Efficacy of Ponatinib Versus Earlier Generation Tyrosine Kinase Inhibitors for Front-line Treatment of Newly Diagnosed Philadelphia-positive Acute Lymphoblastic Leukemia

Introduction

Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph⁺ ALL) who had undergone front-line combination chemotherapy plus ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib).

SOHO State of the Art Update and Next Questions: Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

The widespread adoption of Bcr–Abl-directed tyrosine kinase inhibitors (TKIs) into first-line regimens for patients with Philadelphia chromosome (Ph)-positive (Ph⁺) acute lymphoblastic leukemia (ALL) has revolutionized the outcomes of patients with this disease. Whereas Ph⁺ ALL was historically associated with cure rates of <25% in the pre-TKI era, now long-term survival in more than 75% of patients has been reported. With the promising efficacy of later-generation TKIs (eg, ponatinib) and the emerging understanding of the prognostic significance of various cooperative genomic alterations and of minimal residual disease, the widespread use of allogeneic hematopoietic stem cell transplantation in first remission for patients with Ph⁺ ALL has been increasingly questioned. Furthermore, with the development of more potent Bcr-Abl TKIs, several studies are evaluating novel strategies that reduce or eliminate chemotherapy. Herein, we review the major genomic and molecular prognostic factors in Ph⁺ ALL and also discuss the current and future treatment paradigms for this disease.     

Oncogene-independent resistance in Philadelphia chromosome - positive (Ph+) acute lymphoblastic leukemia (ALL) is mediated by activation of AKT/mTOR pathway

Tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, and ponatinib have significantly improved the life expectancy of Philadelphia chromosome-positive (Ph⁺) acute lymphocytic leukemia (ALL) patients; however, resistance to TKIs remains a major clinical challenge. Point mutations in the tyrosine kinase domain (TKD) of BCR-ABL1 have emerged as the predominant cause of acquired resistance. In approximately 30% of patients, the mechanism of resistance to TKIs remains elusive. This study aimed to investigate mechanisms of nonmutational resistance in Ph⁺ ALL. Here we report the development of a nonmutational resistance cell line SupB15-RT; conferring resistance to approved ABL kinase inhibitors (AKIs) and allosteric inhibitors GNF-2, ABL001, and crizotinib, except for dasatinib (IC90 50nM), a multitarget kinase inhibitor. We found that the AKT/mTOR pathway is activated in these cells and their proliferation inhibited by Torin-1 with an IC50 of 24.7 nM. These observations were confirmed using 3 different ALL patient-derived long term cultures (PDLTCs): (1) HP (BCR-ABL1 negative), (2) PH (BCR-ABL1 positive and responsive to TKIs) and (3) BV (BCR-ABL1 positive and nonmutational resistant to TKIs). Furthermore, Torin-1 and NVP-BEZ235 induced apoptosis in PH and BV cells but not in HP cells.Our experiments provide evidence of the involvement of AKT/mTOR pathway in the evolution of nonmutational resistance in Ph⁺ ALL which will assist in developing novel targeted therapy for Ph⁺ ALL patients with BCR-ABL1 independent nonmutational resistance.     

Changing Paradigm of the Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

In the pre-imatinib era, the treatment outcome of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL) was dismal. Complete remission was generally achieved only in about 50% to 60% of patients, and allogeneic hematopoietic stem cell transplantation (allo-HSCT), when feasible in younger patients, was virtually the sole curative modality. Imatinib has changed the situation dramatically, however, in combination with conventional chemotherapy or with corticosteroid alone, producing about 95% complete remission and thus increasing the number of patients undergoing allo-HSCT. Currently, the overall survival of patients who have undergone allo-HSCT exceeds 50%, and a considerable proportion of patients for whom allo-HSCT is not feasible are predictably curable. The next question is how to prevent relapse, which is observed not only in more than half of patients for whom allo-HSCT is not feasible but also in a considerable number of patients after allo-HSCT. Thus, improvement of postremission therapy is crucial. Whether intensive chemotherapy with currently available cytotoxic drugs contributes to the prevention of relapse is questionable, because intensive chemotherapy alone in the pre-imatinib era nearly always failed to cure this disease. Promising partners to be combined with imatinib or with a second-generation tyrosine kinase inhibitor (TKI) will be corticosteroids and vincristine. New TKIs such as dasatinib should be incorporated into the early phase of postremission therapy. Recognizing the small number of patients with Ph⁺ ALL, intergroup or international studies are necessary to develop the best postremission therapy. In the near future, it is hoped that Ph⁺ ALL will become one of the leukemias for which allo-HSCT is offered only for relapsed or extremely high-risk patients.     

