bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlates of health-related quality of life in primary caregivers of perinatally HIV infected and HIV exposed uninfected adolescents at the Kenyan Coast
Authors: Mwangala Patrick N. , Ssewanyana Derrick , Mwangi Paul , Chongwo Esther , Nasambu Carophine , Kagonya Vincent A. , Scerif Gaia , Newton Charles R. , Abubakar Amina
Published: January 2022

Background

Mothers and other primary caregivers play a crucial role in looking after perinatally HIV infected, and HIV exposed uninfected adolescents in sub-Saharan Africa. Day- to-day caregiving in the context of limited instrumental support and added biomedical risk (HIV seropositivity) may expose these caregivers to adverse states of health. Unfortunately, very few studies have examined their health-related quality of life (HRQoL). Our study documents the HRQoL profile, and associated factors in primary caregivers of perinatally HIV infected, perinatally HIV exposed but uninfected and HIV unexposed/uninfected adolescents aged 12–17 years at the Kenyan Coast.

Methods

This was a cross-sectional analysis of 485 primary caregivers: 195 of perinatally HIV infected adolescents, 128 of perinatally HIV exposed but uninfected adolescents and 162 of HIV unexposed/uninfected adolescents. All caregivers completed a self-report measure of HRQoL (having 8 subscales), depressive symptoms, and parenting stress. They also provided their sociodemographic information and that of the care recipients. We used one-way analysis of variance to assess statistical differences among the groups. Linear regression analyses were used to identify correlates of HRQoL.

Results

Overall, caregivers of HIV unexposed/uninfected adolescents reported significantly higher mean HRQoL scores than the other caregivers in the overall HRQoL domain and majority of the subscales. There were no statistical differences in the overall HRQoL scores and most subscales between caregivers of HIV exposed adolescents. Linear regression analyses across the sample indicated that depressive symptoms, increasing age of caregiver, and caring for an adolescent perinatally exposed to HIV were significantly associated with reduced HRQoL at both the overall and sub-scale level. Having a professional job relative to subsistence farming was the only factor associated with improved overall HRQoL. At subscale level, higher socioeconomic status correlated positively with HRQoL while being a grandparent, level of education, parenting stress were negatively associated with HRQoL.

Conclusions

Caregivers in this sample, especially those who are ageing, at risk of mental ill-health, and taking care of adolescents perinatally exposed to HIV, appear to be vulnerable to poor quality of life. Inclusive and multi-component interventions tailored to the caregivers' psychosocial and mental needs will potentially enhance their quality of life.
Unmet need for family planning among rural married women in Ethiopia: What is the role of the health extension program in reducing unmet need?
Authors: Tadesse Daniel , Medhin Girmay , Kassie Getnet M. , Dadi Tegene Legese , Tigabu Setegn , Demissie Mekdes , Alemayehu Mussie , Gerbaba Mulusew J. , Denberu Bisrat F. , Teklu Alula M.
Published: January 2022

Background

Ethiopia is striving to reduce unmet need for family planning (FP) and implementation of the health extension program (HEP) is one of the major actions that the country took to address health issues of rural communities including FP. However, there is limited published evidence demonstrating the role of HEP in reducing the unmet need of married rural women for FP. The aim of this study is to estimate the role of HEP in reducing unmet need for FP in rural Ethiopia.

Methods

This paper is based on data extracted from a national rural HEP assessment that covered all regions of Ethiopia. We identified 4991 eligible married women both from agrarian and pastoralist settings. The role of HEP was measured by the exposure of eligible women to FP services through the implementation of HEP packages. We used descriptive statistics to summarize different variables and used logistic regression to model the unmet need for FP.

Results

The overall prevalence of unmet need for FP among married rural Ethiopian women was 22.41%, contraceptive prevalence rate (CPR) was 44.60%, and the total demand for FP was 60.86%. Women exposed to HEP had a lower level of unmet need (4.82%), a higher demand for FP (37.78%) and a higher CPR (24.93%) compared to women unexposed to HEP. Having exposure to FP services (adjusted odds ratio (AOR) = 0.46, 95% confidence interval (CI) 0.37–0.59), having level IV Health Extension Workers (HEWs) in the catchment health post (AOR = 0.80, 95% CI 0.67–0.95) and older age are significantly associated with lower levels of unmet need for FP. Having more children (AOR = 2.11, 95% CI 1.67–2.65) and better awareness of the husband about the availability of FP services (AOR = 1.22, 95% CI 1.01–1.48) were associated with a higher likelihood of an unmet need for FP.

Conclusion

The unmet need for family planning is high in rural Ethiopia in general and among women who do not have exposure to HEP packages in particular. Assigning a better-qualified health worker at the health post, reaching out to pastoralist women, maximizing opportunities to counsel rural women about FP during any contact with HEWs, and increasing positive attitudes of husbands towards FP use are likely to have positive impacts in reducing the unmet need for FP of rural women.
Male mate choice in mosquitofish: personality outweighs body size
Authors: Li Chunlin , Zhang Xinyu , Cui Peng , Zhang Feng , Zhang Baowei
Published: January 2022

Background

Despite its important implications in behavioural and evolutionary ecology, male mate choice has been poorly studied, and the relative contribution of personality and morphological traits remains largely unknown. We used standard two-choice mating trials to explore whether two personality traits (i.e., shyness and activity) and/or body size of both sexes affect mate choice in male mosquitofish Gambusia affinis. In the first set of trials involving 40 males, we tested whether males would prefer larger females and whether the preference would be affected by males’ body length and personality traits, and females’ activity level. In the second set of trials (using another 40 males), we tested whether males would prefer more active females and whether the preference would be affected by males’ body length and personality traits.

