Volume 99 ·  Issue 36 ·  2019

Pancreatic neuroendocrine tumors are a group of heterogeneous tumors, with obvious differences in clinical manifestations and clinical course. Most patients have already developed distant metastasis at the time of diagnosis, or even lost the opportunity of surgery. With the research progress of this disease, the current related treatment plan has gradually changed from the original single surgical treatment to multidisciplinary comprehensive treatment such as surgery, drug and radiotherapy. Especially in drug therapy, individualized specific therapy has become the hot spot of future clinical application. Due to the low incidence of this tumor, related tumor molecular research is not very in-depth. At present, there is no suitable method to accurately screen out specific tumor molecular changes in individual patients. Targeted therapy for specific molecular changes has great research potential and clinical application prospects. This paper mainly discusses the latest research progress in genetics and epigenetics of pancreatic neuroendocrine tumors, and expounds the main molecular changes and therapeutic prospects.

To analyze the clinical characteristics and the effect of targeted drug therapy of portopulmonary hypertension (PoPH).

A total of 5 patients with PoPH who were admitted to the Department of Pulmonary and Critical Care Medicine of Beijing Chao-Yang Hospital from January 1, 2017 to December 31, 2018 were included. The clinical information and follow-up data were collected. The patient′s medical history, clinical manifestations, right cardiac catheterization (RHC), classification of cardiac and hepatic function, treatment and prognosis were analyzed.

Among the 5 patients with PoPH, 3 were male and 2 were female. The median age was 56 years. The underlying diseases of portal hypertension were all cirrhosis, and 1 patient combined with hepatopulmonary syndrome (HPS). Dyspnea was the main respiratory symptom in all the 5 patients, and the median time from symptom onset to diagnosis was 1 year (5 months to 8 years). RHC was used as the diagnostic criteria for pulmonary hypertension in all patients, with a median mean pulmonary arterial pressure of 42 mmHg (1 mmHg=0.133 kPa) and a median pulmonary vascular resistance of 538 dyn·s·cm^-5. 3 cases were in Child-Pugh liver function grade B, and 2 were in grade A. The hepatic reserve function was not matched with the severity of cardiac insufficiency. Liver transplantation was performed in 1 patient, whose right ventricular dysfunction can be alleviated by targeted drug therapy after operation. All the 5 patients received targeted drug therapy of pulmonary hypertension. In the 3 patients who were regularly treated with targeted drugs and followed up on time, the cardiac function was improved during the follow-up period. There was no improvement or even deterioration of cardiac function in 2 patients who were not regularly treated or followed up. One patient died after liver transplantation. The cause of death was severe pneumonia and right ventricular dysfunction. The survival time after transplantation was 1 year.

In PoPH patients, the hepatic reserve function is not matched with the heart function classification. PoPH can coexist with HPS. Regular application of pulmonary hypertension targeting drugs may benefit patients with PoPH.

To assess the methylation level of SHP-1 promoter region and the effects on the phosphorylation of the Signal Transducers and Activators of Transcription 3 (STAT3) protein in bone marrow specimen of patients with myelodysplastic syndrome (MDS), and to explore the relationship of SHP-1 methylation and prognosis of the patients.

Bone marrow specimens of 93 patients with MDS were collected from the General Hospital of Tianjin Medical University from September 2010 to June 2014. The enrolled subjects included 54 males and 39 females and they were divided into the low-risk group (IPSS score:0-1.0, median: 0.5) and the high-risk group (IPSS score: 1.5-3.0, median: 2.5) according to the International Prognostic Score System (IPSS). The methylation level of SHP-1 was detected by methylation-specific polymerase chain reaction, and the level of p-STAT3 was detected using Western blot.

In the high-risk group, 64.44% (29/45) of the patients had methylation in the SHP-1 promoter region, which was significantly higher than the low-risk group 22.92% (11/48). Therefore, SHP-1 methylation was frequently presented in the patients of the high-risk group. Similarly, 66.67% (30/45) of the patients in the high-risk group had positive STAT3 phosphorylation status, whereas only 20.83% (10/48) were tested positive in the low-risk group. In addition, correlation analysis also revealed that the SHP-1 methylation rate was positively correlated with the positive rate of STAT3 phosphorylation (r=0.57,P<0.001).

SHP-1 methylation is significantly correlated with the risk of MDS patients. It may be used as an independent predictor of shorter survival in patients of the high-risk group. The increased level of SHP-1 methylation will lead to the uncontrolled activation of the downstream JAK/STAT3 pathway, which in turn can cause further positive feedback to amplify the carcinogenic signal.

