Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas

The purpose of the present study was to establish accurate prognostic markers to predict the post-operative recurrence of stage I lung adenocarcinomas (ADC). One-hundred and ninety cases of stage I ADC were examined for KRAS mutations and Ki-67 expression, and their associations with disease recurrence were analyzed. KRAS-mutated cases showed a significantly higher risk of recurrence than cases without mutations (5-year disease-free survival (DFS) 61.0% vs. 85.8%, P = 0.017: adjusted Hazard ratio (HR) 4.55, 95% Confidence Interval (CI) 1.61–12.82, P = 0.004). Ki-67 high-expressers (labeling index >10%) also showed a higher risk of recurrence than low-expressers (5-year DFS 68.7% vs. 93.2%, P < 0.001: adjusted HR 3.84, 95% CI 1.18–12.45, P = 0.025). Ki-67 high-expressers with KRAS mutations showed an additional higher risk of recurrence compared to low-expressers without mutations (5-year DFS 37.5% vs. 93.3%, P < 0.001: adjusted HR 16.82, 95% CI 3.77–74.98, P < 0.001) and their 5-year DFS was nearly equivalent to that of stage II non-small cell lung cancer (NSCLC) in our facility (37.5% vs. 37.2% for stage II NSCLC, p = 0.577). The combined use of KRAS status and Ki-67 expression level could be an excellent prognostic marker to predict the post-operative recurrence of stage I ADC.     

Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group

Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1-2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal MYCN, 1 died of complications and 16 relapsed, 2 of whom died; 5-year relapse-free survival (RFS) and overall survival (OS) rates were 94.3% (95% confidence interval (CI): 91.6-97) and 98.9% (95% CI: 97.7-100), respectively. Of the 123 stage 2 patients with normal MYCN, 1 died of sepsis and 22 relapsed, 8 of whom died (RFS 82.8%, 95% CI: 76.2-89.5; OS 93.2%, 95% CI: 88.7-97.8). In stage 2, OS and RFS were worse for patients with elevated LDH and unfavourable histopathology. Of 16 children with MYCNA, 7 were stage 1 (5 relapses and 4 deaths) and 9 were stage 2 (3 relapses and 2 deaths) patients. In conclusion, surgery alone yielded excellent OS for both stage 1 and 2 neuroblastoma without MYCNA, although stage 2 patients with unfavourable histopathology and elevated LDH suffered a high number of relapses. Both stage 1 and 2 patients with MYCNA were at greater risk of relapse.     

Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis

Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3–4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7–10.2); oligoastrocytoma, 4.4 years (95% CI 3.5–5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2–4, 2.1 years) (95% CI 1.7–2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5–1.1 vs. 0.6 years, CI: 0.5–1.0 vs. 1.4 years, 95% CI: 1.1–2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.     

A Comparison of Long-Term Outcomes of Donor Lymphocyte Infusions and Tyrosine Kinase Inhibitors in Patients With Relapsed CML After Allogeneic Hematopoietic Cell Transplantation

BackgroundDonor lymphocyte infusion (DLI) and tyrosine kinase inhibitors (TKIs) are the 2 standard treatment options in chronic myeloid leukemia (CML) that relapses after hematopoietic cell transplantation (HCT), but reports comparing long-term outcomes of these modalities are rare.Patients and MethodsA total of 46 patients were treated with either DLI (n = 28) or TKIs (n = 18) during a first relapse of CML after HCT between 1993 and 2012. The stage of relapse was the chronic phase in 37 patients and the advanced phase in 9 patients. All patients had myeloablative conditioning without T-cell depletion during HCT. The median interval between HCT and treatment for relapse was 34 (range, 2-197) months.ResultsAt a median follow-up of 146 and 70 months, respectively, 32% of the DLI group and 33% of the TKI group had died. Six (21%) patients initially treated with DLI received TKIs during a second relapse. In multivariable analyses, DLI was associated with inferior overall survival (OS) (hazard ratio [HR], 37.4; 95% confidence interval [CI], 2.2-625.4; P = .01), shorter failure-free survival (FFS) (HR, 21.15; 95% CI, 1.8-251; P = .02), higher cumulative incidence of failure (CIF) (HR, 19.5; 95% CI, 1.6-236.5; P = .02), and increased incidence of treatment-induced graft vs. host disease (GVHD) (68% vs. 6%; P = .001).ConclusionTKIs appear better than DLI in chronic-phase relapses after myeloablative non–T-cell-depleted HCT. Outcomes were poor in advanced-phase relapses irrespective of treatment modality.     

Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft

Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow‐up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression. Sixty‐one (71.0%) patients received ASCT2 and had better progression‐free survival (PFS) (30.2 versus 13.0 mo; P = .0262) and overall survival (OS) rates (129.6 versus 33.5 mo; P = .0003) compared with 25 (29.0%) patients with conventional treatment. Patients relapsing later than 12 months after ASCT1 benefitted from a second ASCT with better PFS2 (P = .0179) and OS2 (P = .0009). Finally, lenalidomide maintenance after ASCT2 was associated with longer PFS (41.0 vs 21.6 mo; P = .0034) and better OS (not yet reached vs 129.6 mo; P = .0434) compared with patients without maintenance. Our data suggest that a second ASCT and lenalidomide maintenance given at first relapse in MM after prior ASCT are associated with better survival rates.     

Phase II TPDCV protocol for pediatric low-grade hypothalamic/chiasmatic gliomas: 15-year update

To report long-term results for children with low-grade hypothalamic/chiasmatic gliomas treated on a phase II chemotherapy protocol. Between 1984 and 1992, 33 children with hypothalamic/chiasmatic LGGs received TPDCV chemotherapy on a phase II prospective trial. Median age was 3.0 years (range 0.3–16.2). Twelve patients (36%) underwent STRs, 14 (42%) biopsy only, and seven (21%) no surgery. Twenty patients (61%) had pathologic JPAs, nine (27%) grade II gliomas, and four (12%) no surgical sampling. Median f/u for surviving patients was 15.2 years (range 5.3–20.7); 20 of the 23 surviving patients had 14 or more years of follow-up. Fifteen-year PFS and OS were 23.4 and 71.2%, respectively. Twenty-five patients progressed, of whom 13 are NED, two are AWD, and 10 have died. All children who died were diagnosed and first treated at age three or younger. Age at diagnosis was significantly associated with relapse and survival (P = 0.004 for PFS and P = 0.037 for OS). No PFS or OS benefit was seen with STR versus biopsy/no sampling (P = 0.58 for PFS, P = 0.59 for OS). For patients with JPAs and WHO grade II tumors, the 15-year PFS was 18.8 and 22.2% (P = 0.95) and 15-year OS was 73.7 and 55.6% (P = 0.17), respectively. Upfront TPDCV for children with hypothalamic/chiasmatic LGGs resulted in 15-year OS of 71.2% and 15-year PFS of 23.4%. No survival benefit is demonstrated for greater extent of resection. Age is a significant prognostic factor for progression and survival.     

The recurrence patterns of stages I, II and III neuroblastoma: Experience with 77 relapsing patients

Background: Recurrences of neuroblastoma Evans' stage I-IIIare infrequent events and the types of its progression haverarely been reported. Therefore, we investigated the patternsof progression in a large series of patients with long follow-up. Patients and methods: The sites of relapse and time to progressionand death of 381 consecutive patients in three cooperative trials(NB 79, 82, 85) with follow-up of 5–16 years were analysed.The Southern blot technique was used for N-myc investigationof tumor tissue. Results: Of the 77 relapsing patients, 41 (53%) had local and36 (47%) systemic recurrences. The relapses occurred in 9 of76 stage I patients (6 local/3 systemic), in 4 of 82 stage II(1 local/3 systemic) and 64 of 223 stage III neuroblastoma (34local/30 systemic) patients. The main sites of distant metastasiswere bone marrow (41%), lymph nodes (39%) and bone (37%). Themedian transition time from localised to metastatic neuroblastomawas 13 months and the outcome as poor (overall survival 9 ±5%) as that of the primary metastatic disease (14 ± 3%).Fifty-three children died of tumor progression and 15 patientsof treatment-related complications or other non-tumor conditions. The median age at diagnosis was 43 months for the group withsystemic relapse compared to 19 months with only local and 10months without recurrences (p < 0.001). Elevated serum LDHlevels at first diagnosis were seen in 81% with metastatic,in 55% with local and in 33% with no tumor progression (p <0.001). N-myc amplification was found in 4/14 with local andin 6/12 with metastatic recurrences. Conclusion: The high incidence of systemic relapse and the longtransition time suggest that transition from localised to metastaticneuroblastoma is not an uncommon pathway. neuroblastoma, N-myc, recurrence, risk-factor, screening, transition     

Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study

BackgroundSurvival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results.MethodsUsing data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas.ResultsFifty-three patients with a median age of 6.9 years (1.25–25.4) at first recurrence and a median follow-up time of 36 months (2–115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9–120.1) vs. 95 (CI: 20.7–169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7–31.3) vs. 7 (CI: 0–15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%.ConclusionThe extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%).     