Results

Both shyness and activity in males were significantly repeatable and constituted a behavioural syndrome. No overall directional preference for large (or small) females with the same activity levels was detected because larger males preferred larger females and smaller males chose smaller females. Males’ strength of preference for larger females was also positively correlated with the activity level of larger females but negatively with the activity level of smaller females. Males spent more time associating with active females regardless of their body lengths, indicating males’ selection was more influenced by female activity level than body size. Males’ preference for inactive females was enhanced when females became active. There was no convincing evidence for the effect of males’ personality traits or body length on their preferences for females’ activity level.

Conclusions

Our study supports the importance of body size in male mate choice but highlights that personality traits may outweigh body size preferences when males choose mating partners.
Rapid typing diagnosis and clinical analysis of subtypes A and B of human respiratory syncytial virus in children
Authors: Shen Zheng , Zhang Yuanyuan , Li Huamei , Du Lizhong
Published: January 2022

Background

Human respiratory syncytial virus (HRSV) is the leading pathogens causing acute respiratory infections (ARI) in children under five years old. We aimed to investigate the distribution of HRSV subtypes and explore the relationship between viral subtypes and clinical symptoms and disease severity.

Methods

From November 2016 to April 2017, 541 children hospitalized because of ARI were included in the study. Throat swabs were collected for analysis and all samples were tested by multiplex one-step qRT-PCR for quantitative analysis and typing of HRSV. Patients’ demographics, clinical symptoms as well as laboratory and imaging results were retrieved from medical records.

Results

HRSV was detected in 19.6% of children hospitalized due to ARI. HRSV-positive children were younger (P < 0.001), had a higher frequency of wheezing and pulmonary rales (P < 0.001; P = 0.003), and were more likely to develop bronchopneumonia (P < 0.001). Interleukin (IL) 10、CD4/CD8 (below normal range) and C-reactive protein levels between subtypes A and B groups were significantly different (P = 0.037; P = 0.029; P = 0.007), and gender differences were evident. By age-stratified analysis between subtypes A and B, we found significant differences in fever frequency and lymphocyte ratio (P = 0.008; P = 0.03) in the 6–12 months age group, while the 12. 1–36 months age group showed significant differences in fever days and count of leukocytes, platelets, levels aspartate aminotransferase, IL-6, lactate dehydrogenase and proportion CD4 positive T cells(P = 0.013; P = 0.018; P = 0.016; P = 0.037; P = 0.049; P = 0.025; P = 0.04). We also found a positive correlation between viral load and wheezing days in subtype A (P < 0.05), and a negative correlation between age, monocyte percentage and LDH concentration in subtype B (P < 0.05).

Conclusions

HRSV is the main causative virus of bronchopneumonia in infants and children. The multiplex one-step qRT-PCR not only provides a rapid and effective diagnosis of HRSV infection, but also allows its typing. There were no significant differences in the severity of HRSV infection between subtypes A and B, except significant gender-specific and age-specific differences in some clinical characteristics and laboratory results. Knowing the viral load of HRSV infection can help understanding the clinical features of different subtypes of HRSV infection.
An assessment of canine ectoparasiticide administration compliance in the USA
Authors: Lavan Robert , Normile Dorothy , Husain Imran , Singh Amita , Armstrong Rob , Heaney Kathleen
Published: January 2022

Background

This study evaluated the timing of dog owner ectoparasiticide purchases to estimate administration compliance and assess the consequent impact of dose purchase gaps on the proportion of time that dogs were protected over a 12-month period.

Methods

Ectoparasiticide purchase transactions over a 12-month period were evaluated for 626 US veterinary hospitals to determine dose purchase timing and identify consequent gaps between dose administration in dogs. Orally administered prescription ectoparasitic medications with active ingredients from the isoxazoline family (afoxolaner, fluralaner, lotilaner, or sarolaner) were included in the analysis. A period was calculated for each of the four isoxazoline-containing medications that represented the duration of protection provided by two doses of ectoparasiticide plus the average gap between these two doses. The maximum percentage of time possible for ectoparasiticide protection for this aggregate period was then calculated for each active ingredient.

Results

Ectoparasiticide transaction records of owners were analyzed for 506,637 dogs. These showed that 43% of dog owners purchased just one dose over the 12-month period considered. If a dog owner purchased more than one dose, then the timing of their transactions could create a time gap between the completion of ectoparasite protection from the first dose and onset of protection from the subsequent purchase and administration of the second dose. Such gaps were observed in purchases made by 31–65% of dog owners, depending on the selected active ingredient and number of doses. The average gap duration between dose purchases was calculated for all possible dose combinations over 12 months of ectoparasite protection. Time gaps between the first and second doses are as follows: for sarolaner, 20.3 weeks; for afoxolaner, 12.9 weeks; for fluralaner ,12.8 weeks; and for lotilaner, 8.9 weeks. The proportion of time when protection was provided during the aggregate period between administration of the first and second doses was as follows: for fluralaner, 65%; for lotilaner, 49%; for afoxolaner, 40%; and for sarolaner, 30%.

