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Prognostic analysis of pathological complete response after neoadjuvant therapy for locally advanced gastric cancer: A national, multicenter, retrospective study.
346 Background: Several research findings indicate that some patients with locally advanced gastric cancer (LAGC) who undergo neoadjuvant therapy followed by curative surgery can achieve pathological complete response (pCR). Whether pCR is equivalent to cure, serves as a good prognostic indicator for long-term survival, and whether patients achieving pCR require subsequent adjuvant therapy are still unknown. Therefore, we conducted a nationwide multicenter retrospective study to investigate the long-term efficacy of patients with LAGC who achieved pCR after neoadjuvant therapy. Methods: Clinical and pathological data were collected from 351 patients with locally advanced gastric cancer who achieved pCR after neoadjuvant therapy between January 2018 and October 2023 at 14 medical centers in China. These patients were matched 1:1 with non-pCR patients based on age, gender, clinical T stage, and N stage. This study evaluated general clinical data, neoadjuvant treatment regimens, cycles, surgical outcomes, and follow-up information including postoperative adjuvant therapy, recurrence, metastasis, and survival status up to November 2023. Results: Negative Serum tumor markers, non-signet ring cell carcinoma and neoadjuvant treatment regimens were closely associated with pCR. Patients achieving pCR were more likely to reach ypN0 status after neoadjuvant therapy compared to non-pCR patients. Survival analysis showed significantly higher overall survival (OS) and disease-free survival (DFS) in pCR patients compared to matched non-pCR patients. Moreover, OS and DFS were significantly higher in ypN0 patients within the pCR group compared to non-pCR patients. However, there was no significant difference in OS and DFS between ypN+ patients in the pCR group and non-pCR patients. Additionally, postoperative adjuvant chemotherapy did not significantly impact OS and DFS in the pCR group. Conclusions: pCR is an independent prognostic factor for OS and DFS. However, survival benefits from pCR are limited to patients achieving ypT0N0 status, while ypT0N+ patients do not benefit from pCR. Furthermore, adjuvant chemotherapy may not improve the prognosis of patients achieving pCR after neoadjuvant therapy.
Nirogacestat in patients with desmoid tumors and mutations of adenomatous polyposis coli ( <i>APC</i> ): Findings from the DeFi trial.
134 Background: Nirogacestat (niro) is an oral, targeted gamma secretase inhibitor FDA-approved for adults with progressing desmoid tumors (DT) who require systemic treatment. In the phase 3 DeFi trial (NCT03785964), niro demonstrated significant improvement vs placebo (pbo) in progression-free survival (PFS; HR 0.29 [95% CI: 0.15–0.55], P <.001) and objective response rate (ORR; 41% vs 8%, P <.001). Most DT are sporadic tumors characterized by somatic mutations in the CTNNB1 gene. About 10%–20% of DT are associated with APC mutations, the majority being germline that may cause familial adenomatous polyposis (FAP), an inheritable trait linked to an increased risk of colorectal cancer and may also confer more aggressive DT behavior. Methods: In DeFi, adult patients (pts) were randomized to oral niro (150 mg) or pbo twice daily. In pts with evaluable blood and tumor samples, descriptive post hoc analyses assessed effects of niro in pts with germline and/or somatic APC mutations, including pts with co-occurring somatic mutations of APC and CTNNB1 . Results: Of the 142 pts in DeFi, 29 pts had APC mutations (niro=13, pbo=16; 22 somatic, 21 germline, and 14 somatic and germline), including 3 pts (niro=2, pbo=1) with co-occurring somatic mutations of APC and CTNNB1 . Of these 29 pts, 19 (66%) were female, 16 (55%) were aged ≤30 y, 22 (76%) had a family history of FAP, and 22 (76%) were refractory to prior therapy (median of 3 prior lines of therapy). PFS was improved with niro vs pbo (HR 0.21 [95% CI: 0.05–1.00], P =.016). Confirmed ORR was 38% (5/13) for niro vs 13% (2/16) for pbo; median time to response with niro was 8.31 