bluuebunny/crossref_metadata_2025 huggingface dataset:
Routine, prospective DPYD genotyping guided dose-individualisation for patients receiving fluoropyrimidines: Implementation, prevalence and patient safety outcomes from a multi-institutional clinical trial.
Authors: Nalder Mark , Kulasegaran Tivya , Lundie Ben , Woods Rick , Eastgate Melissa A. , Wyld David , Burge Matthew E.
Published: August 2024

12121

Background: Prospective data regarding the prevalence of DPYD variant alleles and the impact of genotype guided dosing on safety and efficacy of fluoropyrimidines (FP) remains limited. We assessed the feasibility and safety impact of routine, prospective, DPYD genotype guided FP dosing. Methods: Adult patients (>18 years), commencing FP for the first time were enrolled. Sanger PCR sequencing was designed to target DPYD variants NM_000110.4:c.1905+1G>A (DPYD*2A), NM_000110.4:c.1679T>G (DPYD*13), NM_000110.4:c.1236G>A and NM_000110.4:c.2846A>T. Dose reductions were implemented as per current international pharmacogenomic guidelines. Gr3/4 toxicity, dose reductions/delays and hospital admissions were reviewed for the first 60 days after commencement. For comparison purposes, a retrospective review of patients receiving FP without testing in a prior year was completed. Results: Between July 2021 – May 2023, 334 patients were enrolled for testing. 95% ECOG 0-1. 57% curative treatment intent. Mean time from phlebotomy to result 6.9 days (range 2-15). Clinician/patient acceptance was high (>95% of eligible patients starting FP were enrolled). 20 (6.0%) variant DPYD allele carriers were detected. 11 heterozygous for c.1236G>A, 5 heterozygous for C.1905+1G>A, 3 heterozygous for c.2846A>T and 1 homozygous for c.1236G>A. 295 of patients tested proceeded to receive FP. 62% received Infusional-FP, 38% Capecitabine. 39 patients commenced treatment prior to DPYD result being available (treating clinician decision). Dose modification recommendations were followed in all but two patients. 24% experienced FP related Grade 3/4 toxicity within 60 days. (23% DPYD wild type, 37% DPYD variant) versus 35% in the retrospective cohort. 16% had FP related dose delays (16% DPYD wild type, 12% DPYD variant) versus 25% retrospective cohort. 14% had FP related dose reductions (13% DPYD wild type, 25% DPYD variant) versus 12% retrospective cohort. 13% had FP related hospital admissions (13% DPYD wild type, 19% DPYD variant) versus 17% retrospective cohort. 1 death in the DPYD wild type cohort was deemed potentially related to FP. Conclusions: Prospective DPYD genotype guided dosing was feasible in clinical practice, with prevalence of variant alleles comparable to published literature. There was a modest reduction in risk of FP related severe toxicity, dose delays, and hospital admissions with DPYD guided dosing compared to a historical, untested cohort. Clinical trial information: ACTRN12621001117808.
Effect of enhanced recovery after radiotherapy (ERAR) on the quality of life in patients with nasopharyngeal carcinoma after radiotherapy: A randomized controlled trial.
Authors: Lin Nan , Zhou Xueyan , Ma Xuelei
Published: August 2024

12128

Background: Nasopharyngeal carcinoma (NPC) is a common disease in Southern China and Southeast Asia. Radiotherapy is an essential treatment for locoregionally advanced NPC (LA-NPC). Although Enhanced Recovery After Surgery (ERAS) is widely used in surgical settings, the guidelines do not systematically address the specific roles of various disciplines involved in radiotherapy rehabilitation. Therefore, we propose the concept of Enhanced Recovery After Radiotherapy (ERAR), which is considered to be a vital complement to radiology. Methods: We enrolled patients with stage III to IVA LA-NPC in this study. Participants completed baseline surveys before random assignment. ERAR interventions were implemented during radiotherapy to develop systematic management plans in the aspects of nursing, oral care, psychology, rehabilitation, nutrition, and skin health. The control group received conventional radiotherapy. Outcomes were evaluated at the 17th and 33rd radiotherapy sessions. We used generalized estimating equations to evaluate group by time effects on the outcomes, controlling for key covariates. Results: A total of 108 LA-NPC patients with a mean age of 48.3 ± 11.0 years were enrolled in the study group from August 2021 to September 2023. Across all time points, the ERAR group showed significant improvements in Hospital Anxiety and Depression Scale (HADS) anxiety ( P <.001), HADS depression ( P <.001), distress thermometer ( P =.049), quality of life ( P =.014), NRS2002 ( P =.040), weight loss ( P <.001), and Oral Health Impact Profile-14 (OHIP-14) ( P =.040) scores compared with the conventional care group. Conclusions: The ERAR pathway has a significant benefit on reducing acute radiation-induced toxicity in patients with LA-NPC. It is hoped that this study will provide a reference for clinicians and promote the implementation of a standardized protocol for rapid recovery from radiotherapy. Clinical trial information: ChiCTR2300075874. [Table: see text]
Racial disparities and survival outcome of patients with locally advanced cervix cancer in the international randomised phase 3 OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274).
Authors: Lee Yeh Chen , Castellano Tara , Myers Tashanna K. N. , Barnes Elizabeth H , Chase Dana Meredith , McCormick Colleen , Diamante Katrina , Shannon Catherine M. , Huh Warner King , Lea Jayanthi Sivasothy , Walker Joan L. , Small William , Miller Katherine , Govindarajulu Geetha , Monk Bradley J. , Stockler Martin R , Moore Kathleen N. , Mileshkin Linda R. , Bae-Jump Victoria Lin
Published: August 2024

