bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects on hematopoietic and immune system of ultra-high dose rate radiotherapy (FLASH-RT).
Authors: Yu Tosol , Choi Min-Young
Published: August 2023

166

Background: Ultra-high dose rate radiotherapy, so-called FLASH radiotherapy (FLASH-RT) has shown to reduce radiation-induced damage including lung fibrosis, brain damage, skin fibrosis, etc. We investigated the effect of FLASH-RT compared of conventional dose rate radiotherapy (CONV-RT) at 5Gy of TBI on survival of hematopoietic system, peripheral blood cells, and immune-related responses. Methods: Mice were divided into 3 groups: control (0 Gy), FLASH-RT (109Gy/s), and CONV-RT (0.067Gy/s). FLASH-RT was performed with DIRAMS LINAC producing 6 MeV electron beams. Irradiated mice were sacrificed at 1, 2, 4, 7, 14, 21 and 28 post-TBI of 5 Gy and cellularity of peripheral blood and bone marrow, histological evaluation of immune organ such as spleen and thymus, and T and B lymphocytes in mouse spleen by flow cytometry were investigated. Results: In peripheral blood cell counts, RBC, neutrophil, lymphocyte counts were not significantly different between FLASH-RT and CONV-RT groups from day 1 to day 28 post-TBI. However, FLASH-RT initially induced more apoptosis of bone marrow cells, platelets, and eosinophils of peripheral blood compared to CONV-RT. FLASH-RT and CONV-RT groups showed similar histological changes in the thymus and spleen after 5Gy of TBI, but T lymphocytes of CONV-RT group in day 28 were less recovered compared to those of FLASH-RT group. Our results indicated that FLASH-RT affected more radiation-induced damage of hematopoietic system in early stages compared to CONV-RT, but FLASH-RT showed higher recovery of T lymphocytes after irradiation. Conclusions: These results show that FLASH-RT can induce similar damage and recovery pattern on hematopoietic system with CONV-RT in first week, but FLASH-RT might affect less T-lymphopenia in long-term than CONV-RT.
Leucocyte-hitchhiking liposomes loading gemcitabine and pyroptosis for potentiated immunotherapy of hepatocellular carcinoma.
Authors: Lu Yuejie , Du Yongzhong , Lin Bingyi , Chai Siyuan , Wu Liming
Published: August 2023

168

Background: Hepatocellular carcinoma (HCC), as a malignant tumor with high incidence worldwide, faces the challenge of low efficacy of traditional chemotherapy drugs and immunotherapy drugs. Pyroptosis is a type of programmed cell death that can alleviate tumor immunosuppressive microenvironment and promote systemic immune response, which has great potential in improving the efficacy of immunotherapy drugs. The selection of more effective pyroptosis-inducing drugs and immunotherapy drugs, supplemented by more precise drug delivery strategies, is one of the research focuses in the treatment of HCC. Methods: In this study, Western Blot were performed to screen suitable pyroptosis-inducing drugs. A leucocyte-hitchhiking liposome nanodrug delivery system was designed to co-deliver a pyroptosis-inducing drug and a small molecule immunotherapy drug. The ability of the nanocarrier to induce pyroptosis of liver cancer cells and to activate immune cells were investigated in vitro. The targeting ability of the nanocarrier to peripheral blood leucocytes, the function of tumor inhibition and immune activation were evaluated in vivo. Results: In this study, gemcitabine was confirmed to induce pyroptosis in liver cancer cells. E-selectin modified liposomes were designed to co-deliver gemcitabine and the small molecule PD-1/PD-L1 complex inhibitor BMS-202. In vitro experiments confirmed that the nanocarrier could induce pyroptosis in liver cancer cells and activate immune cells. In vitro experiments confirmed the targeting ability of the nanocarrier to leukocytes and its ability to inhibit tumor and activate immunity. Conclusions: Leucocyte-hitchhiking liposomes loading gemcitabine and BMS-202 was successfully synthesized. After intravenous injection, liposomes effectively adhere to the surface of peripheral blood leukocytes mediated by E-selectin, thus hitchhiking with leukocytes to achieve high accumulation at the tumor site. The released gemcitabine can evoke tumor cell pyroptosis and generate anti-tumor immunity, while BMS-202 can alleviate immune suppression by inhibiting the formation of PD-1/PD-L1 complex, further enhance gemcitabine-induced anti-tumor immunity. This leucocyte-hitchhiking dual-delivery liposomal nanoplatform might provide a promising strategy for high-efficiency immunotherapy, exhibiting a great potential for clinical translation of HCC treatment.
Initial experience of robot-assisted breast conserving surgery for early breast cancer patients.
Authors: Paek Se Hyun , Lim Woosung , Moon Byung-In
Published: August 2023

