Systemic lupus erythematosus is a risk factor for cancer: a nationwide population-based study in Korea.

OBJECTIVE: Specific differences in cancer risk have been observed between systemic lupus erythematosus patients and the general population. Although meta-analyses have estimated cancer incidence in systemic lupus erythematosus patients, results have been inconclusive. Hence, we aimed to assess malignancy risk in systemic lupus erythematosus patients, compared to the risk in the general population. METHODS: Systemic lupus erythematosus patients ( n = 21,016; mean age 41.67 ± 13.14 years; female 90.22%) were selected from the Korean National Health Insurance Service database between 2008 and 2014. Age- and sex-matched controls were randomly sampled in a 5:1 ratio ( n = 105,080). RESULTS: During the 7 years of follow up, malignancy was detected in 763 (3.63%) systemic lupus erythematosus patients and 2667 (2.54%) controls. Systemic lupus erythematosus patients had a higher risk of malignancy than controls (odds ratio 1.44; 95% confidence interval 1.327-1.559), after multivariate adjustment. Systemic lupus erythematosus patients had a higher odds ratio for developing cervical, thyroid, ovarian, and oral cancer, as well as lymphoma, leukemia, and multiple myeloma than controls. Based on subgroup analysis, male systemic lupus erythematosus patients and patients younger than 40 years showed the highest lymphoma risk. CONCLUSIONS: Systemic lupus erythematosus might be an independent risk factor for cancer. Therefore, the importance of cancer screening programs should be emphasized in systemic lupus erythematosus patients. Our study is the first large nationwide cohort study for evaluating the risk of cancer in systemic lupus erythematosus patients.

[Efficacy and side effect analysis of paclitaxel liposome for neoadjuvant chemotherapy in locally advanced cervical cancer].

Objective: To investigate the efficacy and side effect of paclitaxel liposome for neoadjuvant chemotherapy (NACT) in locally advanced cervical cancer. Methods: This study were included 265 cervical cancer patients staging Ⅰb2 and Ⅱa2 who underwent paclitaxel-platinum NACT followed by radical surgery from June 2008 to December 2016 in the Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences. All patients were classified into two groups with 106 patients in paclitaxel liposome group and 159 patients in traditional paclitaxel group. The difference in clinicopathologic characteristics, efficacy and side effect were analyzed retrospectively between the two groups. Results: (1) Clinicopathologic characteristics: there were no significant difference in clinicopathologic characteristics between the two groups, including age, body mass index, clinical stage, pathological histology, cycles of NACT, combined platinum regimen, lymph-vascular space invasion, lymph node metastasis, deep stromal invasion, and postoperative adjuvant therapy (all P>0.05). (2) Efficacy: after NACT, the overall response occurred in 90 (15 complete response plus 75 partial response) of 106 cases in the paclitaxel liposome group versus 131 (21 complete response plus 110 partial response) of 159 cases in the traditional paclitaxel group without statistical significance (84.9% vs 82.4%; χ(2)=0.291, P=0.590). A total of 248 patients received surgery after NACT and were evaluable in survival. The 5-year recurrence-free survival (RFS) rate and 5-year overall survival (OS) rate of these patients was 85.1% and 88.2%. The 5-year RFS rate in the paclitaxel liposome group was 85.9% compared with 85.2% in the traditional paclitaxel group, while the corresponding 5-year OS rate was 88.5% and 88.7%, respectively. There was no statistically significant difference in efficacy between the two groups (P=0.968, P=0.797). (3) Side effect: the incidence of allergic reaction between the paclitaxel liposome group and the traditional paclitaxel group was 0 versus 1.9% (3/159) without statistical significance (P=0.277). But the incidence of neurotoxicity in the paclitaxel liposome group significantly decreased compared with the traditional paclitaxel group (6.6% vs 15.7%, P<0.05), as well as the incidence of alopecia (67.9% vs 79.2%, P<0.05) and myalgia (17.9% vs 28.9%, P<0.05). However, significant differences were not found in terms of hematological toxicity, gastrointestinal reaction, and hepatic function damage (P>0.05). Conclusion: In paclitaxel-platinum NACT of local advanced cervical cancer, paclitaxel liposome can achieve similar efficacy compared with traditional paclitaxel, but paclitaxel liposome is helpful in decreasing the toxicity of neurotoxicity, alopecia and myalgia.