1594

Background: OUTBACK was an international multi-center phase 3 trial investigating adjuvant chemotherapy following definitive chemoradiation in locally advanced cervix cancer. We analysed if baseline characteristics were associated with survival outcome. More specifically, we determined whether race held prognostic significance relative to established clinical factors. Methods: We compared baseline characteristics (encompassing demographics, biomarkers and participants’ self-ratings of EORTC QLQ-C30 scores) between racial groups using chi-squared tests. We then explored relationships between baseline characteristics and survival outcomes using univariable and multivariable Cox proportional hazards regression models with stepwise selection. Results: Black or African American participants accounted for 13% (n=121/919) of the OUTBACK study population. There were no evident differences in the proportion of Black or African American participants, as compared to other racial groups, across most baseline characteristics, except for country of residence (USA vs non-USA, p<0.01). When examining the impact of race (Black or African American vs other racial groups) on survival outcomes in locally advanced cervix cancer, we found no evident associations with overall survival (HR 1.2; 95%CI,0.84 – 1.72; p=0.32) or progression free survival (HR 1.29; 95%CI, 0.95 – 1.75; p=0.10). Multivariable analysis identified several independent prognostic factors for overall survival, including performance status (HR 1.43; 95%CI, 1.04-1.95; p=0.03), FIGO stage (HR 2.02; 95%CI, 1.48-2.75; p<0.01), nodal involvement (HR 1.59; 95%CI, 1.18-2.14; p<0.01), and elevated white cell count (HR 1.68; 95%CI, 1.21-2.33; p<0.01). Role function, social function, financial difficulties and eGFR showed significance in univariable analysis for overall survival but did not retain significance in multivariable analysis. These findings were consistent when examining progression-free survival. Conclusions: No discernible disparities in survival outcomes were observed between Black or African American participants and other racial groups undergoing primary treatment for locally advanced cervix cancer. The primary prognostic determinants for this disease continue to be cancer staging and clinical performance status. Enrolment into a clinical trial may have abrogated the historical disparities seen among ethnic and racial groups. Clinical trial information: 12610000732088.
Efficacy and safety of recombinant human adenovirus type 5 (H101) combined with immune checkpoint inhibitors (ICIs) in patients with liver metastatic gastric cancer: A prospective multicenter phase II study (the TROJAN 021 study).
Authors: Yuan Min , Xu Jing , Zhu Zhongzheng , Liu Zhuqing , Mao Wei , Wang Hui , Mao Dongliang , Zhan Qiong , Li Xiaoping , Zheng Leizhen , Liang Xiaohua , Wang Mei , Xu Qing
Published: August 2024

2635

Background: Immune checkpoint inhibitors (ICIs) have shown significant efficacy in metastatic gastric cancer, but some patients may not respond to them because of immune resistance. Recombinant Human Adenovirus Type 5 (H101), the world’s first oncolytic virus antitumor drug in China, can induce cell death, expose tumor antigens, provide adjuvants for anti-tumor immune priming, and potentially increase responsiveness to immunotherapies. Here, we presented the efficacy and safety of H101 combined with immune checkpoint inhibitors (ICIs) in patients with liver metastatic gastric cancer. Methods: In this multi-center, phase II trial (the TROJAN 021 study, ChiCTR1900027922), patients with liver metastatic gastric cancer received 2 cycles of H101 ultrasound guided injections into liver lesions, bi-weekly in combination with anti-PD-1 antibodies and chemotherapy bi-weekly until progression or intolerable toxicity. The primary objective was safety and objective response rate (ORR). Secondary objective included progression-free survival (PFS), overall survival (OS) and disease control rate (DCR). Efficacy assessments were performed every 4 weeks following RECIST v1.1 criteria. PFS and OS were estimated using the Kaplan-Meier method. Results: From September 2020 to September 2022, 21 patients were enrolled. Of them, 18 were males, median age was 66 years (range: 36-71) and ECOG performance status was either 0 (n=15) or 1 (n=6). 10 patients (47.6%) received as first-line therapy, 1 (4.8%) as second-line and 5 (23.8%) as third line and above therapy. The primary endpoint was met with a median PFS of 4.8 months. The median OS was 13.2 months. Objective tumor responses were CR (n=0), PR (n=7), SD (n=12) and PD (n=2). ORR was 33.3% (7/21), and DCR was 90.5% (19/21). Treatment related adverse events (TRAE) occurred in 12 patients (57.1%). The most frequently observed TRAEs were injection site pain (48.1%), fever (57.1%) and fatigue (23.8%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included neutropenia (2/21, 9.5%) and hypertension (1/21, 4.8%). Conclusions: These promising results show that combination of Recombinant Human Adenovirus Type 5 (H101) and ICIs demonstrated acceptable toxicity and promising antitumor efficacy in patients with liver metastatic gastric cancer. Further validation of the efficacy in a randomized prospective trial is warranted. Clinical trial information: ChiCTR1900027922.
Neoadjuvant immuno-chemo-radiotherapy in operable esophageal and gastroesophageal junction adenocarcinoma with carboplatin, paclitaxel plus radiotherapy and avelumab (anti-PDL1 antibody): Neo-CREATE trial.
Authors: Roy Amitesh Chandra , Bright Tim F , Singhal Nimit , Burge Matthew E. , Segelov Eva , Haydon Andrew Mark , Chantrill Lorraine A. , Michael Michael , Connell Caroline , Moffat David , Woodman Richard John , Michael Michael , Symonds Erin , Price Timothy Jay , Scott-Hoy Alex , Richards Alison , Karapetis Christos Stelios
Published: August 2024

