with or complete treatment, leading to recidivism. This qualitative study explores perceptions and barriers to treatment in this population.

Results

Justice-involved youth participating in a larger study focused on access to SUD treatment were interviewed about available treatment and justice system involvement. Twenty-one dyads (youth and a guardian) and 3 individual guardians (total N = 45) were interviewed by phone. Inclusion criteria were youth aged 14–17 involved in the justice system that screened positive for SUD. Youth sample was 43% male. Thematic analysis guided the process. The study was Indiana University Institutional Review Board approved (#1802346939).

Data was interpreted within the ecological system theory. Youth barriers included willingness to engage in treatment, time constraints/scheduling conflicts, and low perceived usefulness of treatment. Major guardian themes included high cost of treatment, lack of communication by the justice system about treatment, youth unwillingness or disinterest to engage in treatment, and limited program availability.

Conclusions

The barriers to treatment for justice-involved youth are multifaceted and occur across the spectrum of levels of the ecological system, which include parents, peers, social systems, and cultural elements. Many youth and guardians suggested improvements for their interactions with the juvenile justice system. Further examination is needed of current policy implementation to address these concerns.
Empowering emerging adults with type 1 diabetes: crafting a financial and health insurance toolkit through community-based participatory action research
Authors: Blanchette Julia E. , Lewis Claudia B. , Shannon Chantel S. , Kanchibhatla Anuhya , Rieke Jorden , Roche Mary Jane , Johnson Dove-Anna , Williams Dionne , Webb Shay , Diaz Crystal N. , Lundgrin Erika L. , Allen Nancy A. , Litchman Michelle L. , Hatipoglu Betul
Published: July 2024

Background

Emerging adults aged 18–30 years face challenges during life transitions, with an added burden of navigating the health care system and additional costs associated with diabetes. This stress is compounded by overall low levels of health insurance literacy in this population, as people may not know about available financial and health care resources to minimize suboptimal diabetes outcomes. This study aimed to tailor a financial and health insurance toolkit to emerging adults with type 1 diabetes, including racially, ethnically diverse, and Medicaid-insured individuals, through community-based participatory action research.

Methods

An academic research team and community members from a national organization held six online community advisory board (CAB) content-creation meetings to understand how to tailor a financial and health insurance Toolkit. The CAB was comprised of six racially and insurance-diverse emerging adults with type 1 diabetes and four content experts (clinical, financial, and insurance). Six 60-minute online CAB meetings were held via University Hospitals (UH)-encrypted Zoom over five months. Pre-reading materials were emailed to CAB members before the meetings. A moderator established the purpose of each meeting and briefly discussed meeting rules before each meeting commenced. During the meetings, the moderator guided the discussions and provided the CAB members opportunities to respond and build on one another’s feedback. A deductive thematic qualitative analysis was utilized. Three researchers independently coded the cross-referenced and de-identified CAB meeting transcripts and then convened to reach a group consensus. Two CAB members performed member-checking.

Results

The following key themes emerged to tailor the Toolkit: ensuring that content covers empowerment and self-advocacy, including genuine stories and multimedia visuals for aesthetics, addressing clinician bias, acknowledging racial and ethnic disparities in care, incorporating cultural representation, and demystifying Medicaid stigma.

Conclusions

By successfully partnering with the CAB and a community organization through a community-based participatory action research approach, we will develop a financial and health insurance Toolkit tailored to the needs of racially and ethnically diverse and Medicaid-insured emerging adults with type 1 diabetes.
Outcome evaluation of prophylactic internal iliac balloon occlusion in the management of patients with placenta accreta spectrum
Authors: Osman Asaad , Das Raj , Pinas Ana , Hartopp Richard , Livermore Deborah , Hawthorn Benjamin , Chun Joo-Young , Mailli Leto , Morgan Robert , Ratnam Lakshmi
Published: July 2024

Purpose

To evaluate outcomes and complications of prophylactic internal iliac balloon occlusion (PIIBO) in the management of patients with placenta accreta spectrum (PAS) at a large regional referral centre.

Materials and methods

A retrospective review of all PIIBO for PAS performed over a 12-year period (2010–2022). Information for analysis was gathered from the local RIS/PACS and clinical documentation. Collected data included patient demographics, indication for procedure, sheath insertion and removal time, total duration of balloon inflation and complications that occurred.

Results

106 patients underwent temporary internal iliac artery balloon occlusion within the 12-year period. All procedures utilised bilateral common femoral artery punctures, 6Fr sheath and 5Fr Le Maitre occlusion balloons. Catheters were successfully positioned and balloons inflated in obstetric theatre following caesarean delivery in 100% of the cases. The uterus was conserved in every case. There was no maternal mortality or foetal morbidity.

