Cetuximab or nimotuzumab plus intensity‐modulated radiotherapy versus cisplatin plus intensity‐modulated radiotherapy for stage II‐IVb nasopharyngeal carcinoma

To compare intensity‐modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II‐IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II – IV_b NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well‐balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well‐balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3‐year, 86.7% vs. 86.2%, p > 0.05), LRRFS (96.2% vs. 96.3%, p > 0.05), DMFS (91.1% vs. 92.3%, p > 0.05) and OS (91.7% vs. 91.9%, p > 0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco‐regional relapse (HR 8.85, p = 0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (p < 0.05). Patients of 3.4 – 4.7% experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related‐skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP‐IMRT combination for maximizing survival for patients with stage II‐IVb NPC.     

A nomogram to predict survival and guide individualized induction chemotherapy in T3-4N1M0 nasopharyngeal carcinoma

Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) and CCRT alone were the optional treatment regimens for T3-4N1M0 nasopharyngeal carcinoma (NPC) patients. Therefore, we established a nomogram to predict clinical prognosis and guide individualized IC in T3-4N1M0 NPC. Overall, 699 T3-4N1M0 NPC patients treated with CCRT with or without IC between January 2010 and December 2018 were examined. Overall survival (OS) was the main endpoint. A nomogram was developed that included prognostic variables selected by multivariable analysis. The risk score, which was calculated according to the nomogram, was used for risk stratification. The survival difference of patients undergoing CCRT with or without IC was then compared in risk-stratified subgroups. The nomogram yielded C-indexes of 0.708 (95% confidence interval [CI]: 0.682-0.734) in the training cohort and 0.670 (95% CI: 0.625-0.715) in the validation cohort. Calibration curves for 1-, 3- and 5-year OS suggested a good association between the nomogram predicted and observed probabilities. High-risk patients stratified by nomogram benefited from IC (IC + CCRT vs CCRT: 5-year OS: 77.8% vs 58.8%; P = 0.040; 5-year disease-free survival: 75.0% vs 58.2%; P = 0.017), whereas in the low-risk group, the application of IC was associated with worse locoregional recurrence-free survival and distant metastasis-free survival. This nomogram can serve as a reliable model for prognostic prediction and can be used to guide individualized treatment of T3-4N1M0 NPC. High-risk patients are candidates for IC before CCRT, while the use of IC for low-risk patients should be considered carefully.     

Prognostic value of nutritional risk screening 2002 scale in nasopharyngeal carcinoma: A large‐scale cohort study

Little is known about the value of the nutritional risk screening 2002 (NRS2002) scale in nasopharyngeal carcinoma (NPC). We conducted a large‐scale study to address this issue. We employed a big‐data intelligence database platform at our center and identified 3232 eligible patients treated between 2009 and 2013. Of the 3232 (12.9% of 24 986) eligible patients, 469 (14.5%), 13 (0.4%), 953 (29.5%), 1762 (54.5%) and 35 (1.1%) had NRS2002 scores of 1, 2, 3, 4 and 5, respectively. Survival outcomes were comparable between patients with NRS2002 <3 and ≥3 (original scale). However, patients with NRS2002 ≤3 vs >3 (regrouping scale) had significantly different 5‐year disease‐free survival (DFS; 82.7% vs 75.0%, P  <  .001), overall survival (OS; 88.8% vs 84.1%, P = .001), distant metastasis‐free survival (DMFS; 90.2% vs 85.9%, P = .001) and locoregional relapse‐free survival (LRRFS; 91.6% vs 87.2%, P = .001). Therefore, we proposed a revised NRS2002 scale, and found that it provides a better risk stratification than the original or regrouping scales for predicting DFS (area under the curve [AUC] = 0.530 vs 0.554 vs 0.577; P < .05), OS (AUC = 0.534 vs 0.563 vs 0.582; P < .05), DMFS (AUC = 0.531 vs 0.567 vs 0.590; P < .05) and LRRFS (AUC = 0.529 vs 0.542 vs 0.564; P < .05 except scale A vs B). Our proposed NRS2002 scale represents a simple, clinically useful tool for nutritional risk screening in NPC.     

Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI‐1 study

The global, randomized NAPOLI‐1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (nal‐IRI+5‐FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine‐based therapy. Median overall survival (OS) with nal‐IRI+5‐FU/LV was 6.1 vs 4.2 months with 5‐FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post‐hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression‐free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal‐IRI+5‐FU/LV (n = 34) had significantly longer median OS versus 5‐FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal‐IRI+5‐FU/LV versus 5‐FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal‐IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5‐FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal‐IRI+5‐FU/LV versus 5‐FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal‐IRI+5‐FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine‐based therapy, with a safety profile agreeing with previous findings. The nal‐IRI+5‐FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506)     

Major prognostic value of complex karyotype in addition to TP53 and IGHV mutational status in first‐line chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of remarkable heterogeneity as demonstrated by cytogenetics and molecular analyses. Complex karyotype (CK), TP53 deletions and/or mutations (TP53 disruption), IGVH mutational status, and, more recently, recurrent somatic mutations have been identified as prognostic markers in CLL. On a cohort of 110 patients with CLL treated with first‐line fludarabin, cyclophosphamide, and rituximab treatment compared with 33 untreated (watch and wait) patients with CLL, we report more frequent complex karyotypes (34 vs 15%; P = .05), unmutated IGHV (70 vs 21%; P < .0001), ATM deletion (25 vs 6%, P = .02), and NOTCH mutation (3 vs 17%, P = .04). Among treated patients, 39 relapsed during the follow‐up period. These patients were characterized before treatment by a higher incidence of trisomy 12 (38 vs 11%, P < .001) and TP53 disruption (31 vs 4%, P = .0002). A significantly shorter 5‐year overall survival was found for treated patients with CK (72.4 vs 85.8%; P = .007), unmutated IGHV (70 vs 100%; P = .04), or TP53 disruption (55.7 vs 82.7%; P < .0001). Three risk groups were defined based on the status of TP53 disruption or unmutated IGVH, which differed significantly in terms of 5‐year overall survival. Moreover, the presence of CK impacted pejoratively 5‐year overall survival and progression‐free survival in all these 3 groups. Conventional karyotyping therefore appears to be of value, CK being an additional factor, undetectable in classical FISH, in patients with CLL at the stage when therapy becomes required.     

Early clinical outcomes of helical tomotherapy/intensity‐modulated proton therapy combination in nasopharynx cancer

This study aimed to evaluate the feasibility of combining helical tomotherapy (HT) and intensity‐modulated proton therapy (IMPT) in treating patients with nasopharynx cancer (NPC). From January 2016 to March 2018, 98 patients received definitive radiation therapy (RT) with concurrent chemotherapy (CCRT). Using simultaneous integrated boost and adaptive re‐plan, 3 different dose levels were prescribed: 68.4 Gy in 30 parts to gross tumor volume (GTV), 60 Gy in 30 parts to high‐risk clinical target volume (CTV), and 36 Gy in 18 parts to low‐risk CTV. In all patients, the initial 18 fractions were delivered by HT, and, after rival plan evaluation on the adaptive re‐plan, the later 12 fractions were delivered either by HT in 63 patients (64.3%, HT only) or IMPT in 35 patients (35.7%, HT/IMPT combination), respectively. Propensity‐score matching was conducted to control differences in patient characteristics. In all patients, grade ≥ 2 mucositis (69.8% vs 45.7%, P = .019) and grade ≥ 2 analgesic usage (54% vs 37.1%, P = .110) were found to be less frequent in HT/IMPT group. In matched patients, grade ≥ 2 mucositis were still less frequent numerically in HT/IMPT group (62.9% vs 45.7%, P = .150). In univariate analysis, stage IV disease and larger GTV volume were associated with increased grade ≥ 2 mucositis. There was no significant factor in multivariate analysis. With the median 14 month follow‐up, locoregional and distant failures occurred in 9 (9.2%) and 12 (12.2%) patients without difference by RT modality. In conclusion, comparable early oncologic outcomes with more favorable acute toxicity profiles were achievable by HT/IMPT combination in treating NPC patients.     