Olverembatinib Treatment in Pediatric Patients With Relapsed Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia

Treatment outcomes for children with Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy, imatinib or dasatinib, and consolidative allogeneic hematopoietic cell transplantation. Oleverembatinib, a third-generation ABL inhibitor, was found to be highly effective and safe in adults with chronic myeloid leukemia and in some adults with relapsed or refractory Ph⁺ ALL. We reviewed the efficacy and safety profile of olverembatinib treatment in 6 children with relapsed Ph⁺ ALL and 1 with T-ALL and ABL class fusion, all of whom had previously received dasatinib or intolerance to dasatinib. The median duration of olverembatinib treatment was 70 days (range: 4-340) and the median cumulative dose was 600 mg (range: 80-3810). Complete remission with negative minimal residual level (<0.01%) was achieved in 4 of the 5 evaluable patients, 2 of whom were treated with olvermbatinib as a single agent. Safety profile in 6 evaluable patients was excellent with grade 2 extremity pain occurred in 2 patients and grade 2 myopathy of lower extremity and grade 3 fever in 1 patient each. Olverembatinib appeared to be safe and effective in children with relapsed Ph⁺ ALL.     

老年Ⅳ期非小细胞肺癌三维放疗重要性研究

目的 探讨老年Ⅳ期非小细胞肺癌(NSCLC)三维放疗的重要性。方法 2003—2010年间 201例NSCLC化疗同期三维放疗疗效患者入组,其中老年(≥65岁)和<65岁患者分别为 67例和134例。Kaplan-Meier法生存分析,Cox模型多因素预后分析。结果 随访率为97.8%。≥65岁和<65岁患者完成 4~5周期化疗分别占30%和55%,放疗剂量≥63 Gy分别占42%和49%。≥65岁和<65岁4~5周期化疗同期≥63 Gy放疗的中位生存期(MST)分别为17个月和14个月(χ²=0.76,P=0.384)。全组患者放疗≥63 Gy和<63 Gy的MST、1、2、3年生存率分别为17个月和 8个月、65%和23%、30%和13%、24%和9%(χ²=7.90,P=0.005),任何化疗强度均示≥63 Gy较<63 Gy的MST显著延长(χ²=9.54,P=0.023)。≥65岁、放疗≥63 Gy者同期 4~5周期和 2~3周期化疗的MST分别为14个月和8个月(χ²=1.82,P=0.178)、17个月和17个月(χ²=0.47,P=0.492)。多因素预后分析显示近期疗效(β=0.600,P=0.003)、肿瘤转移数(β=0.670,P=0.040)对生存有影响。结论 化疗同期三维放疗延长部分老年Ⅳ期NSCLC生存期,三维放疗的重要性对老年患者个体化治疗更明显。     

Acute lymphoblastic leukaemia associated antigen. III Alterations in expression during treatment and in relapse