Twenty patients (18.9%) had some form of complication that required further intervention. Of these, 7(6.6%) had post-operative PPH, which was treated with uterine artery embolisation; and 13 (12.3%) had arterial thrombus which required aspiration thrombectomy. All procedures were technically successful with no long-term sequelae.

Conclusion

PIIBO plays an important part in reducing morbidity and mortality in patients with PAS. Clear pathways and multidisciplinary team working is critical in the management of these patients to ensure that any complications are dealt with promptly to avoid long-term sequelae.
Examining audiologist candidates' self-esteem and professional self-esteem
Authors: Koçyiğit Azize Arzu , Dizdar Handan Turan
Published: July 2024

Background

Self-esteem is an individual's perception of themselves. Professional self-esteem is defined as the individual's perception of worthiness regarding their preferred profession. The research aims to examine the relationship between the self-esteem and professional self-esteem of Audiology department students and raise awareness of this issue.

Material and Method

In our study, 532 students in the Audiology undergraduate department were included. Professional Self-Esteem and Self-Esteem questionnaires were delivered to the students online via Google Forms, using snowball sampling, in social media groups of the Audiology undergraduate students. Data were analyzed using Spearman correlation analysis, Mann Whitney U, and Kruskal Wallis Test. p < 0.05 was accepted as significance value.

Results

According to the results, it has been observed that there is a weak and significant positive correlation between the professional self-esteem of the audiologist candidates and their total self-esteem scores (p < 0.05). Self-esteem and professional self-esteem scores of those who chose the profession willingly were significantly higher than those who did not choose the profession willingly (p < 0.05). As the grade level increased, professional self-esteem decreased significantly (p < 0.05). There was no significant difference between the scores in both scales according to income, university type, and gender (p > 0.05).

Conclusion

As a result, it was observed that as the self-esteem of the audiologist candidates increased, their professional self-esteem increased. Also, as the class level increased, their professional self-esteem decreased.
Management of Stage III Non–Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update
Authors: Daly Megan E. , Singh Navneet , Ismaila Nofisat ,   for the Management of Stage III NSCLC Guideline Expert Panel, Daly Megan E. , Singh Navneet , Ismaila Nofisat , Antonoff Mara B. , Arenberg Douglas A. , Bradley Jeffrey , David Elizabeth , Detterbeck Frank , Früh Martin , Gubens Matthew A. , Moore Amy C. , Padda Sukhmani K. , Patel Jyoti D. , Phillips Tanyanika , Qin Angel , Robinson Clifford , Simone Charles B.
Published: July 2024

ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (
Appendix 1
and
Appendix 2
, online only)

.
Clinical outcomes in salivary adenoid cystic carcinoma.
Authors: Dalal Prarthana , Dermody Sarah , Brummel Collin , Brenner Chad , Casper Keith , Chinn Steven B. , Malloy Kelly M , Mierzwa Michelle Lynn , Heft Neal Molly , Prince Mark , Shah Jennifer Lobo , Shuman Andrew , Stucken Chaz , Spector Matthew , Worden Francis P. , Swiecicki Paul
Published: July 2024

6102

Background: Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy with a paucity of clinical outcome data. As such, evidence supporting and informing current guidelines remains limited. Methods: Inclusion criteria stipulated adults with adenoid cystic carcinoma treated at the University of Michigan between 1988 and 2019 with complete records (n=102). Clinical variables including demographics, disease stage, and treatment modality were abstracted. Pathologic variables analyzed included tumor grade, perineural invasion, lymphovascular invasion, and surgical margin status. Multivariate analyses were performed with disease recurrence calculated with Kaplan-Meier methodology as the primary outcome. Results: Mean age at diagnosis was 59 years; stage I and II disease accounted for 35 (38%) patients. Initial treatment was most commonly surgery with adjuvant radiation (77%). Median follow-up was 3 years. Distant metastatic disease developed in 34 (33%) patients. Most common sites included lung (68%), bone (21%), and brain (21%). Median time to distant metastases was 46 months with median overall survival of 58 months. Patients with locoregional recurrence experienced median survival of 91 months. Multivariate analysis adjusted for grade, perineural invasion, and surgical margin status (Table). Grade 3 tumors with predominantly solid histologic pattern pose higher risk of recurrence compared to grade 1 tubular histologic patterns as a reference (HR 3.69, 95% CI 1.15-11.88, p=0.028). Conclusions: Survival among patients with adenoid cystic carcinoma after locoregional recurrence is significantly better compared to those experiencing distant metastasis. Furthermore, tumor grade is most predictive of recurrence. Additionally, distant metastases may emerge over the course of many years. These data from one of the largest retrospective databases to date may inform the development of disease-specific surveillance guidelines and novel salvage treatment paradigms. [Table: see text]
Unraveling the synergistic mechanisms of pyrotinib in combination with trastuzumab: Insights from the PHILA trial.
Authors: Liu Shuning , Lan Bo , Li Lixi , Qian Haili , Ma Fei
Published: July 2024