Systemic lupus erythematosus is a risk factor for cardiovascular disease: a nationwide, population-based study in Korea.

OBJECTIVE: To investigate the incidence and clinical significance of cardiovascular disease in systemic lupus erythematosus patients. METHODS: We included systemic lupus erythematosus patients ( n = 18,575) without previous cardiovascular disease and age- and sex-matched individuals without systemic lupus erythematosus (controls; n = 92,875) from the Korean National Health Insurance Service database (2008-2014). Both cohorts were followed up for incident cardiovascular disease and death until 2015. RESULTS: During follow up, myocardial infarction occurred in 203 systemic lupus erythematosus patients and 325 controls (incidence rate: 1.76 and 0.56 per 1000 person-years, respectively), stroke occurred in 289 patients and 403 controls (incidence rate: 2.51 and 0.70 per 1000 person-years, respectively), heart failure occurred in 358 patients and 354 controls (incidence rate 3.11 and 0.61 per 1000 person-years, respectively), and death occurred in 744 patients and 948 controls (incidence rate 6.54 and 1.64 per 1000 person-years, respectively). Patients with systemic lupus erythematosus had higher risks for myocardial infarction (hazard ratio: 2.74, 95% confidence interval: 2.28-3.37), stroke (hazard ratio: 3.31, 95% confidence interval: 2.84-3.86), heart failure (hazard ratio: 4.60, 95% confidence interval: 3.96-5.35), and cardiac death (hazard ratio: 3.98, 95% confidence interval: 3.61-4.39). CONCLUSIONS: Here, systemic lupus erythematosus was an independent risk factor for cardiovascular disease, thus cardiac assessment and management are critical in systemic lupus erythematosus patients.

[The clinicopathological features and risk factors of recurrence in patients with mucinous borderline ovarian tumors].

Objective: To investigate the clinicopathological features and risk factors in patients with mucinous borderline ovarian tumors (MBOT). Methods: From 1999 to 2006, 66 MBOT patients in our hospital with more than ten-year follow-up were enrolled retrospectively. They were re-classified according to the literature. The clinicopathological features of different subgroups, including age, preoperative serum tumor markers, surgical methods, pathological features, surgical pathology staging, as well as the risk factors of recurrence and survival were analyzed. Results: Median age was 39 years in 66 patients. Before the surgery, 33.3% (20/60) patients had elevated CA125 and 51.7% (30/58) had elevated CA199. The accurate rate for fast frozen pathology of resected specimen was 73.4%. 21 patients underwent conservative surgery and 45 patients underwent extensive surgery. 57 patients underwent comprehensive operation and 43 cases (75.4%) resulted in stage Ⅰ. 48 of the 66 patients (72.7%) had intestinal-type tumors (IMBT) and 18 patients (27.3%) had endocervical-like tumors (EMBT). The median follow-up was 150 months. Eight recurrences (12.1%) were identified. The mean time between surgery to the initial recurrence was 26.4 months (13 to 50 months). Recurrence rate of IMBT was higher than that of EMBT (14.6% versus 5.6%) with no significance (P>0.05). All patients with pseudomyxoma had disease recurrence. Recurrence rate of stage Ⅲ patients was significantly higher than that of stage Ⅰ patients (33.3% versus 9.3%, P<0.05). During the follow-up period, tumor-related death occurred in 2 cases with a 10-year survival rate of 95.4%. Kaplan-Meier method and Log Rank analysis showed that clinical staging and peritonealmyxoma were adverse prognostic factors (P<0.05). Although the recurrence rate of patients undergoing conservative surgery was higher than that of patients with extensive surgery (23.8% versus 6.7%, P=0.047), the overall survival was almost the same between these two groups (P>0.05). Conclusions: MBOT patients have relatively good prognosis. IMBT are more common than EMBT subtypes, but recurrence rate and patient survival were almost the same between these two groups. Patients with pseudomyxoma was more likely to have disease recurrence. Patients who underwent conservative surgery resulted in higher recurrence rate but did not affect the overall survival of patient. Pseudomyxoma and clinical staging were adverse prognostic factors in MBOT patients.

