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Jinghui Lin, Meifang Li, Shijie Chen, Lihong Weng, Zhiyong He Department of Thoracic Medical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou City, Fujian Province, 350014, People’s Republic of ChinaCorrespondence: Zhiyong HeDepartment of Thoracic Medical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou City, Fujian Province, 350014, People’s Republic of ChinaEmail zhiyonghecn@sina.comPurpose: This single-center, open-label, single-arm, phase II clinical trial aimed to examine the efficacy and safety of the first-generation EGFR-TKIs combined with chemotherapy among treatment-naïve advanced non-small-cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations.Materials and Methods: Patients with advanced EGFR-mutant NSCLC were given concurrent gefitinib (250 mg orally daily) and 3-week cycle of carboplatin plus pemetrexed for 4 to 6 cycles, followed by gefitinib maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This trial was registered at ClinicalTrials.gov (NCT02886195).Results: Of the 21 patients enrolled in this study, a 76.2% ORR and 100% DCR were observed and a higher ORR was seen in patients with EGFR 21L858R mutations than in those with 19del mutations (P = 0.012). The subjects had a median PFS of 15.0 months and a median OS of 26.0 months, and numerically longer PFS was seen in patients with EGFR 21L858R mutations than in those with 19del mutations (P = 0.281). There were 15 NSCLC patients without cerebral metastases at baseline, with 4 cases developing cerebral metastases during the treatment, and the 6-, 12- and 24-month cumulative incidence rates of the central nervous system metastasis were 6.67%, 13.3% and 26.7%, respectively. There were 17 subjects with progressive diseases tested for EGFR T790M mutations, and 11 cases were positive for T790M mutations. Grade 3 toxicity included neutropenia (9.5%), leukopenia (4.8%), liver dysfunction (9.5%) and diarrhea (4.8%), and no grade 4 adverse events or treatment-related death occurred.Conclusion: The combination of first-generation EGFR-TKIs and chemotherapy achieves a satisfactory PFS, ORR and DCR and well-tolerated toxicity in advanced NSCLC patients with EGFR mutations, notably in patients with EGFR L858R mutations.Keywords: non-small-cell lung cancer, EGFR-TKIs, chemotherapy, combination strategy, clinical efficacy, toxicity

Background: The associations between serum free triiodothyronine (FT3) and diabetic peripheral neuropatprohy (DPN) / carotid atherosclerotic lesions in type 2 diabetic patients with normal thyroid function is still unclear. The purpose of our study was to explore the relationships of FT3 with DPN and carotid atherosclerotic lesions in Chinese type 2 diabetes inpatients with euthyroid function.Methods: A total of 2477 type 2 diabetes inpatients with euthyroid function were recruited in this cross-sectional study, and they were stratified into quartiles by FT3 levels. Peripheral neuropathy was assessed by neurological symptoms and signs as well as nerve conduction velocity tests. Carotid atherosclerotic lesions, including carotid intima-media thickness, plaque and stenosis, were evaluated by Doppler ultrasound. Results: After adjusting for potential confounders, there was a significant decrease in the prevalence of DPN in the patients with type 2 diabetes across the FT3 quartiles (23.5%, 20.9%, 18.9%, and 11.2%, respectively, p < 0.001). Logistical regression analysis further revealed that FT3 quartiles were significantly and inversely associated with DPN. Compared with the subjects in the highest FT3 quartile, the adjusted odds ratios (95% confidence interval) of DPN in the first to third FT3 quartile were successively 2.338 (1.407-3.884), 1.903 (1.134-3.194) and 1.598 (0.960-1.125). The patients with DPN had significantly higher prevalence of carotid plaques (55.8%) and carotid stenosis (1.3%) than non-DPN patients (44.8%; 0.5%). However, no statistical association was observed between FT3 quartiles and carotid atherosclerotic lesions.Conclusions: Lower FT3 within the normal range was independently associated with DPN, but not with carotid atherosclerotic lesions in Chinese type 2 diabetes inpatients with euthyroid function.