Different outcomes for relapsed versus refractory neuroblastoma after therapy with 131I-metaiodobenzylguanidine (131I-MIBG)

Background¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to ¹³¹I-MIBG between patients with relapsed and treatment-refractory neuroblastoma.MethodsThis was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with ¹³¹I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test.ResultsThe response rate (complete and partial response) to ¹³¹I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after ¹³¹I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). Among all patients, the 24-month OS was 47.0% (95% confidence interval (CI) 39.9–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8–75.9%), compared to 38.7% (95% CI 30.4–46.8%) for relapsed patients (p < 0.001).ConclusionsAlthough there was no significant difference in overall response rates to ¹³¹I-MIBG between patients with relapsed versusrefractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after ¹³¹I-MIBG compared to patients with refractory disease.     

Plasma midkine level is a prognostic factor for human neuroblastoma

Neuroblastoma is the third‐most‐common solid tumor of childhood. To date, no reliable blood marker for neuroblastoma has been established. The growth factor midkine is highly expressed in human carcinomas and its knockdown leads to tumor growth suppression in animal models. The present study evaluated the plasma midkine level in human neuroblastoma patients. Plasma samples were obtained from patients found through mass screening, as well as from sporadic neuroblastoma patients. The total number of cases examined was 756. Among them, prognostic information was available for 175 sporadic cases and 287 mass‐screening cases. Midkine levels were significantly higher in neuroblastoma patients, including both mass‐screening cases and sporadic cases, than in non‐tumor controls (P < 0.0001). The midkine level was significantly correlated with the statuses of MYCN amplification, TRKA expression, ploidy, stage and age (P < 0.0001, < 0.0001, = 0.004, < 0.0001 and < 0.0001, respectively), which are known prognostic factors for neuroblastoma. There was a striking correlation between high plasma midkine level and poor prognosis (P < 0.0001). Within sporadic cases, the midkine level was also strikingly higher than in non‐tumor controls (P < 0.0001), and correlated with the statuses of MYCN amplification and stage (P = 0.0005 and = 0.003, respectively). There was a significant correlation between high plasma midkine level and poor prognosis (P = 0.04). Taken together, the present data indicate that plasma midkine level is a prognostic factor for human neuroblastoma. (Cancer Sci 2008; 99: 2070–2074)     

WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia

Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical Wnt/Ca²⁺ pathway to suppress cyclin D1 expression and negatively regulate B cell proliferation suggesting that it acts as an tumour suppressor for lymphoid leukemogenesis. Although canonical Wnt pathway is a ‘hot spot’ for methylation in acute lymphoblastic leukaemia (ALL), the role of Wnt5a abnormalities has never been evaluated in this clinical setting. The methylation status of the WNT5A promoter was analysed by methylation-specific PCR (MSP) and sequencing in six ALL-derived cell lines (TOM-1, NALM-20, MY, LOUCY, JURKAT and TANOUE) and in 307 ALL patients. WNT5A and CYCLIN D1 expressions were assessed by quantitative RT-PCR. We observed WNT5A hypermethylation in all cell lines and in cells from 43% (132/307) of ALL patients. WNT5A methylation was associated with decreased WNT5A mRNA expression (P < 0.001) and this expression was restored after exposure to the demethylating agent 5-Aza-2′-deoxycytidine. Moreover, WNT5A hypermethylation correlated with upregulation of CYCLIN D1 expression (P = 0.002). Disease-free survival (DFS) and overall survival (OS) at 13 and 14 years, respectively, were 59% and 53% for unmethylated patients and 28% and 31% for hypermethylated patients (P = 0.0003 and P = 0.003). Multivariate analysis demonstrated that WNT5A methylation was an independent prognostic factor predicting DFS (P = 0.003) and OS (P = 0.04). We have demonstrated that WNT5A, a putative tumour suppressor gene in ALL, is silenced by methylation in this disease and that this epigenetic event is associated with upregulation of CYCLIN D1 expression and confers poor prognosis in this group of patients.     