315 adult patients with untreated leukaemia or lymphoma attending St. Bartholomew's Hospital, London, between June 1973 and December 1978 were studied. Forty-five had blast cells which were specifically reactive with antibody to common (non-T, non-B) ALL ( = cALL⁺). The morphological diagnosis was of ALL (33 cases), AUL (5 cases) or Ph¹ positive CML in blast crisis (4 cases). Four of the ALL cases were Ph¹ positive and had had no clinically evident CML phase. Bone marrow suspensions from 19 of these patients have been examined serially for up to 4 years in order to assess the stability of the immunological phenotype and the possible prognostic value of monitoring levels of ALL⁺ cells throughout treatment.In some instances the re-appearance of cALL⁺ cells preceded relapse. Isolated relapses of the CNS, skin or testis were also associated with transient increases in cALL⁺ cells in the bone marrow. The potential monitoring value of anti-ALL was compromised by three observations: the rapid appearance of leukaemic blasts in relapse with no prior detectable increase in cALL⁺ cells, the re-appearance of weakly stained cALL⁺ cells without subsequent relapse particularly during post maintenance chemotherapy associated lymphocytosis and finally the emergence of cALL antigen negative leukaemic cells in relapse. Of 119 other ALL cases studied (mostly children) 20 showed a phenotypic shift of membrane marker expression in relapse. The clinical and biological implications of these observations are discussed.     

Identification of heat shock protein 32 (Hsp32) as a novel target in acute lymphoblastic leukemia

Heat shock proteins (Hsp) are increasingly employed as therapeutic targets in oncology. We have shown that Hsp32, also known as heme oxygenase-1 (HO-1), serves as survival factor and potential target in Ph⁺ chronic myeloid leukemia. We here report that primary cells and cell lines derived from patients with acute lymphoblastic leukemia (ALL) express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Highly enriched CD34⁺/CD38⁻ ALL stem cells also expressed Hsp32. Two Hsp32-targeting drugs, pegylated zinc protoporphyrine (PEG-ZnPP) and styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP), induced apoptosis and growth arrest in the BCR/ABL1⁺ cell lines, in Ph⁻ lymphoblastic cell lines and in primary Ph⁺ and Ph⁻ ALL cells. The effects of PEG-ZnPP and SMA-ZnPP on growth of leukemic cells were dose-dependent. In Ph⁺ ALL, major growth-inhibitory effects of the Hsp32-targeting drugs were observed in imatinib-sensitive and imatinib-resistant cells. Hsp32-targeting drugs were found to synergize with imatinib, nilotinib, and bendamustine in producing growth inhibition and apoptosis in Ph⁺ ALL cells. A siRNA against Hsp32 was found to inhibit growth and survival of ALL cells and to synergize with imatinib in suppressing the growth of ALL cells. In conclusion, Hsp32 is an essential survival factor and potential new target in ALL.     

Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A multicenter propensity score-matched cohort study

ObjectiveSystemic chemotherapy has limited efficacy in the treatment of peritoneal metastasis (PM) in gastric cancer (GC). Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with complete cytoreductive surgery (CRS) has shown promising outcomes but remains controversial. The present study aimed to evaluate the safety and efficacy of HIPEC without CRS in GC patients with PM.MethodsThis retrospective propensity score-matched multicenter cohort study included GC patients with PM treated with either chemotherapy alone (Cx group) or with HIPEC combined with chemotherapy (HIPEC-Cx group) in four Chinese high-volume gastric medical centers between 2010 and 2017. The primary outcomes were median survival time (MST) and 3-year overall survival (OS). Propensity score matching was performed to compensate for controlling potential confounding effects and selection bias.ResultsOf 663 eligible patients, 498 were matched. The MST in the Cx and HIPEC-Cx groups was 10.8 and 15.9 months, respectively [hazard ratio (HR)=0.71, 95% confidence interval (95% CI), 0.58−0.88; P=0.002]. The 3-year OS rate was 10.1% (95% CI, 5.4%−14.8%) and 18.4% (95% CI, 12.3%−24.5%) in the Cx and HIPEC-Cx groups, respectively (P=0.017). The complication rates were comparable. The time to first flatus and length of hospital stay for patients undergoing HIPEC combined with chemotherapy was longer than that of chemotherapy alone (4.6±2.4 dvs. 2.7±1.8 d, P<0.001; 14.2±5.8 dvs. 11.4±7.7 d, P<0.001), respectively. The median follow-up period was 33.2 months. ConclusionsCompared with standard systemic chemotherapy, HIPEC combined with chemotherapy revealed a statistically significant survival benefit for GC patients with PM, without compromising patient safety.     

Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer

Aim： This study explored the correlation between the expression of excision repair cross-complementation group 1 （ERCC1） and the prognosis of gastric cancer patients. Methods： From January 2005 to December 2008, 605 patients who underwent radical surgery in The First Affiliated Hospital of Nanjing Medical University were enrolled. We conducted the follow-up every 6 months and its contents included a comprehensive medical history, tumor markers and abdominal ultrasound or CT and other imaging findings. Deadline was April 30, 2013 and follow-up time between 51 to 91 months. Survival time is calculated from the date of diagnosis to death or last follow-up date. Immunohistochemistry （IHC） was used to assess the expression of ERCCI in resected samples. The relationship between ERCCI expression and survival of patients was investigated. The comparison of count data were analyzed by Chi-square test. Median survival time （MST） and the 5-year survival rate were calculated by life table analysis. The Kaplan-Meier curves were used for survival analysis. Results： ERCC1 expression was positive in 412 patients （68.1%）. There is no significant difference between ERCCl-positive group and ERCCl-negative group in terms of the MST and 5-year survival rate （P=0.455）. The MST and 5-year survival rate have no significant difference （P=0.162） between group with chemotherapy and group with no chemotherapy in patients with ERCCl-positive expression. However, the MST and 5-year survival rate in patients with ERCCl-negative expression benefited more from with chemotherapy （P=0.019）. The ERCCl-positive patients survived longer than those ERCCl-negative patients （P=0.183） in subgroup with no adjuvant chemotherapy. In the subgroup analysis, ERCC 1 expression had no significant relationship with overall survival in patients with stage II or llI gastric cancer （P〉0.05）. Conclusions： ERCC1 might be a good prognostic factor for the patients of gastric cancer after radical resection. Patients with ERCC     

局部进展期胃癌根治术后同期放化疗与单纯化疗的临床比较

目的 比较局部进展期胃癌根治术后同期放化疗(RCT)与单纯化疗(CT)的疗效和不良反应。 方法 83例患者随机分为RCT组(43例)和CT组(40例)。RCT组采用三维适形放疗45 Gy同期口服卡培他滨化疗(1600mg/m²),放疗结束2周后继续用FOLFOX4方案巩固化疗 4~6周期。CT组采用FOLFOX4方案化疗 6~8周期。Kaplan Meier 法计算生存率等并 Logrank 检验。结果 随访率为96%,RCT和CT组随访时间满2、3年者分别为37、12例和31、10例。RCT组和CT组1、2、3年局部控制率分别为100%、97%、94%和95%、87%、73%(χ²=4.54,P=0.033),生存率分别为98%、86%、81%和93%、80%、64%(χ²=3.96,P=0.047)。RCT组和CT组治疗期间≥3级白细胞下降发生率分别为23%和15%(χ²=0.93, P=0.630), ≥3级胃肠道反应发生率分别为16%和10%(χ²=0.95,P=0.624)。结论 局部进展期胃癌根治术后RCT比CT可提高患者局部控制率和生存率,不良反应可耐受。     

