bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Ib portion of the ACTION-1 phase Ib/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.
Authors: Halperin Daniel M. , Morris Michael , Ulaner Gary A. , Strosberg Jonathan R. , Mehr Samuel H. , Li Daneng , Soares Heloisa P. , Anthony Lowell Brian , Kotiah Sandy Diana , Jacene Heather , Tesselaar Margot ET , Kunz Pamela L. , Ferreira Denis Vasconcelos , Li Joanne , Ma Kimberly , Rearden Jessica , Moran Susan , Hope Thomas A. , Singh Simron
Published: June 2024

3091

Background: RYZ101 (225Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improved therapeutic index. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Herein, we report updated results from the phase Ib portion of the trial. Methods: The phase Ib portion of the trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level –1 90 kBq/kg; Level –2 60 kBq/kg. DLT was assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions/safety data were overseen by a Data Review Committee. Tumor response was assessed locally by RECIST v1.1. Results: 17 patients have received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 30 June 2023, the most frequent TEAEs were nausea (58.8%) and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (none were treatment related); grade ≥3 AEs occurred in 9 patients (5 were treatment related). No AEs led to treatment discontinuation. 4 patients had TEAEs leading to dose modification, dose hold, and/or delays. The confirmed objective response rate was 29.4% (n=5; all partial responses); 1 patient had an unconfirmed partial response. 8 patients (47.1%) had stable disease and 3 patients (17.6%) had progressive disease. Updated safety and efficacy data, including duration of response and progression-free survival, will be presented. Conclusions: RYZ101 was well tolerated and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy. Longer-term safety and efficacy data will be presented. Part 2 (phase 3) is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 .
Phase II study to evaluate safety and efficacy of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, and trastuzumab biosimilar in patients with HER2 mutated advanced solid tumors (KCSG AL20-17).
Authors: Lee Kyoungmin , Lee Kyung-Hun , Kim Dong-Wan , Yoon Jeesun , Choi Wonyoung , Lee Youngjoo , Choi Yoon Ji , Lee Soohyeon , Kim Ju Won , Ryu Hyewon , Koo Dong-Hoe , Lee Yun-Gyoo , Jeung Hei-Cheul , Lee Min-Young , Lee Namsu , Kang Myoung Joo , Lee Ji Eun , Hong Sook Hee , Kang Eun Joo , Park Inhae
Published: June 2024

3134

Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single agent clinical activity in HER2 mutated cancer. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 amplifications. Methods: Neratinib was administered 240mg p.o. daily with trastuzumab biosimilar (Herzuma) every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints were duration of response (DoR), progression free survival (PFS), and safety. An exploratory biomarker study was also conducted. Results: Forty patients were enrolled with a median follow-up of 11.08 months (range, 0.39-21.63 months) and a median of 3 (range 1-9) lines of prior systemic therapy. Tumor types included lung (42.5%), colorectal (20%) biliary (12.5%), and breast (7.5%). Sixty percent (60%) of patients (n=24) had HER2 mutation in the kinase domain. Among evaluable patients (n=39), the ORR was 23.1% (CR=0, PR=9) with a median DoR of 11.18 months (95% CI 0-22.63). Median PFS was 3.42 months (95% CI 1.57-5.27) and median overall survival was 9.47 months (95% CI 2.93-16.01). Grade ≥3 adverse events (AEs) occurred in 47.5% of patients (n=19) and diarrhea was the most frequently reported AE (n=10; 25%) followed by bilirubin elevation (n=2; 5%), and anemia (n=2; 5%). Conclusions: In heavily pretreated patients with HER2 mutated solid tumors, neratinib plus trastuzumab showed a moderate response rate, with a durable duration of response. Most AEs were manageable, highlighting the need for prophylactic diarrhea management. Exploratory biomarker results will be presented at the upcoming meeting. Clinical trial information: NCT06083662 .
Fruquintinib plus capecitabine versus capecitabine as first-line maintenance treatment of metastatic colorectal cancer (mCRC): Update results from the randomized, controlled, phase Ib/II study.
Authors: Li Wenhua , Chang Jinjia , Wang Chenchen , Peng Junjie
Published: June 2024

