Genetic factors involved in delayed methotrexate elimination in children with acute lymphoblastic leukemia.

BACKGROUND: Delayed excretion of methotrexate can lead to life-threatening toxicity that may result in treatment cessation, irreversible organ damage, and death. Various factors have been demonstrated to influence the pharmacokinetic process of methotrexate, including genetic and nongenetic factors. METHODS: We investigated the genetic factors primarily related to the metabolic pathway of methotrexate in children with acute lymphoblastic leukemia with delayed elimination, defined as C44-48h ≥ 1.0µmol/L in this study. A total of 196 patients (delayed excretion group: 98; normal excretion group: 98) who received CCCG-ALL-2015 protocol after propensity score-matched analysis were included in the study. Twenty-eight target single-nucleotide polymorphisms (SNPs) were analyzed by multiplex polymerase chain reaction and sequencing, and 25 SNPs were finally included in the study. RESULTS: The genotype distribution of SLCO1B1 rs2306283 SNP was different between the delayed and normal excretion groups. SLCO1B1 rs2306283 AA carriers had a significantly lower methotrexate C44-48h /D ratio than GG carriers in both groups. Furthermore, compared with the normal excretion group, SLCO1B1 rs2306283 AG and GG were risk factors for developing oral mucositis (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.11-4.08; P < .001), hepatotoxicity (OR: 2.12; 95% CI: 1.26-3.56; P < .001), and myelosuppression (OR: 1.21; 95% CI: 1.04-1.41; P = .005) in delayed excretion group. CONCLUSIONS: The results from this study indicate the potential role of SLCO1B1 rs2306283 as a pharmacogenomic marker to guide and optimize methotrexate treatment for delayed elimination in children with acute lymphoblastic leukemia.

Whole exome sequencing reveals a broader variant spectrum of Charcot-Marie-Tooth disease type 2.

Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous inherited neuropathy. Although new causative and disease-associated genes have been identified for CMT2 in recent years, molecular diagnoses are still lacking for a majority of patients. We here studied a cohort of 35 CMT2 patients of Chinese descent, using whole exome sequencing to investigate gene mutations and then explored relationships among genotypes, clinical features, and mitochondrial DNA levels in blood as assessed by droplet digital PCR. We identified pathogenic variants in 57% of CMT2 patients. The most common genetic causes in the cohort were MFN2 mutations. Two patients with typical CMT phenotype and neuromyotonia were detected to harbor compound heterozygous variations in the HINT1 gene. In conclusion, our work supports that the molecular diagnostic rate of CMT2 patients can be increased via whole exome sequencing, and our data suggest that assessment of possible HINT1 mutations should be undertaken for CMT2 patients with neuromyotonia.

The Effect Of Food On The Pharmacokinetic Properties And Bioequivalence Of Two Formulations Of Levocetirizine Dihydrochloride In Healthy Chinese Volunteers.

PURPOSE: The aim of this study is to assess the bioequivalence of a new generic formulation and the branded formulation of levocetirizine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and food-intake effect on the pharmacokinetic properties is also evaluated. PATIENTS AND METHODS: Volunteers were randomly allocated into two groups to receive a single oral dose of generic formulation and branded formulation under fasting or fed conditions, respectively. Blood samples were collected at designated time points. Plasma concentrations of levocetirizine were determined by UFLC-MS/MS. Safety evaluations were carried out through the study. The main pharmacokinetic parameters of the two formulations of levocetirizine were calculated using non-compartmental analysis incorporated in WinNonlin® 7.0 software. RESULTS: Forty-nine volunteers were enrolled; 46 completed the studies. Under fasting and fed conditions, the 90% confidence intervals for the geometric mean of generic/branded ratios were in the range of 94.75-107.24% and 99.98-114.69% for the maximum observed concentration, and 97.13-102.50% and 98.36-103.98% for the area under the concentration-time curve. As a result of food intake before administration, the reduced rate and extent of absorption of levocetirizine were observed. Both formulations were generally well tolerated, with no serious adverse reactions reported. CONCLUSION: The two formulations demonstrated essentially identical pharmacokinetic profiles and were all well within the FDA/CFDA bioequivalence standards. Meanwhile, food intake can delay the absorption rate and reduced the bioavailability of levocetirizine in healthy Chinese volunteers.