4086

Background: Neoadjuvant CROSS regimen followed by adjuvant nivolumab or perioperative FLOT are current standards of care for patients with curable esophageal/ gastroesophageal (GEJ) junction adenocarcinoma. We hypothesized that adding avelumab to neoadjuvant chemo-radiation (CRT-A) before surgery can further improve outcomes. Methods: Patients with cT1-3 and N0/N1 M0 esophageal or GEJ adenocarcinomas eligible for curative surgery received weekly carboplatin and paclitaxel concurrently with radiotherapy (41.4 Gy in 23 fractions) and bi-weekly avelumab (5 doses). The trial had a run-in phase of 10 patients to evaluate feasibility and safety and a planned futility analysis after 15 patients have undergone surgery. The primary endpoint was pathological complete response (pCR) (Mandard criteria) by central pathology review, secondary endpoints were major histological response and survival outcomes. Using an A’hern single stage design for efficacy forty-seven patients were required to rule out a lower limit of a 20% pCR rate (p0) and to demonstrate an increase to a 40% pCR rate (p1), with 90% power and significance level α=0.05. Tissue, blood, and stool samples were collected for corelative analysis. Results: 48 patients were enrolled between Sept 2019 to Oct 2022 across seven Australian sites. Median age 65 [44-81], 95% were male (n=45), with majority of cancers being esophageal/GEJ type I (n = 35), with GEJ type II (n = 13). Forty-seven (97%) patients completed CRT -A and 46 (95%) had surgery. CRT-A was well tolerated, with two patients having > grade 2 adverse event of interest in the form of myocarditis attributed to avelumab. Notable toxicities included grade 2-4 myocarditis (4%), anastomotic leak (4%), infection (6%) and diarrhoea (6%). In 44 evaluable patients, pCR was 23%. MHR was 58.3% (95% CI, 43.3%-72.1%), complete or near complete response (Tumor Regression Grade 1-2) was 31%. Overall, 1-yr disease free survival was 83.8% and OS was 91.2%. 1-yr disease free survival was 91.7% for patients with MHR vs 73.3% without MHR, p=0.20. Conclusions: Combining avelumab with neoadjuvant CRT is feasible in patients with acceptable tolerability in locally advanced esophageal/ GEJ adenocarcinoma. Avelumab with CRT is active however observed pCR rate does not represent a signal of substantial improvement compared to historical controls. Exploratory analysis suggests improved outcomes in patients with optimal tumour regression after neoadjuvant CRT-A. Exploratory biomarker work to corelate with outcomes is underway. Clinical trial information: ACTRN12619000288123.
Phase II study of pirfenidone combined with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer.
Authors: Guo Guifang , Li Shengping , Mao Yize , Yang Qiuxia , Yao Zehui , Wang Jun
Published: August 2024

4152

Background: Pancreatic cancer is a disastrous malignancy characterized by the dense fibrous stroma, elevating interstitial pressure and impairing perfusion of chemotherapeutics. Pirfenidone (PFD) is an oral antifibrotic agent, which might reduce the degree of fibrosis of pancreatic cancer and increase drug delivery. Thus, we aimed to evaluate the efficacy and safety of pirfenidone (PFD) plus nab-paclitaxel and gemcitabine (AG) for patients with metastatic pancreatic cancer. Methods: In this two-stage single-arm phase II trial, treatment-naïve patients with metastatic pancreatic cancer received oral PFD, 200 mg three times daily in the first week and 400 mg three times daily thereafter, in combination with intravenously administered gemcitabine 1000 mg/m2 and nab-paclitaxel 120 mg/m2 on days 1,8 of each 21-day cycle. The primary endpoint was overall response rate (ORR). A total of 33 patients were required based on the assumption of an expected ORR of 45%, with an α-error of 5% (one-sided) and a β-error of 20%. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: We enrolled 33 patients from October 2020 to February 2023, with median age of 61years (IQR 53-65), 21(63.6%) male and 12(36.4%) female. Metastatic sites included the liver (32cases), lung(7cases) and peritoneum (11cases). The last one patient was enrolled on February 24, 2023 and the deadline of follow up was Jan 25, 2024, with only one was unevaluable. The ORR was 50.0% (95% CI 33.6%-66.4%) and the DCR was 93.8%(95%CI 79.9%-98.9%). The median PFS was 4.9 months (95% CI 3.9-5.9) and the median OS was 9.1 months (95% CI 7.8-10.4). Among all cases of 25 with elevated CA19-9 at diagnosis, 56% patients experienced a decrease in CA19-9 levels of more than 50%. Grade 3-4 toxicities were observed in 11 (34.4%) patients, with leukopenia (7[21.9%]), anemia (5[15.6%]) and elevated AST level (4[12.5%]). No treatment-related deaths occurred. Conclusions: Adding PFD to AG showed promising ORR and DCR and an acceptable adverse event in patients with metastatic pancreatic cancer. Clinical trial information: ChiCTR2000034397.
Tislelizumab combined with gemcitabine and albumin paclitaxel as preoperative therapy for patients with borderline resectable pancreatic cancer: A prospective, single-arm, phase II trial.
Authors: He Yonggang Gang , Huang Xiaobing , Zheng Lu , Li Jing , Zhao Chongyu , Li Ying , Zuo Guohua
Published: August 2024

