bluuebunny/crossref_metadata_2025 huggingface dataset:
Subthalamic deep brain stimulation in advanced Parkinson’s disease using the STarFix system
Authors: Elnaggar Amr , Elshanawany Ahmad , Elgheriany Ahmad Ebrahim , Ragab Mahmoud Hasan , Nouby Ahmad Radwan
Published: June 2024

Background

Deep brain stimulation (DBS) is a well-established and highly effective treatment for patients with medically uncontrolled Parkinson’s disease (PD). This study presents the outcome of patients with PD after subthalamic deep brain stimulation (STN DBS) using the microtargeting the platform (MTP) stereotactic system (the STarFixSystem, FHC Inc., Bowdoin, Me., USA) for accurate localization of the target and precise placement of DBs electrodes. Patients were evaluated preoperatively and the follow up period was 1 year utilizing the Unified Parkinson’s Disease Rating Scale (UPDRS II and III) in on and off medication-stimulation conditions. It included 18 STN DBS procedures in 10 patients over a 2-year period. The technical features and the practical application of the STarFix system and the clinical outcome are reported. Also lead location analysis is done by doing postoperative CT to evaluate the clinical accuracy of the stereotactic system.

Results

The mean age of PD patients was 67.7 years. Six patients were males (60%) and 4 patients were females (40%). The mean postoperative improvement in ADL was 83.47 ± 2.39 over Dopa therapy alone. The mean postoperative improvement in UPDRs motor score was 78.96 ± 7.74 over Dopa therapy alone. The STarFix system showed high accuracy with target error 1.89 mm (SD 0.8) without accounting for brain shift.

Conclusion

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) offers fundamental benefits for patients with advanced Parkinson’s disease (PD). The usage of the STarFix system for implanting DBS electrodes in the STN provides an accurate, safe, and effective alternative to traditional stereotactic techniques. This approach simplifies the surgical procedure, boosts patient comfort, and minimizes the duration of the operation.

Clinical trial registration ClinicalTrials.gov identifier: NCT03562403. Registered 19 June 2018, https://classic.clinicaltrials.gov/ct2/show/NCT03562403.
Lactobacillus alleviates intestinal epithelial barrier function through GPR43-mediated M2 macrophage polarization
Authors: Yao Yong , Zhang Yuhan , Song Mengzhen , Fan Jinping , Feng Shengkai , Li Jingjing , Wu Zhifeng , Zuo Bo , Tao Shiyu , Liu Xiangdong
Published: June 2024

Lactobacillus species have excellent abilities to reduce intestinal inflammation and enhance gut barrier function. This study elucidated the potential mechanisms through which Lactobacillus mitigates lipopolysaccharide (LPS)-induced intestinal injury from the perspective of macrophage–intestinal epithelial cell interactions. Lactobacillus intervention improved the histopathological score; elevated ZO-1 and Occludin protein production; reduced CD16+ cell numbers; diminished IL-1β, IL-6, and TNF-α levels; decreased inducible nitric oxide synthase (iNOS) expression; increased CD163+ cell numbers; elevated IL-10 concentration; and increased arginase-1 (Arg1) expression in LPS-challenged piglets. Lactobacillus pretreatment also altered the colonic microbiota, thereby increasing the butyric acid concentration and GPR43 expression in the LPS-challenged piglets. Compared with those in the LPS group, sodium butyrate (SB) pretreatment decreased IL-1β, IL-6 and TNF-α secretion and iNOS expression but increased IL-10 secretion and Arg1 expression in macrophages. The SB-pretreated macrophages reduced the protein expression of TLR4, MyD88, and phosphorylated NF-κB p65 but increased the protein expression of ZO-1 and Occludin in intestinal epithelial cells. Moreover, GLPG0974 blocked the beneficial effects of SB on macrophages and intestinal epithelial cells. This study demonstrated that Lactobacillus improves intestinal barrier function by regulating the macrophage phenotype through the control of butyric acid and GPR43 levels to further control inflammation.
Emotion in Teacher Learning and Professional Development
Authors: Gouvea Julia Svoboda
Published: June 2024

This installment of Current Insights features recent research that explores the challenging emotions that emerge for teachers in learning and professional development contexts.
Safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) with pre-existing neurologic autoimmune diseases (NAID) and Parkinson's disease.
Authors: Fletcher Kylie , Nassar Amin , Menzies Alexander M. , Long Georgina V. , Aboubakar Nana Frank , Malgeri Andrea , Cortellini Alessio , Shah Shailee , Hassel Jessica Cecile , Kim So Yeon , Naqash Abdul Rafeh , Challa Pavan , Johnson Douglas Buckner
Published: June 2024