The Effect of Duration of Lenalidomide Maintenance and Outcomes of Different Salvage Regimens in Patients with Multiple Myeloma (MM)

The optimal duration of lenalidomide maintenance post-autologous stem cell transplant (ASCT) in Multiple Myeloma (MM), and choice of therapy at relapse post-maintenance, need further evaluation. This retrospective study assessed outcomes of patients with MM (n = 213) seen at Mayo Clinic, Rochester between 1/1/2005–12/31/2016 who received lenalidomide maintenance post-ASCT. The median PFS was 4 (95% CI: 3.4, 4.5) years from diagnosis of MM; median OS was not reached (5-year OS: 77%). Excluding patients who stopped lenalidomide maintenance within 3 years due to progression on maintenance, ≥3 years of maintenance had a superior 5-year OS of 100% vs. 85% in <3 years (p = 0.011). Median PFS was 7.2 (95% CI: 6, 8.5) years in ≥3 years vs. 4.4 (95% CI: 4.3, 4.5) years in <3 years (p < 0.0001). Lenalidomide refractoriness at first relapse was associated with inferior PFS2 [8.1 (95% CI: 6.4, 9.9) months vs. 19.9 (95% CI: 9.7, 30.2; p = 0.002) months in nonrefractory patients]. At first relapse post-maintenance, median PFS2 was superior with daratumumab-based regimens [18.4 (95% CI: 10.9, 25.9) months] versus regimens without daratumumab [8.9 (95% CI: 5.5, 12.3) months; p = 0.006]. Daratumumab + immunomodulatory drugs had superior median PFS2 compared to daratumumab + bortezomib [NR vs 1 yr (95% CI: 0.5, 1.5); p = 0.004].Subject terms: Myeloma, Myeloma     

Comparison of Outcomes After Second Allogeneic Hematopoietic Cell Transplantation Versus Donor Lymphocyte Infusion in Allogeneic Hematopoietic Cell Transplant Patients

BackgroundAllogeneic hematopoietic cell transplantation (HCT) is potentially curative for hematological disease however can be complicated by relapse or graft failure (GF), for which second-HCT and donor lymphocyte infusions (DLI) are performed. This study aimed to compare outcomes following the two interventions.MethodsWe retrospectively investigated 89 patients with relapse or GF after first-HCT, 50 (56%) underwent second HCT and 39 (44%) received (DLI), from June 2011 to September 2020.ResultsMedian age at intervention was 55 years (19-72). Second-HCT was performed for relapse in 19 patients and for GF in 31 patients (primary GF in 11 and secondary in 20 patients), same donor was used in 25 (50%) patients. DLI was performed for relapse in 20 and for secondary GF in 19 patients. Median number of DLI administered was 2 (range 1-11). Univariate analysis demonstrated 2 year overall survival (OS) for second-HCT was superior when performed for relapse (65%) compared to GF (44%) (P = .03). For DLI patients, 2 year OS was 49% for GF and 45% for relapse patients (P = .49). For relapse as an indication, second-HCT demonstrated borderline superiority compared to DLI (P = .07). Multivariable analysis demonstrated for OS for the entire cohort demonstrated donor mismatch (HR 0.50, 95% CI 0.26%-0.94%, P = .03), KPS at time of intervention (HR 2.10, 95% CI 1.14%-3.85%, P = .02) and time from first-HCT to intervention (HR 0.51, 95% CI 0.28%-0.93%, P = .03) as significant variables.ConclusionSecond-HCT may improve outcomes when performed for relapse post-transplant if patients achieve remission again, while DLI may be reserved for patients with active disease.     

The impact of body mass index on complication and survival in resected oesophageal cancer: a clinical-based cohort and meta-analysis

Background:

Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial.

Methods:

In total, 2031 consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian-specific BMI (kg m⁻²) cutoff values. The impact of BMI on overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. We performed a meta-analysis to examine the association of BMI with OS and postoperative complication.

Results:

Patients with higher BMI had more postoperative complication (P=0.002), such as anastomotic leakage (P=0.016) and cardiovascular diseases (P<0.001), but less incidence of chylous leakage (P=0.010). Logistic regression analysis showed that BMI (P=0.005) was a confounding factor associated with postoperative complication. Multivariate analysis showed that overweight and obese patients had a more favourable survival than normal weight patients (HR (hazard ratio) = 0.80, 95% CI (confidence interval): 0.70–0.92, P=0.001). Subgroup analysis showed that the association with higher BMI and increased OS was observed in patients with oesophageal squamous cell carcinoma (ESCC) (P<0.001), oesophageal adenocarcinoma (EA) (P=0.034), never-smoking (P=0.035), ever-smoking (P=0.035), never alcohol consumption (P=0.005), weight loss (P=0.003) and advanced pathological stage (P<0.001). The meta-analysis further corroborated that higher BMI was associated with increased complication of anastomotic leakage (RR (risk ratio)=1.04, 95% CI: 1.02–1.06, P=0.001), wound infection (RR=1.03, 95% CI: 1.00–1.05, P=0.031) and cardiovascular diseases (RR=1.02, 95% CI: 1.00–1.05, P=0.039), but decreased incidence of chylous leakage (RR=0.98, 95% CI: 0.96–0.99, P<0.001). In addition, high BMI could significantly improved OS (HR=0.78, 95% CI: 0.71–0.85, P<0.001).