Conclusions

Dog owner ectoparasiticide purchase transactions showed that there were time gaps between doses leading to reduced ectoparasite protection. The longer re-administration interval for fluralaner, a consequence of its extended duration of activity, resulted in dog owners gaining the greatest proportion of ectoparasite protection time with this medication compared with shorter-acting monthly re-treatment medications.

Graphical Abstract
Pasture rewetting in the context of nature conservation shows no long-term impact on endoparasite infections in sheep and cattle
Authors: May Katharina , Raue Katharina , Blazejak Katrin , Jordan Daniela , Strube Christina
Published: January 2022

Background

Nature conservation with reduced drainage of pastures has been increasingly promoted in agriculture in recent years. However, moisture on pastures is a crucial factor for the development of free-living stages of many parasite species in ruminants. Hence, for the first time, we conducted a field study between 2015 and 2017 at the German North Sea coast to investigate the long-term effect of pasture rewetting (since 2004) on endoparasite infections in sheep and cattle.

Methods

We examined faecal samples of 474 sheep and 646 cattle from five farms in spring, summer and autumn each year for the presence of endoparasite infections. Animals were kept on conventionally drained, undrained and rewetted pastures. The association between pasture rewetting and endoparasite infection probability was analysed in generalized linear mixed models and including further potential confounders.

Results

Infection frequencies for gastrointestinal strongyles, Eimeria spp. and Strongyloides papillosus were significantly higher in sheep (62.9%, 31.7% and 16.7%) than in cattle (39.0%, 19.7% and 2.6%). Fasciola hepatica was detected with a frequency of 13.3% in sheep and 9.8% in cattle, while rumen fluke frequency was significantly higher in cattle (12.7%) than in sheep (3.8%). Nematodirus spp., lungworms (protostrongylids, Dictyocaulus viviparus), Moniezia spp., Trichuris spp. and Dicrocoelium dendriticum were identified in less than 7% of samples. Co-infection with more than three endoparasite taxa was present significantly more often in sheep than in cattle. We identified significant positive correlations above 0.2 for excretion intensities between S. papillosus with strongyles, Eimeria spp. and Nematodirus spp. in sheep and between strongyles and Nematodirus spp. in cattle. Pasture rewetting had no long-term effect on endoparasite infections, neither in sheep nor in cattle. Interestingly, F. hepatica infections decreased significantly in sheep and cattle from 2015 (10.9% and 13.9%) to 2017 (1.4% and 2.1%).

Conclusions

Pasture rewetting for nature conservation did not increase endoparasite infection probability in ruminants in the long term. This finding should be confirmed in ongoing studies aimed at further animal welfare parameters. The rapid decrease in F. hepatica infections over 3 years may suggest climatic impact or competition with rumen flukes in addition to potential anthelmintic treatment after feedback of the results to the farmers.

Graphical Abstract
On existence of global classical solutions to the 3D compressible MHD equations with vacuum
Authors: Zhang Mingyu
Published: January 2022

In this paper, the existence of global classical solutions is justified for the three-dimensional compressible magnetohydrodynamic (MHD) equations with vacuum. The main goal of this paper is to obtain a unique global classical solution on $\mathbb{R}^{3}\times [0, T]$

R
3

×
[
0
,
T
]
with any $T\in (0, \infty )$
T
∈
(
0
,
∞
)
, provided that the initial magnetic field in the $L^{3}$

L
3

-norm and the initial density are suitably small. Note that the first result is obtained under the condition of $\rho _{0}\in L^{\gamma }\cap W^{2, q}$

ρ
0

∈

L
γ

∩

W

2
,
q

with $q\in (3, 6)$
q
∈
(
3
,
6
)
and $\gamma \in (1, 6)$
γ
∈
(
1
,
6
)
. It should be noted that the initial total energy can be arbitrarily large, the initial density allowed to vanish, and the system does not satisfy the conservation law of mass (i.e., $\rho _{0} \notin L^{1}$

ρ
0

∉

L
1

). Thus, the results obtained particularly extend the one due to Li–Xu–Zhang (Li et al. in SIAM J. Math. Anal. 45:1356–1387, 2013), where the global well-posedness of classical solutions with small energy was proved.
Influence of childhood maltreatment on prevalence, onset, and persistence of psychiatric comorbidities and suicide attempts in bipolar disorders
Authors: Grillault Laroche D. , Godin O. , Dansou Y. , Belzeaux R. , Aouizerate B. , Burté T. , Courtet P. , Dubertret C. , Haffen E. , Llorca P. M. , Olie E. , Roux P. , Polosan M. , Schwan R. , Leboyer M. , Bellivier F. , Marie-Claire C. , Etain B. ,   The FACE-BD Collaborators
Published: January 2022

Background

Psychiatric comorbidities and suicide attempts are highly prevalent in Bipolar Disorders (BD). We examined the associations between childhood maltreatment, psychiatric comorbidities, and suicide attempts, in terms of lifetime prevalence, sequence of onset, and current symptoms.