17

Background: A traditional breast conserving surgery (BCS) operation inevitably results in an external scar on breast and axilla. Various attempts including endoscopy-assisted breast surgery has been successfully and reproducibly performed for improved cosmetic outcome. In an attempt to maximize esthetic effects, we performed robot-assisted BCS through only axillary incision. Methods: From Jan. 2021 to Dec. 2021, fifteen female patients underwent robot-assisted BCS. All patients underwent robot-assisted BCS with or without sentinel lymph node biopsy (SLNBx.) through only 2.5cm axillary incision. All surgical procedures were performed in concordance with traditional BCS operation. Data on patient demographics, type of surgery, hospital stay, complications, and short-term postoperative outcomes were reviewed. Results: Mean patient age was 53.7 ± 6.35 years and mean tumor size was 1.6 ± 2.1 cm. Indications included in situ cancer in 7 cases and invasive cancer in 8 cases. Three patients underwent only BCS, and twelve patients underwent BCS + SLNBx. Two patients underwent axillary lymph node dissection. The mean operation time was 165.5±8.2 minute and the mean hospital stay was 6.4 ± 5.3 days. No open conversion case was observed. One seroma with infection occurred postoperatively and I & D performed. Two skin burn event during operation was occurred and scar revision was performed. The operative scars in axilla became inconspicuous in a few weeks. Conclusions: Our initial results show that robot-assisted BCS would be technically feasible, safe, and effective. This new technique can be a good alternative surgical option for BCS in early breast cancer patients.
The difference in efficacy of the endocrine therapy between the HER2-low and HER2-zero metastatic breast cancer: A single-center retrospective study.
Authors: Omori Reo , Nishibori Yuichiro , Nakatani Yuki , Akaishi Yuko , Tanaka Ayako , Akiyoshi Kohei , Tokunaga Shinya , Daga Haruko
Published: August 2023

3

Background: HER2-low expression breast cancer is a new classification and began to receive attention after trastuzumab deruxtecan showed its effect on this classification. As for endocrine therapies, HER2-low expression seemed not to affect the efficacy of CDK4/6 inhibitors in a few retrospective studies. However, previous data on the effectiveness of endocrine therapies other than CDK4/6 inhibitors for HER2-low metastatic breast cancer (mBC) are still limited. This study aims to evaluate the difference in endocrine therapy between HER2-low and HER2-zero mBC. Methods: We retrospectively reviewed the clinical data of mBC patients prescribed aromatase inhibitors, tamoxifen or fulvestrant, and/or CDK4/6 inhibitors at our department between May 2012 and December 2022. Patients were excluded if they received chemotherapy before endocrine therapy, lacked data on HER2 score, or discontinued treatment before the first image evaluation. The data cutoff date was 15th March 2023. We analyzed the difference in progression-free survival (PFS) of the first-line endocrine monotherapy and the first-line CDK4/6 inhibitors between HER2-low and HER2-zero mBC by logrank analysis. Results: Of 126 patients who received the first-line endocrine monotherapy, 22 were HER2-zero, and 104 were HER2-low. In the HER2-zero group, six patients received tamoxifen, and 16 received AIs. In the HER2-low group, 29 patients received tamoxifen, 63 received AIs, and 12 received fulvestrant. The median PFS was 27.7 months with the HER2-zero group and 15.6 months with the HER2-low group. This was not statistically significant (P=0.196), but the Kaplan-Meier curve showed that PFS tended to be longer with the HER2-zero group. This trend was also observed in patients who received AIs. Of 52 patients who received CDK4/6 inhibitors as a first-line treatment, ten were HER2-zero, and 42 were HER2-low. The median PFS was NA with the HER2-zero group and 22.8 months with the HER2-low group, and no significant differences were detected. Conclusions: In this study, there were no statistically significant differences in the PFS of the first-line endocrine monotherapy and CDK4/6 inhibitors between HER2-low and HER2-zero mBC. However, the Kaplan-Meier curve showed that the PFS of endocrine therapy tended to be longer in the HER2-zero group. Further studies are warranted.
Palliative treatment for gastric outlet obstruction: A network meta-analysis.
Authors: Tran Van Khoi , Vo Nguyen-Phong , Nguyen Hung Song , Vo Nhi Thi , Thai Trang Thi Bao , Pham Vu Anh , Loh El-Wui , Tam Ka-Wai
Published: August 2023