Clinical impact of early recovery of peripheral blood absolute lymphocyte count after frontline autologous stem cell transplantation for diffuse large B‐cell lymphoma

We conducted a retrospective study to evaluate the clinical impact of an early recovery of posttransplant absolute lymphocyte count (ALC) on the outcome of frontline autologous stem cell transplantation (ASCT) for diffuse large B‐cell lymphoma (DLBCL). We reviewed 65 DLBCL patients who underwent frontline ASCT after primary chemotherapy based on cyclophosphamide, doxorubicin, vincristine, and prednisone. A receiver operating characteristic analysis was performed to determine the optimal cut point (0.4 × 10⁹/L) for an ALC at 15 days after ASCT (ALC‐15). Both event‐free survival and overall survival rates of the higher‐ALC‐15 group were significantly better than those of the lower‐ALC‐15 group (event‐free survival, P = .008; overall survival, P = .013). The infused CD34⁺ cell count was significantly associated with the recovery of ALC‐15 (>0.4 × 10⁹/L) after ASCT (P = .028). A multivariate analysis confirmed that a higher infused CD34⁺ cell dose (>5.0 × 10⁶ cells/kg) was an independent factor affecting an early recovery of ALC after ASCT (odds ratio, 4.145; 95% confidence interval, 1.106‐15.528; P = .035). In conclusion, an early recovery of ALC after ASCT can be regarded as a good prognostic marker in patients with DLBCL who have undergone frontline ASCT. We found that the infused CD34⁺ cell dose for ASCT was associated with the recovery of ALC.     

Primary prophylaxis of invasive fungal infections with posaconazole or itraconazole in patients with acute myeloid leukaemia or high‐risk myelodysplastic syndromes undergoing intensive cytotoxic chemotherapy: A real‐world comparison

This is an observational‐retrospective study comparing the real‐world outcomes associated with posaconazole vs itraconazole as prophylaxis treatments. Two hundred and ninety‐three patient admissions attributable to 174 patients were included in the study. Patients were treated with itraconazole (n = 114 admissions; 39%) or posaconazole (n = 179; 61%). Antifungal prophylaxis failure (APF) due to treatment‐related adverse events (in 34 out of 293 patient admissions; 11.6%) was more frequent in the posaconazole group (6.1% vs 15.1%; P = .024). There were 9 patient admissions for episodes of APF due to probable/proven breakthrough fungal infection (primary endpoint): 6 and 3 in the itraconazole and posaconazole group respectively (5.3% vs 1.7%; P = .095). All of them were associated with invasive pulmonary aspergillosis (IPA). APF was more frequent with itraconazole (65% vs 30%; P < .001), along with failure due to possible/probable/proven IPA (25% vs 10%; P = .002) and overall failure by any of the 3 different causes of prophylaxis failure (70% vs 38%; P < .001). In agreement with clinical trial data, this real‐world evidence supports the use of posaconazole over itraconazole in AML or MDS patients undergoing intensive chemotherapy.     

Complete metabolic response (CMR) in positron emission tomography–computed tomography (PET‐CT) scans may have prognostic significance in patients with marginal zone lymphomas (MZL)