months. All 3 pts with co-occurring somatic mutations of APC and CTNNB1 were female, aged 18–56 y, had DT in the upper extremity or abdominal wall, and had no family history of FAP. The 2 pts on niro had received prior systemic therapy and/or surgery and the 1 pt on pbo had no prior therapy. Of the 2 pts on niro, both achieved a partial response (median time to response: 9.9 months). The 1 pt randomized to pbo experienced disease progression in 2.6 months. In pts with APC mutations, diarrhea was the most frequently reported adverse event. In niro-treated pts, increased rates of skin events (maculopapular rash, 62%; dermatitis acneiform, 38%) and stomatitis (46%) were reported in pts with APC mutations compared with those in the overall DeFi population (32%, 22%, and 29%, respectively). Conclusions: Improvement in PFS and ORR was observed with niro vs pbo in pts with DT harboring APC mutations. Efficacy and safety of niro in pts with APC mutations were generally consistent with findings for the overall DeFi population. Although analyses were limited due to small sample size, these results suggest that niro can provide clinically meaningful benefit to pts with progressing DT and APC mutations, including those with co-occurring somatic mutations of APC and CTNNB1 . Clinical trial information: NCT03785964 .
A preliminary simulator study on exploring responses of drivers to driving system reminders on four stimuli in vehicles
A PDZ-kinase allosteric relay mediates Par complex regulator exchange
Treatment patterns in patients with advanced gastrointestinal stromal tumor in Japan: An administrative claims database study.
811 Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Tyrosine kinase inhibitors, including imatinib, sunitinib, and regorafenib, and the HSP90 inhibitor, pimitespib have been approved for advanced GIST in Japan, but few studies have examined the nationwide trend in treatment patterns. This study aimed to evaluate the real-world treatment patterns for advanced GIST in Japan. Methods: This retrospective cohort study used the Japanese hospital-based administrative claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). Patients diagnosed with advanced GIST according to ICD-10 codes who received any approved standard drug in Japan, such as imatinib, sunitinib, regorafenib, or pimitespib (Approved in June 2022) between July 2013 and March 2023 were included. The primary endpoint was the proportion of patients with GIST who were treated with each approved standard drug. Secondary endpoints included treatment patterns, time to treatment failure (TTF), overall survival, adverse events, and the proportion of patients who underwent surgical intervention for GIST while taking standard drugs. Results: This study included 2702 patients with advanced GIST. The median age was 70.0 years, 17% of the patients were ≥80 years, and 59% were male. The most common primary tumor sites were the stomach (37%), small intestine (25%) and large intestine (12%). The proportions of patients with GIST treated with imatinib, sunitinib, regorafenib, and pimitespib were 94% (2536 patients), 26% (702 patients), 14% (376 patients) and 1% (37 patients), respectively. The most common first-line regimen was imatinib (2485/2702 patients; 92%), second-line regimen was sunitinib (560/672 patients; 83%), third-line regimen was regorafenib (200/317 patients; 63%), and fourth-line regimen was imatinib (55/119 patients; 46%). The median TTF was 30.4 months (95% CI 27.4–32.9) with imatinib, 6.4 months (95% CI 5.6–7.7) with sunitinib, 5.2 months (95% CI 4.4–6.2) with regorafenib and 2.5 months (95% CI 1.7–3.1) with pimitespib. The proportions of patients who underwent surgical intervention for GIST was 15% (403/2702 patients), and curative surgery was 10% (273/2702 patients). Conclusions: This is the first real-world study to provide insights into the patient characteristics and current treatment patterns for advanced GIST in Japan. The treatment patterns are consistent with the Japanese Clinical Practice Guidelines.
A phase I, single-center, open label, dose de-escalation and expansion study of Ivosidenib + mFOLFIRINOX in patients with resectable pancreatic adenocarcinoma.
