bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of oral live biotherapeutic MRx0518 with hypofractionated preoperative radiation for resectable pancreatic cancer.
Authors: Taniguchi Cullen M. , Noticewala Sonal S , Haymaker Cara L. , Das Prajnan , Ludmir Ethan B. , Maitra Anirban , Pant Shubham 
Published: August 2023

58 Background: Pancreatic cancer possesses a profoundly immunosuppressive tumor microenvironment and exhibits almost no response to immunotherapy. Therapies that might enhance anti-tumor immune responses to pancreatic cancer have the potential to significantly improve outcomes. The intestinal microbiome is known to regulate the responses of solid tumors to immunotherapy. However, it is now known where specific commensal microbiota could be harnessed as an anti-cancer-therapy. MRx0518 is a strain of the commensal bacteria, Enterococcus gallinarum, and is associated with enhanced immune function and microbiome diversity. We hypothesized that treatment with neoadjuvant MRx0518 just prior to resection could enhance immune responses to pancreatic cancer. Methods: This is a single arm, Phase I study to evaluate the safety of MRx518 with preoperative hypofractionated radiation for resectable pancreatic cancer. A total of 14 patients with resectable pancreatic cancer who received standard of care neoadjuvant chemotherapy (gemcitabine/nab-paclitaxel or mFOLFIRINOX) for a minimum of 3 months were enrolled. Patients received preoperative radiation therapy (RT) to the tumor and regional lymph nodes to a total dose of 30Gy in 10 fractions with concurrent capecitabine. All patients received oral MRx0518 twice daily one week prior to radiation, during the two weeks of RT, and then daily until the day prior to resection, which occurred 4-6 weeks after the completion of RT. Blood and stool samples will be obtained at baseline, just before treatment, but after 2 weeks of MRx518, just after SBRT, and just prior to resection. Results: A total of 14 patients were enrolled. We observed no grade 3 toxicity in any patient during the study period. Of the 14 patients placed on the study, 10 patients went on to have an R0 resection (71.4%), while 4 patients exhibited progression prior to surgery which precluded a resection. Conclusions: Together these data suggest that the addition of MRx0518 to preoperative radiation was a safe intervention. Further investigations will be needed to determine how MRx0518 modulated the immune responses in the resected tumor. Clinical trial information: NCT04193904 .
Deciphering the tumor microenvironment (TME) dynamics in advanced colorectal (CRC) and pancreatic cancers (PDAC) treated with durvalumab (D) with olaparib (O) or cediranib (C): Results from a phase 2 randomized trial.
Authors: Hernando-Calvo Alberto , Han Ming , Ayodele Olubukola , Wang Ben X , Vila-Casadesús Maria , Yang S Y Cindy , Berman Hal , Vivancos Ana , Lam Bernard , Lungu Ilinca , Salawu Abdulazeez , Stayner Lee-Anne , Haibe-Kains Benjamin , Bedard Philippe L. , Avery Lisa , Abdul Razak Albiruni Ryan , Pugh Trevor John , Spreafico Anna , Siu Lillian L. , Hansen Aaron Richard 
Published: August 2023

63 Background: There is limited efficacy for immunotherapy (IO) in mismatch repair proficient CRC (pMMR-CRC) or PDAC. The mechanisms driving their intrinsic IO resistance are largely unknown. DAPPER (NCT03851614) is a phase 2 study randomizing patients (pts) with pMMR-CRC or PDAC to D+O or D+C. Methods: PDAC or pMMR-CRC pts with ECOG 0-1 were randomized to either D+O (arm A), or D+C (arm B). In a 28 day-cycle, D 1500mg every 4 weeks (w) IV was given with either O 300mg orally twice daily or C 20mg orally once daily 5d/week. Primary endpoint included pharmacodynamic immune changes in the TME. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples (baseline and cycle 2 (C2)) were analyzed by multiplexed immunohistochemistry (CD3, CD8, CD20, CD68 and FOXP3) and RNA-sequencing. A total of 48 publicly available gene expression signatures (GES) were associated with treatment outcomes and investigated with predictIO software (Bareche Y et al. Ann Oncol, 2022). Results: Thirty-one pMMR-CRC pts were randomized to arm A (n=16) or B (n=15). Median age was 59y (range 34-77y), M:F 19:12. In 28 evaluable pts, 3 pts had stable disease (SD) (2 pts on D+O and 1 pt on D+C) while 25 had progressive disease (PD). The median PFS of arm A and B were 2.6 (95% CI 2.5-2.6) and 2.4 (95% CI 1.5-2.7) months (m) respectively. Among 19 pts with PDAC, 9 and 10 pts were randomized to arm A and arm B respectively. Median age was 60y (range 48-76y), M:F 9:10.In 18 evaluable pts, 1 pt had an unconfirmed partial response with D+C, 1 pt had SD with D+O while 16 had PD. The median PFS of arm A and B were 1.3 (95% CI 0.8-NA) and 2.1 (95% CI 1.3-NA) m respectively. Increased CD8+ tumor-infiltrating lymphocytes (TILs) at baseline (p=0.04) and at C2 (p=0.023) and low baseline CD68+ cells (p=0.018) were associated with longer OS. Different GES at baseline were associated with OS and PFS (see table). None of these GES were associated with OS or PFS in CRC or PDAC pts in the TCGA database, suggesting specificity to IO. Conclusions: In pts with pMMR-CRC or PDAC, D+O and D+C showed limited anti-tumor activity. Although increased CD8+ TILs infiltration was observed in a subset of pMMR-CRC or PDAC pts and associated with longer OS, immune infiltration of the TME did not result in radiographic response or durable disease control. Clinical trial information: NCT03851614 . [Table: see text]
Effect of exercise mode specificity on quality of life in prostate cancer patients undergoing androgen suppression.
Authors: Taaffe Dennis R , Newton Robert Usher , Spry Nigel , Chambers Suzanne K , Gardiner Robert Alexander , Lopez Pedro , Joseph David John , Galvao Daniel Abido 
Published: August 2023

72 Background: Androgen deprivation therapy (ADT) is accompanied by a range of adverse effects including those of the musculoskeletal, metabolic, and cardiovascular systems, as well as compromised functioning and quality of life (QoL). Exercise has been shown to be an effective countermeasure to a number of these toxicities, although the effects of different modes or prescriptions on self-report QoL is unclear. Here we report the effects from a yearlong trial of 3 different exercise prescriptions involving aerobic, resistance, and impact loading modes on QoL in men with prostate cancer undergoing ADT. Methods: One hundred and fifty-four prostate cancer patients (43-90 yrs, BMI 28.7 ± 4.1) on ADT (Mdn 3 mths, IQR 2.0-4.0 mths) were randomized to exercise targeting the musculoskeletal system (impact loading + resistance training; ILRT, n=57) supervised for 12 months, cardiovascular and muscular systems (aerobic + resistance training; ART, n=50) supervised for 6 months followed by a 6-month home program, or delayed aerobic exercise (DelAer, n=47) receiving exercise information for 6 months followed by 6 months supervised stationary cycling exercise. Supervised exercise was undertaken twice weekly at a moderate intensity. QoL domains were assessed at baseline, 6, and 12 months using the Short Form-36 questionnaire. Results: There were no significant differences among groups in QoL domains at baseline. Following exercise there was a significant group x time interaction (p < 0.05) for the domain role physical and the physical health composite score with increases at 12 months for ILRT and DelAer. There was also a significant time effect (p < 0.001) for improvements in physical functioning, general health, vitality, and mental health, and also bodily pain (p = 0.037), with no between-group differences. Patients in the lowest tertile for QoL at baseline improved the most with exercise (Ptrend < 0.001). Conclusions: Different exercise modes had similar effects on improving QoL in patients with prostate cancer undergoing ADT. Importantly, those with the lowest QoL derived the greatest benefits from exercise. Recommending patients on ADT to undertake exercise, regardless of mode, will help to preserve or improve quality of life. Clinical trial information: ACTRN12609000200280 .
A comprehensive multi-omics analysis exploring the correlation between NECTIN4 and tumor microenvironment profiles in bladder cancer.