局部晚期直肠癌三维适形放疗同期化疗后pCR患者术后辅助化疗的价值

目的 探讨局部晚期直肠癌术前三维适形放疗同期化疗后病理完全缓解(pCR)患者术后辅助化疗的价值。
方法 2005-2010年本中心收治的同期放化疗后术后病理证实pCR的 49例患者,其中行术后辅助化疗 38例,未行术后辅助化疗 11例。比较二者疗效。
结果 随访率100%,随访时间满 3年者 22例。全组 3年总生存率、无复发生存率和癌症特异生存率分别为92%、90%和95%,术后有与无辅助化疗的分别为90% 与100%(χ²=0.05,P=0.818)、92%与80%(χ²=1.00,P=0.316)、94%和100%(χ²=0.31,P=0.581)。全组 3年复发率为8%,术后有、无辅助化疗的分别为8%、9%(χ²=1.00,P=0.316)。
结论 局部晚期直肠癌术前三维适形放疗同期化疗后获pCR患者累计复发率低,术后辅助化疗并未提高疗效,因随诊期短、病例数不多,其价值需进一步临床随机对照研究加以甄别。     

Long-term follow-up of patients with newly diagnosed adult acute lymphoblastic leukemia: a single institution experience of 378 consecutive patients over a 21-year period.

Although the prospect of long-term leukemia-free survival (LFS) after treatment for adult acute lymphoblastic leukemia (ALL) is widely accepted, few studies have reported long-term survival data. Three hundred and seventy-eight ALL patients, referred to our hospital from 1978 to 1999, were reviewed for long-term follow-up data. The analysis included data on 351 patients treated by standard chemotherapy according to 11 different successive and/or concomitant regimens. Complete remission (CR) was achieved in 299 patients (79%). Initial performance status, LDH level, immunophenotype, age, and risk group (defined according to Hoelzer's criteria) at diagnosis were of significant prognostic value for CR achievement. Median leukemia-free survival (LFS) was 14 months with a 3-year, a 5-year, and an 8-year LFS at 30%, 26%, and 24%, respectively. LFS was better in T cell lineage ALL than in B cell lineage ALL (P = 0.05). Younger age was also a favorable prognostic factor for LFS (P = 0.001). Philadelphia-positive (Ph+) ALL displayed a poor outcome since median LFS was 7 months with only 13% of survival at 3 years. Median overall survival (OS) of the entire cohort was 18 months with a 3-year, a 5-year, and an 8-year OS at 32%, 24%, and 22% respectively. Favorable prognostic factors for OS were younger age (P < 0.0001), and T cell lineage ALL (P = 0.001). Among non-T cell lineage ALL, standard-risk ALL confirmed a significant better outcome than high-risk ALL (P = 0.0003). It was apparent from this analysis that hazard rates for death and relapse were greatest in the first year, decreased substantially between years 1 and 2, then decrease further between years 2 and 3. Rates of death and relapse were quite low after 3-4 years. All patients relapsing after 3 years of CR were B or non-B non-T cell lineage ALL. Long-term survivors (LTS), defined as survival in CR > or =3 years, represented 23% of evaluable patients. Eighty-three patients remain alive in initial CR at >3 years, while only three were LTS after a second CR. Overall, no significant improvement was shown in terms of CR achievement and survival duration over the years. However, regarding survival, a significant improvement was demonstrated in T cell lineage ALL (P = 0.03). Furthermore, patients (aged less than 50 years) transplanted while in first CR did significantly better than those receiving only chemotherapy as post-remission therapy (P < 0.0001). The 3-year OS, after allogeneic transplantation in first CR, was 74% in T cell lineage ALL, while it was less than 50% in B cell lineage ALL. This single center study on a large cohort of ALL patients reflects the degree to which ALL treatment remains unsuccessful in adults. Only T cell lineage ALL outcomes have improved over the years. The results suggest a time (3 years) at which it becomes reasonable to speak of potential cure, provided the patient is in CR.     

Hematopoietic Stem Cell Transplantation for Adult Philadelphia-Negative Acute Lymphoblastic Leukemia in the First Complete Remission in the Era of Minimal Residual Disease

Purpose of Review

The purpose of this review is to discuss the potential role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for Philadelphia-negative (Ph^?) adult acute lymphoblastic leukemia (ALL) in first complete remission (CR1) in the era of minimal residual disease (MRD).