TPS794 Background: Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, with a 34% 5-year survival rate for patients with localized disease. Guidelines recommend consideration of neoadjuvant approaches in localized PDA with the goals of controlling microscopic metastatic disease and increasing rates of microscopically margin-negative resections. One of the hallmark characteristics of PDA is a micronutrient poor, highly stromal microenvironment. Surviving in this environment requires enhanced mitochondrial function, which utilizes isocitrate dehydrogenase 1 (IDH1). In pre-clinical studies, ivosidenib, an FDA approved medication for IDH1 mutant AML, induced high levels of reactive oxygen species in PDA cells with wild-type IDH1, and caused tumor regressions and extended survival in implanted KPC mouse models. Here, we investigate the addition of ivosidenib to standard of care neoadjuvant mFOLFIRINOX in patients with resectable PDA to determine safety, pharmacodynamics, and early efficacy signals. Methods: This is a phase I, single-center, open label, dose de-escalation and expansion study in patients with resectable PDA. Eligible patients must have histologically confirmed and resectable right-sided PDA based on CT or MRI imaging. Patients receive approximately 10 weeks of neoadjuvant treatment composed of 2 weeks of ivosidenib monotherapy, followed by 6 weeks (3 cycles) of mFOLFIRINOX with ivosidenib, followed by up to 4 weeks of ivosidenib monotherapy until the day of surgery. Ivosidenib is administered once daily at 500mg; it is to be de-escalated to 250mg based on Bayesian Optimal Interval Design with Informative Prior and a target dose limiting toxicity (DLT) rate of 30%. The primary endpoint is to determine the safety and tolerability of ivosidenib in combination with mFOLFIRINOX. Secondary endpoints include RECIST version 1.1 response rates, major pathologic response rates, and biochemical (CA19-9, CEA) response rates. Correlative studies will be performed on surgical samples to evaluate metabolomic profiles. At the time of submission, 10 out of 16 planned patients have been enrolled. There have been no DLT at 500mg of ivosidenib. Clinical trial information: NCT05209074 .
The role of sequential PET/CT imaging to predict complete response after definitive chemoradiotherapy for locally advanced squamous cell carcinoma of the anal canal.
12 Background: The standard treatment for locally advanced squamous cell carcinoma of the anal canal (SCCAC) is definitive radiotherapy (RT) with concurrent chemotherapy (CRT), with excellent outcomes. Nevertheless, rates of locoregional failure of 10% to 30% have been reported. Due to the narrow therapeutic window between time-dependent response to RT and prompt salvage surgery, the definition of a surveillance strategy after radical CRT is challenging. In particular the contribution of 18-FDG PET/CT is not clearly established. The purpose of this study was to evaluate the effectiveness of follow-up MR and 18-FDG PET/CT to predict response to CRT in patients with SCCAC. Methods: We analyzed a cohort of consecutive patients who received definitive RT/CRT from January 2019 to February 2024. After completion of therapy, radiologic (rCR) and metabolic complete response (mCR) was assessed with pelvic MR (RECIST v.1.0) and 18-FDG PET/CT at 3 ad 6 months respectively. Local Control (LC) was defined as time from the end of CRT to local failure or last follow-up. Univariate analysis (UVA) was performed to identify variables associated with outcome using the log rank test. Sensitivity and Specificity analysis was performed to assess the correlation between rCR/mCR and LC. Results: A total of 67 patients (median age 67 years, range 44-83) were included. All patients completed RT, and 52 received concurrent CRT. Baseline and surveillance MR and 18-FDG PET/CT were available for 49 patients. After a median follow-up of 28 months, 12 patients experienced disease progression (PD) (10 local; 2 distant), resulting