Neoplasia endócrina múltiple y enfermedad inflamatoria intestinal de inicio muy temprano. Una asociación inesperada / Multiple endocrine neoplasia and very early onset in flammatory bowel disease. An unexpected association

Resumen La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias prima rias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

Abstract Very early onset inflammatory bowel disease (VEOI BD) is a rare entity in pediatrics. Its association with pri mary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endo crine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

Hereditary pheochromocytoma/paraganglioma and associated syndromes:a clinical and genetic study / 陆军军医大学学报

Objective To summarize and analyze the clinical phenotypes,hereditary features and treatment and follow-up strategies of different hereditary pheochromocytoma/paragangliomas(PCC/PGL)and related syndromes.Methods Forty-four clinically diagnosed PCC/PGL patients admitted in our hospital from January 2000 to August 2022 were enrolled,and the clinical data of them and their family members were collected.Second-generation sequencing was performed on 43 patients for genetic detection,and Sanger sequencing was applied to verify the mutation of the probands and family members.Results There were 15 patients diagnosed with hereditary PCC/PGL,including 7 cases of von Hippel-Lindau(VHL)syndrome,3 cases of multiple endocrine neoplasia type 2(MEN2),and 5 cases of familial paraganglioma syndrome.Seven VHL syndrome families were diagnosed as VHL2A(c.500G＞A),VHL2B(c.239G＞T and c.444_457del),and VHL2C(c.293A＞G)according to their clinical manifestations.All probands received surgical treatment,and 2 cases of recurrent PCC and the patients with multiple renal cancer also received targeted therapy with sunitinib.Three MEN2 families carried c.1901G＞C,c.1832G＞A,and c.1901G＞A missense mutations,respectively,and were diagnosed with MEN2A clinically.All of them underwent adrenalectomy and thyroidectomy,including one for preventive thyroidectomy.Among the 5 familial paraganglioma syndrome families,4 patients carried SDHB mutations(SDHB:c.343C＞T,c.541-2A＞G,c.575G＞A,c.268C＞T)and 1 patient carried an SDHD mutation(SDHD:c.337_340del).Sporadic retroperitoneal PGL were most common.Conclusion More than 1/3 of PCC/PGL patients carry germline gene mutations,showing obvious genotype-phenotype correlation.Genetic diagnosis technology plays an important guidance role for clinical precision treatment and follow-up,and genetic counseling.

Evaluation of RET-He values as an early indicator of iron deficiency anemia in pregnant women

Abstract Introduction During pregnancy, women are at an increased risk of developing iron-deficiency anemia. Objective The objective of this study was to assess the diagnostic performance of the reticulocyte hemoglobin equivalent (RET-He) in the early detection of iron-deficiency anemia in a group of pregnant women and to establish a reference range for this parameter in a group of control individuals. Method: A total of 60 patients and 130 control subjects were included in the study. Blood samples collected from the subjects were submitted to a complete blood count and a serum ferritin test and the data were analyzed by comparing the groups and ROC curves. Results The reference range found for the RET-He was between 29.75pg and 38.24pg, with a median of 35pg. The receiver operating characteristic (ROC) curve analysis for the ferritin parameter showed an area under the curve of 0.732 for the RET-He, 0.586 for hemoglobin, 0.551 for the mean corpuscular hemoglobin concentration and 0.482 for the mean corpuscular volume. Conclusion Early diagnosis of iron deficiency anemia in pregnancy is essential to prevent damage to both maternal and fetal health. The RET-He presents an excellent potential as an auxiliary tool for the diagnosis of iron deficiency in pregnant women.

Progress and challenges in RET-targeted cancer therapy / 医学前沿

The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

Diagnóstico mutacional del gen RET y la medicina de precisión en México / RET gene mutational diagnosis and precision medicine in Mexico

Resumen La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.

Abstract Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.