[Effect of number of resected lymph nodes on the prognosis of gastric cancer patients without lymphatic metastasis].

OBJECTIVE: To investigate the long-term correlation between the number of resected lymph nodes (LNs) and the prognosis of patients with node-negative gastric cancer. METHODS: From January 1995 to December 2004, 221 patients with gastric cancer underwent D2 radical resection and were proved with no nodal involvement. The clinical records of the patients were analyzed retrospectively. The relationships of the dissected LNs number to 5-year survival rate and post-operative complication rate were analyzed respectively. RESULTS: The overall 5-year survival rate of this group was 83.5%. The total number of dissected LNs was one independent prognostic factors in this group. Among patients with the same depth of tumor invasion, the more the number of dissected LNs, the better the survival would be (P < 0.05). The patients had better long-term survival outcomes with dissected LNs counts of more than 15 for cases with pT1-2 tumor, and more than 20 for cases with pT3 tumor. The post-operative complication rate was 10.8% and it was not significantly correlated with the number of dissected lymph nodes (P > 0.05). CONCLUSIONS: The number of dissected LNs is an independent prognostic predicting factor for lymph node-negative gastric cancer. Sufficient dissection of LNs is recommended to improve the patients' long-term survival. Suitable increment of dissected LNs count would not increase the post-operative complication rate.

[Efficiency of laparoscopic D2 radical gastrectomy in gastric cancer: experiences of 218 patients].

OBJECTIVE: To explore the feasibility and efficacy of laparoscopic D2 radical gastrectomy in patients with gastric cancer. METHODS: The clinical data of 529 patients with gastric cancer underwent D2 radical resection from January 2007 to March 2009 were analyzed retrospectively. Among the patients, 218 cases underwent laparoscopic D2 gastrectomy (LAG group) and 311 cases received open gastrectomy (OG group). The patients' operation, number of retrieved lymph nodes, recovery, postoperative morbidity and mortality were compared between the two groups. RESULTS: The operative time in LAG group was (237 +/- 42) min, and was significantly longer than that in OG group [(229 +/- 42) min, P < 0.05]. However, the mean blood loss [(81 +/- 100) ml vs. (171 +/- 211) ml], number of patients needed blood transfusion (7 vs. 44 cases), first flatus time [(4.1 +/- 2.3) d vs. (5.0 +/- 1.4) d], time to resume soft diet [(4.5 +/- 2.2) d vs. (5.5 +/- 1.4) d] and postoperative hospital stay [(12 +/- 4) d vs. (14 +/- 4) d] in the two groups were all different statistically (P < 0.05), and all were better in LAG group. In LAG group, the operative time of patients with total gastrectomy was (250 +/- 46) min, and was significantly longer than that with distal gastrectomy (228 +/- 37) min (P < 0.05), but there was no significant differences in other aspects of patients' recovery between the two operation types. The postoperative morbidity of LAG group and OG group were 11.9% and 19.0%, respectively (P < 0.05). For all patients, the mean number of retrieved lymph nodes was (29 +/- 10) and the median number was 28. The mean number of retrieved lymph nodes was not significantly different between the two groups [(28 +/- 10) in LAG group vs. (29 +/- 9) in OG group, P > 0.05]. Thirteen patients (6.0%) converted to open surgery in LAG group. CONCLUSION: Laparoscopic D2 radical gastrectomy is a safe and feasible procedure with quick recovery, and it is comparable with open gastrectomy in lymph node dissection.

Prognostic impact of metastatic lymph node ratio on gastric cancer after curative distal gastrectomy.