36

Background: The optimal palliative treatment for gastric outlet obstruction (GOO) remains inconclusive between gastrojejunostomy (G), endoscopic ultrasound-guided gastroenterostomy (E), stomach partitioning gastrojejunostomy (P), endoscopic stenting (S). This study was part of a comprehensive systematic review investigating the outcomes of the aforementioned treatments for malignant GOO. Methods: We conducted a systematic screening randomized controlled trials (RCTs) and cohort studies that compared at least two palliative procedures for GOO from Pubmed, Embase, Cochrane, Web of Science, Scopus, Clinicaltrial, WHO International Clinical Trials Registry Platform. We included full-text studies that reported at least clinical outcomes (clinical success rate, complication rate, 30-day mortality rate, and reintervention rate). We conducted this network meta-analysis using the frequentist approach, inverse variance model with a naïve combination of the treatment effects from RCTs and non-RCTs. We used P-score for treatment ranking. Certainty of evidence was evaluated following CINeMA approach. Results: This study included four RCTs and four prospective and 32 retrospective cohorts with 3417 patients. The pooled overall rates of clinical success, complication, 30-day mortality, and reintervention were 88.9% (95%CI 85.6-91.6), 20.7% (95%CI 17.2-24.7), 5.4% (95%CI 3.2-8.9), and 13.9% (95%CI 10.7-17.9), respectively. P was ranked the safest for reintervention rate (P-score: 0.90) due to obstruction and complication post-procedure (P-score: 0.88 and 0.81, respectively). E was ranked the safest for the 30-day mortality rate (P-score: 0.82). Cluster rank combined the P-score for 30-day mortality and reintervention or reintervention rate due to obstruction showed the benefit of P and E versus G and S (cophenetic correlation coefficient - c: 0.94 and 0.94, respectively). Cluster rank combined with the P-score for 30-day mortality and reintervention due to complication showed the benefit of P (c:0.99). The overall certainty of evidence was low to very low. Conclusions: P and E are recommended for malignant GOO, and P should be the first choice in centers with limited resources or cases of unfeasible or unsuccessful E.
Peri-operative predictive factors of failure to rescue after highly advanced hepatobiliary-pancreatic surgery.
Authors: Fukada Masahiro , Matsuhashi Nobuhisa , Higashi Toshiya , Yasufuku Itaru , Sato Yuta , Kiyama Shigeru , Tanaka Yoshihiro , Okumura Naoki , Murase Katsutoshi
Published: August 2023

39

Background: Failure to rescue (FTR), defined as postoperative complications leading to mortality, is a recently described outcome metric to evaluate the quality of treatment. However, predictive factors of FTR, particularly after highly advanced hepatobiliary-pancreatic surgery (HBPS), have not been adequately investigated. Thus, it remains unclear. The object of this study is to identify the perioperative predictive factors of FTR after highly advanced HBPS. Methods: This single-institution retrospective study included 177 patients who developed severe postoperative complications (Clavien-Dindo classification≧grade3a) after highly advanced HBPS from 2010 to 2022 at Gifu University Hospital. We statistically analyzed pre-, intra-, and post-operative risks for FTR using logistic regression. Results: Nine postoperative mortalities occurred, for overall mortality rate of 1.3% (9 / 686) and FTR rate of 5.1% (9 /177). In univariate analysis, liver disease comorbidity, intra-operative blood loss, intra-operative blood transfusion, post-operative liver failure, post-operative respiratory failure, and post-operative bleeding were significantly correlated with FTR. A multivariate analysis revealed that intra-operative blood loss (>1600ml; odds ratio [OR] 77255486; 95% confidence interval [CI] 18.26–; p <0.0001) and post-operative respiratory failure (OR 43422062; 95% CI 9.83–; p <0.0005) were independently associated with FTR. Conclusions: FTR have been shown to be associated with hospital factors. This study showed that FTR may be also associated with peri-operative factors. Prevention of massive intra-operative blood loss and postoperative respiratory failure may be able to decrease FTR.
Breast self-examination practice and its determinants among women in Indonesia: A systematic review, meta-analysis, and meta-regression.
Authors: Azhar Yohana , Halim Freda , Hanafi Ricarhdo Valentino
Published: August 2023