2653

Background: Patients with pre-existing NAID often flare with ICIs; neurological (neuro) immune related adverse events (irAEs) are often morbid or fatal, and little is known about safety of ICI in pts with NAID and other neuro conditions (e.g. Parkinson’s). Thus, we aimed to determine their safety and efficacy in these contexts. Methods: We retrospectively analyzed 71 pts from 5 institutions receiving ICIs with NAIDs and Parkinson’s disease. NAIDs included multiple sclerosis (MS), myasthenia gravis (MG), inflammatory neuropathy, transverse myelitis, Lambert-Eaton, myotonic dystrophy, and multifocal motor neuropathy. We collected demographics, cancer outcomes, NAID characteristics, and safety outcomes. We used descriptive statistics to analyze treatment outcomes, NAID flares, and irAEs. Results: We collected 71 pts, 40 with NAID and 31 with Parkinson’s. 24 had melanoma, 12 non-small cell lung cancer (NSCLC), 3 small cell lung cancer (SCLC), 6 urothelial/bladder, 4 renal cell carcinoma, and 22 other; 60 had metastatic and 11 had localized disease. Median age at ICI start was 72 years (61% male, 39% female); 8 received combination ICI and 63 received monotherapy. Of 40 pts with NAID, 30% had either NAID flares or neurologic irAEs and 33% experienced other (non-neuro) irAEs (Table). Toxicities were particularly severe in MG; 70% (n=7) had MG flare/neuro irAE, 3 of which were fatal. In addition, 31 had Parkinson’s; of these, 12.9% (n=4) had Parkinson’s flares, 3% (n=1) had neuro-irAEs, and 42% (n=13) had other irAEs. One pt died of grade 5 myocarditis/myositis following combination ICI (Table). 5 MS patients responded to therapy (23%), but none were those with NAID flare/neuro irAE. Both MG patients who had non-neuro irAEs responded to treatment. Conclusions: In this cohort of ICI treated pts with prior neuro disorders, we demonstrated that MG pts have high rates of MG flare/neuro irAEs, hospitalizations, and fatalities, but low response rates. In contrast, other NAID (particularly MS) as well as Parkinson’s appeared to have modest risks of flares/neuro irAEs. Notably, Parkinson’s pts had high rates of non-neuro irAEs and response rates. [Table: see text]
The impact of proton-pump inhibitor use on the incidence and severity of gastrointestinal toxicity to checkpoint inhibition.
Authors: Wang Yinghong , Shatila Malek , Catinis Christine , Devalaraju Samanthika , Glombicki Stephen , Jeong-AH Lee Irene , Ngo Sean , Takigawa Kei , Lu Linfeng , Mittal Nitish , Baerman Elliot , Aleem Abdullah Sagar , Pizuorno Machado Antonio , Thomas Anusha
Published: June 2024

2657

Background: Checkpoint inhibitors (ICIs) for cancer come with the risk of immune-related adverse events (irAE). Upper and lower gastrointestinal (UGI and LGI, respectively) tract inflammation are common toxicities. Proton pump inhibitors (PPIs) are frequently used to treat immune-mediated UGI irAEs. Studies have suggested that these agents may worsen LGI irAEs. Our study aims to observe the effect of PPI use on the incidence and severity of GI irAEs. Methods: This was a single-center retrospective chart review including all patients who received ICIs. Patients were categorized based on PPI usage and screened for upper or lower GI toxicities. PPI use was counted if the medication was received at least three months before starting ICI and one year after the last ICI dose. Results: 16,849 patients were included. 2,114 (12.5%) patients received PPIs (PPI group – PG), while 14,735 (87.5%) did not (non-PPI group - NPG). 46 (2.2%) PG patients developed UGI irAE compared to 43 (0.3%) in the NPG (p<0.001), with no difference in severity or need for immunosuppression (p>0.05). PG patients were more likely to be hospitalized however (p=0.021). 115 (5.4%) PG patients developed an LGI irAE compared to 173 (1.2%) in the nPG (p<0.001). 80.7% of the PG presented with ≥grade 2 diarrhea and 52.0% with ≥grade 2 colitis, compared to 69.1% and 38.5% of the NPG, respectively (p<0.05). PG patients more frequently needed steroid treatment (60.0% vs. 42.2% in the NPG, p=0.004) and SIT (41.7% vs. 24.9%, p=0.003), and were less likely to have symptom resolution (78.5% in the PG vs. 89.6% in the NPG, p=0.020). A dose-dependent effect was observed. Every 10mg increase in PPI dose led to more frequent hospitalization for UGI irAEs (OR: 1.6, p=0.049) and more reliance on steroids (OR:1.3, p=0.044) and SIT (OR: 1.3, p=0.037) for LGI irAEs. This was also associated with less hospitalization and recurrence rates for LGI irAEs (p<0.05). Conclusions: Our study shows that PPI use during immunotherapy may increase the risk of developing a GI irAE. PPI use does not seem to impact the severity of upper GI irAEs aside from a higher hospitalization rate. However, PPI use may lead to a more severe disease course for lower GI toxicities. Prospective studies are needed to validate these results. [Table: see text]
Clinical validation of Northstar Select, a novel liquid biopsy assay for comprehensive genomic profiling of solid tumors.
Authors: Bower Xavier , Wignall Jan , Zhu Joyce , O'Sullivan Michael , Searle Naomi , Hong Lenny , Varga Matthew Gordon , Luong Jason , Lin Esther , Simon Marie Erica , Tsao David , ten Bosch John , Zhou Wen
Published: June 2024