3567

Background: Capecitabine (Cap) is a standard first-line maintenance treatment option for colorectal cancer. Fuquinitinib (Fru) is a highly selective small molecule tyrosine kinase inhibitor that inhibits VEGFR1/2/3, which has been approved by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and has recommended by NCCN guidelines as a standard treatment. Preliminary research results found that adding Fru to Cap as maintenance treatment was safe and improved progression-free survival (PFS, primary endpoint) for mCRC patients (pts). Methods: Eligible pts had been confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was PFS 1 (defined as time from randomization to disease progression or death). Secondary were PFS 2 (defined as time from first time receiving 1L treatment to disease progression or death), ORR and DCR. Results: At data cutoff (Jan 23, 2024), 46 pts were enrolled and 38 pts who had at least one tumor assessment post treatment were randomly assigned in Fru plus Cap arm (n=20) and Cap arm (n=18). Of these pts, the median age was 59.5 (39-78) and 58.5 (32-75) years, 11 (55.0%) and 10 (55.6%) had left-sided tumors, respectively. Most pts had previously received bevacizumab therapy (65.0% /66.7%) or cetuximab (30% /22.2%). The median cycles of first-line treatment were 8 (5-12) and 8 (4-13), 8 (40.0%) and 8 (44.4%) achieved PR in the pts who had received first-line therapy, respectively. The median PFS 1 was 9.2 mo in Fru plus Cap arm and 3.1 mo in Cap arm (HR=0.385 [95% CI: 0.163 - 0.906], p=0.024). And PFS 2 was also significantly prolonged in Fru plus Cap vs Cap (16.8 vs 8.5 mo, HR=0.314 [95% CI: 0.125 - 0.788], p=0.0098). Consistently, ORR (15.0% vs 5.6%) and DCR (80% vs 55.6%) were improved in Fru plus Cap arm. The safety was similar to the previous results without new safety signals appearing. Conclusions: PFS was significantly prolonged and ORR was improved in mCRC pts treated with Fru plus Cap as first-line maintenance treatment. This trial is ongoing and updated data will be presented in the future. Clinical trial information: NCT05451719 .
Neoadjuvant long-course chemoradiation plus PD1 blockade for locally advanced rectal cancer: Results of a phase 2, open-label, randomized controlled trial.
Authors: Yang Yingchi , Pang Kai , Lin Guole , Liu Xinzhi , Zhou Jiaolin , Kong Yuanyuan , Chen Guangyong , Wang Xin , Ye Yingjiang , Li Ang , Han Jiagang , Wu Guoju , WU Aiwen , Xiao Yi , Yao Hongwei , Zhang Zhongtao ,   Polarstar Trial Collaboration Group
Published: June 2024

3611

Background: Several single-arm trials have reported pathological complete response (pCR) rates of 23-50% after combining neoadjuvant radiotherapy with immune checkpoint inhibitors in locally advanced rectal cancer (LARC). We aim to further clarify the efficacy and safety of adding PD1 inhibitors to the neoadjuvant long-course chemoradiation of LARC patients with this phase 2, randomized, controlled trial. Methods: Patients with mid-low, locally advanced rectal cancer were randomly allocated to receive neoadjuvant chemoradiation plus concurrent Tislelizumab (experiment group A), or neoadjuvant chemoradiation plus sequential Tislelizumab (experiment group B), or neoadjuvant chemoradiation only (control group). Patients of all three groups are scheduled to receive radical surgery after neoadjuvant treatment. The primary endpoint is pCR rate. Results: A total of 186 patients were enrolled. In the modified intention-to-treat population, which consist of patients having received chemoradiation and at least 1 cycle of PD1 blockade for the experiment groups and patients having received chemoradiation only for the control group, the pCR rates were 33.9% and 34.5% for experiment group A and B respectively, both significantly higher than the pCR rate of 15.5% in the control group (p=0.021 and 0.019). There were no significant differences between either one of the experiment groups and the control group regarding disease progression rate, grade 3-4 treatment-related adverse event rate and grade 3-4 surgical complication rate. Conclusions: For patients with mid-low locally advanced rectal cancer, the addition of PD1 inhibitors to neoadjuvant long-course chemoradiation, whether concurrently or sequentially, increases pCR rate, meanwhile raises no significant safety concerns. For the next step, phase 3 trials with larger sample sizes are encouraged. Clinical trial information: NCT05245474 .
A novel and uniquely designed bispecific antibody (LBL-024) against PD-L1 and 4-1BB in patients with advanced malignant tumors and neuroendocrine carcinoma: A report of safety and robust efficacy of LBL-024 monotherapy in phase I/II, first-in-human, open-label, multicenter, dose escalation/expansion study.
Authors: Lu Ming , Zhang Panpan , Luo Suxia , Chen Jie , Yang Jianwei , Song Zhengbo , Li Yongsheng , Tang Ying , Zhao Peng , Liu Baorui , Li Junhe , Hu Sheng , Zhang Zhiye , Wu Lin , Song Lijie , Feng Xielin , Shan Yunfeng , Liu Tao , Cai Shengli , Shen Lin
Published: June 2024