4162

Background: Pancreatic cancer is a highly aggressive disease with low resection rate and poor prognosis. Neoadjuvant treatment for borderline resectable pancreatic cancer (BRPC) is increasing in acceptability, but no standard treatment has been established. Herein, we aimed to assess the safety and efficacy of a new mode of preoperative therapy for patients with BRPC. Methods: This is a single arm, exploratory phase II clinical trial. Gemcitabine (1000 mg/m2) and albumin paclitaxel (125 mg/m2; AG) were administered to patients with BRPC on days 1 and 8, along with tislelizumab (200 mg) on day 1 intravenously (IV) every three weeks. Surgical intervention was assessed after two cycles of treatment. Primary endpoint was adverse events (AE) and R0 resection rate. Secondary endpoints were objective response rate (ORR) and progression free survival (PFS) by mRECIST, relapse-free survival (RFS) and overall survival (OS). Results: Between October 2022 and December 2023, 21 patients were enrolled in the study. At the end of the last follow-up (January 27, 2024), 15 patients had a best response of partial response, the ORR was 71.4% according to mRECIST. The disease control rate (DCR) was 85.7%. The 12-months PFS rate, and 12-months OS rate were 68.2% (95% CI: 38.0%–86.0%), and 63.8% (95% CI: 33.2%–88.3%), respectively. After the two cycles of neoadjuvant therapy, 14 patients underwent resection (66.7%,14/21) and the R0 resection rate was 100%. For those patients who did not undergo surgery, 3 of them achieved PR but refused surgery, 3 patients developed disease progression and lost the chance of surgery. 1 patient died of severe pneumonia caused by H1N1 infection. So far the safety of neoadjuvant treatment was satisfied, no grade 4 or above treatment-related-adverse events (TRAEs) were observed. Grade 3 TRAEs were reported in 3(14.29%) patients. Frequently occurring adverse events were grade 1-2, including myelosuppression (90.47%), albuminuria (80.95%), nausea (61.90%), elevated aspartate aminotransferase (47.62%) and elevated alanine aminotransferase (38.10%). Grade 3 or higher adverse events were pneumonia (4.76%), elevated AST (4.76%), elevated ALT (4.76%) and myelosuppression (4.76%). Conclusions: Anti-PD-1 inhibitor tislelizumab plus AG chemotherapy displayed promising antitumor activity and acceptable safety profile for patients with BRPC. Clinical trial information: ChiCTR2200063680.
Efficacy of cytotoxic chemotherapy in recurrent/metastatic adenoid cystic carcinoma (ACC).
Authors: Wotman Michael , Hoff Camilla Oliveira , Bonini Flavia , Sawyer Matthew , Wang Kaiwen , Andreazza Dal Lago Eduardo , Guimaraes de Sousa Luana , Ferrarotto Renata
Published: August 2024

6111

Background: Despite aggressive local therapy, many ACC patients (~50%) develop recurrent and/or metastatic (R/M) disease. However, there is no standard of care or FDA-approved systemic therapy for this population. Based on small phase II trials, mostly including multiple salivary gland histologies, cytotoxic chemotherapy is recommended for symptomatic patients with high tumor burden, but its efficacy and impact on survival in R/M ACC remain unsubstantiated. Methods: A retrospective cohort study was conducted at MD Anderson Cancer Center with an institutional ACC database (N=769). Patients diagnosed with R/M ACC and treated with single-agent or combination palliative-intent chemotherapy were included. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Secondary endpoints were median overall survival (mOS) and progression-free survival (mPFS) on chemotherapy for the entire cohort and stratified by growth pattern (solid v non-solid), line of therapy (1 v >2), chemotherapy regimen, and stage at diagnosis (M0 v M1). Results: 48 out of 115 patients who received chemotherapy were evaluated for response per RECIST.Median age at diagnosis was 43.6 years. 56% were male, 79% had M0 stage at diagnosis, 67% had minor salivary gland primary tumors, 52% had solid growth pattern, 31% had non-solid growth pattern, and 54% received first-line chemotherapy. The most common regimens were Platinum/Vinorelbine (38%), Platinum/Taxane (27%) and CAP (15%).The ORR and DCR rates were 12.5% and 56.3% respectively; 6 had partial response, 21 had stable disease, and 21 had progressive disease. The ORR and DCR rates were 20% and 52% for solid and 6.7% and 73.3% for non-solid growth pattern, respectively. The mOS from diagnosis was 7 years (95% CI, 3.5-10.7). The mOS on chemotherapy was 16 months (95% CI, 10.8-24.5). There was a significant difference in mOS between solid and non-solid growth pattern (10.8 v 24.1 months, p=0.015), but not by line of therapy, regimen, or stage at diagnosis. The mPFS on chemotherapy was 4.3 months (95% CI, 2.8-6.3 months). There was a significant difference in mPFS between solid and non-solid growth pattern (4.0 v 7.3 months, p=0.018), but not by line of therapy, regimen, or stage at diagnosis. Conclusions: In this largest to date real-world data on chemotherapy in ACC, response and survival outcomes were lower than historical data. The efficacy of chemotherapy may vary by growth pattern and other patient and tumor factors, which requires further investigation. Given the low ORR and overall slow-growing disease pattern, tumor volumetrics may be better than RECIST to assess treatment benefit.
First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics of BY101298: Initial report from dose escalation cohort.
Authors: Yu Jinming , Sun Yuping , Dang Qi , Zhang Yan , Du Jintong , Wei Yonggang , Ye Fei , Liu Rui , Zhao Qi , Li Zhiyong
Published: August 2024