3072

Background: Comprehensive Genomic Profiling (CGP) liquid biopsy tests are vital tools for oncologists that enable the non-invasive detection of diverse somatic mutations, many of which correspond to targeted therapies, in circulating tumor DNA (ctDNA). However, these tests have less utility when ctDNA signal is low, which is common even in late-stage cancer patients. BillionToOne’s Northstar (NS) Select assay is a novel CGP test that seeks to leverage proprietary technology and novel calling algorithms to address this limitation by achieving higher sensitivity. Methods: Clinical samples for 182 unique patients with stage III or IV solid tumors were obtained via a prospective validation study assessing head-to-head concordance with widely adopted, commercially available ‘comparator’ liquid biopsy CGP assays. The study cohort was recruited from 1 large hospital center and 6 community clinics across the US and was diverse in patient demographics and clinical presentations. Over 15 different cancer types were represented in the cohort, with the majority of patients having either Lung, Breast, Colorectal, or Prostate cancer, all of which are commonly tested using liquid biopsies in the US. Pathogenic (including likely pathogenic) variants called by NS Select and/or the comparator assay were analyzed for concordance. For a subset of samples (N=28), white blood cell-derived genomic DNA was also processed to identify which variants were detected due to clonal hematopoiesis of indeterminate potential (CHIP). Results: In the head-to-head comparison, a large number of variants (N=380) were concordant between the two assays. In addition, NS Select detected 43% (N=147) more pathogenic variants than comparators when controlling for matched coverage regions. The majority of these variants were detected below the reported limit of detection of the comparator assays, but above the limit of detection of NS Select. The rate of CHIP mutations was not significantly different in the variants detected by NS Select (19.0% ± 7.6%) vs. comparators (17.2% ± 9.2%). Finally, the proportion of patients with no pathogenic variants detected was shown to be lower by 45% when using NS Select vs. the comparator assays (20/182 vs. 36/182). Conclusions: NS Select reported clinically useful information about the tumor for most patients. For patients in which ctDNA signal was high, NS Select had very high concordance with comparator tests. Furthermore, additional low-VAF pathogenic mutations identified by NS Select translated to a higher diagnostic yield compared to other CGP assays, and CHIP was ruled out as an explanation for these additional detections. This suggests that some patients with low levels of ctDNA would derive clinical benefit from testing with NS Select due to its high sensitivity.
Identification of a patient tissue-based phosphorylation site as a biomarker for epidermal growth factor receptor (EGFR) activity in non-small cell lung cancer.
Authors: Raman Nithya , Flohr Alexander , Pohlmann Daniel , Woodsmith Jonathan , Juhl Hartmut
Published: June 2024

3143

Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally. EGFR tyrosine kinase inhibitors (TKIs) have shown promise in treating NSCLC, yet resistance to these agents is common and current biomarkers rely on genetic data alone. Therefore, identifying reliable biomarkers to more comprehensively monitor EGFR activity and predict therapeutic responses is paramount. Here, we report an uncharacterized threonine phosphorylation site within core regulator of the EGFR pathway SHP2, that is strongly predictive of EGFR activity as defined by genetic mutation status that shows potential as a clinically relevant biomarker. Methods: Using DIA mass spectrometry phosphoproteomics, we could quantify >20,000 phosphosites from patient normal adjacent tumor (NAT) and primary tumor tissue. We further characterized these tissues using whole genome sequencing allowing us to define the mutational status of the EGFR. Statistical analysis was undertaken across all phospho-sites that identified a single uncharacterized phospho-site as a strong predictor of EGFR kinase activity. Finally, we generated monoclonal antibodies against the phospho-peptide and tested these in patient FFPE primary tumor tissue using immunohistochemistry to correlate phosphorylation levels with EGFR activation status. Results: Our results highlight how an individual phosphosite on SHP2 closely correlates with EGFR activity as defined by genetic mutation status in patient tissue. Interestingly, we further identify a group of patients who carry wild type EGFR yet have a phospho-signal potentially indicative of high EGFR activation without genetic aberration. These results were corroborated by a phospho-site specific antibody in FFPE tissue IHC, with strong signals observed in patients with an activating EGFR mutation (n=5), and complete absence of signal in patients harboring a wild type EGFR and no detectable mass spec signal (n=5). Conclusions: Our findings suggest that this uncharacterised SHP2 phosphosite may serve as a potent biomarker for EGFR activity in NSCLC. Further validation of the monoclonal antibodies as tools for this clinically relevant biomarker is required in larger patient cohorts to elucidate the role of the phosphosite in therapy response. This novel biomarker has the potential to guide therapeutic decision-making and contribute to personalized medicine strategies for NSCLC patients.
Survival impact of KRAS mutation in metastatic colorectal cancer (mCCR) under first-line treatment.
Authors: Mathias Maria Cecilia , Lazar Neto Felippe , Gouveia Mariana Carvalho , Stangler Lucas , Claro Mateus Zapparoli , de Mello Evandro Sobroza , Sabbaga Jorge , Braghiroli Maria Ignez , Venchiarutti Moniz Camila M , Hoff Paulo Marcelo
Published: June 2024

3547

Background: Activating mutations in the MAPK pathway are predictive biomarkers in mCCR and 50% of patients (pts) present KRAS mutations. There is a large spectrum of molecular aberrations with a lack of data regarding tumor side correlations and their impact on treatment response and overall survival. Methods: Retrospective cohort of mCRC pts and KRAS activating mutations treated between 2019-2022 in a tertiary cancer center in Brazil. KRAS gene was analyzed by next-generation sequencing in tumor tissue samples. Electronic medical records were reviewed with case report forms registered in RedCap software. The primary endpoint was Overall survival (OS), estimated using Kaplan-Meir and compared with the log-rank test. Cox proportional models were applied to estimate hazard ratios (HR). Results: We included 490 patients with a mean age of 59 years (y), mostly male, 51.4%. Primary left-side location was present in 65.5% and liver metastasis in 66.7%. The spectrum of KRAS mutations found were G12D (31.2%), G12V (20.2%), G13D (15.1%), G12C (9.4%), G12A (4.9%), G12S (3.5%), and G12R (2%). First line regimen was 5-FU and Oxaliplatin (mFLOX) in 84.9% (n=388), with a median PFS of 9.2 months (95%CI 7.8 - 11.6) and OS of 21 months (95%CI;19-23) in this group. Treatment related outcomes in first-line therapy at first evaluation were 40% partial response, 20.4% stable disease, 30,9% disease progression and 1.3% complete response. G12S mutation was associated with better PFS 18.62 vs. 8.75m compared with other codon mutations (HR:0.52;95%CI 0.28-0.98) and OS NR vs. 21.58m HR (HR:0.48;95%CI;0.24-0.97). G12R was associated with worse PFS 5.31 vs. 9.90 m (HR:2.2;95%CI;1.09-4.47) and OS 17.89 vs. 21.88m (HR:1.61;0.79-3.24). Sideness was not associated with prolonged response or overall survival right-sided tumors 20.72 vs. vs. left-sided tumors 22.14m (HR:1.04;95%CI;0.82-1.31). Conclusions: Specific mutated codons in the KRAS gene impact PFS and OS independently of primary tumor sidedness. G12S mutation demonstrated an improved OS and PFS. [Table: see text]
Exploratory biomarker analysis for predicting treatment effects of aflibercept in the VELOUR trial.
Authors: Pu Ting , Peddle Allyson , Wirapati Pratyaksha , Hong Yourae , Samuel Leslie , Desai Jayesh , Riener Maigo , Saridaki Zacharenia (Zenia) , Cunningham David , Tejpar Sabine , Tsantoulis Petros
Published: June 2024