AIM: To investigate the prognostic impact of metastatic lymph node ratio (rN) on gastric cancer after curative distal gastrectomy. METHODS: A total of 634 gastric cancer patients who underwent curative resection (R0) of lymph nodes at distal gastrectomy in 1995-2004. Correlations between positive nodes and retrieved nodes, between rN and retrieved nodes, and between rN and negative lymph node (LN) count were analyzed respectively. Prognostic factors were identified by univariate and multivariate analyses. Staging accuracy of the pN category (5th UICC/TNM system) and the rN category was compared according to the survival rates of patients. A linear regression model was used to identify the relation between rN and 5-year survival rate of the patients. RESULTS: The number of dissected LNs was related with metastatic LNs but not related with rN. Cox regression analysis showed that depth of invasion, pN and rN category were the independent predictors of survival (P < 0.05). There was a significant difference in survival between LN stages classified by the rN category or by the pN category (P < 0.05). However, no significant difference was found in survival rate between LN stages classified by the pN category or by the rN category (P > 0.05). Linear regression model showed a significant linear correlation between rN and the 5-year survival rate of gastric cancer patients (beta = 0.862, P < 0.001). Pearson's correlation test revealed that negative LN count was negatively correlated with rN (P < 0.001). CONCLUSION: rN category is a better prognostic tool than the 5th UICC pN category for gastric cancer patients after curative distal gastrectomy. Increased negative LN count can reduce rN and improve the survival rate of gastric cancer patients.

[Impact of solitary lymph node metastasis on the prognosis of gastric cancer].

OBJECTIVE: To investigate the impact of solitary lymph node (LN) metastasis on the prognosis of gastric cancer. METHODS: Clinical data of 280 patients with gastric cancer who underwent D(2) radical resection from January 1995 to December 2003 were analyzed retrospectively. Among them, solitary LN metastasis was proven pathologically in 83 cases(solitary LN metastasis group), while node-negative metastasis proven in 197 cases (node-negative group). The 5-year survival rate was compared between two groups and between patients with and without skipping LN metastasis. The prognostic factors were evaluated by uncaria and multivaria analyses. RESULTS: The 5-year survival rates in the solitary LN metastasis group and the node-negative group were 62.3% and 83.5% respectively with significant difference (P<0.05). The solitary LN metastasis was one of the independent prognostic factors. Logistic regression revealed that the invasion depth was an independent covariate for solitary LN metastasis. The proportion of skip metastasis was 22.9% in gastric cancer patients with solitary LN metastasis. The 5-year survival rates of the patients with and without skipping LN metastasis were 50.0% and 66.1% respectively, which was not significantly different (P>0.05). CONCLUSIONS: The prognosis of patients with solitary LN metastasis is significantly poorer than those without lymph node metastasis. Due to the high incidence of skip LN metastasis in gastric cancer, D(2) radical resection should be performed to ensure oncological clearance.

[Laparoscopic versus conventional open resection for early distal gastric cancer: a meta-analysis on the number of retrieved lymph nodes].

OBJECTIVE: To compare the number of retrieved lymph nodes (LN) between laparoscopic resection and conventional open resection for early distal gastric cancer with meta-analysis. METHODS: Original articles published from January 2000 to December 2008 were searched in the MEDLINE, EMBASE and Cochrane Controlled Trials Register. According to the criterion, 14 articles were identified which compared the number of retrieved lymph nodes between laparoscopic resection and conventional open resection for early distal gastric cancer. Data were extracted from these trials by 3 reviewers independently and analyzed by Rev Man 5.0 software. RESULTS: A total of 1454 patients with early gastric cancer were enrolled, including 815 patients in the laparoscopic group and 630 patients in the conventional group. The mean number of dissected lymph nodes per patient was 3.26 less in the laparoscopic group as compared to the conventional group (WMD -3.26,95% CI -6.24~-0.27,P=0.03). The differences were not statistically significant in the articles published during 2005-2008 years (WMD -2.84, 95% CI -6.79~1.11, P=0.16), in D(1)(+)alpha/beta lymph node dissection (WMD -2.80, 95% CI -7.57~1.97, P=0.25), and in retrospective non-randomized trials (WMD -2.89, 95% CI -6.48~0.70,P=0.11). CONCLUSION: With the improvement in surgical skills, laparoscopic surgery and open surgery do not differ significantly in the number of retrieved lymph nodes for early distal gastric cancer with D(1)(+)alpha/beta lymph node dissection.

Prognostic impact of dissected lymph node count on patients with node-negative gastric cancer.