4

Background: Breast cancer (BC) is the most diagnosed cancer in Indonesia, according to the World Health Organization in 2020. Economic centralization in Java Island worsens the accessibility and inequality of healthcare facilities. The limited standard BC screening, such as mammography and ultrasound, generates breast self-examination (BSE) as the practical and effortless method to detect the earliest sign of breast cancer. Early detection and prompt management of BC improve survival rate and quality of life. Hence, we aimed to synthesize the pooled prevalence data, identify the determinants, and compare BSE practice between Java Island and non-Java Islands in Indonesia. Methods: This study followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). We conducted intensive searches in Cochrane Library, PubMed, Google Scholar, and SINTA (Science and Technology Index) - Indonesian web-based research information from September 2017 – 2022. For a critical appraisal of the studies, we employed the Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data. We utilized Review Manager 5.4 for conducting the meta-analysis. The pooled analysis was reported as a prevalence and odds ratio (OR) with a 95% confidence interval (CI). Results: Total samples (n = 6,361) from 41 full-text publications were included. The overall national prevalence of BSE practice was 43.14% [95% CI: 36.08, 50.20, P <0.001, I2 = 100%]. BSE practice in Java Island was 44.58% [95% CI: 35.42, 53.75] and significantly higher than that of Non-Java Island at 41.62% [95% CI: 29.83, 53.41]. University students reported the highest prevalence of BSE practice with 49.90 [95% CI: 40.27, 59.33]. Good knowledge, good attitude toward BSE, family history of BC, family support, and BC information exposure were all statistically associated with a higher determinant of BSE practice among women in Indonesia. Conclusions: Only less than 50% of fertile women in Indonesia practiced BSE, with the lowest percentage on non-Java Islands and community-group. Integrative and collaborative programs should be established with the government, health policymakers, and community health groups to promote BSE as routine screening for breast cancer.
First-line (1L) panitumumab (PAN) vs bevacizumab (BEV) in patients (pts) with HER2 amplification (HER2amp+), RAS wild type (WT) metastatic colorectal cancer (mCRC) according to tumor sidedness.
Authors: Oki Eiji , Muro Kei , Watanabe Jun , Shitara Kohei , Yamazaki Kentaro , Ohori Hisatsugu , Shiozawa Manabu , Yasui Hirofumi , Sato Takeo , Naito Takeshi , Komatsu Yoshito , Kato Takeshi , Soeda Junpei , Yamamoto Kouji , Yamashita Riu , Akagi Kiwamu , Ochiai Atsushi , Uetake Hiroyuki , Tsuchihara Katsuya , Yoshino Takayuki
Published: August 2023

53

Background: HER2 gene alterations occur in 3%–5% of pts with mCRC and may be associated with aggressive tumor behavior. Gene amplification is a frequent HER2 alteration in mCRC, often leading to HER2 protein overexpression. Preclinical and retrospective studies suggest HER2 alterations may predict anti–epidermal growth factor receptor (EGFR) therapy resistance in mCRC; however, there is limited information regarding the efficacy of 1L anti-EGFR therapy in mCRC pts with HER2 alterations. The PARADIGM trial demonstrated longer median OS with 1L PAN (anti-EGFR) vs BEV (anti–vascular endothelial growth factor), with mFOLFOX6, in RAS WT mCRC (NCT02394795). We evaluated the efficacy of PAN vs BEV in pts with HER2amp + and HER2amp−, RAS WT mCRC from PARADIGM, taking into account primary tumor sidedness. Methods: Baseline plasma ctDNA was obtained from pts with RAS WT mCRC enrolled in PARADIGM; pts with evaluable pretreatment ctDNA were included in the biomarker analysis (NCT02394834). A custom panel (PlasmaSELECT-R 91, PGDx) was used to detect HER2amp+ and HER2amp− samples. OS, PFS, and response rate (RR) were compared in pts with HER2amp+ vs pts with HER2amp−. Results: Of 802 pts with RAS WT mCRC, 733 (91%) had evaluable pretreatment samples; 32 (4%) had HER2amp + (PAN, n=19; BEV, n=13). A lack of a survival benefit with PAN vs BEV was suggested in pts with HER2amp+, regardless of tumor-sidedness (median OS: overall population, PAN, 23.0 mo; BEV, 26.7 mo; HR, 0.96; 95% CI: 0.45–2.04; left-sided population, PAN, 25.1 mo; BEV, 26.7 mo; HR, 0.89; 95% CI: 0.39–2.04]). Data in the right-sided population are not shown for pts with HER2amp+ due to the small sample size. In the overall population, there was a trend toward shorter OS for HER2amp + vs HER2amp− pts (PAN: 23.0 vs 36.3 mo; HR, 1.57; 95% CI: 0.96–2.57; BEV: 26.7 vs 31.6 mo; HR, 1.41; 95% CI: 0.79–2.52). Median PFS and RR were similar between pts with HER2amp + and HER2amp− in PAN or BEV arms (Table). Conclusions: HER2 amplification appears to be prognostic in pts with RAS WT mCRC but may not be predictive of a survival benefit of 1L PAN treatment over BEV. Clinical trial information: NCT02394834 . [Table: see text]
Efficacy of fibroblast growth factor receptor (FGFR) inhibitors therapy in advanced cholangiocarcinoma with FGFR genes alterations: A meta-analysis of phase II clinical trials.
Authors: Patel Rushin , Chitkara Akshit , Patel Zalak , Patel Femina , Patel Mrunal , Anamika Fnu , Kavani Himanshu , Thawani Rajat
Published: August 2023

