A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response ...to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
Context:
Age-related hepatic fat accumulation increases the risk of cardiometabolic diseases, and the fibroblast growth factor (FGF) 21–resistant state caused by fatty liver underlies the ...pathogenesis of these diseases.
Objective:
Previous studies suggested that a higher level of cardiorespiratory fitness was associated with both lower hepatic fat content and serum FGF21 levels; however, the effect of endurance exercise on hepatic fat content and serum FGF21 concentration has not been studied. Therefore, we aimed to elucidate whether endurance exercise reduced hepatic fat content and serum FGF21 levels.
Design:
This is a randomized crossover trial.
Setting:
The study setting was an institutional practice.
Patients:
Thirty-three elderly Japanese men participated in the study.
Intervention:
The intervention was a 5-week endurance exercise program comprising three cycle ergometer sessions per week.
Main Outcome Measures:
Hepatic fat content was assessed by proton magnetic resonance spectroscopy, and serum FGF21 level was determined by ELISA.
Results:
A 5-week endurance exercise program decreased the hepatic fat content and serum FGF21 levels without weight loss, and the changes were higher in the exercise period than in the control period (P = .021 and P = .026, respectively). Correlation analysis demonstrated that only the change in hepatic fat content was significantly and positively correlated with change in serum FGF21 levels (r = 0.366, P = .006).
Conclusions:
A 5-week endurance exercise program decreased hepatic fat content and serum FGF21 levels without weight loss in elderly men, and exercise-induced hepatic fat reduction mediated the reduction in serum FGF21 levels. These findings suggest that endurance exercise modulates hepatic fat content and FGF21 resistance, regardless of obesity status.
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid growth, early metastasis, and acquired therapeutic resistance. A majority of patients with SCLC have extensive-stage ...(ES) disease, defined as the presence of metastatic disease outside the hemithorax at first diagnosis. SCLC has been considered "a graveyard for drug development," with chemotherapy remaining the standard treatment for first- and second-line management until quite recently. In contrast to NSCLC, identifying therapeutic targets in SCLC has been challenging, partly because driver mutations are primarily loss of function, involving the tumor suppressor genes RB1 and TP53 or currently untargetable (e.g., amplification of MYC family members). Recent gene expression profiling of SCLC cells lines, patient samples and representative murine models, have led to a proposed delineation of four major subtypes for SCLC distinguished by differential expression of four key transcriptional regulators (ASCL1, NEUROD1, POU2F3, and YAP1). Our understanding of the biology of SCLC has indeed significantly improved recently due to the continued efforts of the dedicated investigators in this field, but the therapeutic options remain dismal. While recent results from immunotherapy trials are encouraging, most patients demonstrate either primary or rapid acquired resistance to current regimens, highlighting the clear need to improve the effectiveness and expand the scope of current therapeutic strategies. In this opinion article, we will discuss recent developments in the treatment of SCLC, focused on current understanding of the signaling pathways, the role of immunotherapy and targeted therapy, and emerging biomarkers of response to therapy in SCLC.
Fibroblast growth factor (FGF) 21 is an important regulator of glycemic control, but the association between circulating FGF21 and diabetic complications is poorly understood. Moreover, basal FGF21 ...secretion, especially in response to insulin dose, in patients with type 1 diabetes mellitus (T1DM), has not been well examined. Therefore, this study aimed to determine the association of circulating FGF21 levels with diabetic complications and insulin dosage in middle-aged and elderly patients with T1DM.
A total of 127 middle-aged and elderly patients with T1DM, including 68 patients with diabetic complications, and 106 non-diabetic individuals were analyzed in this cross-sectional study. Information on demographic characteristics and T1DM was extracted from their electronic medical records. Serum FGF21 levels were determined using ELISA.
Serum FGF21 levels were significantly lower in T1DM patients (75.2 37.4-135.1 pg/mL) than in non-diabetic participants (151.6 92.0-224.6 pg/mL; P < 0.001). No diabetic complications were associated with serum FGF21 concentrations. Both basal and bolus insulin doses were significantly and positively correlated with serum FGF21 levels (P < 0.05). Stepwise multiple regression analysis showed that FGF21 level was associated with age and body mass index (P < 0.05), while the basal insulin dose was an independent positive predictor of serum FGF21 levels (β = 0.197, P = 0.032).
Circulating FGF21 levels are reduced in patients with T1DM; however, they are not associated with diabetic complications. In addition, aging, obesity, and insulin dosage are positive determinants of circulating FGF21.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
We are increasingly experiencing difficulty in deciding whether to perform gastrectomy after noncurative endoscopic resection of early gastric cancer (EGC) for patients at high risk for ...surgery. If the differences in risk for lymph node metastasis (LNM) on the basis of noncurative status are understood, the decision becomes easier. The present study aimed to stratify the LNM risk and develop and validate a risk-scoring model for predicting LNM.