to salvage surgery in 10 cases after biopsy. At 3 years, LC rate was 78%. At UVA, only mCR was correlated with LC (3-year LC 90% versus 59%, p=0,0137; HR 0,01660, IC 95% 0,03-0,84). For prediction of LC, accuracy of mCR at 6 months was 83.7% versus 62.5% for rCR. Specificity/Sensitivity analysis is summarized in the table. Conclusions: 18FDG PET/CT at 6 months may identify patients with a higher likelihood of developing complete tumor regression following CRT. Further data is needed to confirm the appropriate surveillance strategy for patient undergoing CRT in clinical practice. Specificity and sensitivity analysis. Sensitivity Specificity Positive Predictive Value Negative Predictive Value mCR 83.3% 84.0% 92.6% 68.7% rCR 25.0% 70.0% 14.0% 82%
Hypofractionated partial breast irradiation after breast-conserving surgery for patients with early stage breast cancer in China Mainland: a single-arm prospective trial
Studies on the preparation of a sufficient carrier from egg protein and carrageenan for cellulase with optimization and application
Abstract Egg protein (EP) concentration, pH, and glutaraldehyde (GA) concentration were optimized using Box Behnken design (BBD) to prepare GA-EP-Carr (Carrageenan) beads as a carrier for Aspergillus niger MK981235 cellulase. It was recommended that the concentrations of GA, and EP be set at 11.21% (w/v), 8% (w/w), and pH 3, respectively. It was determined that 60 °C and 2% for free form and 60 °C and 3% for im-cellulase were the optimum temperature and CMC concentration parameters for maximum enzyme activity. Free and im-cellulase were determined to have Km and Vmax of 2.22 mg.ml-1 and 1.76 µmol.ml-1.min-1, and 4.55 mg.ml-1 and 3.33 µmol.ml-1.min-1, respectively. Covalent coupling of A. niger cellulase to GA- EP- Carr beads improved its thermodynamic parameters T1/2 and D-values by 2.48, 2.01, and 2.36 times at 40, 50, and 60 °C, respectively. GA- EP- Carr im-cellulase was 100% active for 60 days at 4 °C and can be used for CMC hydrolysis for 20 successive cycles. GA- EP- Carr im-cellulase showed remarkable efficiency in the clarification of mango, peach, grape, and orange juices emphasized by TSS (total soluble solids), turbidity, and reducing sugar measurements for 3 successive cycles. GA- EP- Carr im-cellulase can be applied with high efficiency in juice industry.
Dissecting the sterility phenotype in gene edited Drosophila suzukii pgSIT males
Abstract Drosophila suzukii is an invasive pest that affects many fresh, soft-skinned fruits such as strawberries and blueberries. To combat this pest, growers use various methods including insecticide sprays, biological control, and sanitation practices. However, these methods are becoming increasingly ineffective against D. suzukii due to increased resistance against insecticides and increasing labor costs. Sterile Insect Technique (SIT) has been used successfully to control many agricultural pests, but the use of irradiation, sex sorting, and the requirement to scale these insects make it costly to implement. pgSIT (precision guided Sterile Insect Technique) is a novel and efficient way to generate sterile males through genetic engineering and overcomes the drawbacks of traditional SIT. pgSIT has been implemented in multiple Dipteran insects, including D. suzukii, and has been shown to suppress wild insect populations. To further characterize sterile pgSIT males, we evaluated their fertility capacity, lack of mature sperm, and ability to induce a mating refractory period in D. suzukii wildtype females. In this study, we found that pgSIT sterile males do not produce mature sperm and can induce a refractory mating period in wildtype females. Furthermore, sperm DNA is not detected in the reproductive tracts of pgSIT-mated female reproductive tracts. These findings further support the penetrance of the pgSIT technology in D. suzukii and provide further supporting data to governing regulatory bodies in their evaluation of this technology.