Methods

We assessed 3,047 individuals with BD for suicide attempts, anxiety disorders, substance use disorders, and eating disorders. Participants completed a self-report for the assessment of childhood maltreatment. Associations between childhood maltreatment and characteristics of comorbidities (lifetime prevalence, current symptoms, and age at onset) were examined using logistic regressions and network analyses.

Results

Psychiatric comorbidities were frequent with a mean number per individual of 1.23 (SD = 1.4). Most comorbidities occurred prior to the onset of BD. Participants who reported higher levels of childhood maltreatment had more frequent and multiple comorbidities, which were also more currently active at inclusion. Childhood maltreatment did not decrease the age of onset of comorbidities, but was associated with a faster accumulation of comorbidities prior to the onset of BD. Logistic regression and network analyses showed that emotional abuse and sexual abuse might play a prominent role in the lifetime prevalence of psychiatric comorbidities and suicide attempts.

Conclusions

Childhood maltreatment was associated with suicide attempts, and with frequent, multiple, and persistent psychiatric comorbidities that accumulated more rapidly prior to the onset of BD. Hence, childhood maltreatment should be systematically assessed in individuals with BD, in particular when the course of the disorder is characterized by a high comorbid profile or by a high suicidality.
TRAIL Score: A Simple Model to Predict Immunochemotherapy Tolerability in Patients With Diffuse Large B-Cell Lymphoma
Authors: Harris Will , Bataillard Edward J. , Choi Yoonha , El-Galaly Tarec C. , Cuchelkar Vaikunth , Henneges Carsten , Kwan Antonia , Schneider Daniel J. , Paulson Joseph N. , Nielsen Tina G.
Published: January 2022

PURPOSE

Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) represents the standard of care for first-line treatment of diffuse large B-cell lymphoma (DLBCL). However, many patients are unable to tolerate R-CHOP and have inferior outcomes. This study aimed to develop a practical tool to help physicians identify patients with newly diagnosed DLBCL unlikely to tolerate a full course of R-CHOP.

METHODS

We developed a predictive model (Tolerability of R-CHOP in Aggressive Lymphoma [TRAIL]) on the basis of a training data set from the phase III GOYA trial (obinutuzumab with CHOP v R-CHOP in 1L DLBCL) using a composite binary end point, identifying patients who prematurely stopped or required reductions of R-CHOP. Candidate predictive variables were selected on the basis of known baseline characteristics that contribute to patient frailty, comorbidity, and/or chemotherapy toxicity. TRAIL was developed using an iterative trial-and-error modeling process to fit a logistic regression model. The final model was evaluated for robustness using a GOYA holdout data set and the phase III MAIN (R-CHOP with or without bevacizumab in 1L DLBCL) R-CHOP-21 data set as external validation.

RESULTS

TRAIL includes four simple predictors available in the routine clinical setting: Charlson Comorbidity Index, presence of cardiovascular disease or diabetes, serum albumin, and creatinine clearance. Model generalization performance estimated by the area under the curve was around or above 0.70 across GOYA training, GOYA holdout, and MAIN data sets. Classifying patients into low-, intermediate- and high-risk categories, the proportion of patients experiencing a tolerability event was 3.3%, 12.4%, and 32.9%, respectively, in GOYA holdout, and 9.7%, 9.7%, and 34.2%, respectively, in MAIN.

CONCLUSION

TRAIL may be useful as a clinical decision support tool for treatment decisions in patients with DLBCL who may not tolerate standard chemoimmunotherapies.
Microorganospheres as a novel precision oncology platform in colorectal cancer.
Authors: Hsu Carolyn , Wang Zhaohui , Oh Sehwa , Rupprecht Gabrielle , Pittman Kelly , Smith Amber , Delubac Daniel , Shen Xiling , Jia Jingquan , Hsu Shiaowen David
Published: January 2022

149

Background: Patient-derived organoids (PDO) have been shown to have a high degree of similarity to the original patient tumors. PDO have also been used to perform high throughput drug screens and shown to correlate with patient response to therapy. Unfortunately, PDO require too much tissue, take too long to establish and are too inefficient and costly for adoption into the clinic. The ideal assay for clinical use would be one that could be performed in less than14 days from a core biopsy to minimize delay in therapy. We have now circumvented these barriers by leveraging recent technological advances in emulsion microfluidics and droplet generators to develop MicroOrganoSpheres (MOS) that can be established and used to predict drug sensitivity within 14 days of obtaining a biopsy. Methods: 18-gauge core biopsy specimens from patients with colorectal cancer liver metastasis who subsequently received an oxaliplatin based therapy were first obtained. Biopsy specimens were minced, enzymatically digested and mixed with components necessary to generate MOS. The mixture was then processed through a custom fabricated flow-focusing droplet microfluidic chip in our MOS Generator Device to generate MOS. After culturing for 8-10 days, MOS were then used to perform drug screen with oxaliplatin. Results: A total of twelve CRC biopsies from liver metastasis were obtained and processed to generate MOS with a success rate of 12/12 (100%). Furthermore, drug screens with oxaliplatin were performed on all twelve samples with an average time to drug screen of 10.1 days. We next wanted to determine if there was a correlation between MOS drug sensitivity and patient clinical outcome (ie. time on treatment). For the first eight patients, MOS was used to predict sensitivity to oxaliplatin and using a drug sensitivity cut-off of 1 uM, four patients were predicted to be sensitive to oxaliplatin and four patients were predicted to be resistant. Three of the four patients predicted to be sensitive to oxaliplatin continue to be on treatment (> 6 months), whereas 3 of the four patients predicted to be resistant to oxaliplatin progressed on oxaliplatin based therapy within 8 weeks (sensitivity = 80%, specificity = 100%, positive predictive value = 100%, negative predictive value = 75%). Conclusions: MOS can be generated from core biopsies and correlates to time on treatment. Although further studies will need to be conducted, the ability to generate MOS and perform a drug screen in < 14 days will allow for the development of a precision oncology platform that can be rapidly used in the clinic to guide therapy.
The role of genetic variants involved with ferroptosis regulator genes in predicting outcomes in patients (pts) with RAS-mutant metastatic colorectal cancer (mCRC): Data from MAVERICC and TRIBE trials.
Authors: Wang Jingyuan , Millstein Joshua , Arai Hiroyuki , Battaglin Francesca , Kawanishi Natsuko , Jayachandran Priya , Soni Shivani , Wu Zhang , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef
Published: January 2022