4010

Background: LBL-024 blocks the immunosuppressive pathway of tumor cells by targeting PD-L1 and effectively localizes 4-1BB co-stimulation to the tumor microenvironment, to improve the anti-tumor immune response. Here we report the safety and efficacy of LBL-024 in patients with advanced malignant tumors, particularly the robust clinical benefit in extrapulmonary neuroendocrine carcinoma (EP-NEC). Methods: Patient population: Phase Ⅰ, advanced malignant tumors exhausted standard cares and phase Ⅱ, EP-NEC failed at least one line of chemotherapy. Seven dose levels of LBL-024 were evaluated (0.2, 0.8, 3.2, 6, 10, 15 and 25 mg/kg, i.v. Q3W) and 15 mg/kg was selected for phase Ⅱ. The primary endpoints were tolerability, safety and efficacy (RECIST 1.1) and the second objectives were pharmacokinetics, pharmacodynamics, and other efficacy parameters. Results: By October 31, 2023, 162 patients were enrolled (64 in phase Ⅰ, and 98 in phase Ⅱ). Tumor types include EP-NEC (46, 28.4%), NSCLC (33, 20.4%), biliary tract cancer (31, 19.1%), and other tumors (52, 32.1%). During the dose escalation stage, no DLT was observed, and the MTD was not reached. The median follow-up was 4.2 months (95%CI: 3.9, 4.9). 126 out of 162 patients (77.8%) experienced TRAEs of all grades, with 34 (21.0%) having grade ≥3 TRAEs. The most common TRAEs (≥15%) included anemia (31.5%), AST increased (30.9%), ALT increased (25.3%), and white blood cell count decreased (22.2%). Out of 146 who underwent efficacy evaluation, the ORR and DCR were 15.1% and 46.6%, respectively. Robust efficacy signals were observed in 41 patients with EP-NEC (Table 1). 6 months of DoR will be available for report in ASCO. Conclusions: LBL-024 has showed good safety profile and very promising antitumor effects in patients with advanced malignant tumors, particularly EP-NEC patients who failed at least one line of chemotherapy. The efficacy observed in EP-NEC is significantly higher than the historic reports with immunotherapy (≤10%) and chemotherapy (about 18%). The extremely robust efficacy and good safety profile support a pivotal study for accelerated development of EP-NEC, the highly unmet medical needs and deadly disease. Clinical trial information: NCT05170958 . [Table: see text]
Use of artificial intelligence–based digital pathology to predict outcomes for immune checkpoint inhibitor therapy in advanced gastro-esophageal cancer.
Authors: Eweje Feyisope , Li Zhe , Gopaulchan Matthew , Attaranzadeh Armin , Kloker Leon , Jiang Yuming , Diehn Maximilian , Li Guoxin , Li Ruijiang
Published: June 2024

4013

Background: Accurate prediction of response and survival outcomes with anti-PD-1/PD-L1 immune checkpoint inhibition (ICI) remains a significant challenge in gastro-esophageal cancers. In this study, we use an artificial intelligence (AI)-based single-cell analysis of digitized whole-slide H&E images (WSIs) to predict objective response and survival benefit of ICI in two independent cohorts of gastro-esophageal cancer patients. Methods: WSIs were obtained from 82 ICI-treated advanced gastroesophageal cancer patients (gastric, esophageal, and gastro-esophageal junction adenocarcinoma and squamous cell carcinoma) at Stanford University for discovery, and 189 ICI-treated advanced gastric adenocarcinoma patients at Southern Medical University for external validation. Deep learning models were deployed for automated tumor area detection and segmentation of cell nuclei within WSIs. We developed a fully automated cell annotation approach by leveraging multiplex immunofluorescence and trained a deep learning model to classify nuclei into four cell types from H&E (tumor cells, lymphocytes, neutrophils, and macrophages). A total of 66 features were computed to quantify cell composition and cell-cell interactions within the tumor microenvironment. Treatment outcomes were assessed using progression-free survival (PFS) and best objective response per the Response Evaluation Criteria in Solid Tumors (v1.1), with statistical significance reported at the 95% confidence level. Results: In the training cohort, a spatial feature characterizing lymphocyte and neutrophil interaction had the strongest association with PFS (hazard ratio = 0.44, 95% CI 0.24-0.79, P = 0.0046). In the validation cohort, the spatial biomarker positive population had significantly improved PFS compared to the spatial biomarker negative population (hazard ratio = 0.41, 95% CI 0.27-0.61, P < 0.0001; median time to event: 19 months vs 9 months). For predicting objective response in the validation cohort, a multivariate model combining the spatial features achieved AUROC = 0.81 compared to AUROC = 0.65 for PD-L1 CPS (P = 0.0014), while combining the multivariate model with PD-L1 CPS achieved AUROC = 0.84. Conclusions: A single-cell computational pathology approachidentifies spatial biomarkers with predictive utility for determining ICI treatment outcomes in advanced gastro-esophageal cancer. Further validation of these findings is being pursued in additional cohorts.
First-line regorafenib with nivolumab and FOLFOX or CapeOX in patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: A single-arm, phase Ib/II trial (REGONIVOCTx, EPOC2104).
Authors: Kawazoe Akihito , Hashimoto Tadayoshi , Itahashi Kota , Irie Takuma , Ono Hiromi , Tamura Hitomi , Hongo Kyoko , Ikeno Takashi , Wakabayashi Masashi , Sato Akihiro , Nakamura Yoshiaki , Fujisawa Takao , Nakayama Izuma , Koyama Shohei , Yoshino Takayuki , Nishikawa Hiroyoshi , Shitara Kohei
Published: June 2024