AIM: To investigate the long-term effect of the number of resected lymph nodes (LNs) on the prognosis of patients with node-negative gastric cancer. METHODS: Clinical data of 211 patients with gastric cancer, without nodal involvement, were analyzed retrospectively after D2 radical operation. We analyzed the relationship between the number of resected LNs with the 5-year survival, the recurrence rate and the post-operative complication rate. RESULTS: The 5-year survival of the entire cohort was 82.2%. The total number of dissected LNs was one of the independent prognostic factors. Among patients with comparable depth of invasion, the larger the number of resected LNs, the better the survival (P < 0.05). A cut-point analysis provided the possibility to detect a significant survival difference among subgroups. Patients had a better long-term survival outcomes with LN counts > or = 15 for pT1-2, > or = 20 for pT3-4, and > or = 15 for the entire cohort. The overall recurrence rate was 29.4% within 5 years after surgery. There was a statistically significant, negative correlation between the number of resected LNs and the recurrence rate (P < 0.01). The post-operative complication rate was 10.9% and was not significantly correlated with the number of dissected LNs (P > 0.05). CONCLUSION: For node-negative gastric cancer, sufficient number of dissected LNs is recommended during D2 lymphadenectomy, to improve the long-term survival and reduce the recurrence. Suitable increments of the dissected LN count would not increase the post-operative complication rate.

[Analysis of the pattern of solitary lymph node metastasis in gastric cancer and its prognosis].

OBJECTIVE: To explore the pattern of solitary lymph node(LN) metastasis in gastric cancer and its prognosis. METHODS: The clinical records of 83 patients with gastric cancer presenting solitary LN metastasis who underwent D2 radical resection from January 1995 to December 2003 were analyzed retrospectively. The precise stations of the metastasis of LN and their correlation with the location of primary tumor were studied. The 5-year survival rates were compared between patients with and without skipping LN metastasis. The prognostic factors were evaluated by using univariate and multivariate analyses. RESULTS: Among the 83 patients with pathologically proven solitary LN metastasis, 64 cases (77%) presented with the perigastric nodes metastasis (N1 area), and 19 cases (23%) in N2 area without N1 involvement (skipping LN metastasis). For tumors in the upper and middle third stomach, the No. 3 station was the most common first metastasized LN station (40% and 42%, respectively). While for tumors in the lower third stomach, the No.6 station was the mostly affected LN (33%). Of the patients, 77 cases were followed up for 5-14 years, the median survival time was 77.0 months, and the overall 5-year survival rate was 63%. The 5-year survival rates of the patients with and without skipping LN metastasis was 52% and 67% respectively, there was no significant difference between the two groups (P>0.05). The serosal invasion and pathological types were influencing factors of the 5-year survival rate on univariate analysis. But with multivariate analysis, only the serosal invasion was an independent factor affecting the survival. CONCLUSIONS: Perigastric nodes are the most common first sites of tumor metastasis, making them the main targets of operative sentinel lymphatic mapping procedures. The patients with serosal invasion have poorer prognosis.

[Impact of negative lymph node number on prognosis advanced cancer of cardiac and stomach fundus].

OBJECTIVE: To analyze the impact of negative lymph node number on the prognosis of advanced cancer of the cardia and stomach fundus. METHODS: 236 patients with advanced cancer of the cardia and stomach fundus underwent D2 radical resection. 5-year survival rate and recurrence rate were followed up and the relationships of lymph node (LN) number to 5-year survival rate and recurrence rate were analyzed respectively, according to LN count subgroups. RESULTS: The 5-year survival rate of the entire cohort was 37.5%. The number of metastasis negative LNs was positively correlated with the LNs examined (P < 0.05). For the cancer at the same stage, the higher the number of metastasis negative LNs the higher the 5-year survival rate (P < 0.05). Linear correlation analysis showed that along with the increase of the number of negative LNs the post-operative survival rate increased. In the cancers at the stages III and IV, the 5-year survival rate increased by 6.09% and 7.65% respectively compared to the predicted values (P = 0.013 and P = 0.035). The overall recurrence rate was 61.0% within 5 years after surgery. For the cancers at the stages III and IV, the more the number of negative LNs the higher the 5-year survival rates (P < 0.05). In the cancers at the stages II and IV there were significant differences in the recurrence rates among the subgroups with different numbers of negative LNs (all P < 0.002). CONCLUSION: Number of negative LNs has a close relation with stage-based survival prediction. Dissection of sufficient lymph nodes in the procedure of D2 dissection should be recommended so as to improve the long-term therapeutic effects and reduce the recurrence rate.