Recent Findings

Allo-HSCT continues to have a role in the therapy of a selected group of high-risk adult patients with ALL in CR1. Although the clinical significance of MRD has been studied less extensively in adults with ALL than in children, recent studies support its role as the strongest prognostic factor that can identify patients that are unlikely to be cured by standard chemotherapy and benefit from undergoing allo-HSCT. In addition, MRD status both pre- and post-HSCT has been found to correlate directly with the risk of relapse.

Summary

Currently, the clinical challenge consists on applying MRD and molecular failure to integrate novel agents and immunotherapy to lower MRD before allo-HSCT and to modulate the graft versus leukemia (GVL) effect after transplant.

     

费城染色体阳性成年急性淋巴细胞白血病患者治疗效果及预后因素分析

目的 分析费城染色体阳性(Ph+)的成年急性淋巴细胞白血病(ALL)患者治疗效果及预后影响因素.方法 回顾性分析49例Ph+ALL患者的临床资料,探讨治疗效果及不同因素对预后的影响.结果49例患者中,男性24例,女性25例;中位年龄38岁(15~77岁),酪氨酸激酶抑制剂(TKI)治疗组血液学完全缓解(CR)率、主要分子生物学反应(MMR)率及完全分子生物学缓解(CMR)率均高于单纯化疗组(96.8 %比72.2 %,64.5 %比16.7 %,25.8 %比11.1 %),差异均有统计学意义(χ2=4.308,P=0.038;χ2=10.468,P=0.001;χ2=4.250,P=0.039).生存分析提示中位总生存(OS)时间为24个月(3~70个月),3年OS率及无复发生存(RFS)率分别为32.7 %、21.4 %;TKI治疗组3年OS率及1年RFS率高于单纯化疗组(40.3 %比11.1 %,67.8 %比11.1 %),差异有统计学意义(χ2=12.725, P<0.001;χ2=17.401,P<0.001);异基因造血干细胞移植(allo-HSCT)组3年OS率及RFS率高于非移植组(62.5 %比25.7 %、41.7 %比15.0 %),差异有统计学意义(χ2=6.196,P=0.013;χ2=8.032,P=0.005);经2个疗程治疗后达MMR组3年OS率及RFS率分别为45.1 %和28.9 %,高于未达MMR组(17.6 %和11.7 %),差异有统计学意义(χ2=5.446,P=0.020;χ2=6.484,P=0.011);Cox多因素分析结果显示,联合TKI治疗(HR=0.227,95 % CI 0.094~0.550,P=0.001)是OS的独立预后因素;联合TKI治疗(HR=0.225,95 % CI 0.082~0.618,P=0.004)及移植(HR=0.275,95 % CI 0.077~0.983,P=0.047)是RFS的独立预后因素.结论 联合TKI治疗能提高患者CR、MMR及CMR率,提高长期生存,为患者接受移植提供更多机会;在TKI时代,移植仍是治疗Ph+ALL的重要方法,尤其那些经化疗联合TKI治疗但早期未达MMR者预后差,应尽早行造血干细胞移植.     

胸部放疗在广泛期小细胞肺癌治疗中的价值

目的 探讨胸部放疗在广泛期小细胞肺癌中的应用价值及对患者预后的影响.方法 回顾性分析154例广泛期小细胞肺癌患者的临床资料,化放疗组89例,化疗组65例.放疗采用常规分割1.8～2.0 Gy/次,1次/d,总剂量为40～60 Gy,化疗采用EP方案(顺铂+依托泊甙)、CE方案(卡铂+依托泊甙)或者CAO方案(环磷酰胺+阿霉素+长春新碱).结果 全组中位生存时间为13.7个月,2年和5年生存率分别为27.9%和8.1%,其中化放疗组分别为17.2个月、36.0%和10.1%,化疗组分别为9.3个月、16.9%和4.6%,两组生存率差异有统计学意义(P=0.001).全组中位无进展生存时间为8.0个月,2年和5年无进展生存率分别为13.6%和8.2%,其中化放疗组分别为10.0个月、17.4%和10.5%,化疗组分别为6.2个月、9.8%和4.9%.两组无进展生存率差异有统计学意义(P＜0.001).化放疗组胸内复发率为29.6%(21/89),化疗组胸内复发率为70.0%(42/65),差异有统计学意义(P=0.000).结论 胸部放疗能降低广泛期小细胞肺癌局部失败的发生率,延长患者的总生存时间和无进展生存时间.