e13015

Background: There are many options for the treatment of advanced HER2-positive breast cancer. The results of PHILA study suggest that pyrotinib, trastuzumab and docetaxel may be considered as a potential first line treatment for patients with untreated HER2-positive metastatic breast cancer. We aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and compare them to trastuzumab plus pertuzumab, providing further insights for the PHILA trial. Methods: The efficacy of combination treatments was detected by cell vitality assay, Western blot and immunohistochemistry. The relevant mechanism was examined by flow cytometry and co-immunoprecipitation. Cell-derived xenografts and TUBO tumor model were utilized to evaluate the anti-tumor activity of rational combinations. Next-generation sequencing of circulating tumor DNA from a cohort of 18 patients in the PHILA trial was performed to evaluate molecular alterations associated with clinical response. Results: We demonstrated that pyrotinib plus trastuzumab superiorly inhibited cell growth than trastuzumab plus pertuzumab in models of HER2-dependent breast cancer. In addition to inhibiting HER family phosphorylation, pyrotinib plus trastuzumab synergistically reduced membrane HER2 levels by inducing receptor ubiquitination and internalization via HSP90 dissociation, which resulted in a comprehensive blockade of HER signaling pathway. Moreover, TUBO tumor model was utilized to further confirm the synergistic effects of pyrotinib and anti-neu antibody on HER2 signaling cascade. In both treatment groups of PHILA study, patients with aberrant mutations in HER2 signaling cascade showed a significantly shorter median progression-free survival compared to individuals with wild-type pathway. Correspondingly, in models of HCC1954 breast cancer cell harboring PIK3CA H1047R mutation, we did not observe a synergy between pyrotinib and trastuzumab. Conclusions: Pyrotinib and trastuzumab synergistically achieve the comprehensive blockade of HER signaling pathway in HER2-dependent breast cancer. Patients with advanced HER2-positive breast cancer, who are addicted to HER2 signaling cascade, could be considered for pyrotinib in combination with trastuzumab and docetaxel as an alternative first line treatment.
Comparing the mutation profiles of primary HER2-positive breast cancers in patients with and without brain metastases.
Authors: Du Tian , Sun Peng , Chen Yuhong , Deng Rong , Tang Jun
Published: July 2024

e13018

Background: Brain metastasis is a frequent and devastating event of HER2-positive breast cancer. Identifying the driver genes of brain metastasis is important for the prevention and treatment of brain metastasis. In this study, we compared the gene mutation profiles of primary breast cancers between patients with and without brain metastases, aiming to identify new candidate genes associated with brain metastases. Methods: HER2-positive and lymph node-positive early breast cancers of 21 patients who eventually developed brain metastases (BM group) and 27 patients without any metastasis (NM group) at a minimum 5-year follow-up were retrieved from the Sun Yat-sen University Cancer Center. Whole-exome sequencing was performed on primary breast cancers (FFPE) and matched normal breast tissues or peripheral blood. Mutect2 was used to detect somatic mutations, and Fisher’s exact test was used to identify genes mutated at different frequencies in the BM and NM groups. The mRNA expression changes of genes mutated at higher frequencies in the BM group were further analyzed in 16-pair matched HER2-positive primary breast cancers and brain metastases using the public dataset (1). Results: The BM and NM groups exhibited similar TP53 (33.3% vs. 55.6%, p=0.15) and PIK3CA (23.8% vs. 25.9%, p=1) mutation rates. The mutation rates of AP3B1 (38.1% vs. 3.7%), DHTKD1 (23.8% vs. 0), ERCC6L2 (38.1% vs. 7.4%), DNAH5 (33.3% vs. 3.7%), ZNF207 (33.3% vs. 7.4%), SPATA31E1 (19.0% vs. 0), FAM111B (19.0% vs. 0), ATG3 (19.0% vs. 0), CDK14 (19.0% vs. 0), TUT4 (19.0% vs. 0), CCNB3 (19.0% vs. 0), MGA (19.0% vs. 0), CLCA1 (28.6% vs. 3.7%), BBS7 (28.5% vs. 3.7%) and GABRG1 (38.1% vs. 11.1%) were significantly (p<0.05) higher in the BM group than in the NM group. Among these genes, CDK14 and TUT4 were significantly downregulated, and ZNF207 and FAM111B were significantly upregulated in brain metastases compared to their matched primary breast cancers. Conclusions: We identified several genes with higher mutation rates in primary breast cancer of patients who eventually developed brain metastases. These genes warrant further investigation in the development of brain metastases in HER2-positive breast cancer. 1. Cosgrove et al. NC 2022.
Association of low adherence to weekly cisplatin with outcomes in patients with head and neck cancer treated with chemoradiation.
Authors: Virk Jas , Gill Jasmin , Fekrmandi Fatemeh , Iovoli Austin , Farrugia Mark , Ma Sung Jun , Singh Anurag K.
Published: July 2024