SCREENING OF RETINOPATHY OF PREMATURITY USING INDIRECT OPHTHALMOSCOPE AND RETCAM : A PROSPECTIVE OBSERVATIONAL STUDY

Background:Aim And Objectives:To study the incidence of Retinopathy of Prematurity in Low birth weight Neonates and Preterm who are at high risk, by screening with Binocular Indirect Ophthalmoscope and Ret Cam 3 resulting in early diagnosis and further management of disease will prevent blindness and other complications in children due to ROP. Material And Methods:Prospective Observational study included 60 Newborns (25 female,35 male) with GA <34 weeks and/or birth weight <1750 grams, and GA 34-36 weeks and/or birth weight 1750-2000 grams with risk factor, screened with First Binocular Indirect Ophthalmoscope and then after 30 minutes with Ret Cam 3. Result:Both the techniques are equally effective in detection and staging of Retinopathy of Prematurityscreening.Conclusion:Both techniques give satisfactory results for screening of Retinopathy ofPrematurity and are comparable to each other, both having their own pros and cons.

Treatment progress of non-small cell lung cancer with RET gene fusion / 肿瘤研究与临床

Non-small cell lung cancer (NSCLC) is a malignant tumor with rapid progress and high malignancy, accounting for 85% of all lung cancers. Treatment has shifted from traditional surgery, radiotherapy and chemotherapy to targeted therapy. Targeted therapy can prolong the survival of patients with positive driver gene fusion. With the continuous progress of biological research, targets related to NSCLC have gradually been discovered. Among the many driving genes of NSCLC, RET fusion is an important emerging target discovered in recent years. It has been confirmed to have a high incidence in non-smoking, young and low-differentiated NSCLC patients. This article reviews RET gene fusion in NSCLC, the relationship between the two and the treatment progress.

Clinical investigation and ret proto / 西安交通大学学报(医学版)

【Objective】 To investigate the clinical features and gene analysis of one pedigree with multiple endocrine neoplasia type 2A （MEN2A） so as to clarify the diagnosis and classification of the disease， guide treatment and prevention， and improve prognosis. 【Methods】 The clinical data of a 36-member MEN2A family， including 6 probands， with medullary thyroid carcinoma， were investigated， and the peripheral blood genomic DNA of 28 family members （blood sample of one proband was not collected） was extracted. PCR amplification was performed on exons 8， 10， 11， 13， 14， 15 and 16 of the RET gene， and the products were directly sequenced. 【Results】 Review of the medical history showed that two probands with medullary thyroid carcinoma were accompanied with hyperparathyroidism， and one family member had pheochromocytoma. The RET gene mutation test confirmed that 13 family members， consisting of 5 probands and 8 family members， had the RET proto-oncogene exon 10 missense mutation. The heterozygous missense had mutation c.1852T>A， leading to the conversion of cysteine （TGC） at position 618 to serine （AGC） （Cys618Ser）. All subjects carrying RET gene Cys618Ser mutation had abnormal thyroid ultrasound change， accompanied with elevated calcitonin levels. Subjects carrying wild type of RET gene had normal calcitonin levels. The family was finally diagnosed with MEN2A by RET gene detection. 【Conclusion】 RET gene detection plays key role in the diagnosis and treatment of patients with MEN2A family and has guiding value in the follow-up and prognosis of asymptomatic carriers. There is a positive correlation between calcitonin level and the RET protooncogene mutation Cys618Ser. Patients suspected of MEN2A should be screened in time.

Use of the reticulocyte channel warmed to 41 °C of the XN-9000 analyzer in samples with the presence of cold agglutinins

ABSTRACT Objectives The purpose of this study was to compare data obtained from the reticulocyte channel (RET channel) heated to 41 °C with those obtained from impedance channel (I-Channel) at room temperature in the samples with the mean corpuscular hemoglobin concentration (MCHC) < 370 g/L and in samples with the MCHC > 370 g/L, in the presence of cold agglutinins. Methods In this study, 60 blood samples (group 1) with the MCHC < 370 g/L (without cold agglutinins) and 78 blood samples (group 2) with the MCHC > 370 g/L (with cold agglutinins) were used to compare the two analytical channels of the XN-9000 analyzer in different preanalytical conditions. The parameters evaluated in both groups were the following: red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean cell volume (MCV), RBC-most frequent volume (R-MFV), mean hemoglobin concentration (MCH) and mean cellular hemoglobin concentration (MCHC). Results The results of this study showed an excellent correlation with both channels of the XN-9000 analyzer in samples with and without cold agglutinins, except for the MCHC. The bias between the values obtained in the I-channel and those obtained in the RET channel of both groups was insignificant and remained within the limits of acceptability, as reported by Ricos et al. for all considered parameters, except for MCHC. Conclusions The presence of cold agglutinins in blood samples can be detected by a spurious lowering of the RBC count and by a spurious increase in the MCHC. The RET channel represents a great opportunity to correct the RBC count in a rapid manner without preheating. However, neither methodology can completely solve the residual presence of cold agglutinins in all samples, despite the MCHC values being < 370 g/L.