3592

Background: Second-line treatment with aflibercept and FOLFIRI in patients with metastatic colorectal carcinoma (mCRC) previously treated with oxaliplatin improved overall survival (OS) versus placebo [Hazard ratio (HR), 0.81; 95% CI, 0.71–0.93; P=0.003]1. However, colorectal cancer (CRC) is a heterogenous disease and the new intrinsic consensus molecular (iCMS) allows for tumours to be subtyped into unique genetic and transcriptional features2. We present a post hoc analysis of VELOUR patient data, to assess the impact of KRAS or BRAF mutation status and iCMS on efficacy parameters. Methods: Patient samples were classified as either KRAS or BRAF mutant or wild-type (WT) via a targeted mutation panel1. Gene expression data was used to classify samples as either iCMS2 or iCMS3 using a modified classifier based on iCMS signatures which are specifically up-regulated in tumour samples2. Results: Of the 439 patients with available RNA data, 54.9% (241/439) were classified as iCMS2; 45.1% (198/439) as iCMS3; 48.3% (212/439) as RAS mutant and 8.4% (37/439) as RAF mutant. A favourable aflibercept treatment effect was observed for patients within the KRAS WT group (Median OS from 11 to 17.7 months; HR 0.87; 95% CI 0.79-0.96, P=0.005), particularly for patients with KRAS WT iCMS2 tumours (Median OS from 15.5 to 30.4 months; HR 0.81; 95% CI 0.70-0.94, P=0.004). This is in comparison to the KRAS WT iCMS3 patients where no treatment benefit was seen (HR 0.97; 95% CI 0.82-1.14, P=0.683). In addition, no treatment benefit was seen in the KRAS mutant group (OS HR 1.03; 95% CI 0.96-1.12, P=0.405). Progression-free survival (PFS) data followed the same trend. Aflibercept seemed to also strongly benefit the 37 patients with BRAF-mutated tumours, (PFS HR 0.46, 95% CI 0.20-1.09; OS HR 0.65, 95% CI 0.29-1.48), although differences were not statistically significant. Irrespective of treatment, improved OS (HR 0.60; 95% CI 0.48-0.75, P< 0.001) and PFS (HR 0.75; 95% CI 0.60-0.94, P=0.011) were observed in all patients with iCMS2 versus iCMS3 tumours, as expected. Treatment-by-mutation status interaction tests (OS P=0.40, PFS P=0.33) indicated that the aflibercept benefit was not statistically different among the mutation sub-groups, although the small sample size limited the analysis. Conclusions: In the VELOUR study, the benefit of the addition of aflibercept to FOLFIRI appears to be primarily in patients with KRAS WT tumours, especially those with KRAS WT iCMS2. The improved OS and PFS seen in all patients with iCMS2 tumours in comparison to iCMS3 is prognostic but not predictive of aflibercept treatment response in addition to FOLFIRI. On the contrary, the addition of aflibercept to FOLFIRI provided a numerical benefit in BRAF-mutated tumours, however the P-values were not statistically significant.
Association of circulating DNA with recurrence in CRS-HIPEC patients with colorectal and appendiceal peritoneal carcinomatosis: Insights from a phase II randomized trial.
Authors: Kasi Anup , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Sun Weijing , Baranda Joaquina Celebre , Li Haoran , Wick Jo , Mullangi Sanjana , Eberhardt Kenda , Bradbury Shannon , Romero Rebecca , Carroll Erin , Barbosa Lori , Al-Kasspooles Mazin Francis
Published: June 2024

3598

Background: There is a need for biomarkers to guide patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in cases of peritoneal carcinomatosis from colorectal and appendiceal cancer. SigNatera is a blood-based quantitative test to detect colorectal cancer recurrence by indicating the presence of at least two altered colorectal cancer-associated genes in Circulating tumor DNA (ctDNA). We performed a correlative study to help determine if using SigNatera ctDNA would be a predictive and prognostic biomarker of recurrent cancer in patients who underwent CRS-HIPEC on a Phase II Randomized Trial Comparing Morbidity and Mortality of CRS-HIPEC using Mitomycin-C versus Melphalan for Colorectal and Appendiceal Peritoneal Carcinomatosis. Methods: 30 patients on the phase II trial had the option for consenting for the ctDNA correlative study utilizing SigNatera sponsored by Natera. Pre-op samples were collected prior to CRS-HIPEC on Day 0 and post-op samples ~2 weeks post-hospital discharge, followed by every 3 months x 2 years. The exploratory objective of the prognostic impact of ctDNA is evaluated by correlating pre-op ctDNA status and Disease-Free Survival (DFS) Results: All 30 pts that underwent ctDNA testing were treated with neoadjuvant chemotherapy prior to CRS-HIPEC. Pre-op ctDNA was negative in 20 pts (8 recurrences, median DFS = 15.9 months) and positive in 10 pts (7 recurrences, median DFS = 39.9 months), p =0.19. Of the 20 pre-op ctDNA(-) pts, 18 remained ctDNA(-) in post-op (12 recurrences, median DFS = 15.6 months) and 2 turned ctDNA(+) (0 recurrences). Of the 10 pre-op ctDNA(+) pts, 2 remained ctDNA(+) post-op (1 recurrence, median DFS = 9.5 months) and 8 turned ctDNA(-) (2 recurrences, median DFS = 39.9 months), p=0.1. Conclusions: The unexpected numerically favorable DFS in the pre-op ctDNA(+) group, in comparison to the pre-op ctDNA(-) group, challenges the utility of preop ctDNA status in guiding CRS + HIPEC decision-making. Though limited by small sample size, this finding may be likely due to the impact of post-op therapy which notably converted 10 preop ctDNA(+) pts to post-op ctDNA(-) status. Our findings warrant validation in a larger study to unravel the multifaceted factors influencing ctDNA’s prognostic value. Clinical trial information: NCT03073694 . [Table: see text]
Individualized tumor-informed circulating tumor DNA analysis for molecular residual disease detection in predicting recurrence and efficacy of adjuvant chemotherapy in colorectal cancer.
Authors: Cao Di , Zhou Qiaoxia , Fan Xuning , Yang Jinyu , Li Cong , Wang Fulong , Zhang Rongxin , Wu Xiaojun , Li Liren , Lu Zhenhai , Pan Zhizhong , Lin Junzhong , Wu Miaoqing , Liu Yifan , Lv Guangzhao , Qiu Fujun , Xin Haoyang , Xu Yu , Wang Guoqiang , Chen Gong
Published: June 2024