Although clinical use of positron emission tomography–computed tomography (PET‐CT) scans is well established in aggressive lymphomas, its prognostic value in marginal zone lymphoma (MZL) remains yet unclear. Hence, we investigated potential role of PET‐CT in predicting MZL patients' outcomes following systemic chemotherapy. A total of 32 patients with MZL who received first‐line chemotherapy were included in the analysis. They all underwent pretreatment, interim, and posttreatment PET‐CT scans. The primary objective was to evaluate the role of complete metabolic response (CMR) in posttreatment PET‐CT scans in predicting progression‐free survival (PFS). Compared with non‐CMR group, 5‐year PFS rate was significantly higher in patients who achieved CMR in posttreatment PET‐CT (54.2% vs 0.0%, P = .003) and also in patients gaining CMR in interim PET‐CT scans (62.5% vs 15.6%, P = .026). Interestingly, early CMR group, who achieved and maintained CMR in both interim and posttreatment PET‐CT scans, showed significantly higher 5‐year PFS than those with delayed or never CMR group (62.5% vs 37.5% vs 0%, P = .008). Therefore, interim and/or posttreatment CMR can be prognostic at least in these subsets of patients with MZL treated with chemotherapy.     

Prognostic value of serum Epstein–Barr virus antibodies in patients with nasopharyngeal carcinoma and undetectable pretreatment Epstein–Barr virus DNA

Epstein–Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). Serum IgA antibodies against early antigen (EA‐IgA) and viral capsid antigen (VCA‐IgA) are the most commonly used to screen for NPC in endemic areas. However, the prognostic value of serum EA‐IgA and VCA‐IgA in patients with NPC is less clear. We hypothesize that serum EA‐IgA and VCA‐IgA levels have prognostic impact for survival outcomes in NPC patients with undetectable pretreatment EBV (pEBV) DNA. In this series, 334 patients with non‐metastatic NPC and undetectable pEBV DNA were included. Serum EA‐IgA and VCA‐IgA were determined by ELISA. After analysis, serum EA‐IgA and VCA‐IgA loads correlated positively with T, N, and overall stage (all P < 0.05). Serum EA‐IgA was not associated with survival outcome in univariable analyses. But patients with serum VCA‐IgA >1:120 had significantly inferior 5‐year progression‐free survival (80.4% vs 89.6%, P = 0.025), distant metastasis‐free survival (88.4% vs 94.8%, P = 0.050), and locoregional relapse‐free survival (88.4% vs 95.6%, P = 0.023; log–rank test). Multivariable analyses revealed that N stage was the only independent prognostic factor (all P < 0.05), but the VCA‐IgA became insignificant. Further analyses revealed that serum VCA‐IgA was not an independent prognostic factor in early N (N0–1) or advanced N (N2–3) stage NPC. In summary, although both EA‐IgA and VCA‐IgA correlate strongly with TNM stage, our analyses do not suggest that these antibodies are prognostic biomarkers in patients with NPC and undetectable pEBV DNA.     

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8⁺ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8⁺ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8⁺ expression might be the subset that would poorly benefit from such treatment.     

Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

Patients with lower‐risk myelodysplastic syndromes (LR‐MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter‐individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS‐relevant genes in 159 patients with LR‐MDS using next‐generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF <18% or without TET2 mutations (median: 20.4 vs 47.8 months; P = .020; HR = 2.183, 95%CI: 1.129‐4.224). After adjustment for IPSS, shorter OS was associated with mutation status of ASXL1 (P < .001; HR = 4.306, 95% CI: 2.144‐8.650), TP53 (P = .004; HR = 4.863, 95% CI: 1.662‐14.230) and JAK2 (P = .002; HR = 5.466, 95%CI: 1.848‐16.169), as well as adjusted TET2 VAF ≥18% (P = .008; HR = 2.492, 95% CI: 1.273‐4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P < .001). A novel prognostic scoring system incorporating the presence/absence of the four independent mutational factors into the IPSS further stratified LR‐MDS patients into three prognostically different groups (P < .001). The newly developed scoring system redefined 10.1% (16/159) of patients as a higher‐risk group, who could not be predicted by the currently prognostic models. In conclusion, integration of the IPSS with mutation status/burden of certain MDS‐relevant genes may improve the prognostication of patients with LR‐MDS and could help identify those with worse‐than‐expected prognosis for more aggressive treatment.     