4052

Background: We previously reported anti-tumor activity of regorafenib plus nivolumab for advanced gastric cancer (AGC) patients at a third or later line (1). Recently, first-line regorafenib with nivolumab and FOLFOX in AGC showed promising results in a phase 2 in the United States. CapeOX requires less frequent outpatient visits than FOLFOX and is preferred in Asian countries. We investigated the safety and efficacy of regorafenib with nivolumab and chemotherapy including CapeOX for AGC in the first-line treatment. Methods: Enrolled patients received regorafenib with nivolumab and CapeOX (Cohort A) or FOLFOX (Cohort B) in the phase Ib part (safety lead-in) to determine the recommended dose. Additional patients were enrolled in the phase II part. Regorafenib of 90 mg was administered once daily for 21 days on/7 days off with nivolumab 360 mg every 3 weeks (Cohort A) or 240 mg every 2 weeks (Cohort B) and chemotherapy. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks in the phase Ib part and objective response rate (threshold 60%, expected 80%, α = 0.1, β = 0.2) in patients with the recommended dose in the phase Ib/II part. The primary endpoint would be met if at least 22 of 30 patients showed objective tumor response. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 30 patients (14 in Cohort A and 16 in Cohort B) were enrolled from June 2022 to April 2023. All patients had MSS/pMMR tumors. No DLTs were observed in both cohorts. Objective tumor response was observed in 22 of 30 (73%; 80%CI 60.3-83.8) patients, thus the primary endpoint was achieved. Disease control rate was 97%. Six-month progression-free survival was 66.7% (95%CI 46.9-80.5). The most common grade 3 or worse treatment-related adverse events included neutropenia (33%), AST/ALT increased (13%), hypertension (13%), and leucopenia (7%) without unexpected safety signals. Conclusions: First-line regorafenib with nivolumab and chemotherapy including CapeOX showed anti-tumor activity with acceptable safety profiles in AGC patients. The results of biomarker analysis will be presented. A randomized, phase III trial is planned. 1. Fukuoka S, J Clin Oncol 2020. Clinical trial information: NCT05394740 .
FG-M108 plus nab-paclitaxel and gemcitabine (AG) as first-line (1L) treatment for patients with Claudin-18.2 (CLDN18.2) positive locally advanced unresectable or metastatic pancreatic cancer (PC): Preliminary results from the phase 1b study.
Authors: Jin Zhaoyu , Zhang Yanqiao , Liu Funan , Zhang Shu , Gong Jifang , Zhang Miao , Liang Xinjun , Wang Junye , Li Yun , Yang Xiaochun , Yang Yaping , Shen Lin
Published: June 2024

4142

Background: PC is one of the most lethal cancers with limited treatment options and poor outcomes. The CLDN18.2 antigen is frequently expressed in malignant gastrointestinal cancers including pancreatic cancer. FG-M108 is a human monoclonal antibody specifically targeting CLDN18.2 with optimal affinity and enhanced antibody-dependent cellular cytotoxicity. Methods: A multi-center phase 1b study of FG-M108 (NCT04894825) is ongoing, with one cohort evaluating the safety, tolerability, preliminary efficacy, pharmacokinetics, and immunogenicity of FG-M108 plus AG in patients with locally advanced unresectable or metastatic PC. Only patients with positive CLDN18.2 expression (IHC 1+/2+/3+≥10%) were eligible. This cohort of patients received FG-M108 (intravenous, 300 mg/m2 day 1) plus gemcitabine (intravenous, 1000 mg/m2, days 1 and 8) and nab-paclitaxel (intravenous, 125 mg/m2, days 1 and8) every 3 weeks until disease progression, unacceptable toxicity, or discontinuation. The primary safety endpoint was the incidence of adverse events (AEs) and the secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS). Responses were assessed by RECIST 1.1 every 6 weeks. AEs were graded using CTCAE v5.0. Results: As of January 15, 2024, 31 patients received 300 mg/m2 FG-M108 plus chemotherapy. The most common FG-M108 related AEs were nausea (43.5%), emesis (30.4%), neutropenia (21.7%), and anemia (21.7%). The most common grade ≥3 AEs of any cause were neutropenia (26.1%). FG-M108–related serious AEs occurred in 29.0% of patients. No FG-M108–related grade 4 or 5 AEs and no treatment-related deaths were reported. Median PFS and median OS have not been reached yet. Of the 14 patients who received tumor evaluation at least once, ORR was 50.0% (7/14) and DCR was 100% (14/14). Conclusions: FG-M108 plus AG showed excellent safety profile and promising clinical efficacy as 1L treatment for patients with CLDN18.2+ locally advanced unresectable or metastatic PC. The safety and efficacy, especially PFS and OS, of FG-M108 plus AG treatment will be further evaluated. Clinical trial information: NCT04894825 .
Association of gut microbe and stress-related cancer metastasis and oleic acid degradation.
Authors: He Zhen , Liu Chen , Lan Ping
Published: June 2024