e18053

Background: The National Comprehensive Cancer Network (NCCN) guideline recommends consideration of weekly cisplatin as an alternative option for patients with head and neck cancer undergoing definitive chemoradiation. However, in a recent phase III trial (ConCERT), 20% of patients treated with weekly cisplatin could not receive a total of 200 mg/m2, and the association of low adherence to weekly cisplatin and cancer control outcomes remains unclear. To fill this knowledge gap, we performed an observational cohort study of patients with head and neck cancer undergoing definitive chemoradiation with weekly cisplatin. Methods: Our institutional database at the Roswell Park Comprehensive Cancer Center was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation with weekly cisplatin (40 mg/m2) between November 2007 and April 2023. Adherence to weekly cisplatin was defined as receiving at least 5 cycles with a total cumulative dose of 200 mg/m2. Survival outcomes were evaluated using Kaplan-Meier method, log-rank tests, Cox proportional hazard multivariable (MVA) analyses. Logistic MVA was performed to identify variables associated with low adherence to weekly cisplatin. Fine-Gray MVA was performed to analyze failure outcomes with death as a competing event. Results: Among 119 patients who met our criteria, 51 patients (42.9%) had low adherence to weekly cisplatin. Median follow up was 19.8 months (interquartile range 8.8-65.6). Low adherence to weekly cisplatin was associated with worse overall survival (adjusted hazards ratio [aHR] 2.94, 95% confidence interval [CI] 1.58-5.47, p<0.001) and progression-free survival (aHR 2.32, 95% CI 1.29-4.17, p=0.005). It was also associated with worse distant failure (aHR 4.55, 95% CI 1.19-17.3, p=0.03), but not locoregional failure (aHR 1.61, 95% CI 0.46-5.58, p=0.46). KPS <90 was the only variable associated with low adherence to weekly cisplatin (adjusted odds ratio [aOR] 2.67, 95% CI 1.10-6.65, p=0.03). Conclusions: Our study suggested that over 40% of patients underwent fewer than 5 weekly cisplatin cycles and that low adherence to weekly cisplatin was an independent, adverse prognostic factor for worse survival and distant failure outcomes. Those with reduced adherence to weekly cisplatin were more likely to have poor performance status. Further studies are warranted to improve the adherence to chemotherapy and outcomes.
Association of absolute neutrophil count with outcomes in patients with head and neck cancer treated with chemoradiation.
Authors: Gill Jasmin , Virk Jas , Fekrmandi Fatemeh , Iovoli Austin , Farrugia Mark , Ma Sung Jun , Singh Anurag K.
Published: July 2024