[Efficiency of D2 radical resection combined with splenectomy in T3 cancer of upper stomach].

OBJECTIVE: To analyze the efficacy and influence of D2 radical resection combined with splenectomy in T3 cancer of upper stomach. METHODS: From January 1980 to June 2002, 613 patients with T3 cancer of upper stomach received D2 radical resection. Of these cases, 102 underwent simultaneous splenectomy (splenectomy group), while 511 did not (spleen-preserved group). The metastatic rate of lymph nodes in splenic hilum and along the splenic artery (No. 10, No. 11), 5-year survival rates, recurrence rate, the postoperative complication rate and mortality rate were followed up and compared in the two groups. RESULTS: The metastasis rate of No. 10 was 23.5% for splenectomy group and 14.9% for spleen-preserved group (P < 0.05). No significant difference was found in No. 11 metastasis between the two groups. The 5-year survival rate of splenectomy group was 39.8%, and was 32.3% in spleen-preserved group (P > 0.05). The recurrence rate of splenectomy group was 55.9%, and was 60.3% in spleen-preserved group (P > 0.05). In the splenectomy group, the 5-year survival rates were similar between patients with and without No. 10 metastasis (P > 0.05). The postoperative complication rate and mortality rate of the splenectomy group were 19.6% and 4.9%, and were 13.7% and 3.1% in the spleen-preserved group, respectively; and no significant difference was found between the two groups (P > 0.05). CONCLUSIONS: D2 radical excision combined splenectomy should be recommended for stage T3 cancer of upper stomach when suspected with No. 10, No. 11 lymph nodes metastasis. Simultaneous splenectomy would not increase the postoperative complication rate and mortality rate.

[Prognosis analysis of surgical treatment for cancer of stomach fundus and cardia with invasion to body and tail of the pancreas].

OBJECTIVE: To investigate the prognostic factors of surgical treatment for the cancer of stomach fundus and cardia with invasion to body and tail of the pancreas. METHODS: A total of 135 patients with cancer of stomach fundus and cardia invading body and tail of the pancreas undergone surgical treatment were enrolled in this study. Twenty of them underwent laparotomy, while 115 underwent gastrectomy with pancreaticosplenectomy, even combined with the resection of other organs for macroscopic invasion to adjacent organs during surgery. The 3-,5-year survival rates, morbidity of postoperative complications and mortality were followed up. The prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: The median survival time of the patients undergone laparotomy was 4.7 months, of patients treated by gastrectomy combined with pancreaticosplenectomy was 30.5 months,and the difference was significant (chi(2)=403.8, P<0.01). The cumulative 3- and 5-year survival rates of the patients treated by gastrectomy combined with pancreaticosplenectomy were 48.3% and 26.6% respectively. Univariate analysis revealed that significant differences in prognosis of 115 patients undergone combined resection were demonstrated for the following factors: maximal dimension of tumor, macroscopic type, extent of lymph node metastasis according to the Japanese classification, No.10 or No.11 lymph node metastasis,curability and number of invaded organs.And histological depth of invasion, extent of lymph node metastasis according to the Japanese classification, number of invaded organs and curability were significant prognostic factors, examined as variables by multivariate analysis (Cox's proportional hazard model, forward stepwise selection LR method). The postoperative complication rate and mortality of 135 patients were 20.0% and 3.5% respectively. CONCLUSIONS: For cancer located in stomach fundus and cardia with limited invasion to distal pancreas, gastrectomy combined with pancreaticosplenectomy should be performed to improve long-term outcomes. Best long-term survival outcomes would be attained if there are no lymph node metastases, or no incurable factors, or no other organ invasions.

Effect of lymphadenectomy extent on advanced gastric cancer located in the cardia and fundus.