Prognostic impact of hyponatraemia in patients with colorectal cancer.

AIM: Hyponatraemia is a common in surgical practice, but its clinical impact in patients with colorectal cancer has not been evaluated. METHOD: We retrospectively assessed 2944 patients who had been admitted to Chonnam National University Hwasun Hospital, Korea with a diagnosis of colorectal cancer. In order to determine the relationship between the serum sodium level and 3-year mortality, we categorized the patients as having normonatraemia (135-147 mEq/l), or mild (130-134 mEq/l), moderate (125-129 mEq/l) or severe hyponatraemia (< 125 mEq/l). RESULTS: Hyponatraemia, defined as a serum sodium level of < 135 mEq/l, was evident in 27.6% of patients during hospitalization. Declining serum sodium levels were associated with increasing age, a higher number of comorbidities, a more advanced TNM stage and worsening biochemical parameters. In a multivariate Cox-proportional regression analysis, the mortality risk was correlated with the severity of hyponatraemia [hazard ratio (HR) 1.65, 95% CI 1.38-1.96; HR 2.24, 95% CI 1.69-2.98; HR 2.20, 95% CI 1.25-3.90, for patients with mild, moderate, and severe hyponatraemia, respectively, compared with patients with normonatraemia]. An independent association between hyponatraemia and long-term mortality was sustained among various subpopulations and patients with persistent hyponatraemia had a worse prognosis than those with hyponatraemia that resolved. CONCLUSION: A substantial proportion of patients developed hyponatraemia during hospitalization, and the long-term mortality risk increased even in mild cases of hyponatraemia. Hyponatraemia should be considered as an important prognostic factor in colorectal cancer.

Glucose-6-phosphate-dehydrogenase deficiency and haematopoietic stem cell transplantation in Chinese patients.

Deficiency in glucose-6-phosphate dehydrogenase (G6PD), an X-linked recessive red cell enzymopathy, is endemic in Southern Chinese. Universal screening of newborn is done in Hong Kong, Taiwan and Singapore, among other places. In Hong Kong, 4.8% of males are affected and seven common G6PD alleles account for over 99% of all defects. Male hemizygotes suffer from severe deficiency, while female heterozygotes may also be affected. Deficiency of G6PD may affect haematopoietic stem cell transplantation (HSCT) recipients and donors, before and after HSCT. Female patients with clonal erythropoiesis (eg myelodysplasia/myeloproliferative diseases) will have the male population incidence of G6PD. Quantitative enzyme level screening is prudent for donors and recipients, and should be repeated after engraftment. Cotrimoxazole prophylaxis should be avoided in known male and female carriers, including those with low-normal G6PD enzyme levels. Our experience suggested that G6PD-deficient marrow, stem cell and cord blood donor units have no engraftment problems. Post-engraftment G6PD levels correlate with those in donors. An acquired change in G6PD status may serve as a surrogate marker for engraftment. For female heterozygote donors with normal G6PD levels, skewing of lyonized X-chromosome ratio during engraftment may result in over-expression of the deficient allele. This can result in unexpected significant G6PD deficiency. Hence, a repeat G6PD screening at stable engraftment is recommended, especially before commencement of oxidative medications.

The distribution of inhibitory and excitatory synapses on single, reconstructed jaw-opening motoneurons in the cat.

In a previous study, we reported that the distribution of inhibitory input, in contrast to excitatory input, decreased somatofugally along dendrites of cat jaw-closing alpha-motoneurons [J Comp Neurol 414 (1999) 454]. The present study examined the distribution of GABA, glycine, and glutamate immunopositive boutons covering horseradish peroxidase-labeled cat jaw-opening motoneurons. The motoneurons were divided into four compartments: the soma, and primary, intermediate, and distal dendrites. Ninety-seven percent of the total number of studied boutons had immunoreactivity for at least one of the three amino acids. The proportion of boutons immunoreactive for GABA and/or glycine was lower than the proportion of boutons immunoreactive for glutamate. Boutons immunoreactive to glycine alone were more numerous than boutons double-labeled for GABA and glycine, which, in turn, occurred more frequently than boutons immunoreactive to GABA alone. The percentage synaptic covering (proportion of membrane covered by synaptic boutons) of the putatively excitatory (glutamate containing) and putatively inhibitory (GABA and/or glycine containing) boutons decreased somatofugally along the dendrites. Such systematic variations were not seen in the packing density (number of boutons per 100 microm(2)); the packing density showed a distinct drop between the soma and primary dendrites but did not differ significantly among the three dendritic compartments. Overall, the packing density was slightly higher for the putatively excitatory boutons than for the inhibitory ones. When taken together with previous analyses of jaw-closing alpha-motoneurons the present data on jaw-opening alpha-motoneurons indicate that the two types of neuron differ in regard to the nature of synaptic integration in the dendritic tree.