Advances in the Treatment of RET Fusion-positive Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Rearranged during transfection (RET) fusions are found in 0.7% to 2% of non-small cell lung cancer (NSCLC). Fusions between RET gene and other domains represent the distinct biological and clinicopathological subtypes of NSCLC. Recent years have witnessed the remarkable advancement of RET fusion-positive advanced NSCLC therapy. Conventional chemotherapy produced moderate clinical benefits. Prior to the introduction of targeted therapy or in the context of unavailability, platinum-based systemic regimens are initial therapy options. Immunotherapy predicted minimal response in the presence of RET fusions while currently available data have been scarce, and the single-agent immunotherapy or in combination with chemotherapy regimens are not recommended as initial systemic therapy in this population. The repurpose of multi-target kinase inhibitors in patients with RET fusion-positive NSCLC showed encouraging therapeutic activity, with only cabozantinib and vandetanib being recommended as initial or subsequent options under certain circumstances. However, there are still unmet clinical needs. Pralsetinib and selpercatinib have been developed as tyrosine kinase inhibitors (TKI) selectively targeting RET variation of fusions or mutations, and both agents significantly improved the prognosis of patients with RET fusion-positive NSCLC. Pralsetinib and selpercatinib have been established as preferred first-line therapy or subsequent therapy options. As observed with other TKIs treatment, resistance has also been associated with RET targeted inhibition, and the acquired resistance eventually affect the long-term therapeutic effectiveness, leading to limited subsequent treatment options. Therefore, it is essential to identify resistance mechanisms to TKI in RET fusion-positive advanced NSCLC to help reveal and establish new strategies to overcome resistance. Here, we review the advances in the treatment of RET fusion-positive advanced NSCLC.
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Assessment of Reticulocyte-haemoglobin Equivalent (Ret-He) as a Diagnostic Indicator for Iron Deficiency Anaemia

@#Introduction: Iron deficiency anaemia (IDA) is the most common cause of anaemia. The diagnosis of IDA, however, remains a challenge and is a problem worldwide. Serum iron study is commonly used for IDA diagnosis but there are some limitations. This study was conducted to evaluate reticulocyte-haemoglobin equivalent (Ret-He) as a screening tool for IDA diagnosis in adults. Method: This is a comparative case control study conducted in Hospital Tengku Ampuan Afzan, Kuantan consisting of adult patients with iron deficiency anaemia and a healthy control group. Haematological parameters (Hb, RBC count, MCV, MCH, RDW) inclusive of Ret-He and serum iron parameters (serum iron, transferrin saturation and serum ferritin) were measured. Correlation between Ret-He with other haematological and serum iron parameters were analysed. Results: There were 103 IDA adult patients with majority of them being female (85.4%) with median age of 36 years old. Malay ethnicity (79.6%) contributed to the larger proportion of adult IDA patients. The Ret-He value for patient and control groups were 16.50 ± 4.90 pg and 34.80 ± 1.97 pg, respectively. Ret-He was 89.32% sensitive and 100% specific with 100% positive predictive value (PPV) and 73.11% negative predictive value (NPV) when compared to transferrin saturation. There was significant correlation between Hb, MCH, MCV, RDW and serum iron, transferrin saturation and serum ferritin parameters with Ret-He. Conclusion: Ret-He together with a complete blood count, may serve as an alternative to the serum iron parameters for screening of IDA in adults.