Conclusion:

Preoperative BMI was an independent prognostic factor for survival, and strongly associated with postoperative complications in oesophageal cancer.     

Comparison of portal and capsular microscopic vascular invasion in the outcomes of early HCC after curative resection

Microscopic vascular invasion (MVI) is a strong risk factor associated with tumor recurrence and poor overall survival (OS) among hepatocellular carcinoma (HCC) patients after resection. Two types of MVI are identified: portal vein and capsular vein invasion. However, little is known about the impact of different types of MVI on HCC recurrence. The present study aimed to compare HCC recurrence and OS between the portal vein and capsule vein MVI. Patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 were consecutively recruited. Factors that influenced OS and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. Of the 857 eligible patients, 327 (38.2%) had MVI, and 530 (61.8%) were without MVI. Of the 327 patients with MVI, 85 (26.0%) were with portal vein, 178 (54.4%) with capsular vein, and 64 (19.6%) with both-MVI type. Patients with both-MVI type suffered from a higher proportion of BCLC stage A (P < 0.001), capsular invasion (P = 0.002), and satellite nodules (P < 0.001). Both-MVI type is an independent risk factor for HCC recurrence (hazard ratio [HR]: 1.69; 95% CI, 1.22-2.36, P = 0.002) and mortality (HR: 2.29; 95% CI, 1.59-3.29, P < 0.001) compared with non-MVI. We further found that both-MVI type was significantly associated with a higher risk of extrahepatic recurrence (EHR) (HR: 8.74; 95% CI, 2.38-32.03, P = 0.001). Among HCC patients after curative resection, concurrent portal and capsular MVI is a risk factor for HCC recurrence, especially for EHR, in comparison with non-MVI or only portal or capsular MVI alone.     

Breast-feeding and neuroblastoma,USA and Canada

Objective: Researchers have suggested an inverse association between breast-feeding and risk of childhood cancer. We investigated the association between breast-feeding and neuroblastoma in a large case–control study in the United States and Canada. Methods: Maternal reports of breast-feeding were compared among 393 children six months or older who had neuroblastoma and were identified through the Children's Cancer Group and the Pediatric Oncology Group and 376 age-matched controls identified by random-digit telephone dialing in a telephone interview case–control study. Results: Children with neuroblastoma were less likely to have breast-fed than control children (odds ratio (OR) = 0.6; 95% confidence interval (CI) = 0.5–0.9). The association between breast-feeding and neuroblastoma increased with breast-feeding duration (0–3 months OR = 0.7, CI = 0.4–1.0; 13+ months OR = 0.5, CI = 0.3–0.9). Conclusion: Breast-feeding was inversely associated with neuroblastoma and should be encouraged among healthy mothers. Additional research on possible mechanisms of this association may be warranted.     

Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth

Objective: Neuroblastoma is a common neuroendocrine (NE) tumor that presents in early childhood, with a high incidence of malignancy and recurrence. The glycogen synthase kinase-3 (GSK-3) pathway is a potential therapeutic target, as this pathway has been shown to be crucial in the management of other NE tumors. However, it is not known which isoform is necessary for growth inhibition. In this study, we investigated the effect of the GSK-3 inhibitor AR-A014418 on the different GSK-3 isoforms in neuroblastoma. Methods: NGP and SH-5Y-SY cells were treated with 0–20 μM of AR-A014418 and cell viability was measured by MTT assay. Expression levels of NE markers CgA and ASCL1, GSK-3 isoforms, and apoptotic markers were analyzed by western blot. Results: Neuroblastoma cells treated with AR-A014418 had a significant reduction in growth at all doses and time points (P &lt; 0.001). A reduction in growth was noted in cell lines on day 6, with 10 μM (NGP-53% vs. 0% and SH-5Y-SY-38% vs. 0%, P &lt; 0.001) treatment compared to control, corresponding with a noticeable reduction in tumor marker ASCL1 and CgA expression. Conclusion: Treatment of neuroblastoma cell lines with AR-A014418 reduced the level of GSK-3α phosphorylation at Tyr279 compared to GSK-3β phosphorylation at Tyr216, and attenuated growth via the maintenance of apoptosis. This study supports further investigation to elucidate the mechanism(s) by which GSK-3α inhibition downregulates the expression of NE tumor markers and growth of neuroblastoma.     