Temporal changes in regional variations in cancer survival rates in Osaka, Japan (1997–2015)
Evaluating GPT models for clinical note de-identification
Retrieval of nicotine content in cigar leaves by remote analysis of aerial hyperspectral combining machine learning methods
Proteogenomic analysis reveals Arp 2/3 complex as a common molecular mechanism in high risk pancreatic cysts and pancreatic cancer
Abstract Pancreatic cysts, particularly intraductal papillary mucinous neoplasms (IPMNs), pose a potential risk for progressing to pancreatic cancer (PC). This study investigates the genetic architecture of benign pancreatic cysts and its potential connection to PC using genome-wide association studies (GWAS). The discovery GWAS identified significant genetic variants associated with benign cysts, specifically the rs142409042 variant near the OPCML gene. A pairwise GWAS comparing PC to benign cysts revealed the rs7190458 variant near the BCAR1 and CTRB1 genes. Further analysis with identified GWAS genes highlighted the Actin Related Protein (Arp) 2/3 complex as a potentially important molecular mechanism connecting benign cysts and PC. The Arp2/3 complex-associated genes were significantly upregulated in PC, suggesting their role in the malignant transformation of pancreatic cysts. Differential expression of these genes was observed across various cell types in PC, indicating their involvement in the tumor microenvironment. These findings suggest that the Arp2/3 complex-associated genes can serve as potential biomarkers for predicting the malignant transformation of pancreatic cysts, opening new avenues for targeted therapies and early detection strategies.
Wind turbine blade damage detection based on acoustic signals
Emergence of Fusarium incarnatum and Fusarium avenaceum in wilt affected solanaceous crops of the Northern Himalayas
Abstract The objective of this study was to identify and characterize the fungal pathogens responsible for wilt diseases in solanaceous crops, specifically tomato, brinjal, and chili, in the Kashmir valley. Through both morphological and molecular analyses, including DNA barcoding of the ITS, TEF, RPB1, and RPB2 genomic regions, Fusarium incarnatum and Fusarium avenaceum were identified as the primary causal agents of wilt in tomato and brinjal, and chili, respectively. Pathogenicity tests confirmed the virulence of these pathogens, with typical wilt symptoms observed upon inoculation. This represents the first report of F. incarnatum and F. avenaceum as wilt pathogens in solanaceous crops in India. Phylogenetic analysis further confirmed the genetic variability of these pathogens, revealing their expanding host range. The findings underscore the growing adaptability of these Fusarium species to diverse agricultural systems and highlight the urgent need for targeted disease management strategies to mitigate the significant yield losses caused by Fusarium wilt in solanaceous vegetable production.
Curcumin nanoparticles alleviate brain mitochondrial dysfunction and cellular senescence in γ-irradiated rats
Abstract Despite the diverse applications of γ radiation in radiotherapy, industrial processes, and sterilization, it causes hazardous effects on living organisms, such as cellular senescence, persistent cell cycle arrest, and mitochondrial dysfunction. This study evaluated the efficacy of curcumin nanoparticles (CNPs) in mitigating mitochondrial dysfunction and cellular senescence induced by γ radiation in rat brain tissues. Four groups of male Wistar albino rats (n = 8 per group) were included: (Gr1) the control group; (Gr2) the CNPs group (healthy rats receiving oral administration of curcumin nanoparticles at a dose of 10 mg/kg/day, three times per week for eight weeks); (Gr3) the irradiated group (rats exposed to a single dose of 10 Gy head γ irradiation); and (Gr4) the irradiated + CNPs group (irradiated rats treated with CNPs). The data obtained demonstrated that oral administration of CNPs for eight weeks attenuated oxidative stress in γ-irradiated rats by lowering the brain’s lipid peroxidation level [malondialdehyde (MDA)] and enhancing antioxidant markers [superoxide dismutase (SOD), reduced glutathione (GSH), and total antioxidant capacity (TAC)] (P < 0.05). In addition, CNPs significantly increased mitochondrial function by improving complex I, complex II, and ATP production levels compared to the irradiated group. In irradiated rats, CNPs also showed anti-neuroinflammatory effects by reducing brain interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-ĸB) levels (P < 0.05). Moreover, CNPs administered to irradiated rats significantly reduced brain β-galactosidase activity and the expression levels of p53, p21, and p16 genes (P < 0.05) while concurrently inducing a significant increase in AMPK mRNA expression compared to the irradiated group. In conclusion, CNPs ameliorated the neurotoxicity of γ radiation and hold promise as a novel agent to delay cellular senescence via their combined antioxidant, anti-inflammatory, and mitochondrial-enhancing properties.