Background Non-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases. Patients and methods The medical records of 104 treatment-naive, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts. Results The baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526). Conclusion Our data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

Aims: To compare the effects of maternal subclinical hypothyroidism (SCH) diagnosed by the 2011 or 2017 “Guidelines of the American Thyroid Association (ATA) for the diagnosis and management of thyroid disease during pregnancy and the postpartum” during the first trimester on adverse pregnancy outcomes in thyroid peroxidase antibody (TPOAb)–negative pregnant women. Methods: There were 1,556 Chinese singleton pregnant women with negative TPOAb diagnosed with either SCH or euthyroidism who were investigated, and the prevalence and risk of obstetric outcomes were compared between the two groups using 2011 and 2017 ATA standards, respectively. The effects of a mildly elevated thyroid-stimulating hormone (TSH) concentration on adverse pregnancy outcomes were evaluated by binary logistic regression. Results: Maternal SCH identified by the 2011 ATA guidelines correlated with higher rates and risks of pregnancy-induced hypertension (PIH), preeclampsia, and low-birth-weight infants, while maternal SCH diagnosed by the 2017 ATA guidelines was more likely to develop PIH, preeclampsia, cesarean delivery, preterm delivery, placenta previa, and total adverse maternal and neonatal outcomes. Moreover, a mildly elevated TSH level was significantly associated with PIH after adjustment for confounding factors. Conclusions: Compared with the 2011 ATA guidelines, the 2017 ATA guidelines could be more applicable to Chinese pregnant women to screen the effects of SCH on the majority of adverse pregnancy outcomes.

Objective: Serum uric acid (SUA) is associated with many cardiovascular risk factors such as hypertension (HTN) and metabolic syndrome (MetS). However, the association of SUA with atherosclerosis remains controversial. Our aim was to investigate the relationships of SUA with HTN, MetS and atherosclerosis in Chinese inpatients with type 2 diabetes. Methods: This cross-sectional study was performed with a sample of 2388 hospitalized Chinese patients with type 2 diabetes. Both carotid and lower limb atherosclerotic lesions were assessed for intima–media thickness, plaque and stenosis by Doppler ultrasound. Atherosclerotic plaque and stenosis were defined as the presence of either carotid or lower limb plaques and stenoses, respectively. Results: There were significant increases in the prevalence of both HTN and MetS across the SUA quartiles (HTN: 43.4, 49.6, 56.1 and 66.3% for the first, second, third and fourth quartiles, respectively, P

Aims/Introduction Microalbuminuria is positively related to metabolic syndrome (MetS). Our aim was to investigate whether urinary albumin-to-creatinine ratio (UACR) within the normal range is independently associated with MetS in Chinese community-based patients with type 2 diabetes. Materials and Methods A total of 514 participants (206 males and 308 females; mean age 66 years) with UACR less than 3.5 mg/mmol were enrolled from two downtown areas of Shanghai. The participants were stratified into quartiles according to UACR levels. The prevalence of MetS was assessed and compared among the four groups by binary logistic regression. Results Compared with participants with UACRs in the first quartile, the other quartiles had a higher prevalence of MetS (65.9%, 74.4% and 81.3%, respectively, P = 0.001) after adjustment for sex and age. After adjusting for potential confounders, participants in the second to the fourth quartile group had a 1.36-, 1.84- and 2.73-fold risk of MetS, respectively, relative to those in the lowest quartile. Furthermore, UACR, whether as quartile groups or as a continuous variable, is an independent predictor of MetS after fully adjusting for other variables. Conclusions These results suggest that UACR even within the normal range is independently associated with MetS in Chinese community-based patients with type 2 diabetes mellitus.