To compare the serial changes of circulating angiopoietin-2 (Ang-2), surfactant protein D (SP-D) and soluble receptor for advanced glycation end product (sRAGE) in patients with pulmonary acute respiratory distress syndrome (ARDS) and extrapulmonary ARDS.

A total of 36 eligible patients with ARDS were included from the Department of Respiratory Intensive Care Unit(RCU) and Department of Intensive Care Unit (ICU), the Central Hospital of Wuhan, during April 2017 to February 2018, and divided into pulmonary ARDS group (n=20) and extrapulmonary ARDS group (n=16) according to primary causes. The levels of Ang-2, SP-D and sRAGE in serum of each group were measured on Day 1, 4 and 7 after diagnosis.

The serum level of Ang-2 in extrapulmonary ARDS group declined gradually during the course. The serum level of Ang-2 on Day 1 was significantly higher than that on Day 7 [2 801 (1 386, 7 526) vs 1 461 (737, 2 135) ng/L, P<0.05]. There was no significant difference in serum levels of Ang-2 on Day 1, 4, 7 in pulmonary ARDS group [1 462 (545, 3 715) vs 1 353 (659, 5 847) vs1 616 (754, 3 460) ng/L, all P>0.05]. There was no significant difference in serum levels of SP-D on Day 1,4, 7 in each group [pulmonary ARDS group: 5.6(1.8, 14.0) vs 5.7(1.8, 14.5) vs 7.9(3.0, 16.8) mg/L, all P>0.05; extrapulmonary ARDS group: 3.4(0.5, 9.1) vs 1.6(0.6, 6.3) vs 1.6(0.7, 7.9)mg/L, all P>0.05]. The serum level of sRAGE in each group declined gradually during the course. The serum level of sRAGE on Day 1 in each group was significantly higher than that on Day 7 [pulmonary ARDS group: 328(107, 595) vs 66 (50,171) ng/L, extrapulmonary ARDS group: 237 (98, 410) vs 81 (38, 154) ng/L, all P<0.05].

The serum level of Ang-2 in extrapulmonary ARDS declines significantly in the early stage of disease, while there is no significant difference in that of pulmonary ARDS.

To investigate the genetic characteristics and clinical outcomes of pediatric acute myeloid leukemia patients with NUP98-NSD1 fusion gene.

A total of 80 pediatric AML patients were enrolled in this study, and bone marrow specimens were collected at initial diagnosis and relapse. NUP98-NSD1 was screened by fluorescence in situ hybridization (FISH) and PCR. Other laboratory test results and clinical outcomes were further analyzed for the NUP98-NSD1 positive cases.

A total of eight patients (10.0%) were positive for NUP98-NSD1, which were all fusions of NUP98 exon12 and NSD1 exon 6. There were two M2, three M4, and three M5 cases according to the French-American-British classification. Seven patients had karyotype results at the time of initial diagnosis, and none of them had complicated karyotype abnormalities. Among these patients, two cases had normal karyotype, three cases had trisomy 8, one case had trisomy 6, and two cases had anomalies involving 9q13 or 9q21. Additional karyotypic abnormalities and clonal evolutions were observed during disease progression or relapse, five cases had 9q13 or 9q32 abnormalities. Five cases (62.5%) were positive with FLT3-ITD mutation. Patients were treated with DAE/NAE/HAE/IA chemotherapy. Three cases did not achieve remission after several courses of chemotherapy, and five cases achieved remission but relapsed in 1 to 19 months. Five cases underwent salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among whom, four died in 40 days to 4 months after transplantation, and one survived 8.5 months till the last follow-up.

NUP98-NSD1 is a recurrent genetic abnormality with significant clinical prognostic significance, and this group of disease has unique clinical and genetic characteristics. NUP98-NSD1 should be screened by FISH or PCR for children with AML who are newly diagnosed or refractory and relapsed to identify the high-risk genetic marker.

To compare eradication rates and compliance of patients with Helicobacter pylori(H. pylori)infection based on clarithromycin sensitivity.

From July 2015 to January 2018,patients with H. pylori infection in Peking university people′s hospital were randomly assignedto a 14-day treatment with clarithromycin quadruple therapy versus tailored quadruple therapy for a prospective study. In the group of tailored therapy, medications were adjusted based on clarithromycin sensitivity. In the control group, all patients were given proton pump inhibitors (PPI), amoxicillin, clarithomycin and bismuth. Eradication status was assessed 4 weeks after treatment withurea breath test.