e18055

Background: Systematic inflammation plays an integral role in tumor development and metastasis. High neutrophil counts, among various peripheral blood biomarkers, have been shown to be associated with worse survival outcomes in multiple cancer types. To evaluate the absolute neutrophil count (ANC) as a prognostic biomarker in head and neck cancer, we performed an observational cohort study of patients undergoing definitive chemoradiation. Methods: Our institutional database at the Roswell Park Comprehensive Cancer Center was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation between June 2007 and April 2023. ANC was analyzed as a continuous variable. Survival outcomes were assessed using Kaplan-Meier method, log-rank tests, Cox proportional hazard multivariable (MVA) analyses. Fine-Gray MVA was used to analyze failure outcomes with death as a competing event. To reduce selection bias, propensity score matching was performed using ANC as a dichotomous variable with its median value as a cutoff. Subgroup analyses were performed among p16-negative and p16-positive cohorts. Results: A total of 668 patients who met our criteria. Median follow up was 30.3 months (interquartile range 9.9-60.7). Elevated ANC as a continuous variable was associated with worse overall survival (OS; adjusted hazards ratio [aHR] 1.02, 95% confidence interval [CI] 1.01-1.04, p=0.003), progression free survival (PFS; aHR 1.03, 95% CI 1.01-1.04, p<0.001), and distant failure (DF; aHR 1.03, 95% CI 1.01-1.05, p=0.007), but not locoregional failure (LRF; aHR 1.02, 95% CI 1.00-1.05, p=0.10). Similar findings were noted among 278 matched pairs (OS: hazards ratio [HR] 1.66, 95% CI 1.23-2.26, p=0.001; PFS: HR 1.74, 95% CI 1.31-2.29, p<0.001; LRF: HR 1.66, 95% CI 0.98-2.80, p=0.06; DF: HR 1.64, 95% CI 1.03-2.60, p=0.04). On subgroup analysis, among 118 patients with p16-negative tumors, elevated ANC as a continuous variable was not associated with OS (aHR 1.00, 95% CI 0.90-1.11, p=0.97) and PFS (aHR 0.97, 95% CI 0.87-1.08, p=0.54). The number of LRF (n=21) and DF (n=17) were too few to analyze in this subgroup. However, among 344 patients with p16-positive tumors, high ANC was associated with worse OS (aHR 1.03, 95% CI 1.00-1.06, p=0.046), PFS (aHR 1.05, 95% CI 1.02-1.07, p<0.001), LRF (aHR 1.08, 95% CI 1.05-1.12, p<0.001), and DF (aHR 1.04, 95% CI 1.01-1.08, p=0.02). Conclusions: Our study suggested that elevated ANC was an independent, adverse prognostic factor for worse survival and distant metastasis outcomes. Similar findings were also observed among patients with p16-positive tumors, with high ANC also associated with worse locoregional failure. Further studies are warranted to tailor interventions based on such biomarkers.
Study on the efficacy and toxicity of pamiparib combined with tamoxifen in the treatment of patients with epithelial ovarian cancer with biochemical recurrence during first-line PARPi maintenance therapy.
Authors: Meng Yifan , Li Jundong , Wan Ting
Published: July 2024

TPS5621

Background: A high proportion of ovarian cancer patients tend to have elevated CA-125 1-6 months before imaging recurrence. The time between biochemical recurrence (i.e., only elevated CA-125 without imaging finding or clinical symptoms) to imaging recurrence can be considered a "window period", and if the “window period” can be extended, it may convert platinum-resistant relapsed patients to platinum-sensitive patients, and ultimately improving patient outcomes. The timing of treatment for the biochemical recurrent patients has been controversial. Tamoxifen, an anti-estrogenic drug, is considered an effective option for these patients. Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. According to OReO study(NCT03106987), the "PARPi after PARPi" strategy is effective in recurrent ovarian cancer patients previously treated with a PARP inhibitor. Therefore, we aim to further explore the use of PARP inhibitors in maintenance therapy for patients with ovarian cancer. Methods: This study (NCT05669768) will evaluate the efficacy and toxicity of pamiparib and tamoxifen in ovarian cancer patients with biochemical recurrence during first-line PARPi maintenance therapy. The included ovarian cancer patients are required to achieve No Evidence of Disease (NED) or demonstrated a response following platinum-based chemotherapy, with normalized CA-125 levels. First-line maintenance treatment with a PARP inhibitor is mandatory, with a minimum interval of ≥6 months to biochemical recurrence. The trial design is interventional, employing a Simon two-stage design to estimate sample size. The primary outcome of the study is the CA-125 response rate, which was assessed according to the GCIG criteria.1 The secondary outcome was Time to First Subsequent Therapy (TFST). Patients undergo regular assessments for tumor markers and imaging throughout treatment. If persistent elevation of tumor markers or the detection of recurrent lesions or distant metastases is observed, the patient is promptly removed from the study group. Standardized antitumor therapy is then initiated based on the patient's condition. The total planned enrollment is 46 participants, utilizing a single-group assignment and an open-label design. 1 of planned 12 patients for the first stage of accrual have been enrolled. Reference: 1. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21(2):419-423. Clinical trial information: NCT05669768 .
A phase 2 study to evaluate efficacy and safety of PRGN-2009, a novel gorilla adenovirus-based immunotherapy, in combination with pembrolizumab versus pembrolizumab monotherapy in patients with recurrent or metastatic cervical cancer.
Authors: Tschernia Nicholas , Birrer Michael J. , Liao John B. , Lankford Amy , Disis Mary L. , Gulley James L.
Published: July 2024