197

Background: Ferroptosis, an iron-dependent programmed cell death, is one of the anti-tumor mechanisms of anti-angiogenesis drugs. RAS mutation can confer ferroptosis in colorectal cancer (CRC). Previous studies suggested that polymorphisms of ferroptosis regulator genes are associated with the increased risk of CRC. Therefore, we hypothesized that genetic variants in the ferroptosis regulator genes may predict first-line treatment outcome in RAS-mutant mCRC pts treated with bevacizumab (bev)-based chemotherapy. Methods: Genomic DNA from blood samples of mCRC pts enrolled in two independent randomized trials, MAVERICC (FOLFIRI+bev arm: discovery cohort, RAS-mutant, n = 56; control-1: RAS-wildtype, n = 87) and TRIBE (FOLFOXIRI+bev arm: validation cohort, RAS-mutant, n = 57; control-2: RAS-wildtype, n = 34), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 13 selected SNPs in 5 main ferroptosis regulator genes (ACSL4, LPCAT3, SLC3A2, SLC7A11, ALOX15) was analyzed. Results: In the MAVERICC bev cohort, pts with RAS-mutant tumors carrying ALOX15 rs7217186 any C allele (n = 35) showed significant longer overall survival (OS) than carrier of T/T allele (n = 5) in both univariate (24.97 vs. 12.22 months, hazard ratio [HR] = 0.23; 95% confidence interval [CI]: 0.06-0.9; p = 0.02) and multivariate (HR = 0.06; 95%CI 0.007-0.5; p = 0.009) analysis. In the TRIBE bev cohort, RAS-mutant carriers of any C allele (n = 30) showed numerically longer progression-free survival (PFS), compared to carriers of T/T allele (n = 13) in both univariate (11.91 vs. 9.47 months, HR = 0.45; 95%CI 0.2-1.02; p = 0.05) and multivariate (HR = 0.42; 95%CI 0.16-1.1; p = 0.09) analysis. Conversely, RAS-wildtype carriers of any C allele (n = 17) showed significant shorter PFS than T/T carriers in the TRIBE bev cohort (8.91 vs. 15.59 months, univariate HR = 3.39, 95%CI: 1.03-11.18, p = 0.04). Conclusions: Our study demonstrated for the first time that ALOX15 polymorphisms may have different predictive values for the bev-based treatment in mCRC patients based on RAS mutational status. These findings may provide novel insights for the combination of ferroptosis inducers and anti-VEGF treatment.
Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for patients with advanced ESCC: A multicenter, single-arm, open-label phase Ⅱ clinical trial.
Authors: Wang Junsheng , Wu Tao , Luo Suxia , Li Ning , Hong Yonggui , Guo Yanzhen , Cheng Yufeng , Li Baosheng
Published: January 2022

315

Background: Chemotherapy is the standard first-line therapy for advanced Esophageal Squamous Cell Carcinoma (ESCC). However, the poorly 5-year survival rate (4.8%) was unsatisfied. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Here we reported the update results and futhur evaluated the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. Maintenance treatment was administered to those without disease progression with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. The predefined sample size was 47. Tumor response was assessed by investigators according to RECIST version 1.1 criteria using CT scans every two cycles. Results: From Oct 2019 to Mar 2021, a total of 47 pts with ESCC were included and 46 pts were included in intention-to treat analysis, among whom 4 CR (8.7%), 31 PR (67.4%) and 7 SD (15.2%) were observed and 4 patients (8.7%) were not available for efficacy assessment. Consequently, ORR was 76.1% (95%CI: 61.2%-87.4%) and DCR was 91.3% (95%CI: 79.2%-97.6%). At the cut-off date on July 15, 2021, 23 pts discontinued treatment due to PD, the preliminary median PFS of ITT patients was 8.38 months (95%CI: 6.44-10.32). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia. And the common grade ≥3 adverse events were myelosuppression (29.8%), gastrointestinal reaction (10.6%), hypertension (6.3%), fatigue (4.3%) and hypokalemia (4.3%). Conclusions: The update results suggested that paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusion should be validated in more pts with ESCC subsequently. Clinical trial information: NCT04063683.
Conversion of initially unresectable hepatocellular carcinoma (HCC) with triple-combination therapy (lenvatinib, anti-PD-1 antibodies, and transarterial therapy): A retrospective analysis.
Authors: Song Tianqiang , Lang Mengran , Lu Wei , Zhang Ti , Li Huikai , Wu Qiang , Cui Yunlong , Zhang Wei , Li Qiang , Zang Fenglin , Xing Wenge , Ren Shaohua , Gan Leijuan
Published: January 2022