Aims/Introduction To compare carotid and lower limb atherosclerotic lesions, and examine if carotid atherosclerotic lesions are in line with lower limb atherosclerotic lesions, and can reflect generalized atherosclerosis in inpatients with type 2 diabetes. Materials and Methods This was an observational study carried out in 867 Chinese inpatients with type 2 diabetes, including 573 previously known and 294 newly diagnosed patients. Ultrasonographic assessments of intima-media thickness (IMT), plaques, and stenosis in the carotid and lower limb arteries were evaluated. Atherosclerotic lesions between the carotid and lower limb arteries were compared in both previously known and newly diagnosed diabetes, respectively. Results In both the known (77.3% vs 49.4%, P

Background Both carotid and lower limb atherosclerosis are associated with increased cardiovascular and cerebrovascular risks. However, it is still unclear whether the concomitant presence of carotid and lower extremity atherosclerosis further increases the cardiovascular and cerebrovascular risks. Therefore, our aim is to investigate whether the coexistence of carotid and lower extremity atherosclerosis was associated with higher cardiovascular and cerebrovascular risks in patients with type 2 diabetes. Methods This cross-sectional study was performed in 2830 hospitalized patients with type 2 diabetes. Based on carotid and lower limb Doppler ultrasound results, the patients were divided into three groups including 711 subjects without atherosclerosis, 999 subjects with either carotid or lower limb atherosclerosis, and 1120 subjects with both carotid and lower limb atherosclerosis. And we compared the clinical characteristics and prevalence of both cardio-cerebrovascular events (CCBVEs) and self-reported cardio- cerebrovascular diseases (CCBVDs) among the three groups. Results After adjusting for age, sex, and duration of diabetes, there were significant increases in the prevalence of both CCBVEs (3.8 vs. 11.8 vs. 26.4 %, p

Background The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes. Methods A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes. Results After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients. Conclusions The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes.

Controversies concerning the association of retinal microvascular abnormalities (RMAs) with atherosclerosis in patients with diabetes exist. The objective of this study was to investigate the association between RMAs and carotid atherosclerotic lesions in Chinese inpatients with type 2 diabetes.This cross-sectional study involved 2870 type 2 diabetic patients including 1602 men aged 15-90 years and 1268 women aged 17-88 years. Both retinal arteriosclerosis (RA) and diabetic retinopathy (DR) were determined by digital fundus photography using a standardized protocol. RMAs are defined as the presence of either RA or DR. Carotid atherosclerotic lesions including carotid intima-media thickness (CIMT), carotid atherosclerotic plaque and stenosis were assessed and compared between patients with and without RMAs based on Doppler ultrasound. The association of RMAs with carotid atherosclerotic lesions was analyzed by linear and binary logistic regression analyses.The CIMT values in both male and female diabetics with RMAs were significantly greater than in those without RMAs after controlling for age (0.88±0.21 vs. 0.77±0.20 mm for men, p=0.002; and 0.84±0.19 vs. 0.76±0.21 mm for women, p=0.002). The prevalence of carotid plaque was also markedly higher in patients with RMAs than in those without RMAs after adjusting for age (54.3% vs. 23.9% for men, p0.001; 48.4% vs. 32.0% for women, p=0.046). However, no significant difference was observed in the prevalence of carotid stenosis in either men or women with or without RMAs. After controlling for multiple confounding factors, RMAs were independently associated with increased CIMT in both men (β: 0.067, 95% CI: 0.026-0.269, p=0.018) and women (β: 0.087, 95% CI: 0.058-0.334, p=0.005) with type 2 diabetes, and they were also closely associated with the presence of carotid plaque (OR: 2.17, 95% CI: 1.54-3.05, p0.001 for men; OR: 1.38, 95% CI: 0.91-2.08, p=0.129 for women) in men with type 2 diabetes.RMAs were closely associated with early carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes. Our results suggested that changes in retinal microvasculature may play a role in the pathogenesis of atherosclerosis and may be used as an indicator of early atherosclerosis in patients with type 2 diabetes.