TPS5623

Background: The association between cervical cancer and human papillomavirus (HPV) is well understood, with nearly all cervical cancer known to be caused by high risk HPV infection. HPV16 and HPV18 are the most common high-risk HPV types and are responsible for about 70% of cervical cancer cases. Recurrent or metastatic cervical cancer is currently treated with pembrolizumab alone or in combination with chemotherapy, however t there remains a significant need for treatments for patients that recur or do not respond at all to pembrolizumab treatment. PRGN-2009 is a gorilla adenovirus-based immunotherapy targeting cancers caused by HPV16 or HPV18. PRGN-2009 includes a novel HPV antigen design to induce HPV16/18-specific T cell immune responses against cancer cells. The rationale for combining the PRGN-2009 with immune checkpoint inhibitor is based on preclinical and clinical data demonstrating that combination of cancer vaccines and immune checkpoint inhibitors can trigger intensified immunogenicity leading to increased antitumor efficacy compared to either treatment alone. PRGN-2009 has been characterized in both in vitroand in vivostudies to support the scientific rationale and the safety of PRGN-2009 has been demonstrated in evaluated in initial Phase 1/2 studies in patients with HPV+ malignancies. Methods: This is a randomized, Phase 2 study to evaluate efficacy and safety of PRGN-2009 in combination with pembrolizumab compared to pembrolizumab alone in patients with recurrent or metastatic cervical cancer. Key inclusion criteria include recurrent or metastatic cervical cancer (histologically or cytologically confirmed) resistant to pembrolizumab. Subjects will be randomized 1:1 to Cohort 1: Combination of PRGN-2009, 5 x 1011 PU (Day 0, Day 21 and Day 42, then q6w), plus pembrolizumab, 400mg q6w, or to Cohort 2: pembrolizumab alone (400 mg q6w). Subjects randomized to Cohort 2 (pembrolizumab monotherapy) and who have confirmed disease progression (per RECIST 1.1) after at least one cycle of pembrolizumab and have had no Grade ≥ 3 adverse events related to treatment will be offered the option to crossover to Cohort 1 (PRGN-2009 plus pembrolizumab). All subjects will be evaluated for safety and efficacy of PRGN-2009 in combination with pembrolizumab, and for biological correlative assays. The primary endpoint is objective response rate (ORR) following treatment with PRGN-2009 in combination with pembrolizumab or pembrolizumab monotherapy, and will be tested using Fleming’s two-stage design and the stopping boundaries for futility and efficacy applied. The study is currently recruiting patients with recurrent or metastatic cervical cancer (NCT06157151). Clinical trial information: NCT06157151 .
Open-label, prospective phase 2 study to evaluate the efficacy and safety of camrelizumab combined with etoposide and cisplatin as neoadjuvant therapy in patients with neuroendocrine carcinoma of the cervix.
Authors: He Haixin , Yu Haijuan , Lin Cuibo , Lu Yongwei , Chen Jian
Published: July 2024

TPS5624

Background: Camrelizumab, a humanized monoclonal antibody, specifically targets PD-1 to inhibit its interaction with PD-L1, thereby reactivating the T cell immune response against tumors. The NACI study demonstrated that, in the treatment of locally advanced cervical cancer, the combination of camrelizumab and neoadjuvant chemotherapy achieved an overall response rate (ORR) of 100%. Specifically, complete remission was observed in 4 patients (8.33%), while 44 patients (91.67%) experienced partial remission. This regimen significantly outperformed traditional treatments in efficacy, with manageable toxicity levels. Neuroendocrine carcinoma of the cervix (NECC) is a highly rare and aggressive malignancy characterized by its distinctive biological behavior, propensity for early lymph node and hematogenous metastasis, and limited effective treatment options, leading to a dismal prognosis. Although PD-1 inhibitors have shown promise in some NECC case reports, there is a notable absence of comprehensive, prospective clinical trials to substantiate their effectiveness. This study aims to assess the efficacy and safety of neoadjuvant chemo-immunotherapy in patients with NECC. Methods: This open-label, single-arm, prospective phase II study evaluates the antitumor efficacy and safety of camrelizumab in combination with etoposide and cisplatin in roughly 30 patients with NECC. Eligible participants are aged 18-75, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and histologically confirmed NECC, specifically targeting small cell and large cell neuroendocrine cervical carcinoma but excluding atypical and typical carcinoid tumors. Inclusion criteria stipulate that if NECC is present alongside other tumor types, the neuroendocrine carcinoma component must account for more than 60% of the tumor mass. The treatment protocol involves neoadjuvant chemo-immunotherapy, comprising two to three cycles of camrelizumab (200 mg, IV, day 1), cisplatin (75 mg/m², IV, day 1), and etoposide (100 mg/m², IV, days 1-3) administered every three weeks. Following this, patients achieving complete or partial response will proceed to radical surgery and adjuvant therapy, while those with stable or progressive disease, or considered unsuitable for surgery by gynecological oncologists, will transfer to concurrent chemoradiotherapy. The primary objective is to ascertain the objective response rate as per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary objectives include disease control rate, progression-free survival, overall survival, and evaluations of safety and tolerability. The study began on December 28, 2023, with ongoing enrollment. Clinical trial information: NCT05910177 .
SB221: A proof-of-concept study to assess the combination of SON-1010 (IL12-FHAB) and atezolizumab in patients with platinum-resistant ovarian cancer.
Authors: Chawla Sant P. , Gao Bo , Bampton Carolyn L. , Hamilton Brett , Cini John K. , Dexter Susan , Kenney Richard T. , Wenham Robert Michael
Published: July 2024