Abstract：

Objective To evaluate the effect of thoracic radiation therapy(TRT) on patients with extensive stage small-cell lung cancer(SCLC). Methods One hundred and fifty-four patients with extensive stage SCLC treated in our department between January 2003 and December 2006 were enrolled in this study.Eighty nine patients received chemotherapy and thoracic radiation therapy(ChT/TRT),and 65 patients were treated with chemotherapy alone(ChT without TRT).The chemotherapy was CE(carboplatin and etoposide),PE(cisplatin and etoposide) or CAO(CTX,ADM and VCR) regimens.The total dose of thoracic irradiation was 40-60 Gy with 1.8-2.0 Gy per fraction. Results For the whole group,the median survival time(MST) was 13.7 months,the 2-year and 5-year overall survival rates were 27.9% and 8.1%,respectively.The MST,overall survival rates at 2 years and 5 years in the ChT/TRT group and ChT without TRT group were 17.2 months,36.0%,10.1% and 9.3 months,16.9%,4.6%,respectively(P =0.001).The median progression-free survival(PFS) for all patients was 8.0 months,the 2-year and 5-year PFS were 13.6% and 8.2%,respectively.The median PFS,2-year and 5-year PFS in the ChT/TRT group and ChT without TRT group were 10.0 months,17.4%,10.5% and 6.2 months,9.8%,4.9%,respectively(P ＜0.001).The incidence of intra-thoracic local failure was 29.6% in the ChT/TRT group and 70.0% in the ChT/without TRT group(P = 0.000). Conclusions Chemotherapy plus thoracic radiation therapy can improve the overall survival,progress free survival and reduce local regional failure rate in patients with extensive stage SCLC compared with that by chemotherapy alone.     

Prevalence and Clinical Outcome of Philadelphia-Like Acute Lymphoblastic Leukemia: Systematic Review and Meta-analysis

BackgroundThe presence of Philadelphia (Ph)-like ALL among patients with acute lymphoblastic leukemia (ALL) may indicate a poor prognosis similar to Ph⁺ ALL, although the data are still inconclusive and the prevalence of Ph-like ALL varied considerably across studies.Patients and MethodsWe performed a systematic review and meta-analysis in order to identify all cohort studies of patients with ALL that reported the prevalence of Ph-like ALL and to summarize their results together. The pooled prevalence and rate were calculated by the DerSimonian-Laird random-effect model with double arcsine transformation.ResultsAcross the 15 included studies describing 11,040 ALL patients, the peak prevalence of the presence of Ph-like ALL among patients with ALL was between ages 11 and 40 years, where the pooled prevalence was 25.8% to 26.2%. The pooled 5-year overall survival rate of Ph-like ALL was 42.8% (95% confidence interval, 23.9-64.1; I² 93%). Comparative analysis with B-other ALL patients was conducted by the Mantel-Haenszel method; it found that Ph-like ALL patients had a significantly lower chance of being alive at 5 years (pooled odds ratio, 0.35; 95% confidence interval, 0.25-0.50; P < .00001, I² = 40%). The chance of Ph-like ALL patients surviving at 5 years was similar to Ph-positive ALL patients (pooled odds ratio, 0.72; 95% confidence interval, 0.26-2.02; P = .53, I² = 77%).ConclusionPh-like ALL is not uncommon among ALL patients, and its presence is associated with an unfavorable outcome. More investigations are needed for better therapeutic options.     