Authors: Nishimura Kazuki , Komura Kazumasa , Hirosuna Kensuke , Ishida Mitsuaki , Inamoto Teruo , Azuma Haruhito , Yoshimi Akihide 
Published: August 2023

74 Background: NECTIN4 is a transmembrane protein that is found in the adherent junctions and highly expressed in urothelial carcinoma (UC). NECTIN4 is a TIGIT ligand and the TIGIT-NECTIN4 interaction inhibits natural killer cell activity. Therefore, Enfortumab vedotin (EV), an antibody-drug conjugate targeting NECTIN4, potentially induces immunogenic cell death. In fact, an encouraging result has been recently reported from a clinical trial of combined EV and pembrolizumab as the first line treatment for platinum-ineligible UC patients. However, there has been no study exploring the correlation between NECTIN4 expression and tumor microenvironment (TME) so far. Methods: To explore the potential association between NECTIN4 and TME, we analyzed a comprehensive dataset of whole-exome and RNA-sequencing, immunohistochemistry, and clinicopathological record from 389 bladder cancers (BC) and 35 adjacent normal tissues, which enables us to evaluate the potential relationship between genetic and transcriptomic profile and TME. Results: NECTIN4 mRNA expression was positively correlated with NECTIN4 H-score, gender, T-stage, tumor grade, lymph vascular invasion and tumor mutation burden, and was negatively correlated with CD274 mRNA expression levels in BC. Our cohort included 44 patients (44/389 = 11.3%) who were diagnosed as having variant histology. NECTIN4 expression levels of samples with variant histology (especially small cell carcinoma, sarcomatoid and adenocarcinoma) were significantly lower compared to conventional BC. When we classified 378 patients into three groups according to H-score, 93 patients were included in low group (H-score:0), 202 patients in medium group (H-score:10-190) and 83 patients in high group (H-score:200-300). Overall survival was significantly worse in the low group compared to medium/high groups (p<0.0001). CIBERSORTx analysis suggested increased proportions of M0 macrophages and neutrophils in low group. Gene set enrichment analysis identified that EMT-related programs and immune-related cytokines were activated in the low group. 45 platinum-refractory BC patients were treated with pembrolizumab and objective response rate was 57.1% in H-score high group, which was significantly higher compared to low/medium groups (p=0.0498). We also compared 73 immune check point related gene expression in H-score low and high groups and found that putative immune checkpoint gene expression was significantly different between the two groups, which collectively suggests that differential immune therapy strategies according to NECTIN4 expression levels would be beneficial for patients with BC. Conclusions: NECTIN4 expression levels are closely associated with tumor pathology and microenvironment. NECTIN4 expression levels may be a predictive marker that potentially contributes to the precision immune therapy in BC.
Delayed versus immediate use of zoledronic acid for postmenopausal patients with ER/PR positive early breast cancer who are using adjuvant letrozole.
Authors: Abdel Gelil Mai 
Published: August 2023

8 Background: Aromatase inhibitors are the standard adjuvant therapy for postmenopausal women with hormone receptor (HR) positive early breast cancer (EBC). In such patients, a significant reduction in bone density was observed. To stop bone loss, bisphosphonates have a powerful effect on reducing bone resorption and improving the survival of patients with EBC. This study compared potential bone-protection of immediate versus delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. Methods: In a prospective two-arm comparative study, 65 postmenopausal patients with HR+ EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years), we included either (45) immediate ZOL treatment or (20) delayed ZOL treatment (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for fracture or increased bone pain or developed bone mineral density (BMD)T score = or < -2.0. We aimed to assess the change in lumber spine BMD every 3 months for 24 months for both immediate and delayed arm patients, in addition to evaluating bone pain deterioration and the disease-free survival (DFS). Results: Analysis of data showed significant differences between immediate and delayed arms in the first three BMD measurements with mean values were -1.55± 0.4 vs. -1.9± 0.2, -1.56± 0.3 vs. -2.5± 0.3, and -1.4±0.3 vs. -3.5± 0.3 with p<0.002, 0.001, 0.0001 respectively. Despite ZOL administration in delayed arm patients was initiated 6 months later than immediate arm patients, improvement of BMD was detected in delayed arm later on. The median DFS for immediate and delayed arms were 39± 0.6 months and 21± 0.4 months respectively with p<0.001 in both. Although, in pre-ZOL bone pain scoring, most patients of delayed arm (75%) were found to have a score of 3 compared to 51.1% of immediate arm, significant improvement in bone pain scores in both arms separately after ZOL administration was noted with p-values 0.031, and 0.025 respectively. Conclusions: Immediate ZOL administration prevented bone loss, improved bone pain, and ameliorate DFS in postmenopausal women with HR+ EBC receiving adjuvant letrozole. Clinical trial information: PACTR202112813934276.