e15517

Background: Cancer patients often face psychological distress. Cancer metastasis is critical for prognosis. Recent research highlights the link between chronic stress and metastasis. However, the underlying mechanisms is far from known. Methods: Animal models of cancer metastasis were used to explore the effect of chronic stress in promoting tumor metastasis. A combination of antibiotic cocktail treatment, fecal microbiota transplantation and germ-free mice were carried out to confirm whether the pro-metastatic ability of chronic stress was dependent on gut microbiota. 16S rDNA sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Additionally, we assessed hormone changes post-stress and demonstrated the correlation between glucocorticoid elevation and gut microbiota through in vivo and in vitro experiments. Finally, we validated our hypothesis using a prospective colorectal cancer cohort. Results: Mice undergone chronic stress had significantly increased cancer metastasis compared with stress-free control mice. Gut microbial dysbiosis was observed in mice undergone chronic stress, with Bifidobacterium being significantly depleted. Stress hormone, corticosterone could alter intestinal epithelium metabolism, and thus inhibit the growth of Bifidobacterium. Metabolomic analysis showed increased Oleic Acid (OA) in the colonic contents from chronic stress-treated mice, and the pro-metastatic role of OA were examined in vitro and in vivo experiments. Supplement of Bifidobacterium animalis (isolated from feces of the stress-free control mice) could decrease the level of OA and inhibit pro-metastasis effect of stress in mice. OhyA which encoded oleate hydratase was identified in Bifidobacterium animalis by whole genome sequencing. Heterogeneous expression of OhyA in Escherichia coli BL21 showed that supplement of OhyA could decrease the level of OA and abrogate the pro-metastatic effect of chronic stress. We found that glucocorticoid secretion increases during chronic stress, promoting the nuclear translocation of glucocorticoid receptors in epithelial cells and activating the transcription of downstream target genes. Through integrated metabolomic analysis, we demonstrated that glucocorticoids degrade guanine, reducing its concentration in the intestine and thereby inhibiting the growth of Bifidobacterium. Furthermore, our investigation into clinical cohorts revealed that patients with higher stress scores are more prone to tumor metastasis, accompanied by a decrease in the abundance of Bifidobacterium in the gut and an increase in serum and fecal oleic acid levels. Conclusions: Chronic phycological stress promotes cancer metastasis by inhibiting the growth of probiotic microbe Bifidobacterium through modulating epithelium purine metabolism and increasing the level of OA.
Rising trend of early-onset colorectal cancer in the US: Incidence and projections to 2030.
Authors: Pan Chun-Wei , Villaroman Adrian , Cuartas Maria Cristina , Gupta Shweta
Published: June 2024

e15523

Background: Colorectal cancer (CRC) remains a critical health issue in the United States, particularly notable for its rising incidence in individuals under 55 years. Factors such as lifestyle habits, and genetic predispositions may contribute to pathogenesis while inadequate screening protocols may lead to delayed diagnoses in this younger demographic. Currently, the initial CRC screening guidelines recommend lowering the start age to 45. We seek to provide current data on the US CRC incidence and estimate the burden by 2030. Methods: Using the CDC National Center of Health Statistics database, we queried the incidence rates of CRC from 1999 to 2020. These are reported in Crude rate and age-adjusted rates to standard year 2000 populations per 100,000 person-years. The Autoregressive Integrated Moving Average model was used to predict the projected incidence rate by 2030. R software version 2023.09 was used for analysis. Results: The study identified 3,201,843 CRC cases from 1999-2020, with a notable increase in incidence rates, especially in younger demographics. The largest increase was in the 30-34 age group, with an AAPC of 2.76, followed by the 25-29 and 35-39 age groups, with AAPCs of 2.57 and 2.24, respectively. In contrast, older age groups showed a decline, with the 75-79 age group decreasing from 9.20 to 3.76, and an AAPC of -4.05%. By 2030, early-onset colorectal cancer is expected to rise, particularly in the 40-44 age group (AAPC of 3.26%) and the 35-39 age group (AAPC of 2.92%). The increase is projected mainly in the 25-54 age groups. Conversely, older populations, particularly the 75-79 age group, are projected to see a decrease in incidence rates, from 3.76 to 1.17 per 100,000 by 2030. Conclusions: Our study highlights a significant rise in early-onset CRC, especially in the 25-54 age group, with an increasing projection by 2030 while older age groups are expected to experience a decrease in incidence rates. Consideration should be given to expanding CRC screening in patients younger than 45. [Table: see text]
Impact of delirium on outcomes among hospitalized patients with colorectal cancer: A United States population-based cohort study.
Authors: Arya Yajur , Syal Arshi , Casipit Carlo , Casipit Bruce Adrian , Ratnani Akshay , Leighton John Charles , Dourado Claudia M.
Published: June 2024

