[Clinical Characteristics and Prognosis of Children with Myelodysplastic Syndrome].

OBJECTIVE: To analyze the clinical characteristics and prognosis of 40 children with myelodysplastic syndrome (MDS), and provide ideas for clinical diagnosis and treatment. METHODS: The clinical characteristics, risk stratification, and different treatment regimens of 40 cases with MDS admitted in Department of Hematology of Children's Hospital of Soochow University from January 1, 2011 to December 31, 2017 was retrospectively analyzed. Kaplan-Meier survival curve were used to estimate 3-year overall survival (OS) rate and event-free survival (EFS) rate. RESULTS: In 40 cases, the ratio of male to female was 1.4∶1.0, male was more than female, and median age was 6.0 years old. Among them, refractory cytopenia (MDS-RCC) was the most common type, and 11 cases were chromosomal abnormalities, 21 cases genetic abnormalities. Fifteen cases accepted hematopoietic stem cell transplantation (HSCT) treatment, while 25 cases did not but drug therapy alone. The 3-year OS rate of the cases who accepted HSCT or not was (72.2±12.2)% and (35.3±10.2)% (P=0.039), 3-year EFS rate was (65.0±12.9)% and (19.2±8.4)% (P=0.012), respectively. Cox regression analysis showed that age < 7 years old (P=0.0333), initial diagnosed platelet < 50×109/L (P=0.007), presence of complex karyotypes and/or gene mutations (P=0.0002), and treatment without HSCT (P=0.016) were the high-risk factors of prognosis. All the children were classified according to IPSS, WPSS and IPSS-R, while analysis result showed that the above three risk assessment had limitations for risk assessment of MDS in children, they could not comprehensively assess the prognosis of children with MDS. CONCLUSION: MDS-RCC in children is more common. Cox multivariate analysis shows that age < 7 years old, initial diagnosed platelet < 50×109/L, presence of complex karyotypes and/or gene mutation, and treatment without HSCT are the high-risk factors of prognosis in children with MDS. HSCT is the most effective treatment to cure children with MDS at present. The current methods such as IPSS-R commonly used in assessment of prognosis in children with MDS show obvious limitation.

Adult sacrococcygeal teratoma: a retrospective study over eight years at a single institution.

OBJECTIVE: To determine the clinical, imaging, and histological features, and surgical resection modalities and outcomes of adult sacrococcygeal teratoma (SCT). METHODS: Adult patients with histopathologically diagnosed SCT were enrolled in our hospital between August 2010 and August 2018. Each patient's characteristics and clinical information were reviewed. RESULTS: There were 8 patients in the study (2 males, 6 females) with a median age of 34 years (range, 18-67 years). The time to clinical symptoms was 14 d to 35 years, with a median time of 4 years. Six patients presented with symptoms of sacrococcygeal pain, and four with signs of sacrococcygeal mass and ulceration in the sacrococcygeal region. Six patients were evaluated using a combination of computed tomography (CT) and magnetic resonance imaging (MRI). All patients showed a presacral tumor with heterogeneous intensity on CT images. All patients underwent surgical treatment, including 6 parasacral, 1 transabdominal, and 1 combined anterior-posterior surgery cases. Seven patients were histopathologically diagnosed with benign mature SCT, and have shown no recurrence. One patient had malignant SCT, with recurrence at 84 months after surgery. After a second surgery, the patient had no recurrence within 6 months follow-up after re-resection. CONCLUSIONS: Our retrospective study demonstrated: (1) adult SCT is difficult to diagnose because of a lack of typical clinical symptoms and signs; (2) a combination of CT and MRI examination is beneficial for preoperative diagnosis; (3) the choice of surgical approach and surgical resection modality depends on the size, location, and components of the tumor, which can be defined from preoperative CT and MRI evaluation; (4) most adult SCTs are benign; the surgical outcome for the malignant SCT patient was good after complete resection. Even for the patient with recurrent malignant SCT, the surgical outcome was good after re-resection.

Antibiotics and immunotherapy in gastrointestinal tumors: Friend or foe?

The incidence of gastrointestinal (GI) tumors is increasing year by year, and its pathogenesis is closely related to the intestinal flora. At present, the use of antibiotics is very common in the clinic. And cancer patients with low immunity are vulnerable to all sorts of infections, such as respiratory tract infections and urinary tract infections. Moreover, cancer patients easily run into fever and neutropenia induced by myelosuppression. Therefore, antibiotics are used extensively and even overused in many conditions. However, because of the special anatomical location of the gastrointestinal tract, the antibiotic usage will bring changes to the intestinal flora. Besides, with the expanding popularity of immunotherapy, various factors affecting the efficacy of immune checkpoint inhibitors (ICIs) have been extensively explored, including cancer-associated inflammation and the local and systemic factors that lead to immunosuppression. Some biomarkers for ICIs, including the expression of PD-L1, tumor mutation load, and microbiota, also have been investigated, and many studies have confirmed that gut microbiota can affect the efficacy of immunotherapy. But further studies on the influence of antibiotics directly on immunotherapy are rare. In this review, we discuss the relationship between GI tumors and antibiotics, the current status of immunotherapy in GI tumors, and the influence of antibiotics on immunotherapy.