Multiple endocrine neoplasia-IIb with RET gene mutation p.M918T： A case report / 中南大学学报(医学版)

Multiple endocrine neoplasia-IIb (MEN-IIb) is a rare hereditary autosomal dominant syndrome caused by mutations in the RET proto-oncogene. It's characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), mucosal neuromas, and Marfanoid habitus. Because of the rarity of MEN-IIb and finiteness of clinical cognition, the majority of the patients suffer a delayed diagnosis. A MEN-IIb patient with the lingual mucosal neuromas since childhood was admitted in the Third Xiangya Hospital of Central South University in November, 2018. He had surgical history of mitral valve prolapse and spinal deformity. He was diagnosed with MTC and PHEO at the age of 22 and 28, respectively, and received surgical treatments. Sequencing of RET gene revealed a de novo heterozygous p.M918T mutation in the patient. Being aware of the unique clinical phenotype and screening of RET gene mutation may lead to the early diagnosis and better long-term outcome for MEN-IIb.

Multiple Endocrine Neoplasia Type 2B (MEN2B) delayed diagnosis: importance of opportune recognition of MEN2 Syndromes in pediatric thyroid cancer

ABSTRACT Background: RET proto-oncogene mutations are responsible for familial thyroid medullary carcinoma and multiple endocrine neoplasia (MEN) type 2A and 2B. These syndromes develop specific biomarkers and, in the case of MEN2B, clinically observable stigmas. However, the diagnosis of patients with MEN2B is usually delayed. Because of the close genotype-phenotype correlation, molecular testing is the final approach for the diagnosis to establish preventive care and therapeutic behaviors. Discussion: pM918T is classified as ''highest risk'' for medullary carcinoma with a 50% of lifetime risk for developing pheochromocytoma. Most cases of MEN2B are due to a de novo mutation. Even with the increased risk of developing pheochromocytoma, our 24-year-old patient does not yet present one. Other factors may be involved in the modulation of the phenotype in different populations. Case report: We present the case of a woman diagnosed with a thyroid nodule at the age of nine. She underwent a total thyroidectomy plus radical cervical lymph node dissection, with a diagnosis and initial management of papillary thyroid carcinoma. During the evolution of the disease, she developed pulmonary metastases. At the age of 24, after her first endocrinological evaluation, typical physical manifestations of MEN2B were observed. A re-evaluation of the original thyroidectomy revealed a medullary carcinoma, with positive manifestation CEA and calcitonin. The analysis of RET proto-oncogene identified a de novo mutation in exon 16 (pM918T). Conclusion: The timely diagnosis of MEN2B offers opportunities to make appropriate preventive and therapeutic decisions that may change the natural evolution of the disease and its complications.

Detection of interleukin-6 levels in serum and thyroid tissue of patents with papillary thyroid carcinoma and their significances / 吉林大学学报(医学版)

Objective: To investigate the relationship between interleukin-6 (IL-6) and papillary thyroid carcinoma (PTC), and to elucidate the role of IL-6 in the occurrence and development of PTC and its possible mechanism Methods: The serum levels of IL-6 were measured by ELISA method in 5 patients with PTC (case 1 group), 5 patients with Hashimoto thyroiditis (HT) complicated with PTC (case 2 group) and 5 normal persons (normal group). The thyroid tissues of 20 patients with PTC (PTC group), 15 patients with HT complicated with PTC (HT +PTC group) and 18 normal persons (control group) were collected. The positive expression rates of IL-6, IL-6 receptor (IL-6R), nuclear factor kappa-B (NF-κB) and RET/PTC proteins in thyroid tissue of the subjects in various groups were detected by immunohistochemistry (IHC) method; the relationships between IL-6, IL-6R and NF-kB, RET/PTC expressions were analyzed. Results: In the patients with PTC, the complex papillary hyperplasia of thyroid epithelial cells accompanying with ground glass like nuclei and nuclear sulcus and inclusions were seen; in the patients with HT complicated with PTC, in addition to the typical pathological changes of PTC, the diffuse lymphoid tissue infiltration accompanying with lymphoid follicle formation, and the coexistence of hyperplasia and atrophic thyroid follicular epithelium with eosinophic degeneration of thyroid epithelium and interstitial fibrosis were also found. The lobular structrure of normal thyroid tissue was found, and the follicular cells were in the same size The ELISA results showed that the serum IL-6 levels of the patients in PTC group and HT+ PTC group were higher than those in normal group (P<0. 05); the IHC results showed that the positive expression rates of IL-6, IL-6R, NF-κB, and RET/PTC in thyroid tissue of the patients in PTC group were higher than those in control group (P<0. 05). The expressions of IL-6, and IL-6R were positively correlated with the expressions of NF-kB and RET/PTC protein (P<0. 05). Conclusion: IL-6 may be involved in the occurrence and development of PTC through the RET/PTC-NF-B signal pathway.