Intense exercise for survival among men with metastatic prostate cancer: 12 months feasibility results from the INTERVAL-GAP4 trial.
Authors: Newton Robert Usher , Lopez Pedro , Hart Nicolas H. , Galvao Daniel Abido , Taaffe Dennis R , Clay Timothy Dudley , Ryan Charles M , Kenfield Stacey A. , Saad Fred 
Published: August 2023

81 Background: Exercise is now considered an important therapy to ameliorate treatment side effects, improve quality of life and physical function however, causation of survival benefit and the underlying mechanisms is not yet established. In 2015, the Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4) – a worldwide multicentre phase III trial – was launched to determine if high-intensity combined resistance and aerobic exercise plus psychosocial support improves overall survival in men with metastatic prostate cancer. Here, while exercise delivery and follow-up assessments are still taking place in 6 different countries, we aim to examine the feasibility, exercise compliance and safety of a 12-month exercise medicine program in patients with mCRPC. Methods: Experimental design was a longitudinal analysis of attrition rates, exercise attendance and compliance metrics and programme safety over the initial 12 months of patients participating in the INTERVAL-GAP4 trial at the Edith Cowan University site in Perth, Australia. Results: 201 patients were screened for participation and 46 patients (22.9%) were randomly assigned to the two study arms. Median time since prostate cancer diagnosis was 72.0 (interquartile range (IQR): 19.5-118.5) months. Most patients were previously treated with radiotherapy (53.3%). Metastases present mostly in the lymph nodes (53.3%), followed by bones (51.1%), lungs (2.2%) and bladder (2.2%). Participants attended a total of 2,907 out of 3,744 exercise sessions scheduled, with a median exercise attendance of 78.8% (IQR: 71.6%-82.7%) per participant. Majority of sessions were performed at an RPE of 7-8 indicating “vigorous intensity” or at an RPE of 5-6 indicating “moderate intensity” (67.2%). Tolerance was moderate-to-high in most sessions (83.0%). 191 adverse events (AEs) were observed throughout the study period. A total of 136 adverse events were reported by 19 participants from the exercise group, and these were mainly disease related (n= 69, 50.7%). Most AEs were grade 1 and 2 (n= 126, 92.7%). In the control group, 55 AEs were observed, and these were mainly disease related (n= 22, 40.0%) and grade 1 and 2 (n= 51, 92.7%). The most common intervention-related adverse events experienced in the exercise group were pain (n= 6, 50.0%; i.e., back pain, bone pain, lymph node pain, and general pain). Conclusions: Patients with mCPRC can participate in high-intensity aerobic and resistance training with moderate to high attendance and tolerance. The exercise intervention appears safe with limited intervention-related adverse events experienced and mostly minor and expected. However, with only 22.9% of screened patients deemed suitable and willing, this aspect of feasibility requires attention. Clinical trial information: NCT02730338 .
Development of an artificial intelligence-based diagnostic system for the detection of abnormal colposcopic findings.