413

Background: Combination therapy with tyrosine kinase inhibitors and anti-PD-1 antibodies can allow selected patients with initially unresectable HCC to convert to surgical resection. We evaluated conversion therapy with a triple combination of lenvatinib (LEN), anti-PD-1 antibodies and transarterial therapy. Methods: We retrospectively searched medical records from 117 consecutive patients with unresectable/advanced HCC who received triple combination therapy between Dec 2018 and Oct 2020 at Tianjin Medical University Cancer Institute & Hospital. Eligible patients were required to have potentially resectable HCC, defined as meeting ≥1 of the following criteria: 1) estimated future liver remnant after radical (R0) resection of < 40% or < 30% in patients with/without cirrhosis, respectively; 2) R0 resection technically difficult to complete; 3) Child-Pugh score ≥7, ECOG performance status ≥1; 4) tumor thrombus in the main portal vein or inferior vena cava; 5) resectable extrahepatic metastases. The primary endpoint was the proportion of patients who underwent a successful resection (conversion rate). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), 6-month disease-free survival (DFS) and safety. Results: Of 37 patients included in the analysis, all received LEN and anti-PD-1 antibodies with transarterial chemoembolization (TACE, n = 22), hepatic arterial infusion chemotherapy (HAIC, n = 9) or both (n = 6). The conversion rate was 40.5% (15) and the ORR and DCR were 67.7% and 86.5% by RECIST v1.1 and 75.7% and 86.5% by mRECIST, respectively. The median conversion time was 4 months (range: 2-15). After a median postoperative follow-up time of 10 months (95% CI, 6.42-13.58), the 6-month DFS rate was 93%. Overall, 89.2% of patients had ≥1 treatment emergent adverse event (TEAE) and 29.7% experienced a Grade 3/4 TEAE, the most common was hypertension (18.9%, n = 7). Conclusions: A triple combination of LEN, anti-PD-1 antibodies and transarterial therapy was well tolerated and effective at converting potentially resectable HCC to resectable disease. These findings warrant confirmation by future prospective studies.
Early nivolumab addition to regorafenib in patients with hepatocellular carcinoma progressing under first-line therapy (GOING trial), interim analysis and safety profile.
Authors: Sanduzzi Zamparelli Marco , Matilla Ana , Lledó Jose Luis , Martínez Sergio Muñoz , Varela Maria , Iñarrairaegui Mercedes , Perelló Christie , Minguez Beatriz , Llarch Neus , Márquez Laura , Guerrero Antonio , Iserte Gemma , Castaño-García Andrés , Carrión Laura , Rimola Jordi , Garcia-Criado Ángeles , Domenech Gema , Boix Loreto , Bruix Jordi , Reig Maria
Published: January 2022

428

Background: Regorafenib (Rego) improves survival in patients with hepatocellular carcinoma (HCC) (RESORCE trial) while nivolumab (Nivo) is also safe and active in terms of radiologic response (15-20% objective response) in second-line. The GOING trial (NCT04170556) is an investigator-initiated phase I/IIa study assessing the safety of Rego plus Nivo in HCC patients who progress and tolerate sorafenib (Cohort A) or who discontinue atezolizumab plus bevacizumab (Cohort B). Methods: Patients from cohort A receive Rego as monotherapy for the first 2 cycles (starting dose 160 mg/day, 3 weeks on/1 week off and adjusted for adverse events [AEs]) and Nivo is added at day 1 of cycle 3 (the first 10 patients at 3 mg/kg; since they did not present serious-AE (SAE), the final dose is 240 mg every two weeks). Treatment continues until unacceptable AEs, symptomatic tumor progression, patient decision or death. Safety is measured by the rate of AEs, rate of treatment related-AEs (Tr-AE), rate of AEs leading to treatment discontinuation and rate of death. Severity of AEs are evaluated according to CTCAE v.5.0. A futility analysis using the non-binding Lan & DeMets beta-spending functions with a boundary of p=0.814 is mandated when 32.8% of cohort A has data of tumor assessment at least at week 16 by RECIST 1.1. Results: Fifty-one patients have been enrolled in cohort A as of May 15, 2021. The first 30 (BCLC-C 73%) were considered in this safety analysis. All patients developed at least one AE, 29 (96.7%) had Tr-AEs of any grade and 10 (33.3%) had grade 3 (no grades 4 or 5 have been reported). Ten (33.3%) patients had a Rego-related AE, 4 (13.3%) Nivo-related, and 4 (13.3%) Tr-AE grade 3 of special interest. The table describes the profile Tr-AE occurring in > 10% of patients. Only 4 (13.3%) patients developed Tr-SAE, 3 (10 %) Rego-related and 3 (10 %) Nivo-related. Four patients discontinued the study due to physician decision, 2 for progression, and 2 for AEs (one related to study treatment). One patient had surgical resection after treatment discontinuation and a complete necrosis was observed at pathology. Conclusions: The sequential combination of Rego-Nivo has a manageable safety profile. Less than one third of the patients developed grade 3/4 Tr-AE and there was no treatment-related death. Futility analysis allowed to continuing recruitment. Clinical trial information: NCT04170556. [Table: see text]
Phase II study of combination pembrolizumab and olaparib in patients with advanced cholangiocarcinoma: Interim results.
Authors: Yin Chao , Armstrong Samantha Ann , Agarwal Seema , Wang Hongkun , Noel Marcus Smith , Weinberg Benjamin Adam , Marshall John , He Aiwu Ruth
Published: January 2022