Eosinophilic leukemic transformation in polycythemia rubra vera (PRV).

We report a rare case of eosinophilic leukemia transformation in a patient with polycythemia rubra vera on hydroxycarbamide (hydroxyurea) therapy only. Cytogenetic study showed complex abnormalities including -5, -7, +8, suggestive of a secondary leukemia. The leukemogenic risk of hydroxycarbamide, a ribonucleoside reductase, and the risk of natural leukemic transformation of polycythemia rubra vera is discussed in the context of previous PVSG studies.

Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study.

TEL/AML1 gene fusion that results from a cryptic t(12;21) is the most common genetic aberration in childhood B-lineage acute lymphoblastic leukemia (ALL). While the translocation may initiate the leukemic process, critical secondary genetic events are currently believed to be pivotal for leukemogenesis. We investigated 12 cases of childhood ALL with TEL/AML1 gene fusion by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) and documented additional or secondary genetic changes in seven patients (58%). Three patients showed extra copies of chromosome 21 including a case in which the trisomy 21 (+21) clone was distinct from the one harboring TEL/AML1 gene fusion. Interestingly, one patient without +21 showed amplification of the AML1 gene on chromosome 21q, supporting the contention that AML1 amplification may be an important additional genetic event. Gene expression study by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) in two of these four patients showed an increase in AML1 transcripts that paralleled the increase in gene copy number. Deletion of the normal TEL allele was detected in two patients, with one of them showing loss of chromosome 12 together with duplication of the der(12)t(12;21). Finally, one patient showed duplication of the fusion signal. Our findings confirm that additional or secondary genetic changes including AML1 amplification are commonly encountered in childhood ALL with TEL/AML1 gene fusion, which are envisaged to play significant roles in disease progression.

Norepinephrine transporter (NET) is expressed in cardiac sympathetic ganglia of adult rat.

The sympathetic nervous system plays a cardinal role in regulating cardiac function through releasing the neurotransmitter norepinephrine (NE). In comparison with central nervous system, the molecular mechanism of NE uptake in myocardium is not clear. In present study, we proved that in rat the CNS type of NE transporter (NET) was also expressed in middle cervical-stellate ganglion complex (MC-SG complex) which is considered to control the activity of heart, but not expressed in myocardium. The results also showed that NET expression level in right ganglion was significantly higher than in the left, rendering the greater capacity of NE uptake in right ventricle, a fact which may contribute to the maintenance of right ventricular function under pathologic state.

Analysis of the 5' flanking sequence of the human norepinephrine transporter gene.

The human norepinephrine transporter (NET) gene was cloned and structurally analyzed. The far 5' fragment containing exon 1 (a non-coding exon) and exon 2 was sequenced. The transcription start site of the gene in human brain stem tissue was determined by primer extension analysis. It was found that the gene could be transcribed from multiple starting points. The 5' flanking sequence contains a proximal G-C rich region, one possible GSG element and several SP1 sites. However it does not contain TATA box and CAAT box motifs. Gel shift analysis with nuclear extracts from different tissues of mouse shows that the G-C rich region may be involved in tissue specific expression of the gene.

Hepatosplenic gamma delta T-cell lymphoma. A distinctive aggressive lymphoma type.