e15524

Background: Delirium is commonly encountered among hospitalized patients. It leads to cognitive and functional decline, resulting in longer recovery time. Patients with cancer, especially those undergoing surgery, are at higher risk for delirium and its adverse effects. Our study aims to explore the impact of delirium on hospitalized patients with colorectal cancer. Methods: We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with colorectal cancer and delirium using appropriate ICD-10 diagnostic codes. We stratified patients with colorectal cancer based on the presence or absence of delirium. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of < 0.05 was considered statistically significant. The aim of this study was to investigate the impact of delirium on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charge among hospitalized patients with colorectal cancer. Results: We identified a total of 77130 hospitalized patients with colorectal cancer, of which 1.91% (1475/77130) had concomitant delirium. The overall in-hospital mortality among patients with colorectal cancer was 2.74% (2115/77130). Among those with concomitant delirium, the mortality rate was significantly higher at 10.51% (155/1475, p < 0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, delirium was found to be an independent predictor of increased in-hospital mortality (adjusted OR 3.34; 95% (confidence interval [CI], 2.05-5.42; p < 0.001), longer LOS (coefficient 4.72; CI 3.26-6.18; p < 0.001), and higher total hospitalization charge (coefficient $36247; CI $22123- $50371; p < 0.001). Conclusions: Our analysis showed that delirium significantly worsens outcomes, including increased in-hospital mortality, LOS, and cost of healthcare utilization among hospitalized patients with colorectal cancer. Efforts should be made to prevent and proactively manage delirium in the inpatient setting, particularly with non-pharmacological techniques. Further prospective studies are needed to better describe these associations.
Efficacy and safety of fruquintinib across different subgroups of patients with previously treated metastatic colorectal cancer: A meta-analysis.
Authors: Leite da Silva Luis Felipe , Peixoto Renata D'Alpino , Zheng-Lin Binbin , de Menezes Junior Alonso , Batalini Felipe
Published: June 2024

e15589

Background: Most patients with mCRC eventually develop disease progression or intolerance to first- and second-line therapy. Fruquintinib, a selective oral tyrosine kinase inhibitor of VEGFRs 1, 2, and 3, has emerged as a novel treatment option for refractory mCRC. We conducted a meta-analysis to assess the safety and efficacy of Fruquintinib for the treatment of refractory mCRC compared to placebo in specific patient subgroups of interest. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) reporting Fruquintinib efficacy. The data extraction followed PRISMA guidelines and our protocol was registered in PROSPERO (CRD42023477783). Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. The likelihood of Fruquintinib being associated with adverse events (AEs) was expressed by odds ratios (ORs). Results: Of the 1138 studies yielded by the search, three were included, totaling 1178 patients, of whom 786 (67%) received Fruquintinib. This meta-analysis of three randomized trials assessed the clinical outcomes of Fruquintinib in the intervention group compared with placebo in refractory mCRC. Pooled results from all three studies suggested the superiority of Fruquintinib in PFS (HR: 0.29 [0.25, 0.34], 95% CI, I² = 10%, p < 0.01) and OS (HR: 0.66 [0.57, 0.76], 95% CI, p < 0.01). Notably, subgroup analysis showed that Fruquintinib was associated with improved PFS in patients with prior use of VEGF inhibitors (HR: 0.32 [0.27, 0.38], 95% CI, p < 0.01) and those with more than three prior lines of treatment (HR: 0.37 [0.25, 0.53], 95% CI, p < 0.01), RAS wild-type status (HR: 0.25 [0.13, 0.35], 95% CI, p < 0.01), or RAS mutated (HR: 0.33 [0.28, 0.40], 95% CI, p < 0.01). In the safety analysis, fruquintinib and placebo showed no significant differences in serious AEs; nonetheless, the VEGFR inhibitor was associated with more frequent grade ≥ 3 AEs (OR: 3.13 [1.15, 8.53], 95% CI, p = 0.03). Conclusions: This meta-analysis supports the efficacy of Fruquintinib for refractory mCRC regardless of previous use of VEGF inhibitors, the number of previous treatment lines, and gene RAS mutational status, without a significant increase in serious adverse events. [Table: see text]
The utility of multiple clinical variables in predicting survival outcome for patients with rectal cancer: An integrated regression and retrospective cohort analysis.
Authors: Zhong Jiasheng , Lei Fuming , Gao Qingkun , Shi Jingyi , Sun Zhuang , Huang Wensheng , Zhai Zhichao , Ding Changming , An Ke , Wang Shufang , Zhang Jialin
Published: June 2024