3615

Background: Molecular residual disease (MRD) using circulating tumor DNA (ctDNA) may identify recurrent risk and guide adjuvant chemotherapy (ACT) in colorectal cancer (CRC). This study explored the feasibility of a tumor-informed personalized approach to predict recurrence, comparing with tumor-informed (TI) and tumor naïve (TN) fixed panel approaches. Methods: Patients with stage I-IV CRC eligible for R0 resection were recruited. Blood samples were collected preoperatively, at postoperative day 7 and 30 (POD7/30), and every 3-6 months thereafter, which were tested by brPROPHET assay, using up to 50 highly ranked variants identified by whole-exome sequencing of surgical tissue samples. A fixed 168-gene panel was applied for TI and TN fixed panel tests. Results: A total of 214 patients were enrolled. With a median follow-up of 13.2 months, 20 (9.3%) participants relapsed. The brPROPHET assay had a positivity rate of 96% in preoperative samples. ctDNA positivity indicated by brPROPHET predicted worse recurrence-free survival (RFS) at both POD7 (hazard ratio [HR]=7.35, 95% confidence interval [95% CI], 3.04-17.78, P<0.001) and POD30 (HR=5.18, 95% CI, 2.00-13.38, P<0.001). Higher mean tumor molecules (MTM) level >0.0316/mL was observed in surveillance of 15 relapsed patients, which was associated with worse RFS (HR=44.47, 95% CI, 12.83-154.12, P<0.001). In ctDNA positive patients at POD7, patients benefit from ACT (HR=0.23, 95% CI, 0.05-1.00, P=0.03), which was not observed in ctDNA negative patients (HR=1.80, 95% CI, 0.48-6.81, P=0.38). Among the patients with results of all three approaches (n=168), the brPROPHET assay outperformed TI and TN fixed-panel assays in predicting RFS at POD7 (HR, 7.52 vs 3.43 and 5.60). Of note, the brPROPHET assay identified 6 additional relapsed patients beyond the fixed panels, with more than 87.5% of the positive sites derived from personalized designs. Conclusions: The individualized tumor-informed brPROPHET assay effectively identified postoperative patients with high risk of recurrence and benefit from ACT. Using a personalized tumor-informed panel that covers sites outside fixed panels may improve the utility of MRD detection. [Table: see text]
NRG Oncology/RTOG 0848: Results after adjuvant chemotherapy +/- chemoradiation for patients with resected periampullary pancreatic adenocarcinoma (PA).
Authors: Abrams Ross A. , Winter Kathryn A. , Goodman Karyn A. , Regine William , Safran Howard , Berger Adam C. , Guha Chandan , Kachnic Lisa A. , Gillin Michael , Seaward Samantha A. , Wu Abraham Jing-Ching , Wu Jennifer J. , Aljumaily Raid , DiPetrillo Thomas A. , Geva Ravit , Anne Pramila R. , Yannucci Jennifer , Liles Darla K. , Moughan Jennifer , Crane Christopher H.
Published: June 2024