The T-cell receptor (TCR) expressed on the surface of most T-lymphocytes is of alpha beta type, and only a minority bear the gamma delta-TCR. Similarly, postthymic T-cell lymphomas rarely express gamma delta-TCR. Hepatosplenic gamma delta T-cell lymphoma is an uncommon entity that has so far not been widely recognized. We report one such case that has been comprehensively studied by multiple modalities and showed the unique occurrence of leukemic picture at presentation. The 39-year-old man presented with fever, marked weight loss, and massive splenomegaly. Peripheral blood showed thrombocytopenia and a white cell count of 5.8 x 10(9)/l, with 66% medium-sized lymphoid cells that had a round or folded nucleus, condensed chromatin and a moderate amount of pale blue cytoplasm. Splenectomy was performed and histologic examination of the spleen, bone marrow, liver, and abdominal lymph nodes demonstrated lymphoma infiltration with a predominantly sinusoidal pattern. Immunohistochemical studies of the lymphoma cells showed a T-cell phenotype: CD2+ CD3+ CD5+ CD7+ gamma delta-TCR+ alpha beta-TCR- CD56+ CD4- CD8- CD16- CD57-. Cytogenetic studies showed complex clonal chromosomal abnormalities of 44,X, -Y, -11, -22, + mar in 3/16 cells. Rearrangement of the TCR gamma chain gene was demonstrated by polymerase chain reaction; the TCR beta chain gene was partially chain reaction; the TCR beta chain gene was partially rearranged. The patient did not respond to single agent chemotherapy, but achieved clinical remission with combination chemotherapy. Based on the available data in the literature, hepatosplenic gamma delta T-cell lymphoma exhibits distinctive clinicopathologic features, and probably represents the neoplastic counterpart of splenic gamma delta T-lymphocytes. This disease is associated with a poor prognosis and usually relapses despite initial response to chemotherapy.

Trisomy 5 in two cases of acute monocytic leukemia with hyperdiploid clones.

Although numerical chromosomal aberrations are commonly seen in acute myeloid leukemia (AML), trisomy 5 (+ 5) is very rarely detected. We report two patients, both of whom suffered from acute monocytic leukemia, in which + 5 was found in hyperdiploid clones. A review of the English literature shows 17 additional cases of AML with + 5 in at least one of the abnormal clones, making a total of 19 such cases including ours. Trisomy 5 has been reported in all FAB subtypes of AML except acute promyelocytic leukemia. In the 19 cases identified in this report, + 5 was found in association with other numerical changes (four cases), structural changes (five cases) or both (eight cases). Trisomy 5 as a sole karyotypic abnormality was exceedingly rare (two cases). Its biologic and prognostic significance remains to be determined.

Trisomy 21 as the sole acquired karyotypic abnormality in acute myeloid leukemia and myelodysplastic syndrome.

We report five cases of myeloid disorders in which trisomy 21 (+21) was found as the sole acquired karyotypic abnormality, comprising two cases of acute myeloid leukemia (AML) and three cases of myelodysplastic syndrome (MDS). In this series, MDS patients with +21 presented as high grade disease, which included two cases of refractory anemia with excess of blasts (RAEB) and one case of refractory anemia with excess of blasts in transformation (RAEBt), and showed rapid disease progression. Significant thrombocytopenia was observed in all three patients, and bone marrow examination showed a marked reduction in megakaryocytes. AML patients with +21 included one case each of AML-M2 and M4. Despite the poor prognosis reported in AML patients with +21 as the sole abnormality, the patient in our series who was able to complete intensive treatment was cured of disease. The role of +21 in leukemogenesis is reviewed.

Pathogenesis of jumping translocations: a molecular cytogenetics study.

BACKGROUND/AIMS: Jumping translocations are rare cytogenetic aberrations in haematological malignancies, the pathogenesis of which remains to be fully characterised. We investigated the mechanism of formation of jumping translocations in a case of adult common acute lymphoblastic leukaemia (ALL) positive for the Ph translocation. METHODS: Interphase and metaphase fluorescence in situ hybridisation (FISH) was performed using several probe systems. Results were correlated with findings on conventional cytogenetics. Granulocytes, T-cells and leukaemic B-cells in peripheral blood were sorted by immunomagnetic method and the terminal restriction fragment (TRF) length of these cellular populations was determined by Southern blot analysis. RESULTS: Duplicated BCR-ABL fusion signals were found on a dic(14;22)der(22)t(9;22) chromosome. Clonal jumping translocations, existing as evolutionary changes, involved the donor chromosomal segment distal to 1q12 jumping onto the telomere ends of 11q, 15p, 19p and 20p. Telomere length was decreased in the neoplastic B-cell population and contributed to the formation of the dicentric chromosome that showed absence of telomere repeats at fusion ends. Subsequent pericentromeric heterochromatin decondensation of chromosome 1q occurred, and this donor segment was randomly fused to the shortened telomere ends of non-homologous chromosomes. CONCLUSIONS: Both telomere shortening and pericentromeric heterochromatin decondensation contribute to the formation of jumping translocations, which is most probably a multi-stage process.