452

Background: Unresectable cholangiocarcinoma (CCA) remains a cancer of dismal prognosis as these tumors tend to be highly chemotherapy-refractory, providing patients (pts) a median survival of only around nine months. We herein provide an interim update to this phase II, single-arm, open-label study, where we investigate the safety and efficacy of olaparib plus pembrolizumab in pts with CCA after first-line gemcitabine-based therapy. We hypothesize that olaparib will increase tumoral response to pembrolizumab by inducing DNA damage and increasing tumor antigen number to produce a durable immune response against CCA - thereby increasing the overall response rate (ORR) of pts from 17.5% (historic chemotherapy control) to 35%. Methods: In total, 36 histologically confirmed advanced cholangiocarcinoma pts will be enrolled onto this trial. Pts receive pembrolizumab, 200 mg, on day 1 of each 21-day cycle, and oral olaparib, 300 mg, twice daily. The primary objective is to assess ORR, while a secondary aim is to evaluate safety. Tumor biopsies are collected at baseline, the third week after treatment initiation, and disease progression; the tissue is tested for ERCC1, PD-1/PD-L1 expression, IDH1/2 mutation status, and immune cell (CD3 and CD8) response. CT or MRI is carried out every 6 weeks for the first 6 months and every 9 weeks for the next 6 months to assess clinical response. Results: At the cutoff date of September 26, 2021, 12 pts had been enrolled and received at least one dose of olaparib plus pembrolizumab. The median age is 62 years (range 47-74); most are female (N = 10) and Caucasian (N = 8). Ten pts were diagnosed with cholangiocarcinoma and 2 with gallbladder carcinoma. According to RECIST v1.1, partial response (PR) was seen in one pt (-50%), stable disease (SD) in 4 pts (one with promising ongoing response at 23% tumor shrinkage), and disease progression in 7 pts. Three pts are actively on trial (1 PR and 2 SD). Complete molecular analysis by FoundationOne CDx revealed mutations in ATM (N = 2), SKT11 (N = 1) , ARID1A (N = 2) , and IDH1 (N = 2); the full tumor profile will be presented at the ASCO-GI meeting. Primary grade 3 treatment-related adverse events (AEs) included anemia (N = 2) and diarrhea (N = 1. Grade 1/2 AEs included thrombocytopenia (N = 2), anemia (N = 1), rash (N = 1), and diarrhea (N = 1). Conclusions: Interim trial results indicate that combination olaparib and pembrolizumab has acceptable safety and manageable toxicity in pts with advanced cholangiocarcinoma. Clinical trial information: NCT04306367.
Prognostic ability of the Gustave Roussy Immune Score for patients with advanced pancreatic adenocarcinoma.
Authors: Ma Lucy Xiaolu , Holzapfel Nicholas Timothy , Wang Yifan , Ramotar Stephanie , Allen Michael J , Jang Gun Ho , Zhang Amy , Dodd Anna , Hutchinson Shawn , Tehfe Mustapha , Ramjeesingh Ravi , Biagi James Joseph , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Grant Robert C , Knox Jennifer J. , O'Kane Grainne M.
Published: January 2022

469

Background: The Gustave Roussy Immune Score (GRIm-S) considers a composite of neutrophil to lymphocyte ratio (> 6 = 1), albumin (< 35 = 1) and LDH (> ULN = 1) and has been established as a prognostic score and may in aid in the selection of patients for phase 1 trials of immune checkpoint inhibitors. Methods: We explored the prognostic impact of the GRIm-S (high > 1) in patients enrolled on the COMPASS trial and correlated the score with genomic and clinical characteristics. Patients in this trial had biopsies for whole genomic and RNA sequencing prior to standard chemotherapy regimens in the advanced setting. Results: 252 patients were included in the analyses with a median follow-up time of 28 months. 16% of patients had a high GRIm-S with significantly shorter median overall survival (OS) of 4.1 months versus 10.0 months in those with a low score (HR 2.18, 95% CI 1.4-3.4, p < 0.0001). In the GRIm-S-high cohort, early progression with non-evaluable disease and disease progression were more common than in the GRIm-S low cohort (56% vs 31%, p = 0.003). In a multivariable analysis, a high GRIm-S was poorly prognostic (HR 1.6 95% CI 1.3-1.9, p < 0.001), whereas the classical RNA subtype (vs. basal-like) (HR 0.41, 95% CI 0.3-0.6, p < 0.001) and a high HRDetect score (HR 0.47 95% CI 0.3-0.7, p < 0.001) associated with superior OS. The GRIm-S did not correlate with RNA subtypes or with specific KRAS mutations. There were no differences in structural variant load or tumour mutational burden between groups. However those with a high GRIm-S did have a higher total target lesion diameter at baseline (p < 0.001). Conclusions: The GRIm-S identifies a subset of patients who have aggressive pancreas cancer and short life expectancy. This information may help clinicians in treatment decision making and selection for clinical trials.
Development of PCR assays to detect signature circulating tumor DNA methylation markers and KRas mutations for pancreatic ductal adenocarcinoma (PDAC).
Authors: Guo Shiwei , Su Mingyang , Shi Xiaohan , Gao Suizhi , Wang Huan , Pan Yaqi , Gong Chengxiang , He Qiye , Liu Rui , Jin Gang
Published: January 2022