AIM: To analyze the prognostic impact of lymphade-nectomy extent in advanced gastric cancer located in the cardia and fundus. METHODS: Two hundred and thirty-six patients with advanced gastric cancer located in the cardia and fundus who underwent D2 curative resection were analyzed retrospectively. Relationships between the numbers of lymph nodes (LNs) dissected and survival was analyzed among different clinical stage subgroups. RESULTS: The 5-year overall survival rate of the entire cohort was 37.5%. Multivariate prognostic variables were total LNs dissected (P < 0.0001; or number of negative LNs examined, P < 0.0001), number of positive LNs (P < 0.0001), T category (P < 0.0001) and tumor size (P = 0.015). The greatest survival differences were observed at cutoff values of 20 LNs resected for stage II (P = 0.0136), 25 for stage III(P < 0.0001), 30 for stage IV (P = 0.0002), and 15 for all patients (P = 0.0024). Based on the statistically assumed linearity as best fit, linear regression showed a significant survival enhancement based on increasing negative LNs for patients of stages III (P = 0.013) and IV (P = 0.035). CONCLUSION: To improve the long-term survival of patients with advanced gastric cancer located in the cardia and fundus, removing at least 20 LNs for stage II, 25 LNs for stage III, and 30 LNs for stage IV patients during D2 radical dissection is recommended.

Prognostic impact of metastatic lymph node ratio in advanced gastric cancer from cardia and fundus.

AIM: To investigate the prognostic impact of the metastatic lymph node ratio (MLR) in advanced gastric cancer from the cardia and fundus. METHODS: Two hundred and thirty-six patients with gastric cancer from the cardia and fundus who underwent D2 curative resection were analyzed retrospectively. The correlations between MLR and the total lymph nodes, positive nodes and the total lymph nodes were analyzed respectively. The influence of MLR on the survival time of patients was determined with univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. And the multiple linear regression was used to identify the relation between MLR and the 5-year survival rate of the patients. RESULTS: The MLR did not correlate with the total lymph nodes resected (r = -0.093, P = 0.057). The 5-year overall survival rate of the whole cohort was 37.5%. Kaplan-Meier survival analysis identified that the following eight factors influenced the survival time of the patients postoperatively: gender (c2 = 4.26, P = 0.0389), tumor size (c2 = 18.48, P < 0.001), Borrmann type (c2 = 7.41, P = 0.0065), histological grade (c2 = 5.07, P = 0.0243), pT category (c2 = 49.42, P < 0.001), pN category (c2 = 87.7, P < 0.001), total number of retrieved lymph nodes (c2 = 8.22, P = 0.0042) and MLR (c2 = 34.3, P < 0.001). Cox proportional hazard model showed that tumor size (c2 = 7.985, P = 0.018), pT category (c2 = 30.82, P < 0.001) and MLR (c2 = 69.39, P < 0.001) independently influenced the prognosis. A linear correlation between MLR and the 5-year survival was statistically significant based on the multiple linear regression (beta = -0.63, P < 0.001). Hypothetically, the 5-year survival would surpass 50% when MLR was lower than 10%. CONCLUSION: The MLR is an independent prognostic factor for patients with advanced gastric cancer from the cardia and fundus. The decrease of MLR due to adequate number of total resected lymph nodes can improve the survival.

[Impact of dissected lymph node number on the prognosis of advanced cancer of cardiac and stomach fundus].

OBJECTIVE: To investigate the impact of dissected lymph node number on the prognosis of patients with advanced cancer of cardia and stomach fundus. METHODS: Clinical data of 236 patients with advanced cancer of cardia and stomach fundus undergone D(2) radical resection were reviewed retrospectively. Five-year survival rate and post-operative complication rate were followed up and their relationships with dissected lymph node number were analyzed respectively. RESULTS: The 5-year survival rate of the entire cohort was 37.5%. Among those patients with the same stage, the more lymph nodes (LNs) resected, the better survival outcomes achieved(Log-rank trend test P=0.0013). A cut point analysis yielded the ability to detect the significant survival differences. The best long-term survival outcomes were observed with LN counts of more than 20 for stage II(P=0.0136), more than 25 for stage III(P<0.0001), more than 30 for stage IV(P=0.0002) or more than 15 for the entire cohort (P=0.0024), with greatest comparative discrepancies. The post-operative complication rate was 15.7% and was not significantly correlated with dissected lymph node number(P=0.101). CONCLUSIONS: The prognosis of patients with advanced cancer of cardia and stomach fundus is associated with the number of resected LNs when D(2) lymphadenectomy is carried out. Suitable increment of dissected lymph node number would not increase the post-operative complication rate.