54

Background: Fibroblast growth factor receptor ( FGFR) gene fusions and rearrangements are involved in the pathogenesis of approximately 10 to 16 percent of patients with cholangiocarcinoma. There is no meta-analysis available of phase 2 clinical trials of FGFR inhibitors in these patients. In this article, we analyze the efficacy of FGFR inhibitors in advanced cholangiocarcinoma with FGFR gene fusions or other rearrangements. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were Objective response rate (ORR), Disease control rate (DCR), Progression-free survival (PFS), and Overall survival (OS). We calculated the pooled ORR for these studies by using weighted average ORR = Σ (ORR_i * weight_i). Calculate the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). However, it is important to note that the pooled ORR is only as reliable as the individual ORR estimates from each study and may be subject to bias or confounding factors. This method was used to calculate the pooled DCR, PFS, and OS for our study as well. All data extraction and calculations were verified by three reviewers. Results: Eight phase II clinical trials met the inclusion criteria (1-8). Outcome data were available for all eight studies, comprising 562 patients with FGFR-positive advanced cholangiocarcinoma who received FGFR-targeted treatment regimens. The pooled objective response rate (ORR) and disease control rate (DCR) were 32.6% (95% CI 28.1-37.1) and 81.86% (95% CI 74.96-88.76), respectively. The pooled weighted progression-free survival (PFS) was 7.5 months, and pooled overall survival (OS) was 17.4 months. These findings suggest that FGFR-targeted treatment regimens have a promising ORR, DCR, PFS, and OS. Conclusions: FGFR inhibitors as a class in patients with advanced or metastatic cholangiocarcinoma with FGFR gene alterations showed clinically meaningful efficacy with durable objective responses. [Table: see text]
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]
The impact of low muscle mass and strength on chemotherapy toxicity in women with early breast cancer.
Authors: Kurniawan Andree , Hatma Ratna Djuwita , Adisasmita Asri , Panigoro Sonar Soni , Sutandyo Noorwati , Witjaksono Fiastuti , Tamin Tirza Z , Sumantri Rachmat , Rivami Dwi Savitri
Published: August 2023

9

Background: Systemic anticancer therapy is indicated in particular patients with early breast cancer (EBC) before or after surgery to eradicate micrometastatic spread and reducing the risk of recurrence. Muscle mass and strength were related to chemotherapy toxicity in cachexia patients. However, there is limited data about the impact of low muscle mass and strength in normal or obese breast cancer patients on chemotherapy toxicity. Methods: A prospective cohort study of women with EBC in whom adjuvant or neo-adjuvant chemotherapy was planned. The subjects were evaluated the muscle mass using bioelectrical impedance analysis, muscle strength using JAMAR hand grips strength, and body mass Index (BMI). The validated cut off of low muscle mass and strength were derived from Indonesian healthy population aged 20-40 years old. The outcome is to know chemotherapy toxicity in the first 3 cycles of chemotherapy, evaluated using National cancer Institute (NCI) common terminology criteria for adverse events version 5.0. The performance status, comorbidity, menopause status, chemotherapy regiment, diet intake, and physical activity were also evaluated to adjust the relationship using logistic regression multivariate analysis. Results: A total of 72 EBC patients were who come to secondary referral cancer center were included. Median of age was 47(25- 59) year old. Most subjects were in normal weight criteria, 26(36.1%) were in obese criteria. The mean of BMI, muscle mass, and muscle strength were 23.73+4.02, 5.61+1.23, 15,32+6.16, respectively. Low muscle mass and strength were observed in 34(55.7%) and 24(39.3%), respectively. Low muscle mass was only associated with chemotherapy toxicity after 3rd cycles of chemotherapy with relative risk (RR) 2.667(1.235-5.757). Low muscle strength was only associated with chemotherapy toxicity after 3rd cycles of chemotherapy with RR 4.206(1.168-15.143). After adjusted with performance status, comorbidity, menopause status, chemotherapy regiment, diet intake, and physical activity, low muscle mass and strength were associated with chemotherapy toxicity after 3rd cycles of chemotherapy with odds ratio 11(1.730-69.956) and 14.625(2.191-97.612), respectively. Conclusions: Low muscle mass and strength were associated with chemotherapy toxicity after three cycles of chemotherapy in women with EBC.