TPS5629

Background: Recombinant interleukins (rIL) have had limited clinical success due to inefficient tumor targeting and short PK, requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 potently activates T and NK cells to produce IFNγ and kill tumor cells, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. We developed a novel platform that delivers immunomodulator(s) linked to a fully-human albumin binding (FHAB) domain (Cini, Front Immunol 2023). Single-chain native IL-12 genetically linked to the FHAB provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC in the tumor microenvironment (TME), with an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Tumor growth inhibition in an immunologically ‘cold’ B16-F10 mouse melanoma model showed the efficacy of IL12-FHAB compared with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. SON-1010 is being studied clinically as monotherapy (study SB101) in advanced solid tumors and in healthy volunteers (study SB102) (Chawla, AACR 2023). Atezolizumab (Tecentriq), an anti-PD-L1 immune checkpoint inhibitor (ICI), has shown preliminary clinical activity in Phase 1 studies of patients with platinum-resistant ovarian cancer (PROC) (Liu, Gyn Onc 2019; Moroney, Clin Canc Res 2020). SON-1010 may ‘warm up’ the TME to improve ICI effectiveness in these immunologically-active tumors that have high levels of SPARC. Methods: Study SB221 is a Phase 1b/2a multicenter, dose-escalation and proof-of-concept study to assess the safety, tolerability, PK, PD, and efficacy of SON-1010 administered SC, either alone or in combination with a fixed dose of atezolizumab given IV (NCT05756907). The study is designed in Part 1 to rapidly establish the maximum tolerated dose (MTD) of the combination in patients with advanced solid tumors with up to 5 dose-escalation groups and to expand the dataset using patients with PROC to establish the Recommended Phase 2 Dose (RP2D). Once the likelihood of efficacy is shown in a Simon 2-stage design, this will be followed in Part 2 by an assessment of the potential for improved efficacy of the combination in patients with PROC over SON-1010 alone or the standard of care (SOC). The first dose-escalation cohorts have been enrolled and additional sites are being added to help with recruitment of patients with PROC. Combination of SON-1010 with an ICI offers a unique opportunity to use this extended PK version of IL-12 to augment the potential for tumor control in PROC, which represents a significant unmet medical need. Clinical trial information: NCT05756907 .
Approach to the Patient: New Era Emerges for Craniopharyngioma Management
Authors: Hayes Annabelle G , Jonker Benjamin , Teng Christina , Lemech Charlotte , Killen Andrew J , Sim Hao-Wen , McCormack Ann I
Published: July 2024

Papillary craniopharyngioma (PCP) and adamantinomatous craniopharyngioma (ACP) are distinct, slow-growing tumors of the suprasellar region. Their location, composition, and biology have historically evaded successful surgical radiation and medical therapy. Meanwhile compromise of critical structures either by tumor or treatments increase morbidity, impacting patient and carer quality of life. There has been a paradigm shift in the management of PCP, stemming from the discovery of BRAFV600E mutation in its tumorigenesis. Such a treatment breakthrough may soon be the case for ACP, changing the landscape of craniopharyngioma management. We use a case of ACP partially responding to ERK inhibitor therapy to demonstrate chronicity of disease progression and discuss modern management strategies highlighting the importance of access to tumor agnostic clinical trials, and future directions.
Racial and Ethnic Underserved Populations Prescription Analgesic Use Before and After Lower Extremity Amputation in US Medicare
Authors: Yang Seonkyeong , Wilson Debbie L. , Zhou Lili , Fernandes Deanna C. , Bell Melanie , Tan Tze-Woei , Kwoh Chian Kent , Chang Ching-Yuan , Huang Pei-Lin , Barker Paige C. , Yan Shunhua , Lo-Ciganic Wei-Hsuan
Published: July 2024