The H.pylori eradication rate were higher in the tailor therapy group than that in the control group in intention-to-treat[77.8% vs 65.3%,(P=0.001)] and per,protocol analyses [86.4% vs 70.2%,(P<0.001)], the differences between the two groups were statistically significant.The incidence of compliance between the two groups were also comparable.

The tailored therapy basedon clarithromycinsensitivity has a better eradication efficacy and a higher eradication ratesin the patients with H. pylori infection.

To investigate the expression of Golgi phosphoprotein 3 (GOLPH3) in papillary thyroid carcinoma (PTC) and its relationship with clinicopathological characteristics of PTC and American Thyroid Association (ATA) risk of recurrence stratification.

The mRNA expression level of GOLPH3 in PTC tissues and the matched adjacent noncancerous tissues from 30 cases of PTC undergoing surgical operation in Fujian Provincial Hospital between March 2017 and April 2018 was detected by reverse transcription-quantitative PCR (RT-qPCR). The protein expression of GOLPH3 in PTC tissues and the matched adjacent noncancerous tissues of 135 cases of PTC between January 2013 and April 2018 was measured by immunohistochemistry. The correlation between the expression of GOLPH3 in PTC and clinicopathologic characteristics and ATA risk of recurrence stratification was analyzed.

The mRNA level of GOLPH3 in PTC tissues was significantly higher than that in adjacent noncancerous tissues (7.53±1.32 vs 3.64±1.44, P<0.001). The protein expression level of GOLPH3 in PTC tissues was significantly higher than that in adjacent noncancerous tissues [66(30, 95) vs 34(20, 72), P<0.001]. The expression of GOLPH3 was significantly correlated to the tumor size (P=0.026), extrathyroid invasion (P=0.016), lymph node metastasis (P=0.001) and TNM stage (P=0.027) in PTC. Multivariate logistic regression analysis showed that GOLPH3 expression was independently correlated to tumor size (OR=3.58, 95%CI: 1.19-15.46, P=0.017) and lymph node metastasis (OR=7.28, 95%CI: 2.43-10.08, P=0.002). The expression of GOLPH3 was positively correlated to ATA risk of recurrence stratification (P=0.041).

Overexpression of GOLPH3 is associated with the development of PTC and poor prognosis in patients with PTC. Detection of GOLPH3 expression can help evaluate proliferative and metastatic potential of PTC, as well as the risk of postoperative recurrence in patients with PTC.

To explore the significance of prostate central gland/total gland volume (PVc/PV) ratio combined with PSA in the diagnosis of PSA 4-20 ng/ml prostate cancer patients.

Data of patients undergoing prostate puncture in Minghang Branch, Zhongshan Hospital from July 2015 to December 2018 were retrospectively analyzed. The anteroposterior, transverse and axial diameters of the prostate and the central prostate gland were measured by magnetic resonance imaging (MRI). The differences of tPSA, f/tPSA, PSAD and PVc/PV between the prostate cancer group and non-prostate cancer group were compared. Receiver operating characteristic (ROC) curves of prostate cancer diagnosis were plotted according to tPSA, f/tPSA, PSAD, PVc/PV alone and PVc/PV combined with tPSA, respectively, and the area under the curve (AUC) was calculated and compared using tPSA as the reference.

There was no significant difference in tPSA between the two groups (P>0.05). However, significant differences were observed in f/tPSA, PSAD and PVc/PV between the two groups (P<0.05). The AUC value of PVc/PV combined with tPSA, PVc/PV and PSAD was 0.901 2,0.866 7 and 0.848 1,respectively, which were statistically different from that of tPSA (P<0.05). The AUC value of f/tPSA was 0.716, which was not statistically different from that of tPSA (P>0.05).

The PVc/PV ratio combined with tPSA can be used as an important reference index for the diagnosis of prostate cancer in PSA 4-20 ng/ml patients.

To evaluate the feasibility and clinical value of suprapubic-assisted laparoendoscopic single-site surgery (SA-LESS) in nephroureterectomy using method of transvaginal natural orifice specimen extraction (NOSE) (SA-LESS+TV-NOSE NU).

Four patients (three cases of renal pelvic carcinoma and one case of ureteral carcinoma) undergoing SA-LESS+TV-NOSE NU were enrolled between April 2015 and January 2016. After general anesthesia, the patients were placed in the lithotomy position with the affected side elevated by 60°. Two trocars were inserted at the medial margin of umbilicus, and the third one was inserted into abdominal cavity at the superior margin of pubic symphysis. The operation was performed under a direct vision with a 5.4 mm 0° flexible-tip laparoscope. Firstly, the distal ureter was isolated completely and blocked by a Hem-O-lok clip. Then, the laparoscopic nephrectomy was performed according to the standard method. Finally, the bladder cuff excision was executed and the incision was sutured. The intact specimen was placed inside a homemade bag and removed through the incision at posterior vaginal fornix.