The corpus allatum of both male and female adult black blow fly, Phormia regina (Meigen), produced radioisotope-labeled juvenoids when incubated in vitro following a radiochemical assay. The production of juvenoids was greatly enhanced after the flies were fed a protein (liver) meal. These juvenoids were determined as juvenile hormone III bisepoxide (JHB 3 ), juvenile hormone III (JH III) and methyl farnesoate (MF). These three juvenoids were separated and identified by chromatography (TLC and HPLC) using synthesized standards, respectively. Then, JHB 3 standard and the biological samples of JHB 3 were further identified with PCI GS-MS using published spectrum data. Bioassay of synthetic JHB 3 revealed its ability to restore oogenesis in allatectomized, liver-fed female blow flies. The ability of these three juvenoids and their blends to restore oogenesis was the rational juvenoid blend (i.e. a mixture of JHB 3 , JH III and MF according to the percent ratio secreted by the isolated CA of liver-fed females) > JHB 3 = JH III > MF = the irrational juvenoid blend (i.e. a mixture of an arbitrary ratio of JHB 3 , JH III and MF). This is the first evidence suggesting that multiple juvenoid production and reception may be a normal event for insects.

A midgut hormone was discovered in liver-fed, Phormia regina adult females. Results indicated that this hormone is released from the midgut to reach its target, the brain, between 4–8 h after the onset of the liver meal. The stimulated brain neurosecretory cells then initiate the neuroendocrine cascade leading to the beginning and the completion of oogenesis. A bioassay was developed to measure the midgut hormone activity. High activity of this hormone was detected in midgut extract prepared from midguts of liver-fed females 6 h after the onset of the liver meal. The midgut hormone is partially heat resistant and is not denatured in 80% methanol. Its Mr was estimated to reside between 5000 and 11,000. The true Mr remains to be determined. This is the first hormone identified from insect midgut that connects nutrition and the neuroendocrine system with oogenesis. A working hypothesis concerning the dietary initiated endocrine regulation of oogenesis was proposed for P. regina.

When Phormia regina larvae were raised on an artificial diet, topical applications of either methoprene (2.5 μg/fly) or juvenile hormone III (5 μg/fly) to adult, sugar-fed, females on days 3, 4 and 5 after emergence caused from 10.2 to 17.5% to have stage 4 follicles (i.e. as judged by the presence of a little opaque material in the oocytes); whereas, in both the untreated and the acetone controls, oocytes remained in stage 3, in nearly all flies, without any opaque material. Previous studies by other researchers on methoprene-treated, sugar-fed P. regina referred to the opaque material in stage 4 follicles as yolk. In this present study, however, examination, using a specific enzyme-linked immunosorbent assay (ELISA) for vitellin and vitellogenin, of stage 4 follicles as well as the haemolymph from sugar-fed and methoprene (or juvenile hormone III)-treated flies, revealed no vitellin or vitellogenin, respectively. These results are consistent with our previous data, which have shown that juvenile hormone is mainly involved with vitellogenin uptake but not vitellogenin biosynthesis. Thus our present results are inconsistent with a previous conclusion indicating that methoprene treatment would cause vitellogenin biosynthesis and complete egg development in sugar-fed P. regina raised as larvae on pork liver. When we raised larvae on pork liver, we found that topical application of methoprene (three times) to 195 sugar-fed females resulted in only one female containing stage 10 ovaries and 112 contained stage 3, 74 stage 4, and eight stages 5–9 ovaries. None of the methoprene induced stage 4 follicles showed any detectable quantity of vitellin. Since methoprene treatment resulted in only one fly (out of 195) to have stage 10 follicles (albeit the vitellin deficiency), our results do not support the idea that juvenile hormone treatment alone is sufficient to initiate and sustain vitellogenin biosynthesis and uptake in sugar-fed P. regina .