BACKGROUND:

Racial disparities exist in access to health care and management of multiple health conditions including chronic pain; however, racial disparities in pre- and postoperative pain management in lower extremity amputation are not well-studied. Our objective was to examine the association between different racial and ethnic groups and prescription opioid and other analgesics use before and after lower extremity amputation. We hypothesize prescription opioid and other analgesic use among Black, Hispanic, and Native American US Medicare beneficiaries undergoing lower extremity amputations will be lower compared to White US Medicare beneficiaries.

METHODS:

This retrospective cohort study included a 5% national sample of all Medicare beneficiaries from 2011 to 2015 and 15% national sample of fee-for-service Medicare beneficiaries from 2016 to 2018 undergoing nontraumatic, lower extremity amputations. The exposure of interest was racial and ethnic group membership (ie, Black, Hispanic, Native American, White, and others—with others being the combination of the categories Asian and other) as provided in Medicare claims data. Using multivariable generalized estimating equations with a logistic link to account for repeated measurements over time, we estimated the odds of prescription opioid use within 6 months before and after lower extremity amputation across different racial and ethnic groups separately, adjusting for sociodemographic and health status factors (eg, Elixhauser index). Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) were reported.

RESULTS:

Among 16,068 eligible beneficiaries who underwent major and minor amputations (mean age = 65.1 ± 12.7 years; female = 36.1%), 10,107 (62.9%) were White, 3462 (21.5%) were Black, 1959 (12.2%) were Hispanic, 247 (1.5%) were Native American, and 151 (2.9%) were beneficiaries of other races. During the 6 months before lower extremity amputation, Hispanic beneficiaries (aOR, 0.71, 95% CI, 0.65–0.78) and beneficiaries of other races (aOR, 0.60, 95% CI, 0.47–0.76) had significantly lower odds of using prescription opioids compared to White beneficiaries. Similarly, Hispanic beneficiaries (aOR, 0.78, 95% CI, 0.71–0.84) and beneficiaries of other races (aOR, 0.63, 95% CI, 0.51–0.78) were associated with lower odds of opioid use in the 6 months after amputation compared to White beneficiaries.

CONCLUSIONS:

Among fee-for-service Medicare beneficiaries, Hispanic and other (eg, Asian) fee-for-service Medicare beneficiaries had lower odds of prescription opioid use than their White counterparts before and after nontraumatic, lower extremity amputations. Efforts to determine the underlying reasons are needed to ensure equitable health care access.
Artist, Audience, Accomplice
Authors: Stutterheim Sydney
Published: July 2024

In Artist, Audience, Accomplice, Sydney Stutterheim introduces a new figure into the history of performance art and related practices of the 1970s and 1980s: the accomplice. Occupying roles including eyewitness, romantic partner, studio assistant, and documenter, this figure is situated between the conventional subject positions of the artist and the audience. The unseen and largely unacknowledged contributions of such accomplices exceed those performed by a typical audience because they share in the responsibility for producing artworks that entail potential ethical or legal transgressions. Stutterheim analyzes the art of Chris Burden, Hannah Wilke, Martin Kippenberger, and Lorraine O’Grady, showing how each cannily developed strategies of shared culpability that evoked questions about the accomplice’s various rights and roles. In this way, Stutterheim argues that the artist’s authority is not sovereign, total, or exclusive but, rather, fluid and relational. By examining the development of an alternative model of participatory art that relies on a network of accomplices, Stutterheim radically revises current understandings of artistic agency, aesthetic property, and acknowledged authorship.
Tsunamis versus extreme meteorological waves: Evidence from the 2004 Aegean Sea cyclone in Samos Island
Authors: Stiros Stathis
Published: July 2024

In January 2004 a Mediterranean cyclone in the Aegean Sea seriously affected the north coast of Samos Island, damaged the harbour mole of a coastal village, and catapulted its building material along with heavy boulders to the inner harbour basin.   This area was also affected by a 2020, magnitude 7.0 earthquake which produced localized tsunamis.   The evidence from the 2004 cyclone, with boulders shifted from known positions and with known trajectories, can contribute to the debate for the causes of mobilization of coastal boulders because of storms, tsunamis, or their combination.