e15610

Background: Prior studies have investigated clinical factors impacting the survival rates of rectal cancer patients. However, a robust and precise model for discerning these risks, which can be identified by integrated regressions analysis has yet to be established. The aim of this study is to develop and evaluate the diagnostic value of the constructed prediction model based on selected clinical variables. Methods: Patients diagnosed with stage II-III rectal cancer (April 2015-June 2021) were retrospectively enrolled as the primary cohort. Individual variables were extracted and then subjected to a K-adaptive partitioning algorithm for cut-off point determination and grouping. The Cox and least absolute shrinkage and selection operator regression (LASSO) regression were applied for independent predictors selection over significant overall survival (OS), and a nomogram was subsequently constructed. The performance of the constructed model was evaluated using the receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis (DCA), and stepwise compared with data cohorts derived from TCGA and SEER databases. Results: The Cox-LASSO analysis results considered the four independent variables as significant predictors, yielding the risk score equation: 1.086(for CEA level≥7.5 ng/ml) -1.7756(if gender is male) +1.829*(pT stages) +0.582*(pN stages). Notably, the distal resection margin (DRM) was excluded from the final model following the analysis (p = 0.060, 95%CI: -0.04-2.17). The constructed model (C-index:0.790, 95%CI: 0.673-0.743, AUC:0.873) outperformed the conventional TNM staging models (C-index:0.539, 95%CI:0.121-0.957, AUC:0.735). It stratified patients into low- or high-risk groups with significant OS differences (93% vs. 37%, p≤0.0001, respectively). The calibration curves for OS probability showed strong homogeneities between predictions and actual observations. DCA revealed positive net benefits at evaluated first, third, and fifth years. Moreover, the external validations confirmed the accurate prediction following the constructed model, with AUC of 0.745 and 0.705 for the TCGA and SEER datasets, respectively. Conclusions: This study resulted in a novel and effective prediction model for rectal cancer patients based on conventional clinical characteristics. It demonstrated solid performance and can serve as a convenient tool for OS prediction, aiding in rectal cancer patients' risk scoring and clinical decision-making.
A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.
Authors: Sen Shiraj , Salkeni Mohamad Adham , Albany Costantine , Gandhi Neel Jitendra , Edenfield William Jeffery , Parsons Kellogg , Chen Isan , Powderly John D.
Published: June 2024

TPS3161

Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .
A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1.
Authors: Yamamoto Noboru , Doi Toshihiko , Patel Manish R. , Garrido-Laguna Ignacio , Wu Sutan , Nishioka Satoshi , Nakajima Keiko , Carneiro Benedito A.
Published: June 2024

TPS3165

Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (DXd). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Methods: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll up to 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid TA-MUC1-expressing tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS-3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Clinical trial information: NCT05875168 .
Timing of Intraoperative Transitions of Care Among Anesthesiologists Is Not Associated With Postoperative Adverse Outcomes: Retrospective Cohort Study
Authors: Mathur Piyush , Halvorson Sven , Cywinski Jacek B. , Machado Sandra , Khatib Reem , Kurz Andrea M. , Galway Ursula , Mascha Edward J.
Published: June 2024

BACKGROUND:

The majority of published research suggests that anesthesia handovers during major surgical procedures are associated with unintended harmful consequences. It is still unclear if the number or quality of the transition of care is the main driver of the adverse outcomes. There is even less data if the timing of the anesthesiologist handovers during the critical portion of the anesthetic continuum (induction or emergence versus surgical period) plays a role in patient outcomes. Therefore, we investigated if the anesthesiologist handovers during induction and emergence are associated with adverse patient outcomes.

METHODS:

This retrospective investigation included noncardiac surgical procedures occurring between January 1, 2012 and December 31, 2019 that had exactly 1 attending anesthesiologist handover. We categorized transitions of care between attending anesthesiologists as being before incision, between incision and closing, and after closing. Our primary outcome was a composite of 6 categories of surgical complications and in-hospital mortality. We created logistic generalized estimating equation models to estimate the average relative effect odds ratio between each pair of the 3 transition timing groups across the components of the composite outcome. Inverse probability of treatment weights were used to mitigate confounding on a host of baseline variables. We used Bonferroni correction to adjust for multiple comparisons between the transition groups.

RESULTS:

In total, we studied 36,937 procedures with exactly 1 attending anesthesiologist handover. Of these records, 4370 had the transition during induction, 24,999 between incision and closure, and 7568 during emergence. No differences were found between the transition periods and the composite outcome. The estimated average relative effect odds ratio (98.3% confidence interval [CI]) across the components of the composite outcome was as follows: (1.0002 [0.81–1.24], P = .99) between the induction and surgical period; (1.10 [0.87–1.40], P = .32) between the induction and emergence periods; and (0.91 [0.79–1.04], P = .08) between the emergence and surgical periods.