All the procedures were successfully performed. The median operative time was 150 (range: 120 to 210) minutes, and the median estimated blood loss was 180 (range: 80 to 350) ml. No major perioperative complications occurred. The mean visual analogue score (VAS) of 24 hours and 48 hours after operation were 3.25 (range: 2 to 5) and 2.25 (range: 2 to 3). All the patients resumed ambulation on postoperative day 1. Pelvic drainage tube was removed on postoperative day 2-4. On postoperative day 7, urethral catheter was removed. The patients were discharged on postoperative day 7-9. During the follow-up of 20-29 months, the patient recovered well with no case of incisional hernia and pelvic, abdominal infections. The vaginal fornix incision healed well, and the umbilical and suprapubic puncture scars were not obvious. All the patients completed the patient-assessed acromegaly symptom questionnaire PASQ. The average PSAQ score of 3 months after surgery was 34.5. Three of them restarted their sex lives, with an average female sexual function index score of 16.0, which was not significantly different with that of preoperation (15.6). There was no tumor recurrence, metastasis and implantation in all cases.

SA-LESS+TV-NOSE NU is safe and feasible for upper tract urothelial carcinoma with faster postoperative recovery, less pain, shorter hospitalization time, better cosmetic results, and does not cause negative effect on the female sexual function.

To evaluate the efficacy and safety of Anlotinib as a third-line therapy in patients with metastatic colorectal cancer.

Anlotinib was administered to patients with advanced colorectal cancer who had received ≥ second-line standardized treatment, with 12 mg daily lasting for 2 weeks and withdrawal of drugs for a week. The relevant clinical information and treatment protocols were recorded.The efficacy and safety of anlotinib were followed up.

A total of 26 patients were enrolled in the study group, and 24 patients could be evaluated, including 2 cases of partial response (PR) and 16 cases of stable disease (SD).The object response rate (ORR) and disease control rate (DCR) were 8.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 4.3 months (95% CI: 2.9-5.7 months) and 14.7 months (95% CI: 10.0-19.4 months), respectively. The most common adverse reactions were fatigue in 17 cases (17/26) and hand-foot skin reactions in 16 cases (16/26). Analysis of Kaplan-Meier revealed that without liver metastasis (95% CI: 11.7-32.3, P=0.011) and left-sided colonic cancer (95% CI: 11.7-46.1, P=0.014) were related to longer OS.

Anlotinib as a third-line therapy for advanced colorectal cancer is feasible with high disease control rate and minor side effects.

To explore the role and its molecular mechanism of miR-328 during the differentiation of embryonic stem cells (ESCs) into insulin-producing cells (IPCs) in vitro.

Mouse embryonic stem cell line-mESCs-Nanog-GFP was induced in conditioned medium and divided into negative control group, miR-328 agomir transfected group, miR-328 antagomir transfected group and transforming growth factor β2 (TGF-β2) siRNA transfected group. The function of IPCs was identified by real-time quantitative PCR (qPCR) detecting system and immunofluorescence in above-mentioned groups. Methods of qPCR, immunofluorescence and enzyme-linked immunosorbent assay (ELISA) were used to detect effects of overexpression and inhibition of miR-328 on differentiation of multilineage precursor cells. We predicted the binding sites of miR-328 and TGF-β2 by performing the bioinformatics analysis. Dual luciferase reporter gene and Western blotting were employed to identify the regulatory relationship between miR-328 and TGF-β2.

mESCs could be transfected with miR-328 agomir, with an efficacy of 70%-80%. Up-regulated miR-328 in MPCs reduced the RNA expression of several key transcription factors which were crucial for early pancreatic development. Additionally, the insulin released by IPCs decreased in response to glucose stimulation (all P<0.05). However, overexpression of miR-328 led to the decrease of protein level of insulin and Nkx6.1 (all P<0.05). Transfection of miR-328 antagomir had the opposite effects (P<0.05). The dual luciferase reporter gene assay revealed that miR-328 functioned via binding to the 3′ non-coding region (3′-UTR) of the TGF-β2. Western blotting indicated that miR-328 regulated protein expression. After knockdown of miR-328, the relative expression of TGF-β2 was 1.00±0.01. After co-transfection of miR-328 antagomir and TGF-β2 siRNA, the relative expression of TGF-β2 was 0.80±0.03. After downregulating TGF-β2, the relative expression of TGF-β2 was 0.20±0.01. Knockdown of TGF-β2 down-regulated the expression of early pancreatic transcription factors (P<0.05) and inhibited Pdx1⁺cell differentiation.

miR-328 can inhibit the differentiation of ESCs into IPCs via binding to 3′ UTR of TGF-β2, and provide a new regulatory pathway for the treatment of diabetes with stem cells.