4005

Background: If 5FU/Capecitabine sensitized radiotherapy (RT) is beneficial in the adjuvant (adj) management of PA after adj chemotherapy (chemo) is controversial. NRG/RTOG 0848 was designed to address this issue. Methods: This was a 2 step NCTN randomized (rndmzd) trial. Step 1 rndmzd patients (pts) to 5 cycles of gemcitabine +/- Erlotinib. Step 2 rndmzd pts to a 6th cycle of the same chemo +/- 5FU/Capecitabine with 50.4 Gy in 28 fractions RT (chemo+CRT). Step 1 eligibility included: R0/R1 resection, M0, ECOG PS 0-1, CA19-9≤180. Step 2 eligibility included > 4 cycles chemo (gem, gem combo, (m)FOLFIRINOX). RT included real time 3D/IMRT treatment (RX) plan review, scoring, and approval. At Step 2, pts stratified by nodal status (+ vs -), CA19-9 (≤90 vs > 90-180), surgical margins (R0 vs R1), and adjuvant chemo. Primary endpoint was OS. Secondary endpoints are DFS and AEs (CTCAEv4). Assuming 17 months median OS (chemo) and hypothesized 22.5 months (chemo+CRT), sample size was 354 pts (HR = 0.76, 80% power, 1-sided α = 0.05, 316 OS events). Due to lower than projected event rate, trial was amended to report at the earlier of (a) 316 observed OS events or (b) 5 years of follow-up time from Step 2 accrual closure (265 OS events, 72% power, same α). OS and DFS were estimated by Kaplan-Meier and arms compared using log-rank test. Multivariable analyses (MVA) used Cox proportional hazards models. Results: Accrual began 11/2009; closed 10/2018. 354 pts rndmzd (174 chemo, 180 chemo+CRT). Median follow-up for all & alive pts = 2 & 7 years, respectively, with 270 OS events. Median age 63, 45% female, 81% white, 13% AA. 83% R0, 26% node negative, 96% CA19-9 < 90. 13% of chemo+CRT pts did not receive RT. AEs were comparable (grade 4: 10% [chemo] vs 11% [chemo+CRT] and 1 grade 5 AE in each arm). Univariate OS/DFS results shown in Table. In initial MVA, RX, CA19-9, surgical margins were not statistically significantly associated with OS or DFS, but nodal status (OS, DFS) and race (OS) were. In further analyses, significant interactions were found between RX and nodal status for both OS and DFS. Node negative pts treated with chemo+CRT had better outcome than chemo pts; node positive pts did not (Table). Conclusions: Chemo+CRT did not improve OS overall, but did improve DFS. Both OS and DFS were improved with Chemo+CRT in node negative pts. Chemo+CRT did not increase Gr 4 or 5 AEs compared to chemo. Clinical trial information: NCT01013649 . [Table: see text]
FGF19-FGFR4 axis as the inaugural target for determining the efficacy of advanced esophageal cancer treatment.
Authors: Wang Wei , Lin Shuimiao , Zeng Qin , Li Wenjie , Liu Tongxin , Zhou Xiaomei , Wang Rong , Luo Ziyi , Wu Dehua
Published: June 2024

4035

Background: Advanced esophageal cancer (EC) remains a fatal stage with limited survival benefits from current treatments due to lack of specific targets. Esophageal squamous cell carcinoma (ESCC) is the most common type observed in EC cases. Studies have shown that around 40% of ESCC cases exhibit amplification of chromosome 11q13, which includes genes like FGF19, FGF3, FGF4, and CCND1. Among these, FGF19 and its receptor FGFR4 play crucial roles in cancer progression. Blocking the FGF19-FGFR4 axis could potentially disrupt tumor progression. Anlotinib, a multi-targeting tyrosine kinase inhibitor, targets VEGFR2, PDGFR, and FGFR1-4. In this study, we analyzed the next-generation sequencing (NGS) data from our cohort of advanced EC patients to identify potential therapeutic targets based on their genetic mutations. We also investigated whether FGF19 amplifications could enhance sensitivity to anlotinib-based treatments. Methods: The study was conducted as a retrospective analysis at our institution from October 2017 to August 2021. To be included in the study, patients had to be between 18 and 75 years old, have confirmed metastatic and/or recurrent EC with measurable lesions, and have detailed clinical information without any other primary tumors. We used NGS to analyze the mutation landscape in advanced EC patients. Additionally, we investigated the therapeutic effects of blocking the FGF19-FGFR4 axis by retrospectively analyzing the outcomes of advanced EC patients who received anlotinib-based treatments, which target the FGFR family. We compared overall survival (OS), progression-free survival (PFS), and best response between advanced EC patients with and without FGF19 amplifications who received anlotinib-based treatments. Results: A total of 50 patients with advanced EC (47 with squamous carcinoma and 3 with adenocarcinoma) underwent NGS testing. FGF19 amplifications were the third most common mutation, occurring in 46% of patients, following TP53 (88%) and CCND1 (48%). Among the 26 patients receiving anlotinib-based treatment, 13 (50%) had FGF19 amplifications. Patients with FGF19 amplifications had a 69.2% objective response rate (ORR) and a 100% disease control rate (DCR). None of the 13 patients with FGF19 amplifications developed progressive disease (PD). Patients with FGF19 amplifications showed significant improvements in ORR (69.2% vs. 12.5%, p=0.011) and median PFS (5.3 vs. 2.7 months, HR=0.10, 95%CI: 0.02-0.56, p=0.0015) compared to those without FGF19 amplifications. Improvements in DCR (100% vs. 75%, p=0.06) and median OS (8.7 vs. 7.2 months, HR=0.44, 95CI%: 0.12-1.59, p=0.2) were also observed, albeit not statistically significant. Conclusions: Anlotinib-based therapy showed improved clinical outcomes in patients with FGF19 amplifications. This suggests that targeting FGF19 amplifications could be a promising approach for treating advanced ESCC.
Perioperative chemotherapy for patients with gastric cancer with microsatellite instability or deficient mismatch repair: A systematic review and meta-analysis.
Authors: Liu Baike , Cai Zhaolun , Yin Yuan , Wang Jingjing , Shen Chaoyong , Yin Xiaonan , Jiang Tianxiang , Han Yihui , Zhang Bo
Published: June 2024