e15132

Background: Radiotherapy (RT) is a cornerstone of cancer treatment, leveraging the effect of ionizing radiation to induce DNA damage, primarily through DNA double-strand breaks (DSBs). Non-homologous end joining (NHEJ) stands as the predominant pathway for repairing DSBs, with DNA-dependent protein kinases (DNA-PK) playing a pivotal role in NHEJ pathway. DNA damage repair can compromise tumor cells sensitivity to RT, potentially leading to the development of radiation resistance. BY101298, an innovative and highly selective DNA-PK inhibitor, works to diminish DSBs repair. In synergy with RT or chemotherapy, BY101298 enhances tumor cells eradication, preventing local recurrence and metastasis, thereby improving clinical benefits for cancer patients. Methods: This phase Ⅰa multicenter, open-label, dose-escalation study assessed the safety, tolerability, and clinical efficacy of BY101298. Oral doses ranged from (50 mg to 400 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcome was PK; exploratory outcome was DNA-PK phosphorylation (PD). Adverse events (AEs) were monitored per the Common Terminology Criteria for Adverse Events (CTCAE version5.0). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: Data from 9 pts with advanced solid tumors (cutoff: 26 December 2023; 2 men, 7 women; median age 58.0) revealed a linear increase in BY101298 AUC exposure and Cmax with dose escalation. Daily dosing for 15 consecutive days showed no AUC increase. Serum drug concentration correlated significantly with DNA-PK phosphorylation. All pts, previously systemic treated, received doses of 50 mg QD (n = 2), 100 mg QD (n = 3), and 200 mg QD (n = 4). Median treatment duration was 30 days (range: 1-57), with one patient (11.1%) continuing. Median relative dose intensity was 100%. Common treatment-related AEs (≥25%), primarily grade 1, included hypoalbuminemia (n = 5, 55.56%); anemia (n = 4, 44.44%); nausea (n = 3, 33.33%); weight decreased (n = 3, 33.33%). No pts experienced ≥Gr3 AEs. Two pts experienced serious AEs (none of which were considered treatment-related). No treatment discontinuations, dose reductions, or deaths attributed to treatment-related. The final dose group, representing the fourth cohort, is scheduled to commence shortly and is expected to conclude in April as per our estimation. Conclusions: In pts with advanced solid tumors, BY101298 exhibits a favorable safety profile and manageable toxicity. Vomiting was noted as a potential risk associated with BY101298. Further studies are imperative to elucidate the efficacy of BY101298 in combination with radiotherapy among pts with advanced solid tumors. Research Sponsor: This study received support from Chengdu Baiyu Pharmaceutical Co., Ltd. Clinical trial information: CTR20230997.
First-line sintilimab combined with platinum-based chemotherapy in extensive stage small cell lung cancer: A phase II study and post-hoc biomarker analysis.
Authors: Su ChunXia , Xie Mengqing , Zhao Jing , Chu Xiangling , Liu Li
Published: August 2024

e20127

Background: Immune checkpoint inhibitors (ICIs) combined with etoposide and platinum-based chemotherapy improves prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC). However, nearly 40% of patients do not benefit from Immunochemotherapy. Herein, this phase II study of first-line immunochemotherapy was conducted aiming to investigate potential biomarkers associated with therapeutic efficacy. Methods: A multi-center, single-arm, prospective phase II trial (ChiCTR2000038354) was designed and conducted to evaluate the efficacy and safety of sintilimab combined with platinum-based chemotherapy in patients with ES-SCLC who had not previously received treatment. The primary endpoint of this study is progression-free survival (PFS), with patients being defined as disease progression according to RECIST 1.1. Pre-treatment FFPE samples were analyzed using whole exome sequencing (WES) and whole transcriptome sequencing (WTS) to investigate biomarkers. Results: A total of 44 patients were included in the study, with a median follow-up of 10 months and a median PFS of 7.57 months. 8 patients with a PFS greater than 6 months were defined as the responder group (R group) and 5 patients with a PFS less than 6 months belonged to the non-responder group (NR group). WES and WTS were performed on the pre-treatment samples of these 13 patients. WES results revealed mutation frequencies of TP53 (69%), RB1 (31%) and FAT1 (31%) aligning with prior research. Significantly, ZFHX4 mutations correlated with R group (p = 0.05). Genomic instability, as defined by Homologous Recombination Deficiency (HRD) scores, displayed higher scores in NR group than in R group (p = 0.023), which suggests potential benefits of PARP inhibition in the NR group. WTS data revealed that higher M2/M1 macrophage ratio (p = 0.028) in NR group. Additionally, the NR group demonstrated significant VEGFA overexpression. Besides, NOTCH-signaling (p = 0.034), KRAS-signaling-DN (p<0.001), Angiogenesis (p<0.001) and EMT (p<0.001) pathway were also enriched in NR group. Conversely, M1 macrophages (p = 0.079), CD4+T cells (p = 0.093), Mast cells (p = 0.045), NK cells (p = 0.045) and neutrophils (p = 0.06) was higher in R group. Conclusions: This study highlights genomic instability as well as activation of cancer hallmarks such as angiogenesis, EMT may result the resistance to immunotherapy in ES-SCLC patients. These findings may shed light on combinational strategy overcoming therapeutic resistance. Clinical trial information: ChiCTR2000038354.
Cost-effectiveness of an oral THC: CBD cannabis extract for secondary prevention of refractory, chemotherapy-induced nausea and vomiting.
Authors: Dieng Mbathio , Grimison Peter S. , Kirby Adrienne , Mersiades Antony , Pokorski Izabella , Stockler Martin R , Morton Rachael L
Published: August 2024