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.     

Preliminary results of a phase III randomized study comparing chemotherapy neoadjuvantly or concurrently with radiotherapy for locoregionally advanced nasopharyngeal carcinoma

The current study was conducted to compare neoadjuvant chemotherapy (NACT) with concurrent chemotherapy for efficacy, toxicities and compliance of locoregionally advanced nasopharyngeal carcinoma (NPC). Eligible patients were randomized to NACT + radiotherapy (RT) + adjuvant chemotherapy (AC) arm or concurrent chemoradiotherapy(CCRT) + AC arm. Two arms received same conventional RT at a planned dose of 70 Gy. Neoadjuvant chemotherapy comprised cisplatin 90 mg/m² (30 mg/m²/day) and 5-fluorouracil 1,500 mg/m² (500 mg/m²/day) over 3 days for two 21-day cycles. The same regimen at equal dosage was administered on the 1st and 22nd days of the radiotherapy as concurrent chemotherapy. Four cycles of the same chemotherapy regimen were given to both two arms as AC. A total of 338 NPC patients were recruited. 170 patients were randomized to NACT arm and 168 patients to CCRT arm. The median duration of follow-up was 38 months. The 3-year OS and DFS rates were 95.9 versus 94.5% (P = 0.54) and 78.5 versus 82.5% (P = 0.16), respectively, in NACT and CCRT arms. An unplanned subgroup analysis according to the N-classification suggested that CCRT improves MFS in patients with N0-1 disease (80.1 vs. 94.9%, P = 0.034). Among the acute toxicities observed, the rates of grade 3/4 mucositis (52.4 vs. 35.9% P = 0.023) and vomiting (13.7 vs. 4.7% P = 0.000) were significantly higher in CCRT arm. Our preliminary results only showed an advantage of CCRT over NACT in NPC patients with limited N disease in MFS. More acute toxicities were observed in CCRT arm and a trend of better tolerance was observed in NACT arm.     

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9‐81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6‐176.0), with 2‐year disease‐free survival rate of 45.1% (95% confidence interval 39.6‐50.6). The median overall survival was 14.4 months (range 0.3‐177.0), with 2‐year overall survival rate of 42.2% (95% confidence interval 37.5‐46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low‐risk karyotype (P < .001), no high‐risk karyotype (P = .006), positivity for AML‐ETO (P = .004)/CBFβ‐MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3‐ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 10⁹/L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 10⁹/L (P = .017), and low‐risk/no high‐risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement . The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.     

Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D‐STOP, after a 3‐year follow‐up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment‐free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7‐74.3] and 59.3% (95% CI: 45.0‐71.0), respectively. CD3^?CD56⁺ NK, CD16⁺CD56⁺ NK, and CD57⁺CD56⁺ NK large granular lymphocyte (NK‐LGL), CD8⁺CD4^– cytotoxic T cell, and CD57⁺CD3⁺ T‐LGL cell numbers were relatively elevated throughout the 24‐month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24‐month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3^?CD56⁺ NK >376 cells/μL, CD16⁺CD56⁺ NK > 241 cells/μL, or CD57⁺CD56⁺ NK‐LGL >242 cells/μL during consolidation compared with others were 26.7% (8.3%‐49.6%) vs 78.3% (55.4%‐90.3%), HR 0.032 (0.0027‐0.38; P = .0064), 31.2% (11.4%‐53.6%) vs 85.0% (60.4%‐94.9%), HR 0.039 (0.0031‐0.48; P = .011), or 36.8% (16.5%‐57.5%) vs 77.3% (53.7%‐89.8%), HR 0.21 (0.065‐0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D‐STOP, NCT01627132).     