Results showed that injections of the divalent cation cobalt, a calcium channel blocker, at effective haemolymph concentrations of 2.1, 3.4 or 5.0 mM, immediately prior to liver feeding, retarded or inhibited egg development by influencing vitellogenin uptake in Phormia regina. Topical application of methoprene (a juvenile hormone analogue) to cobalt-injected flies partially restored the otherwise inhibited egg development. Since vitellogenin uptake in this fly is controlled by juvenile hormone, cobalt may affect oocyte development at least partly through its effect on juvenile hormone biosynthesis. Rates of juvenile hormone biosynthesis by the corpus allatum, in vitro, in cobalt-injected flies fell into three levels of 0.48 ± 0.01, 0.72 ± 0.12 and 0.97 ± 0.08 pmol/gland pair/h. These three levels of rates of juvenile hormone biosynthesis corresponded well with the three categories of ovary development observed in cobalt-injected flies: undeveloped, partially developed and fully developed. In comparison, the rates of juvenile hormone biosynthesis were 0.03 ± 0.00, 1.16 ± 0.08 and 1.23 ± 0.10 pmol/gland pair/h for sugar-fed, liver-fed, and liver-fed but water-injected control flies, respectively. Effects or lack of effects of several different calcium-replacement divalent cations and a dihydropyridine calcium channel blocker (i.e. nifedipine) on oocyte development in P. regina suggested that calcium channels of the corpora allata may be involved in the regulation of juvenile hormone biosynthesis, which then affected oocyte development.

Background The features of carotid atherosclerosis in ketosis-onset diabetes have not been investigated. Our aim was to evaluate the prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed Chinese diabetic patients with ketosis but without islet-associated autoantibodies. Methods In total, 423 newly diagnosed Chinese patients with diabetes including 208 ketosis-onset diabetics without islet-associated autoantibodies, 215 non-ketotic type 2 diabetics and 79 control subjects without diabetes were studied. Carotid atherosclerosis was defined as the presence of atherosclerotic plaques in any of the carotid vessel segments. Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on Doppler ultrasound examination. The clinical features of carotid atherosclerotic lesions were analysed, and the risk factors associated with carotid atherosclerosis were evaluated using binary logistic regression in patients with diabetes. Results The prevalence of carotid atherosclerosis was significantly higher in the ketosis-onset diabetic group (30.80%) than in the control group (15.2%, p=0.020) after adjusting for age- and sex-related differences, but no significant difference was observed in comparison to the non-ketotic diabetic group (35.8%, p=0.487). The mean CIMT of the ketosis-onset diabetics (0.70±0.20 mm) was markedly higher than that of the control subjects (0.57±0.08 mm, p Conclusions The prevalence and risk of carotid atherosclerosis were significantly higher in the ketosis-onset diabetics than in the control subjects but similar to that in the non-ketotic type 2 diabetics. The characteristics of carotid atherosclerotic lesions in the ketosis-onset diabetics resembled those in the non-ketotic type 2 diabetics. Our findings support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes.

Background Low-grade albuminuria is associated with cardiovascular risk factors and mortality. Our aim was to investigate the association between low-grade albuminuria and carotid atherosclerotic lesions in community-based patients with type 2 diabetes. Methods A cross-sectional study was performed in 475 community-based patients with type 2 diabetes (190 males and 285 females) with normal urinary albumin-to-creatinine ratios (UACR) (< 3.5 mg/mmol) from Shanghai, China. The subjects were stratified into tertiles based on UACR levels (the lowest tertile was UACR ≤ 1.19 mg/mmol, and the highest tertile was UACR ≥ 2 mg/mmol). Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on ultrasonography. The urinary albumin excretion rate was determined as the mean of the values obtained from three separate early morning urine samples. Results Compared with the subjects with UACR in the lowest tertile, the subjects with UACR in the middle and highest tertiles had greater CIMT values (0.88 ± 0.35 mm, 0.99 ± 0.43 mm and 1.04 ± 0.35 mm, respectively; all p