TPS11188

Background: The CannabisCINV trial showed the incorporation of a THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract in addition to usual, guideline-recommended antiemetic prophylaxis, reduced the incidence of refractory chemotherapy-induced nausea and vomiting. The aim of this within-trial cost-effectiveness analysis was toassess the incremental costs and benefits of oral THC: CBD versus placebo, for preventing chemotherapy-induced nausea and vomiting. Methods: The analysis was performed from a health system perspective, using prospectively collected data from the CannabisCINV trial and linked Medicare data. The evaluation focused on the costs and benefits associated with oral THC: CBD cannabis extract versus placebo in addition to usual care, on complete response: defined as no emesis and no use of rescue medications during the overall treatment phase (0-120 h, cycle 1). The primary economic outcome was an incremental cost-effectiveness ratio (ICER) of achieving a complete response. One-way sensitivity analyses and non-parametric bootstrapping (with 1,000 replications) were conducted to assess the robustness of results. Results: Of 147 participants randomized, 60 of 73 assigned THC:CBD and 66 of 74 assigned placebo consented to Medicare data linkage. The incidence of complete response was higher for THC:CBD than placebo (24% vs 5%, absolute difference 19%, 95%CI 13 to 26%). The mean cost (AUD) of hospitalisation was $580 (SD $7,831) for the intervention group and $1,873 (SD $7,235) for placebo. The mean healthcare costs (AUD) were $1,464 (SD $4,667) for THC:CBD group and $2,725 (SD $9,237) for the placebo. The THC:CBD group had a mean total healthcare cost saving of $1,261 per patient (95% CI -$3,550 to $1029) compared with the placebo group. THC:CBD was less expensive and more effective than placebo (i.e. dominant), in the primary analysis, and over the range of pre-specified sensitivity analyses. Conclusions: This within-trial analysis indicates oral THC: CBD is cost-effective for the treatment of refractory, chemotherapy-induced nausea and vomiting from a health system perspective and supports reimbursement in this setting. The trial and economic evaluation were prospectively registered in the Australian and New Zealand. Clinical trial information: ACTRN12616001036404.
A first-in-human study of IK-595, an oral MEK/RAF molecular glue, in patients with RAS- or RAF-altered advanced solid tumors.
Authors: Lakhani Nehal J. , Spira Alexander I. , Tolcher Anthony W. , Lingaraj Trupti , Timothy Marissa , Bartolini Wilmin , Ortiz-Otero Nerymar , Kacena Katherine , Santillana Sergio
Published: August 2024

TPS3185

Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and low therapeutic indices. IK-595, a potent novel MEK-RAF molecular glue, is being developed to overcome these limitations. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors, in addition to kinase independent CRAF activity. IK-595 exhibits potent single agent activity in a wide range of in vivo cancer models harboring various RAS/RAF alterations, including, but not limited to, lung, pancreatic, colorectal cancer (CRC), melanoma, and AML. The preclinical pharmacokinetic profile of IK-595 also enables flexible dosing schedules resulting in a broader therapeutic window. Methods: This is a phase 1, first-in-human, open-label, multicenter study to evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit. Dose escalation uses a Bayesian Optimal Interval Design (BOIN) in patients with advanced and unresectable, or metastatic solid tumors with confirmed RAS/RAF gene alterations. Backfilling of cleared dose levels with key target indications will initiate upon achievement of efficacious plasma exposures. Dose expansion will occur in genetically defined cohorts, for example NRAS-mutant CRC and malignant melanoma, as well as BRAF non-V600 and KRAS mutant tumors using a Simon 2-stage adaptive design. IK-595 will initially be administered on an intermittent dosing schedule in 30-day cycles. Additional dosing schedules may be explored. Primary objectives of the study are to evaluate safety and tolerability of IK-595 and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1, pharmacokinetic (PK) parameters, and pharmacodynamic effects of IK-595 on pERK in paired tumor biopsies. Key exploratory endpoints include changes in pERK in peripheral blood cells, changes in pERK target genes in tumor biopsies, and assessment of candidate baseline response biomarkers. The study began in December 2023 and enrollment in Cohort 1 was completed with no DLTs; dose escalation continues to enroll. Clinical trial information: NCT.
MELODY: A prospective non-interventional multicenter cohort study to evaluate different imaging-guided methods for localization of malignant breast lesions (EUBREAST-4/iBRA-NET).
Authors: Banys-Paluchowski Maggie , Kuehn Thorsten , Masannat Yazan , Ditsch Nina , Cabioglu Neslihan , Harvey James , Pankratjevaite Lina , Murawa Dawid , Gasparri Maria Luisa , Karadeniz Cakmak Guldeniz , Kontos Michalis , Khan Mah Muneer , Lowery Aoife J , Rebaza Lia Pamela , Esgueva Antonio J , Rody Achim , Krawczyk Natalia , Hartmann Steffi , Aktas Sezen Bilge , Tvedskov Tove Filtenborg ,   MELODY Study Group
Published: August 2024