From May 1, 2015 to August 31, 2018, among the 128 patients with advanced tumors treated with programmed cell death protein receptor-1 (PD-1) monoclonal antibody in the Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University, 4 cases (3.1%) were clinically diagnosed with immune-related pneumonia, including 3 males and 1 female, aged 27-79 years old; The primary diseases were renal clear cell carcinoma (2 cases), lung squamous cell carcinoma (1 case) and Hodgkin's lymphoma (1 case). The onset time of immune-related pneumonia was 14 days to 3 months after the first dose of PD-1 monoclonal antibody, with a median onset time of 1.9 months; Classification is 1 to 2 grades; The clinical manifestations are diverse, and early diagnosis is difficult.

The clinical data of 5 patients with posterior cortical atrophy were retrospectively analyzed. The clinical manifestations of the 5 patients were different, with different degrees of parietal and occipital lobe atrophy on imaging, different degrees of visual-spatial and cognitive decline on neuropsychological evaluation, and dementia in the terminal stage. The treatment and prognosis were poor.

Zinc deficiency can lead to clinical syndromes with iron deficiency anemia, hepatosplenomegaly and growth retardation, which are usually common in children, while severe zinc deficiency is rare in adults. The cases reported in this article are adult onset, mainly manifested as iron deficiency anemia, small intestinal ulcer, hepatosplenomegaly and infertility, and the treatment effect of iron deficiency anemia in other hospitals is not good. Through literature review, it was found that the clinical manifestations of this patient were consistent with zinc deficiency, and the diagnosis was confirmed after blood zinc measurement, and the treatment effect of zinc supplementation was good. It is hoped that the analysis of this case will deepen the understanding of zinc deficiency.

A child with milk caffeine spots, with right frontal bulge, asymmetric growth and progressive aggravation of both lower limbs, and nodular skin thickening of the back of the right hand and right foot, was diagnosed with McCune-Albright syndrome (MAS) after several visits to other hospitals. If this child is diagnosed with MAS, the whole picture of his clinical manifestation cannot be explained. After hospitalization in our hospital, considering that both MAS and Proteus syndrome (PS) were suspected, biopsy was taken of the diseased sites (caffeine spots, nodular thickened skin of both hands and feet), and the specimens were submitted for screening of pathogenic genes. The genetic test results of the three sites supported the diagnosis of PS. Through the analysis of the diagnosis and treatment of this case, it is suggested that the cases with sporadic, progressive and clinical manifestations of milk caffeine spots, asymmetric excessive growth of limbs and nodular skin thickening should be alert to the possibility of PS. The application of genetic diagnosis can help the early diagnosis of PS patients and reduce missed diagnosis and misdiagnosis.

A patient with malignant atrophic papulosis diagnosed in the Department of Neurology of the Third Affiliated Hospital of Sun Yat-sen University was reported. The patient had painless rash as the first symptom, and several years later, he developed neurological symptoms mainly with large brain parenchymal lesions with microhemorrhage and cranial nerve injury. Skin and brain tissue biopsy showed inflammation and occlusion-like changes of small vessels. Malignant atrophic papulosis is a kind of necrotizing vascular inflammatory disease involving the whole body with poor prognosis. Understanding its clinical characteristics, early recognition and early intervention are very important to improve the prognosis of patients.

The changes of electrocardiogram and management points of de Winter syndrome were discussed by reviewing the evolution of electrocardiogram and related clinical data of 2 young patients with de Winter syndrome. For patients with chest pain, especially young patients, the characteristics of de Winter electrocardiogram should be memorized, high-risk patients should be quickly identified in the early stage, and emergency interventional treatment should be performed as soon as possible.

Fibroblast growth factor 21 (FGF21) is an important regulator of glucose and lipid metabolism. Studies have shown that FGF21 also plays a regulatory role in bone metabolism. This paper reviews the recent research on the relationship between FGF21 and bone metabolism and the possible mechanism of its role in bone metabolism, and further explores the clinical application prospect of FGF21.

As a new experimental model, organoids play an important role in the study of colorectal cancer mechanism, genomics, screening of anti-tumor drugs, and the establishment of tumor animal models. This paper summarizes the latest research progress of organoids in colorectal cancer, in order to provide a research method for individualized treatment of colorectal cancer.