Phase II trial of preoperative S-1 plus cisplatin followed by surgery for initially unresectable locally advanced gastric cancer

Background

The aim of this study was to evaluate the efficacy and feasibility of preoperative chemotherapy with S-1 plus cisplatin in patients with initially unresectable locally advanced gastric cancer.

Methods

We enrolled patients with initially unresectable locally advanced gastric cancer because of severe lymph node metastases or invasion of adjacent structures. Preoperative chemotherapy consisted of S-1 at 80 mg/m² divided in two daily doses for 21 days and cisplatin at 60 mg/m² intravenously on day 8, repeated every 35 days. If a tumor decreased in size, patients received 1 or 2 more courses. Surgery involved radical resection with D2 lymphadenectomy.

Results

Between December 2000 and December 2007, 27 patients were enrolled on the study. No CR was obtained, but PR was seen in 17 cases, and the response rate was 63.0%. Thirteen patients (48.1%) had R0 resections. There were no treatment related deaths. The median overall survival time (MST) and the 3-year overall survival (OS) of all patients were 31.4 months and 31.0%, respectively. Among the 13 patients who underwent curative resection, the median disease-free survival (DFS) and the 3-year DFS were 17.4 months and 23.1%, respectively. The MST and the 3-year OS were 50.1 months and 53.8%, respectively. The most common site of initial recurrence after the R0 resection was the para-aortic lymph nodes.

Conclusions

Preoperative S-1 plus cisplatin can be safely delivered to patients undergoing radical gastrectomy. This regimen is promising as neoadjuvant chemotherapy for resectable gastric cancer. For initially unresectable locally advanced gastric cancer, new trials using more effective regimens along with extended lymph node dissection are necessary.     

The clinical effects of DC-CIK cells combined with chemotherapy in the treatment of advanced NSCLC

Objective

The aim of the study was to evaluate the safety and therapeutic effects of autologous dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) combined with chemotherapy in advanced non-small cell lung cancer (NSCLC) patients.

Methods

Fifty patients with advanced NSCLC (stages III to IV), who had received therapies in our Center (Department of Biotherapy, Affiliated to Cancer Hospital of Shanxi Medical University, Taiyuan, China) from August 2008 to January 2010, were treated by DC-CIK + chemotherapy as the combined treatment group; fifty advanced NSCLC patients treated with chemotherapy at the same time served as controls. The immunologic function, short-term therapeutic effects, the 1-year survival rate, the life quality, the chemotherapy side effects were compared between the two groups, the safety and therapeutic effects of DC-CIK cells therapy were observed too.

Results

There was no obvious change of subsets of T cells in peripheral blood before and after therapy in DC-CIK + chemotherapy group, and IFN-?? was improved after therapy in this group (P < 0.05); in chemotherapy alone group, the ratios of CD3⁺CD4⁺, CD3⁺CD8⁺, CD3^?CD56⁺ cells and the secretion of IL-2, TNF-?? decreased significantly after therapy (P < 0.05); the ratios of CD3⁺CD8⁺, CD3⁺CD56⁺ were improved after cell culture (P < 0.05). The disease control rate (DCR) of DC-CIK + chemotherapy group was higher than that in the chemotherapy alone group (78.0% vs 56.0%, P < 0.05); the 1-year survival rates of DC-CIK + chemotherapy group and chemotherapy alone group were 50% and 44% respectively, had no significant difference. Compared with chemotherapy alone group, the occurrence of chemotherapy side effects (including bone marrow suppression, nausea and vomiting, peripheral nerve toxicity) was less in the DC-CIK + chemotherapy group (P < 0.05). The physical and appetite were better in DC-CIK + chemotherapy group after therapy.

Conclusion

To compare with simple chemotherapy, DC-CIK + chemotherapy for advanced NSCLC is safe and effective, and it can improve patients?? life quality and remission rate, and prolong their survival time.