TPS623

Background: In the last decades, the proportion of breast cancer patients receiving breast-conserving surgery has increased, reaching 70-80% in developed countries. In case of non-palpable lesions, surgical excision requires some form of breast localization. While wire-guided localization has long been considered gold standard, it carries several limitations, including logistical difficulties, the potential for displacement and patient discomfort, and re-excision rates reaching 21%. Other techniques (radioactive seed or radio-occult lesion localization, intraoperative ultrasound, magnetic, radiofrequency, and radar localization) have been developed with the aim of overcoming these disadvantages. However, comparative data on the rates of successful lesion removal, negative margins, and re-operations are limited. In most studies, the patient perspective, addressing e.g. discomfort and pain, has not been evaluated. The aim of MELODY (Methods for Localization of Different Types of Breast Lesions) is to evaluate different imaging-guided localization methods with regard to oncological safety, patient-reported outcomes, and surgeon and radiologist satisfaction. Methods: The EUBREAST and the iBRA-NET have initiated the MELODY study to assess breast localization techniques and devices from several perspectives (NCT05559411, http://eubreast.org/melody ). MELODY is a prospective intergroup cohort study which enrolls female and male patients. planned for breast-conserving surgery with imaging-guided localization for invasive breast cancer or DCIS. Multiple or bilateral lesions and neoadjuvant chemotherapy are allowed. Primary outcomes are: 1) Intended target lesion and/or marker removal and 2) Negative resection margin rates. Secondary outcomes are, among others: rates of second surgery and secondary mastectomy, Resection Ratio (defined as actual resection volume divided by the calculated optimum specimen volume), duration of surgery, marker dislocation rates, rates of marker placement or localization failure, patient-reported outcomes, rates of “lost markers”, radiologist and surgeon satisfaction, and health economic evaluation of the different techniques. Target accrual: 7,416 patients. The study will be conducted in 30 countries. Clinical trial information: NCT05559411 .
Reducing Cancer Drug Cost: 3-Year Analysis of Automated Dose Rounding in Electronic Health Records
Authors: Shah Vishal S. , Irvine Clayton , McWilliams Robert R. , Singh Parminder , Soefje Scott A.
Published: August 2024

PURPOSE

Globally, cancer drug expenditure exceeds $185 in US dollars (USD) billion, with the United States contributing $75 (USD) billion. Many cancer drug doses are calculated on the basis of body weight or body surface area, which often results in leftover drug in partially used single-dose vials (SDVs). The cost of wasted drug is a huge financial burden on the US health care system. We evaluated the cost savings resulting from the reduction of SDV wastage, achieved through the implementation of automated dose rounding rules in electronic health records (EHRs).

METHODS

Mayo Clinic implemented automated dose rounding rules within the EHR. These rules were designed to round calculated doses to the nearest SDV if the vial size closely matched the original calculated dose, within a 10% threshold. We assessed doses administered between January 2019 and December 2021, and computed cost-savings, waste reduction, and cost of waste for chemotherapy drugs.

RESULTS

In 3 years, 36.1% of doses were rounded down, 35.8% were rounded up, and 28.1% were exact doses. By rounding doses down to a vial size, we achieved cost-savings of $39.75 (USD) million and prevented 62,065 SDV of cancer drugs from going to waste. By rounding doses up, we avoided wasting $9.95 (USD) million worth of drugs. However, there were still instances where the rounding fell outside of the 10%, resulting in wasted drugs worth $25 (USD) million.

CONCLUSION

The substantial burden imposed on patients and the US health care system because of cancer drug wastage is of significant concern. Although the automated dose rounding system represents a partial solution for this issue, a comprehensive approach involves the imperative development of policy and legislative solutions to effectively mitigate the challenges associated with cancer drug waste.
Koopmans, Dantzig, and the Wartime Origins of Activity Analysis
Authors: Dimand Robert W.
Published: August 2024

In the introduction to Activity Analysis of Production and Allocation (Cowles Monograph No. 13), Tjalling C. Koopmans recalled that he developed the model of his “Optimal Utilization of the Transportation System” (in the proceedings of 1947 International Statistical Congress, which were reissued as an Econometrica supplement, 1949) “under the stimulation of statistical work for the Combined Shipping Adjustment Board, the British-American board dealing with merchant shipping problems during the second world war.” Similarly, the contributions of George B. Dantzig and Marshall K. Wood to Cowles Monograph No. 13 (two revised journal articles and five new chapters) emerged from wartime work for the US Army Air Force and postwar work for the Department of the Air Force. This article examines the context and consequences of the wartime roots of these foundational contributions to activity analysis and linear programming, with particular attention to Koopmans's 1942 memorandum for the Combined Shipping Adjustment Board titled “Exchange Ratios between Cargoes on Various Routes” (first published in his Scientific Papers, 1970).
Japanese Wartime Economics and Economists
Authors: Bollard Alan
Published: August 2024

The Japanese prewar intellectual and policy environment was dominated by officials with law degrees and increasingly by the military. There were important schools of economics, both Marxist, and neoclassical, but their influence was mainly confined to academia. During wartime they suffered severe intellectual repression. The wartime economy relied on an allocation policy led by technocratic planners working under the “reform bureaucrats.” Immediately postwar there was a revival: economists were able to display moral leadership and play a leading role in adapting the MacArthur reforms and devising the formula for modern Japanese growth.
Ethical Antinomies
Authors: Ozdemir Mehtap
Published: August 2024