Tumor‐infiltrating M2 macrophage in pretreatment biopsy sample predicts response to chemotherapy and survival in esophageal cancer

The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre–therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4⁺ lymphocytes (with/without Foxp3 expression), CD8⁺ lymphocytes (with/without PD‐1 expression), monocytes (CD14⁺) and macrophages (CD86⁺, CD163⁺ and CD206⁺) by multiplex immunohistochemistry (IHC). The number of tumor‐infiltrating CD206⁺ macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD‐1) was not associated with clinico‐pathological features. The high infiltration of CD163⁺ or CD206⁺ macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively). Expression of arginase‐1 in CD163⁺ macrophages tended to be higher in non–responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5‐year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long‐term survival in EC patients.     

Mutation of the TP53 gene in acute lymphoblastic leukemia does not affect survival outcomes after haploidentical hematopoietic stem cell transplantation

Previous studies have demonstrated that TP53 mutation is correlated with insufficient therapy response and unfavorable prognosis in acute lymphoblastic leukemia (ALL). Few studies have investigated the impact of TP53 mutation in ALL patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We completed a retrospective study of 65 ALL patients with available TP53 status who underwent haplo-HSCT. They were divided into a TP53 mutation group (TP53^mut) and a TP53 wild-type (TP53^wt) group. TP53^mut showed comparable 2-year cumulative incidence of relapse (CIR) rates (13.1% vs 12.5%, P = .96) and 2-year leukemia-free survival (LFS) (74.2% vs 77.4%, P = .80) with TP53^wt. No significant differences in 2-year overall survival (OS) rates (82.9% vs 87.3%, P = .61) or 2-year NRM rates (12.7% vs 10.2%, P = .69) were observed in TP53^mut and TP53^wt patients. Multivariate analysis suggested that white blood cell (WBC) count at initial diagnosis (>50 × 10⁹/L: hazard ratio [HR] = 3.860, P = .016) and age (>40 years old: HR = 4.120, P = .012) are independent risk factors for 2-year LFS. Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The present results suggested that haplo-HSCT may eliminate the poor prognosis effect of TP53 mutation in ALL.     

Cetuximab or Nimotuzumab Versus Cisplatin Concurrent with Radiotherapy for Local-Regionally Advanced Nasopharyngeal Carcinoma: a Meta-analysis

Background: It is unclear whether Cetuximab (CTX) or Nimotuzumab (NTZ) concurrent with radiotherapy deliversequivalent or improved results with fewer toxicities over standard cisplatin (CDDP) concurrent with radiotherapyin locally advanced nasopharyngeal carcinoma (NPC). Methods: The strategy involved searching the PubMed,Embase, Cochrane Library, China National Knowledge Internet Web, Wanfang and Chinese Biomedical databases.Controlled clinical trials that compared concurrent CTX/NTZ with radiotherapy versus CDDP with radiotherapyin local-regionally advanced NPC were included. Results: In all, 1,239 patients in six clinical trials were includedin the analysis. The hazard ratios (HRs) between the CTX/NTZ and CDDP groups were 1.01 (95% confidence interval(CI) 0.63-1.64), 1.06 (95% CI 0.50-2.25), 1.04 (95% CI 0.61-1.76), and 1.05 (95% CI 0.73-1.50) for overall survival,local-regional failure-free survival, distant metastasis failure-free survival, and disease-free survival, respectively.Significant differences were found in the incidences of grade 3-4 anaemia [Risk ratio (RR) 0.11 95% CI 0.02-0.58], grade3-4 neutropenia (RR 0.23 95% CI 0.12- 0.44), grade 3-4 thrombocytopenia (RR 0.31 95% CI 0.12- 0.79), and grade3-4 vomiting (RR 0.04 95% CI 0.00-0.29) in favour of the CTX/NTZ group. However, the patients in the CTX/NTZgroup experienced a higher incidence of grade 3-4 skin rash (RR 6.45 95% CI 3.84-10.84). Conclusions: Regardingthe efficacy and side effects, the combination of CTX / NTZ and radiotherapy may be an alterative treatment regimenof standard CDDP concurrent with radiotherapy in local-regionally advanced NPC, especially in patients who cannottolerate or who refuse chemotherapy.