Transformation of diffuse large B-cell lymphoma into pre-B acute lymphoblastic leukemia: clinicopathologic features and clonal relationship.

A patient with fibrosing alveolitis developed a diffuse large B-cell (DLBC) lymphoma that expressed CD20 and CD30. After an initial response, the lymphoma relapsed and was salvaged with further chemotherapy. After another remission of 3 years, a pre-B-cell acute lymphoblastic leukemia (ALL), which expressed CD10, CD19, CD22, CD79a, CD34 and terminal deoxyribonucleotidyl transferase, developed and led to death. Molecular analysis of the immunoglobulin heavy-chain gene showed that the initial lymphoma and its relapse were clonally related. At leukemic relapse, 2 clones related to the initial and relapsed lymphoma clones were present. DLBC lymphomas arise from post-follicle center B cells, whereas ALL arises from pregerminal B cells. Therefore, a direct transformation of DLBC lymphoma to ALL appears unlikely. The overall features suggest instead separate lymphoma and leukemic evolution from a common mutated B-cell precursor rather than transformation of DLBC lymphoma to ALL.

The role of trisomy 8 in the pathogenesis of chronic eosinophilic leukemia.

A case of chronic eosinophilic leukemia (CEL) manifesting as spinal cord compression by an extradural eosinophilic chloroma in a 32-year-old Chinese man was presented, who subsequently developed extramedullary transformation at the skin and then peritoneal cavity. Cytogenetic study of bone marrow cells at diagnosis showed a clonal karyotypic abnormality of trisomy 8 (+8), which on fluorescence in situ hybridization (FISH) was shown to be present in a clone of abnormal eosinophils, hence showing the neoplastic nature of the eosinophilic proliferation. There was another population of abnormal eosinophils that did not show +8. At blastic transformation, all blast cells in ascitic fluid were shown by FISH to harbor +8. These findings suggest that +8 in this case may have arisen from clonal evolution and is not the primary genetic event in leukemogenesis, but +8 most probably imparts a further survival advantage to the clone responsible for subsequent blastic transformation.

Bone marrow necrosis in bone marrow transplantation: the role of MR imaging.

We describe an ALL patient who developed extensive bone marrow necrosis at the time of relapse 2 months after allogeneic bone marrow transplantation from an HLA-identical sibling. The excruciating and diffuse bone pain, fever and precipitous drop in peripheral blood counts were characteristic. This case illustrates the importance of repeat bone marrow biopsies for the diagnosis of disease relapse and the potential application of MR imaging in the assessment of patients with bone marrow necrosis.

Late onset post-transplantation lymphoproliferative disease of recipient origin following cytogenetic relapse and occult autologous haematopoietic regeneration after allogeneic bone marrow transplantation for acute myeloid leukaemia.

A post-transplantation lymphoproliferative disease (PTLD) of recipient origin was identified in one of 376 consecutive cases of allogeneic bone marrow transplantation (BMT). This occurred in a 36-year-old woman who received an allogeneic BMT for acute myeloid leukaemia in relapse. At 15 months after BMT, recipient haematopietic and leukaemic cells were found in the bone marrow, which disappeared on withdrawal of immunosuppression. However, severe graft-versus-host disease (GVHD) necessitated the continuation of immunosuppression, leading to the occurrence of PTLD in the liver and lung 12 months afterwards. Fluorescence in situ hybridisation showed that the neoplastic cells were of recipient origin. Although the PTLD also responded completely to withdrawal of immunosuppression, the patient finally died from the complications of GVHD. This case of late onset PTLD post-BMT showed features similar to those in solid organ transplantation, in that the tumour was of recipient origin and responded well to the withdrawal of immunosuppression. Of further interest is that recipient lymphoid regeneration had accompanied autologous haematopoietic regeneration and become a target for subsequent neoplastic transformation.