4039

Background: Currently, the efficacy of perioperative chemotherapy for gastric cancer (GC) patients with deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) remains controversial. It is still inconclusive whether chemotherapy can be spared for dMMR/MSI-H GC patients. Meanwhile, in the different therapeutic settings (e.g. neoadjuvant, adjuvant, or both), the efficacy of chemotherapy remains to be clarified. Therefore, a systematic review and meta-analysis in this regard was conducted. Methods: Studies comparing perioperative chemotherapy with surgery alone in resectable dMMR/MSI-H GCs (up to December 1, 2023) were included. The hazard ratio (HR) and its 95% confidence interval (CI) of survival outcomes were extracted from the original research or recalculated using Kaplan-Meier curves if the number of patients at risk was provided. In the pooled analysis, a random-effects model was employed. Subgroup analyses (perioperative chemotherapy in stage II and stage III diseases) and sensitivity analysis including studies reporting the results from multivariable analyses were conducted. This study was previously registered on PROSPERO platform (CRD42023494276). Results: Nineteen studies, encompassing over 1500 dMMR/MSI-H GC patients, were included in this study. The results revealed that perioperative chemotherapy (including neoadjuvant and adjuvant chemotherapy) did not significantly improve the overall survival (OS) (HR 0.86, 95% CI 0.57–1.31) and disease-free survival (DFS) (HR 0.70, 95% CI 0.46–1.05) in dMMR/MSI-H GCs. Furthermore, adjuvant chemotherapy did not confer a significant survival advantage for dMMR/MSI-H GCs (OS, HR 0.83, 95% CI 0.50–1.37) and (DFS, HR 0.67, 95% CI 0.41–1.07). Similar results were observed for neoadjuvant chemotherapy (OS, HR 1.09, 95% CI 0.55–2.15). In addition, stage stratification analysis demonstrated no significant survival benefit of adjuvant chemotherapy for stage II (OS, HR 0.77, 95% CI 0.31–1.90) or stage III (OS, HR 0.72, 95% CI 0.36–1.46) dMMR/MSI-H GCs. In the sensitivity analysis, the results remained consistent. Conclusions: Perioperative (including adjuvant and/or neoadjuvant) chemotherapy does not significantly improve survival in resectable dMMR/MSI-H GC patients. Immunotherapy may be better suitable for these patients in the future.
Effect of phosphoproteomic subtyping of gastric cancer on chemotherapy and guidance of targeted cancer therapy.
Authors: Shoji Hirokazu , Hirano Hidekazu , Nojima Yosui , Gunji Daigo , Shinkura Akina , Muraoka Satoshi , Abe Yuichi , Narumi Ryohei , Nagao Chioko , Aoki Masahiko , Obama Kazutaka , Honda Kazufumi , Mizuguchi Kenji , Tomonaga Takeshi , Yoshikawa Takaki , Kato Ken , Boku Narikazu , Adachi JUN
Published: June 2024

4050

Background: Gastric cancer is the fifth most common malignancy and the fourth leading cause of death from malignant neoplasms worldwide, and advanced unresectable or recurrent advanced gastric cancer (AGC) has a poor prognosis, so further therapeutic development is needed. However, only a few molecular targeted agents are effective for AGC, and precision medicine using genomic profiling has limited scalability due to the low rate of alterations matched to single pharmacotherapy and complex networks of signal transduction activated by multiple oncogenic proteins. Thus, it is imperative to establish a new concept of precision medicine adapt to the dynamic changes in cancer. Methods: We collected endoscopic biopsy specimens from 84 chemo-naïve gastric cancer patients. We also serially collected endoscopic biopsy specimens from 9 AGC patients receiving 2nd line therapy (pre-treatment: 9 patients, post-treatment [2 months later]: 6 patients, and end of treatment: 2 patients). Each specimen was immediately snap frozen in liquid nitrogen within 20 s after collection. Ultra deep proteome and phosphoproteome analysis were performed by multiplex analysis using TMT reagent. Genomic analysis was performed by using a targeted high-multiplex PCR-based NGS panel. Results: Ultrasensitive mass spectrometry-based proteomics using 84 chemo-naïve gastric cancer specimens quantified an average of 21000 phosphorylation sites and clearly divided gastric cancer into subtype 1 (proliferative type, 35%), subtype 2 (EMT type, 15%), and subtype 3. (OxPhos type, 50%). The association between these subtypes with TCGA subtypes was low. Subsequent analysis using serially collected gastric cancer specimens from 9 patients unveiled the dynamic transitions within cancer tissues, along with the concomitant rewiring of the kinome network, ultimately resulting in the acquisition of the EMT subtype throughout the course of treatment. We investigated elaborate intracellular signaling related to EMT in gastric cancer and validate therapeutic approaches targeting AXL in vitro and in vivo. Conclusions: Our proof-of-concept of phosphoproteome analysis of fresh-frozen endoscopic biopsy specimens is capable of not only defining cancer subtyping but also capturing dynamic cancer signaling changes in response to therapy. In particular, serial biopsy analysis can track the cancer evolution which is expected to provide resources for the development of new treatments and biomarkers for AGC adaptively in the future.
A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastric cancer: Efficacy and safety analysis (BOLD-100-001).
Authors: Spratlin Jennifer , Rha Sun Young , O'Kane Grainne M. , Oh Do-Youn , Elimova Elena , Goodwin Rachel Anne , Kim Seung Tae , Koo Dong-Hoe , McAllister E. Russell , Jones Michelle , Snow Malcolm , Lemmerick Yasmin , Spera Gonzalo , Pankovich Jim
Published: June 2024