Comparison of Two Pediatric-Inspired Regimens to Hyper-CVAD in Hispanic Adolescents and Young Adults With Acute Lymphoblastic Leukemia

BackgroundPediatric-inspired regimens (PIR) in adolescents and young adults with acute lymphoblastic leukemia have led to better long-term outcomes. In Latin America, the adolescent and young adult population has an increasing incidence of acute lymphoblastic leukemia with poor outcomes (5-year OS of approximately 20%) with traditional regimens.Patients and MethodsA retrospective cohort study was performed of adolescent and young adult acute lymphoblastic leukemia patients treated with PIR in two reference centers in Mexico City between March 2016 and June 2019, in which the primary endpoint was OS, compared to a historic cohort of patients treated with hyper-CVAD treated between February 2009 and June 2015.ResultsWe compared 73 patients treated with PIR (46 and 27 received modified versions of the ALL-BFM 90 and CALGB C10403 regimens, respectively) and 173 patients treated with hyper-CVAD. Patients treated with PIR experienced higher 4-week complete response rates (79.5% vs. 64.2%; P = .02) and lower relapse rates (44.1% vs. 60.0%; P = .04). OS was significantly higher with PIR than with hyper-CVAD (24 months: 41.5% vs. 28.1%; P = .012). The benefit on OS for PIR was only significant for CALGB (24-month OS: 61.1% vs. 28.0%; P = .01) but not for BFM. In the multivariate analysis, hyperleukocytosis (hazard ratio [HR] = 1.90; 95% confidence interval [CI], 1.11-3.22; P = .02), autologous stem-cell transplantation (HR = 0.38; 95% CI, 0.17-0.86; P = .02), and 4-week complete response (HR = 0.43; 95% CI, 0.26-0.70; P < .01) were independent prognostic factors. For the group of patients older than 20 years, only CALGB had an independent prognostic factor for OS (HR = 0.44; 95% CI, 0.20-0.97; P = .04).ConclusionIn terms of 4-week complete response, relapse rates, and OS, PIR provides benefits to Hispanic patients.     

Impact of transfusion dependency on survival in patients with early myelodysplastic syndrome without excess of blasts

We present a retrospective analysis of 137 patients with early MDS without excess of blasts that revealed transfusion dependency in 87% of the cases. A significant difference in overall survival was noted between patients receiving ≤2 units and those receiving >2 units of RBC transfusions/month (65.0 vs. 35.3 months, respectively, P = 0.02). Univariate statistical analysis identified the presence of disease progression to advanced MDS (χ² = 26.4, P = 0.001) and the administration of >1 or >2 units of RBC per month (χ² = 15.9 and 14.6, respectively, P = 0.001) as the most important parameters affecting survival. Nevertheless, even the administration of 1 RBC unit every 4–8 weeks had a significantly adverse impact on survival compared to non-transfused patients. Transfusion dependency itself did not affect disease progression as determined by the presence of multilineage dysplasia and adverse karyotype (expressed by the IM-1 or IM-2 score). Multivariate analysis confirmed disease progression towards leukemia as a highly significant independent variable affecting survival (P = 0.0001). None of the other evaluated parameters had a significant impact on survival in patients with progressive disease. In non-transplanted patients without MDS progression, administration of >2 units of RBC transfusions/month was the only independent variable with adverse impact on survival in patients with unilineage erythroid dysplasia (P = 0.02). In patients with multilineage dysplasia, only heavy transfusion dependency (>3 TU RBC/month) and serum ferritin >2000 μg/l adversely affected survival (P = 0.03). Modification of the WPSS by replacing transfusion dependency with initial Hb level <80 g/l retained its prognostic relevance and allowed the identification of a potential risk subset of early MDS patients with intermediate and high scores and limited survival (<40% at 5 years) as early as at the time of diagnosis. Our results confirm a significant negative impact of transfusion dependency on survival in patients with early MDS without excess of blasts. The main risk subgroup is characterized by unilineage dysplasia limited to erythropoiesis in combination with dependency on >2 TU of RBC per month. These patients usually have prolonged survival that leads to the development of heavy transfusion iron overload and they thus represent the most important target group for intensive chelation therapy.