Long-Term Survival Outcomes After Liver Resection for Binodular Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND: The long-term prognosis after liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) is generally considered to be unfavorable. However, the role of liver resection for binodular HCC is less investigated. SUBJECTS, MATERIALS, AND METHODS: From a multicenter database, consecutive patients who underwent curative-intent liver resection for binodular HCC and without macrovascular invasion between 2003 and 2015 were retrospectively reviewed. Patients' clinical variables as well as perioperative and long-term survival outcomes were analyzed. Univariable and multivariable analyses were performed to identify the risk factors associated with overall survival (OS) and recurrence-free survival (RFS) after curative resection. RESULTS: Of 263 enrolled patients, the perioperative 30-day mortality and morbidity rates were 1.5% and 28.5%. The 1-, 3-, and 5-year OS and RFS rates were 81.5%, 52.4%, and 39.1% and 57.1%, 35.8%, and 26.6%, respectively. Multivariable Cox-regression analyses identified preoperative alpha-fetoprotein level >400 µg/L, tumor size with a sum of two nodules >8 cm, tumor size ratio of large/small nodule >1.5 (asymmetrical proportion), unilateral hemiliver distribution of two nodules, distance of ≤3 cm between two nodules, and microvascular invasion in any nodule as independent risk factors associated with decreased OS and RFS. CONCLUSION: Liver resection was safe and feasible in patients with binodular HCC, with acceptable perioperative and long-term outcomes. Sum of two tumor sizes, size ratio and distribution, and distance between two nodules were independent risk factors associated with long-term survival outcomes after surgery. These results may guide clinicians to make individualized surgical decisions and estimate long-term prognosis for these patients. IMPLICATIONS FOR PRACTICE: Liver resection was safe and feasible in patients with binodular hepatocellular carcinoma, with acceptable perioperative and long-term outcomes. The sum of two tumor sizes, the size ratio and distribution of the two nodules, and the distance between two nodules were independent risk factors associated with long-term overall survival and recurrence-free survival after liver resection. The results of this study may guide clinicians to make individualized surgical decisions, estimate long-term prognosis, and plan recurrence surveillance and adjuvant therapy for these patients.

MAPK/JNK signalling: a potential autophagy regulation pathway.

Autophagy refers to a lysosomal degradative pathway or a process of self-cannibalization. This pathway maintains nutrients levels for vital cellular functions during periods of starvation and it provides cells with survival advantages under various stress situations. However, the mechanisms responsible for the induction and regulation of autophagy are poorly understood. The c-Jun NH2-terminal kinase (JNK) signal transduction pathway functions to induce defence mechanisms that protect organisms against acute oxidative and xenobiotic insults. This pathway has also been repeatedly linked to the molecular events involved in autophagy regulation. The present review will focus on recent advances in understanding of the relationship between mitogen-activated protein kinase (MAPK)/JNK signalling and autophagic cell death.

The prognostic value of plasma soluble CD40 ligand levels in patients with nasopharyngeal carcinoma.

BACKGROUND: Serum soluble CD40 ligand (sCD40L) concentrations are increased in patients with nasopharyngeal carcinoma (NPC). This study further evaluated the relationship between plasma sCD40L concentrations and long-term survival of NPC. METHODS: Plasma sCD40L concentrations of 312 patients and 312 healthy controls were determined using an ELISA. The associations of plasma sCD40L concentrations with 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival were investigated by univariate and multivariate analyses. RESULTS: Plasma sCD40L concentrations were substantially higher in patients than in healthy subjects and also correlated highly with tumor classification, lymph node classification and tumor node metastasis stage. sCD40L emerged as an independent predictor for 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival using univariate and multivariate Cox regression analysis. CONCLUSIONS: High plasma sCD40L concentration is correlated with stage progression of NPC as well as associated with poor survival of NPC. It is suggested that sCD40L should have the potential to be a prognostic biomarker for NPC.

Aberrant Expression of HOXA5 and HOXA9 in AML.

BACKGROUND: Aberrant expression of HOX gene expression has been observed in cancer. The purpose of this study was to investigate the alteration of HOXA5 and HOXA9 expression and their clinical significance in acute meloid leukemia (AML). MATERIALS AND METHODS: The expression of HOXA5 and HOXA9 genes of bone marrow samples from 75 newly diagnosed AML patients and 22 healthy controls for comparison were examined by Real- time quantitative PCR (RQ-PCR) assay. Statistical analysis was conducted to evaluate HOXA5 and HOXA9 expression as possible biomarkers for AML. RESULTS: The results showed that the complete remission rate (52.6%) of the patients who highly expressed HOXA5 and HOXA9 was significantly lower than that (88.9%) in patients who lowly express the genes (P=0.015). Spearmann correlation coefficients indicated that the expression levels for HOXA5 and HOXA9 genes were highly interrelated (r=0.657, P<0.001). Meanwhile, we detected significant correlations between HOXA9 expression and age in this limited set of patients (P=0.009). CONCLUSIONS: The results suggest a prognostic impact of increased expression of HOXA5 and HOXA9 in AML patients.

Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice.

Colorectal cancer remains one of the most common types of cancer and leading causes of cancer death worldwide. Although we have made steady progress in chemotherapy and targeted therapy, evidence suggests that the majority of patients undergoing drug therapy experience severe, debilitating, and even lethal adverse drug events which considerably outweigh the benefits. The identification of suitable biomarkers will allow clinicians to deliver the most appropriate drugs to specific patients and spare them ineffective and expensive treatments. Prognostic and predictive biomarkers have been the subjects of many published papers, but few have been widely incorporated into clinical practice. Here, we want to review recent biomarker data related to colorectal cancer, which may have been ready for clinical use.

HP1-mediated formation of alternative lengthening of telomeres-associated PML bodies requires HIRA but not ASF1a.

Approximately 10% of cancers use recombination-mediated Alternative Lengthening of Telomeres (ALT) instead of telomerase to prevent telomere shortening. A characteristic of cells that utilize ALT is the presence of ALT-associated PML nuclear bodies (APBs) containing (TTAGGG)n DNA, telomere binding proteins, DNA recombination proteins, and heterochromatin protein 1 (HP1). The function of APBs is unknown and it is possible that they are functionally heterogeneous. Most ALT cells lack functional p53, and restoration of the p53/p21 pathway in these cells results in growth arrest/senescence and a substantial increase in the number of large APBs that is dependent on two HP1 isoforms, HP1α and HP1γ. Here we investigated the mechanism of HP1-mediated APB formation, and found that histone chaperones, HIRA and ASF1a, are present in APBs following activation of the p53/p21 pathway in ALT cells. HIRA and ASF1a were also found to colocalize inside PML bodies in normal fibroblasts approaching senescence, providing evidence for the existence of a senescence-associated ASF1a/HIRA complex inside PML bodies, consistent with a role for these proteins in induction of senescence in both normal and ALT cells. Moreover, knockdown of HIRA but not ASF1a significantly reduced p53-mediated induction of large APBs, with a concomitant reduction of large HP1 foci. We conclude that HIRA, in addition to its physical and functional association with ASF1a, plays a unique, ASF1a-independent role, which is required for the localization of HP1 to PML bodies and thus for APB formation.

Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins.

Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that heterochromatin protein 1 (HP1) is present in APBs, and knockdown of HP1alpha and/or HP1gamma prevented p53-mediated APB induction, which suggests that HP1-mediated chromatin compaction is required for APB formation. Therefore, although the presence of APBs in a cell line or tumor is an excellent qualitative marker for ALT, the association of APBs with growth arrest/senescence and with "closed" telomeric chromatin, which is likely to repress recombination, suggests there is no simple correlation between ALT activity level and the number of APBs or APB-positive cells.

Disruption of telomere maintenance by depletion of the MRE11/RAD50/NBS1 complex in cells that use alternative lengthening of telomeres.

Immortalized human cells are able to maintain their telomeres by telomerase or by a recombination-mediated DNA replication mechanism known as alternative lengthening of telomeres (ALT). We showed previously that overexpression of Sp100 protein can suppress ALT and that this was associated with sequestration of the MRE11/RAD50/NBS1 (MRN) recombination protein complex by Sp100. In the present study, we determined whether MRN proteins are required for ALT activity. ALT cells were depleted of MRN proteins by small hairpin RNA-mediated knockdown, which was maintained for up to 100 population doublings. Knockdown of NBS1 had no effect on the level of RAD50 or MRE11, but knockdown of RAD50 also depleted cells of NBS1, and knockdown of MRE11 depleted cells of all three MRN proteins. Depletion of NBS1, with or without depletion of other members of the complex, resulted in inhibition of ALT-mediated telomere maintenance, as evidenced by decreased numbers of ALT-associated promyelocytic leukemia bodies and decreased telomere length. In some clones there was an initial period of rapid shortening followed by stabilization of telomere length, whereas in others there was continuous shortening at a rate within the reported range for normal human somatic cells lacking a telomere maintenance mechanism. In contrast, depletion of NBS1 in telomerase-positive cells did not result in telomere shortening. A recent study showed that NBS1 was required for the formation of extrachromosomal telomeric circles (Compton, S. A., Choi, J. H., Cesare, A. J., Ozgur, S., and Griffith, J. D. (2007) Cancer Res. 67, 1513-1519), also a marker for ALT. We conclude that the MRN complex, and especially NBS1, is required for the ALT mechanism.

Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex.

Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve recombination-mediated DNA replication, but the molecular details are largely unknown. In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene. We demonstrate here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs. This resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling, a rate within the range found in telomerase-negative normal cells, suppression of rapid telomere length changes, and suppression of APB formation. Spontaneously generated C-terminally truncated Sp100 that did not sequester the MRE11, RAD50, and NBS1 proteins failed to inhibit ALT. These findings identify for the first time proteins that are required for the ALT mechanism.