Building on recent scholarship on the novel and Middle Eastern modernities, this article examines how Ottoman intellectuals theorized the novel as a realist genre in the nineteenth century as a way of including Ottoman literary knowledge within global novel theories. In the late Ottoman context, the novel was articulated in terms of conceptual separations (primarily as truth/imitation–fiction/creation, which then develops into nature-beauty and romance-realism binaries). Such conceptual divides inform both the history and the theory of the novel by Ottoman intellectuals. Revisiting the problem of realism in light of the dialectics that these divides built up, this article argues that they dialogically establish realism as a symbiotic regime of representation that merges mimeticism and transcendentalism, which had aesthetic as well as political implications. More importantly, negotiating the tension between imitation and creation through Ottoman-Islamicate terms, Ottoman realism complicates the relation between literature and secularization as it speaks to the institutionalization of modern literature.
Outcomes After Definitive Surgery for Spinal and Sacral Chordoma in 101 Patients Over 20 Years
Authors: Xia Yuanxuan , Papali Pritika , Al-Mistarehi Abdel-Hameed , Hansen Landon J. , Azad Tej D. , Ahmed A. Karim , Meyer Christian , Gross John , Khan Majid , Bettegowda Chetan , Mukherjee Debraj , Witham Timothy , Bydon Ali , Theodore Nicholas , Wolinsky Jean-Paul , Gokaslan Ziya , Larry Lo Sheng-Fu , Sciubba Daniel , Lee Sang H. , Redmond Kristin J. , Lubelski Daniel
Published: August 2024

BACKGROUND AND OBJECTIVES:

Spinal chordomas are primary bone tumors where surgery remains the primary treatment. However, their low incidence, lack of evidence, and late disease presentation make them challenging to manage. Here, we report the postoperative outcomes of a large cohort of patients after surgical resection, investigate predictors for overall survival (OS) and local recurrence-free survival (LRFS) times, and trend functional outcomes over multiple time periods.

METHODS:

Retrospective review of all patients followed for spinal chordoma at a quaternary spinal oncology center from 2003 to 2023 was included. Data were collected regarding demographics, preoperative and perioperative management, and follow-up since initial definitive surgery. Primary outcomes were OS and LRFS, whereas secondary outcomes were functional deficits.

RESULTS:

One hundred one patients had an average follow-up of 6.0 ± 4.2 years. At the time of census, 25/101 (24.8%) had experienced a recurrence and 10/101 (9.9%) had died. After surgery, patients experienced a significant decrease in pain over time, but rates of sensory deficits, weakness, and bowel/bladder dysfunction remained static. Tumors ≥100 cm3 (hazard ratio (HR) = 5.89, 95% CI 1.72-20.18, P = .005) and mobile spine chordomas (HR = 7.73, 95% CI 2.09-28.59, P = .002) are related to worse LRFS, whereas having neoadjuvant radiotherapy is associated with improved LRFS (HR = 0.09, 95% CI 0.01-0.88, P = .038). On the other hand, being age ≥65 years was associated with decreased OS (HR = 16.70, 95% CI 1.54-181.28, P = .021).

CONCLUSION:

Surgeons must often weigh the pros and cons of en bloc resection and sacrificing important but affected native tissues. Our findings can provide a benchmark for counseling patients with spinal chordoma. Tumors ≥100 cm3 appear to have a 5.89-times higher risk of recurrence, mobile spine chordomas have a 7.73 times higher risk, and neoadjuvant radiotherapy confers an 11.1 times lower risk for local recurrence. Patients age ≥65 years at surgery have a 16.70 times higher risk of mortality than those <65 years.
Using Wearable Technologies to Monitor Physical Activity and Exercise in Patients: A Narrative Review
Authors: Sher Jessica , Lewis Christopher W. , Lin Cindy
Published: August 2024

With an increasing prevalence of sedentary lifestyles driving a prominent public health crisis, digital health tools such as wearable technologies are revolutionizing clinicians’ ability to track physical activity and exercise. Despite their ubiquity in the consumer market, these technologies have not yet been fully incorporated into clinical practice. Though these tools promise efficacy and accessibility, a careful review of the current literature is important to understand the challenges and future promise of clinical implementation. Important considerations of implementation include health maintenance and disease prevention, ease of use by patients and providers, incorporation into the electronic health record, cost considerations, safety, privacy, and ethical considerations. This narrative review describes the recent literature on the implementation of wearable technologies in the prescription of physical activity and exercise. Application of these technologies is promising for this field’s future.
A circular split nanoluciferase reporter for validating and screening putative internal ribosomal entry site elements
Authors: Unti Mildred J. , Doetsch Lisa , Jaffrey Samie R.
Published: August 2024

Internal ribosomal entry sites (IRESs) recruit the ribosome to promote translation, typically in an m7G cap-independent manner. Although IRESs are well-documented in viral genomes, they have also been reported in mammalian transcriptomes, where they have been proposed to mediate cap-independent translation of mRNAs. However, subsequent studies have challenged the idea of these “cellular” IRESs. Current methods for screening and discovering IRES activity rely on a bicistronic reporter assay, which is prone to producing false positive signals if the putative IRES sequence has a cryptic promoter or cryptic splicing sites. Here, we report an assay for screening IRES activity using a genetically encoded circular RNA comprising a split nanoluciferase (nLuc) reporter. The circular split nLuc reporter is less susceptible to the various sources of false positives that adversely affect the bicistronic IRES reporter assay and provides a streamlined method for screening IRES activity. Using the circular split nLuc reporter, we find that nine reported cellular IRESs have minimal IRES activity. Overall, the circular split nLuc reporter offers a simplified approach for identifying and validating IRESs and exhibits reduced propensity for producing the types of false positives that can occur with the bicistronic reporter assay.