A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals

ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

A comparison of clinical characteristics between 2 pedigrees of multiple endocrine neoplasia type 2A with different RET mutations / 中华内科杂志

Multiple endocrine neoplasia type 2A (MEN2A) is a hereditary syndrome. Here, two different RET proto-oncogen mutation were identified from family members of two MEN2A pedigrees by genetic screening. One RET mutations were found at codons 1893 and 1895 in exon 11 (1893-1895delCGA) from pedigree 1, which is a novel mutation, the other occurs at codon 634 (Cys634Arg) in exon 11 from pedigree 2. However, the clinical characteristics were similar in the patients of the two pedigrees. All the patients were in middle-age at onset. Most of them were firstly diagnosed with bilateral adrenal pheochromocytoma with different degrees of thyroid abnormalities (elevated serum calcitonin with or without thyroid mass, or had been diagnosed with medullary thyroid carcinoma). Some family members were with elevated serum parathyroid hormone but with no other evidences for hyperparathyroidism.

The mutation site and the targeted therapy of RET proto-oncogene in medullary thyroid carcinoma / 中华内分泌外科杂志

Medullary thyroid carcinoma (MTC) is an endocrine tumor originating from the parafollicular cells of the thyroid gland.The mutation of RET gene has been considered as the molecular basis of MTC.Different types of MTC have different RET mutation sites,and the corresponding clinical manifestations and prognosis are also very different.RET gene detection is helpful for individual accurate gene diagnosis,molecular risk assessment,individual analysis and early prevention management.Nowadays,targeted therapy for RET gene mutations in MTC has developed rapidly.Some of those drugs,which have been approved for clinical application,bring new hope for advanced MTC.

A novel RET mutation identified in a patient with pheochromocytoma and renal cell carcinoma / 고신대학교의과대학학술지

Pheochromocytomas might be sporadic or genetic. Genetic pheochromocytoma is associated with multiple endocrine neoplasia (MEN) type 2A, MEN type 2B, and von Hippel-Lindau (VHL) disease. RET mutations are identified in more than 90% of index cases of MEN2 and familial medullary thyroid cancer and in about 4–12% of apparent sporadic cases. Here, we report a 54-year-old man presenting with pheochromocytoma and renal cell carcinoma, who was identified as having a novel missense RET mutation.

Toxicity study of oral administration of Shufeng Jiedu Capsule for 14 d in SD rats during peri-weaning period / 中草药

Objective To characterize the oral toxicity of Shufeng Jiedu Capsule (SFJD) in SD rats during peri-weaning period, and provide reference for the clinical application of SFJD in infants. Methods Ten-day-old healthy SD rats were exposed to 0 and 4 g/kg of SFJD once per day for 14 d via intra-gastric administration. Mortality, general physical signs, body weights, spontaneous motor activity, learning and memory functions, hematology (with T and B lymphocyte subgroups included), serum chemistry, serum testosterone, insulin-like growth factor, organ weights, as well as gross pathological findings were evaluated between the control and exposure group. Physical development indicators such as pinna unfolding, coat growth, incisor eruption, and eyes opening time, were also recorded. The body length and tail length of rats under anesthesia were detected. Results After SFJD administration, loose stools and orange colored urine were found in rats, and the color of the urine was related to the color of drugs. The body weight growth rates were decreased compared with the control group. Urine specific gravity was increased in rats. RBC and Ret concentrations were decreased in two of the 16 tested animals. Liver, spleen, and kidney ratios to body and brain weight were increased in rats; The weight of spleen was also increased compared with the control group. Conclusion It was well tolerated to peri-weaning rats after the ig administration of 4 g/kg SFJD. The concerns of diarrhea, mild body weight growth rate, as well as RBC and Ret decrease should be noted for long term and high dose usage in infants and toddlers.

EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells

PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.