CONCLUSIONS:

Timing of intraoperative handover among attending anesthesiologists during noncardiac surgery is not associated with adverse patient outcomes.
Pediatric Intraoperative Electromyographic Responses at the Adductor Pollicis and Flexor Hallucis Brevis Muscles: A Prospective, Comparative Analysis
Authors: Tobias Joseph D. , Epstein Richard H. , Rice-Weimer Julie , Yemele Kitio Sibelle Aurelie , Brull Sorin J. , Kalsotra Sidhant
Published: June 2024

BACKGROUND:

Peripheral nerve stimulation with a train-of-four (TOF) pattern can be used intraoperatively to evaluate the depth of neuromuscular block and confirm recovery from neuromuscular blocking agents (NMBAs). Quantitative monitoring can be challenging in infants and children due to patient size, equipment technology, and limited access to monitoring sites. Although the adductor pollicis muscle is the preferred site of monitoring, the foot is an alternative when the hands are unavailable. However, there is little information on comparative evoked neuromuscular responses at those 2 sites.

METHODS:

Pediatric patients undergoing inpatient surgery requiring NMBA administration were studied after informed consent. Electromyographic (EMG) monitoring was performed simultaneously in each participant at the hand (ulnar nerve, adductor pollicis muscle) and the foot (posterior tibial nerve, flexor hallucis brevis muscle).

RESULTS:

Fifty patients with a mean age of 3.0 ± standard deviation (SD) 2.9 years were studied. The baseline first twitch amplitude (T1) of TOF at the foot (12.46 mV) was 4.47 mV higher than at the hand (P <.0001). The baseline TOF ratio (TOFR) before NMBA administration and the maximum TOFR after antagonism with sugammadex were not different at the 2 sites. The onset time until the T1 decreased to 10% or 5% of the baseline value (T1) was delayed by approximately 90 seconds (both P =.014) at the foot compared with the hand. The TOFR at the foot recovered (TOFR ≥0.9) 191 seconds later than when this threshold was achieved at the hand (P =.017). After antagonism, T1 did not return to its baseline value, a typical finding with EMG monitoring, but the fractional recovery (maximum T1 at recovery divided by the baseline T1) at the hand and foot was not different, 0.81 and 0.77, respectively (P =.68). The final TOFR achieved at recovery was approximately 100% and was not different between the 2 sites.

CONCLUSIONS:

Although this study in young children demonstrated the feasibility of TOF monitoring, interpretation of the depth of neuromuscular block needs to consider the delayed onset and the delayed recovery of TOFR at the foot compared to the hand. The delay in achieving these end points when monitoring the foot may impact the timing of tracheal intubation and assessment of adequate recovery of neuromuscular block to allow tracheal extubation (ie, TOFR ≥0.9).
Wittgenstein in the Moonlight
Authors: Kumar Eesha
Published: June 2024

Wittgenstein’s claims against private language and the existence of riddles have consolidated his reputation as a philosopher of the ordinary. This article makes a case for Wittgenstein as a thinker of enigma. His understudied remarks on riddles configure the ordinary and the transcendent in a novel and counterintuitive dynamic. This constitutes Wittgenstein’s most significant contribution to the study of the ordinary: a demarcation between language as the domain of the ordinary and mystery as the realm of meaning. The intricate interrelationship of these realms animates Wittgenstein’s abiding interest in the “limits” of knowledge and his pursuit of finely calibrated modes of analysis. The leitmotif of the riddle leads us through an exploration of Wittgenstein’s mottled oeuvre and serves as an occasion to ponder the question of “the question” in philosophy (as a matter of discursive form) as well as philosophy’s approach to “answers.” Acts of reading and interpretation, associated etymologically with “riddling,” are imbued with a special urgency in Wittgenstein’s thought, which this article brings to bear on recent debates on surface reading and close reading. To scholars of the ordinary, this article offers a critical reappraisal of Wittgenstein’s contribution, and to Wittgenstein scholars a (perhaps unfamiliar) moonlit Wittgenstein.
Dead Tired
Authors: Owen Ianna Hawkins
Published: June 2024

This essay concerns the descriptions of exhaustion connected to the suicidal thoughts and actions of Anyanwu, the protagonist of Octavia E. Butler’s novel Wild Seed (1980). Expanding the disability studies concept of desirelessness to graze Black diaspora studies, this essay resists the total absorption of enslaved Black women’s suicidal thoughts and actions into the collective political motivations of the living, even as it resists their banishment. Rather than speak authoritatively about an action ultimately undertaken alone, the essay feels for the ordinary edges of the limits of “diaspora” to consider more carefully those who are lost to the collective, those who turn away from it, and those for whom suicide cannot be categorized comfortably as only resistance or defeat. Or, plainly stated: Without purpose and without pity, we can still love you.