4059

Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies, particularly in treatment resistant cell lines. Methods: This is a prospective, Phase 2 study. Advanced gastric cancer (GC) patients received BOLD-100 (625 mg/m2) with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate progression free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR) of BOLD-100+FOLFOX. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 21 pts with advanced gastric cancer, median age 61 years [range 35, 84] were treated. All patients had stage IV disease and ECOG ≤ 1. Patients had a median of 4 prior systemic therapies [0, 7], 1 with no prior therapy, 2 had 2 prior therapies, 5 with 3 prior therapies, and 13 patients with 4 or more prior therapies. 20/21 patients received prior platinum with 18/21 receiving prior FOLFOX/CAPOX. While on study, pts received a median of 6 cycles BOLD-100 + FOLFOX [range 1-27]. Median PFS and OS was 4.3 [95% credible interval (CI) 2.8, 7.1] months and 7.9 [CI 4.8, 15] months, respectively. ORR was 11% [CI 2, 31] and DCR was 72% [49, 89] in the 18 evaluable patients. Two pts achieved a partial response, 4 pts had target tumor reductions, and 11 pts had stable disease. Treatment was well tolerated. 19 pts had ≥1 treatment-related adverse events (AEs), most commonly neutrophil count decreased (n = 7, 33%), nausea (n = 6, 29%), and peripheral sensory neuropathy (n = 4, 19%). Most AEs were grade (G) 1-2. 7 patients (33%) had G3/4 neutrophil count decreased. Conclusions: BOLD-100 plus FOLFOX is an active, well-tolerated treatment regimen in the heavily pre-treated advanced GC. The reported mPFS, mOS, ORR and DCR data in this analysis shows promising clinical activity. The combination of BOLD-100 with FOLFOX is worthy of further study. Clinical trial information: NCT04421820 .
Conversion surgery for tislelizumab combined chemotherapy for T4a/N3 esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.
Authors: Zhang Chen , Shang Xiaobin , Yue Jie , Chen Chuangui , Duan Xiaofeng , Ma Zhao , Chen Zuoyu , Wang Shangren , Zhao Gang , Liu Liang , Zhang Weihong , Li Runmei , Xiong Yanjuan , Yang Fan , Xiao Jianyu , Cao Fuliang , Guo Feng , Zhou Dejun , Ren Xiubao , Jiang Hongjing
Published: June 2024

4069

Background: T4a/N3 ESCC is treated with neoadjuvant concurrent chemoradiotherapy plus surgery or radical chemoradiotherapy according to NCCN guidelines. This study aimed to evaluate the safety and efficacy of conversion therapy of Tislelizumab combined with chemotherapy in patients with T4a/N3 ESCC. Methods: This is a prospective, single-arm, single-center clinical trial. A total of 40 patients with newly diagnosed ESCC (cT4a/N3) received 2-4 cycles of paclitaxel (135 mg/m2) on day 1, and cisplatin (80 mg/m2) on day 1, Tislelizumab (200 mg) on day 2, every 3 weeks. After an efficacy evaluation, the patients will undergo radical esophagectomy resection within 4-6 weeks after conversion therapy. The primary endpoints are the safety and the R0 resection rate. The secondary endpoints include the objective response rate (ORR), a postoperative pathological complete response (pCR), major pathological response (MPR), overall survival (OS), disease-free survival (DFS). Exploratory endpoint is to examine immune biomarker of the efficacy of conversion therapy for ESCC. Results: 40 patients were enrolled, the ORR was 95%(38/40), and 60% (24/40) patients who completed conversion treatment underwent esophagectomy. R0 resection rate was 100% (24/24) with no reoperations or perioperative deaths. 70% (28/40) patients experienced at least one treatment-related adverse event (TRAE) and 12.5% (5/40) patients reported grade 3 and above TRAEs. For these surgical patients, the MPR and pCR rates were 33% (8/24) and 20.8% (5/24) respectively. Flow cytometry showed that the percentage of CD3+CD4+CD8-T cells was significantly increased in peripheral blood after conversion therapy (p-value 0.02). Conclusions: Tislelizumab combined with chemotherapy, followed by radical esophagectomy resection has promising efficacy and good safety for T4a/N3 ESCC. Clinical trial information: NCT05449483 .
Survival outcomes with adjuvant immunotherapy after hepatic resection in patients with intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma: Insights from a propensity-matched multicenter study.
Authors: Yang Tian , Wang Ming-Da , Xu Xiao , Xu Jia-Hao , Fan Zhong-Qi , Diao Yong-Kang , Chen Zhong , Jia Hang-Dong , Liu Fu-Bao , Zeng Yong-Yi , Wang Xian-Ming , Li Chao , Pawlik Timothy M. , Lau Wan Yee , Shen Feng , Lv Guo-Yue
Published: June 2024

4096

Background: With the growing interest in adjuvant immunotherapy for reducing recurrence and improving prognosis after hepatic resection in hepatocellular carcinoma (HCC), particularly in high-risk patients, this study aims to evaluate the impact of adjuvant immunotherapy on long-term recurrence and survival in patients with intermediate/advanced HCC. Methods: A prospective multicenter database was utilized to identify patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Propensity score matching (PSM) was employed to equate recurrence-free survival (RFS) and overall survival (OS) between patients receiving adjuvant immune checkpoint inhibitors (ICIs) and those who did not. Multivariate Cox-regression analysis was used to identify independent predictors of RFS and OS. Results: Out of 627 patients, 109 (23.3%) received adjuvant immunotherapy, with most ICI-related adverse reactions being grade I-II. The ICI agents used among these 109 patients were tislelizumab (51.4%, n=56), sintilimab (29.3%, n=32), camrelizumab (9.2%, n=10), pembrolizumab (6.4%, n=7), and toripalimab (3.7%, n=4). All patients receiving adjuvant immunotherapy completed at least 3 months of ICI treatment, with no patients discontinuing the treatment due to irAEs. PSM resulted in 99 matched pairs with comparable baseline characteristics. In this cohort, patients receiving adjuvant immunotherapy showed significantly improved median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) compared to those who did not. Multivariable analyses confirmed adjuvant immunotherapy as an independent factor for better RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyses suggested prognostic benefits of adjuvant immunotherapy in both intermediate and advanced-stage HCC. Conclusions: This real-world observational study indicates that adjuvant immunotherapy is associated with improved RFS and OS in patients undergoing curative-intent resection for intermediate/advanced HCC. These findings support the need for future randomized controlled trials to establish definitive evidence for this high-risk population.