524

Background: PDAC is a cancer of high mortality. Accurate and cost-effective PCR assays detecting diagnostic and prognostic PDAC markers in blood are desirable for conducting PDAC screening in high-risk populations, evaluating treatments for patients and surveying for post-treatment relapse. Methods: We combined PDAC-diagnosing ctDNA methylation markers with PDAC-driving Kras mutations as targets to develop said PCR tests. Methylation markers were previously validated to classify PDAC plasma at a high accuracy by a targeted methylation sequencing assay. Seven known PDAC driver mutations in KRas exon2 were selected. Taqman-based quantitative methylation-specific PCR (MSP) and ARMS PCR were designed for methylation markers and KRas mutations, respectively, and were validated for technical performances. A step of pre-amplification of input DNA by conventional PCR was included prior to quantitative PCR to improve sensitivity. Over 200 clinical PDAC and control tissue and plasma samples were used to determine their analytical performances in classifying PDAC plasma. Results: All targets were detected at a limit-of-detection of 0.25% or better on standards DNA in PCR. To test clinical plasma samples, methylation markers were first filtered by comparing their levels in PDAC-, para-tumor tissues and whole blood cells. Twenty-four most discriminatory markers for PDAC tissues were selected and used to classify 110 PDAC plasma samples from equal number of normal samples. They were evaluated for their sensitivity at a pre-set specificity of 90%. The 4 best-performing markers were selected to build and cross-validate a general-linear-model (GLM) PDAC classifier, which achieved a sensitivity of 66% at 90% specificity (AUC = 0.829) in cross-validation. Adding status of KRas mutations further improved prediction accuracy by increasing sensitivity to 75% (AUC = 0.89), demonstrating the methylation markers and KRas mutations complement each other in detection PDAC plasma. Conclusions: Our results suggest that a small number of our DNA methylation markers can classify PDAC plasma at a reasonably high accuracy by MSP. Incorporating KRas driver mutations further improved classification accuracy. Together they are promising to be further translated into diagnostics for PDAC early screening, treatment assessment and postoperative surveillance.
Real-world cost-effectiveness of first-line gemcitabine + nab-paclitaxel versus FOLFIRINOX in patients with advanced pancreatic cancer: A population-based retrospective cohort study in Ontario, Canada.
Authors: Arciero Vanessa , Luo Jin , Parmar Ambika , Dai Wei Fang , Beca Jaclyn M. , Raphael Michael J. , Isaranuwatchai Wanrudee , Habbous Steven , Tadrous Mina , Earle Craig , Biagi Jim , Mittmann Nicole , Arias Jessica , Gavura Scott , Chan Kelvin K.
Published: January 2022

529

Background: Currently, there are no direct randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and FOLFIRINOX for advanced pancreatic cancer (APC). Thus, previous model-based cost-effectiveness analyses were based on indirect comparisons of RCT data. While it is well known that RCT-based efficacy does not often translate to real-world effectiveness, there is limited literature investigating the comparative cost-effectiveness of Gem-Nab versus FOLFIRINOX for APC in the real-world. The objective of this study is to examine the real-world cost-effectiveness of Gem-Nab versus FOLFIRINOX in patients with APC in Ontario, Canada. Methods: This population-based retrospective cohort study compared all patients treated with first-line Gem-Nab or FOLFIRINOX for APC with ECOG performance status 0-1 in Ontario from April 2015 to March 2019. Patients were linked to administrative databases to identify key characteristics and costing data. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring and discounted at 1.5% (per Canadian guidelines). Incremental cost-effectiveness ratio and net monetary benefit were computed (measured in life-years and quality-adjusted life years) to estimate cost-effectiveness from the public healthcare payer’s perspective. A sensitivity analysis was conducted using the propensity score matching method. Results: 1,988 patients were identified (Gem-Nab: 928, FOLFIRINOX: 1,060). Mean survival was lower for patients in the Gem-Nab group than the FOLFIRINOX group (0.98 versus 1.26 life-years, incremental -0.28 (95% confidence interval -0.47, -0.13)). Patients in the Gem-Nab group also incurred greater mean 5-year total costs (Gem-Nab: $103,884, FOLFIRINOX: $101,518). Key cost contributors include ambulatory cancer care, acute in-patient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it is less effective and more costly. Results from the sensitivity analysis were similar. Conclusions: In routinely treated unselected patients, Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore, not considered cost-effective at any commonly accepted willingness-to-pay threshold.