Methods
By retrospectively reviewing 3131 patients with solitary EGC who underwent gastrectomy with lymphadenectomy at our institution between July 1997 and May 2013, LNM risk was stratified and a risk-scoring model was developed on the basis of the identified independent risk factors for LNM. The scoring was validated using 352 other surgically resected EGC cases. The discriminatory accuracy of the scoring was measured by area under receiver operating characteristic curve (AUROC).
Results
LNM was detected in 386 of 3131 cases. LNM risk in each subgroup, stratified by the identified independent risk factors, such as tumor size, depth, histological type, ulcerative findings, and lymphovascular involvement, considerably varied from 0 % to >50 % even among the current guidelines’ noncurative subgroups. An 11-point scoring model was built, and AUROCs were 0.84 (95 % confidence interval, 0.82–0.86) and 0.82 (0.75–0.88) in the development and validation sets, respectively.
Conclusions
The present study revealed detailed LNM risk stratification data, and developed and validated an 11-point scoring model.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity.
Methods
We examined the spectra ...of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs.
Results
Sequencing analyses identified
BRAF
V600E,
BRAF
non-V600E,
KRAS
, and
NRAS
mutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including
RSPO
fusions/overexpression,
RNF43
mutations,
ZNRF3
mutations,
APC
mutations, and
CTNNB1
mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored
GNAS
mutations. There was significant interdependence between the altered MAPK and WNT pathway genes.
RSPO
fusions/overexpression was significantly associated with
KRAS
mutations (31/47, 66%), whereas most
RNF43
mutations coexisted with the
BRAF
V600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the
BRAF
V600E mutation (71%) and those with
RNF43
mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with
RSPO
fusions/overexpression (58%) and those with
GNAS
mutations (100%).
Conclusions
Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ultra-endurance events have gained global participation, whereas the critical factors of competition results remain to be well elucidated. This study used a nutritional approach to evaluate the ...association of competition results with carbohydrate intake and blood glucose control during a 100-mile ultramarathon. This observational study was conducted in the 2021 LAKE BIWA 100, which covered 100 miles (169 km) and 10,500 m elevation. The course was divided into 9 segments by aid station. According to the competition results, 22 participants (18 men and 4 women) were divided into higher finishers (n = 7), lower finishers (n = 9), and non-finishers (n = 6). The participants self-recorded their overall dietary intake throughout the race. Glucose levels were monitored every 15 min by a flash glucose monitoring system. Running speed in each segment was standardized to the average of the top five finishers for each gender. Among finishers, the carbohydrate intakes were significantly higher in the higher finishers than in the lower finishers during overall segments, especially in the first half of the race (p < 0.05). There was a significant positive correlation between running speed and carbohydrate intake in the lower finishers (rho = 0.700, p = 0.036). Two-way ANOVA analysis revealed that lowering glucose levels in each segment were more frequently observed in the lower finishers compared to the higher finishers (p = 0.012). Compared to the higher finishers, the lower finishers exhibited significantly greater fluctuations (⊿highest-lowest) in glucose levels (p < 0.001). The fluctuations in glucose levels were significantly and negatively correlated with the running speed of the finishers (rho = - 0.612, p = 0.012). Faster runners consume high amounts of carbohydrates and maintain glucose levels during the 100-mile ultramarathon on the trail, especially at the beginning. Lowering and fluctuating glucose levels during the race are associated with lower running speed in endurance athletes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. ...Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.
Next‐generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and ...therapeutic significance. Here, we undertook a hospital‐based prospective study (TOP‐GEAR project, 2nd stage) to investigate the feasibility and utility of NGS‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).
The results of the TOP‐GEAR project (UMIN 000011141) indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Automated image analysis has been developed currently in the field of surgical pathology. The aim of the present study was to evaluate the classification accuracy of the e-Pathologist ...image analysis software.
Methods
A total of 3062 gastric biopsy specimens were consecutively obtained and stained. The specimen slides were anonymized and digitized. At least two experienced gastrointestinal pathologists evaluated each slide for pathological diagnosis. We compared the three-tier (positive for carcinoma or suspicion of carcinoma; caution for adenoma or suspicion of a neoplastic lesion; or negative for a neoplastic lesion) or two-tier (negative or non-negative) classification results of human pathologists and of the e-Pathologist.
Results
Of 3062 cases, 33.4% showed an abnormal finding. For the three-tier classification, the overall concordance rate was 55.6% (1702/3062). The kappa coefficient was 0.28 (95% CI, 0.26–0.30; fair agreement). For the negative biopsy specimens, the concordance rate was 90.6% (1033/1140), but for the positive biopsy specimens, the concordance rate was less than 50%. For the two-tier classification, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.5% (95% CI, 87.5–91.4%), 50.7% (95% CI, 48.5–52.9%), 47.7% (95% CI, 45.4–49.9%), and 90.6% (95% CI, 88.8–92.2%), respectively.
Conclusions
Although there are limitations and requirements for applying automated histopathological classification of gastric biopsy specimens in the clinical setting, the results of the present study are promising.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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