Authors: Ueda Akihiko , Yamaguchi Ken , Kitamura Sachiko , Taki Mana , Yamanoi Koji , Murakami Ryusuke , Hamanishi Junzo , Ueda Masatsugu , Mandai Masaki 
Published: August 2023

82 Background: When performing colposcopic examinations in patients with abnormal cervical cytology, sufficient training is required to detect cervical intraepithelial neoplasia (CIN) with (1) high diagnostic accuracy and (2) minimizing time and reducing tissue biopsies. The aim of this study was to develop an artificial intelligence (AI)-based system that replicates expert colposcopic examination techniques to (1) identify CIN lesions with high accuracy and to (2) guide tissue sampling locations with high diagnostic performance, independent of examiner skill. Methods: A retrospective analysis was performed using 8341 colposcopic videos from 2013 to 2019, consisting of seven early-stage cervical cancer cases, 203 CIN3 cases, 276 CIN2 cases, and 456 CIN1 cases. An AI-based lesion detection model was constructed by annotating abnormal colposcopic findings after acetic acid processing in cervical cancer and CIN3 cases whose histologic diagnoses were confirmed by biopsies. The developed lesion detection model was applied to CIN1 and CIN2 cases, and the diagnostic accuracies of the lesions were evaluated. The accuracies of the lesions of CIN1 and CIN2 were evaluated according to the lesion area (sensitivity, specificity, area under the curve (AUC)) and the number of lesions identified. Results: The AI-based model was trained on 60 cases of cervical cancer and CIN3 and validated on 150 cases. The model was able to identify severe lesions with high accuracy, with a sensitivity of 85%, a specificity of 73%, an AUC of 0.89 for lesion area, and an accuracy of 95% for the number of lesions identified. The model also predicted abnormal colposcopic findings in CIN1 and CIN2 cases with high accuracy for detection of lesion area (sensitivity: 87% and 86%, specificity: 70% and 67%, AUC: 0.81 and 0.81, respectively) and identification of the number of lesions (97% and 93%, respectively). Furthermore, a heatmap display based on lesion prediction allowed visualization of the area with the highest acetic acid intensity corresponding to the actual biopsy locations. Conclusions: We have developed an AI-based diagnostic system for colposcopy that can identify CIN lesions with high accuracy and suggest appropriate biopsy sites. We are currently establishing an AI-based application for the visualization of abnormal lesions in colposcopy developed from the model, and anticipating its implementation in the clinical practice of colposcopic examinations.
Does infection of multiple HPV high-risk genotypes carry a higher malignant potential than a single genotype in uterine cervix? A retrospective study.
Authors: Heo Yujin , Lee Juhun , Lee Hyun Jung 
Published: August 2023

86 Background: The high-risk genotype of human papilloma virus (HPV) has been known as the most important carcinogen in uterine cervical carcinoma. It remains unclear that the infection with multiple high-risk genotypes carry a higher malignant potential risk compared with a single genotype in uterine cervix. Methods: This is a retrospective study of 695 patients underwent conization at Kyungpook National University Hospital in South Korea from 2012 to 2023. Participants were required to have undergone an HPV test by cervical swab within 12 months prior to the surgery. Patients with a negative result or a previous history of cancer were excluded. Additionally, patients older than 50 years were excluded to reduce bias. We included patients with the most common genotype in the cohort with only one high-risk genotype, and patients with multiple high-risk genotypes including the most common genotype. We categorized them based on pathologic results. Patients with HSIL, carcinoma in situ (CIS), invasive carcinoma were classified as ≥HSIL, while those with CIS, invasive carcinoma were classified as ≥CIS. The HPV test was performed using DNA microarray or real-time polymerase chain reaction, can detect 18 high-risk genotypes and 14 low-risk genotypes. The infection status of low-risk HPV and the vaccination for HPV were not considered in this study. The statistical analysis was conducted using SPSS (version 26). Results: A total of 146 patients younger than 50 years found to be infected with HPV high-risk genotype 16 or 16 with other high-risk genotypes. The HPV 16 single infection and multiple infection were found in 79 (54.1%), 67 (45.9%), respectively. Among patients with HPV 16 single infection, 61 (77.2%) were diagnosed with ≥HSIL and 45 (57.0%) were ≥CIS. In the HPV 16 multiple infection group, 56 (83.6%) were diagnosed with ≥HSIL and 34 (50.7%) were ≥CIS. There was no statistically significant correlation based on the HPV 16 single or multiple infection status for either ≥HSIL (HPV 16 single infection vs. multiple infection, odds ratio (OR)=0.666 [95% CI=0.289-1.531], p=0.407) or ≥CIS (HPV 16 single infection vs. multiple infection, OR=1.285 [95% CI=0.668-2.471], p=0.507). Conclusions: Among young women with only a single HPV high-risk genotype, the genotype 16 was the most common. Compared to the infection group with a single HPV high-risk 16 genotype, the malignant potential was not found to be significantly increased in the infection group with multiple HPV high-risk genotypes, including HPV genotype 16. [Table: see text]