Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array

Bortezomib‐ and thalidomide‐based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment‐induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome‐wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest‐ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.     

Pediatric chemotherapy induced peripheral neuropathy: A systematic review of current knowledge

BackgroundThe dramatic increase in the number of childhood cancer survivors over the last 60 years has made monitoring and minimising long term side effects of cancer treatment increasingly important. Chemotherapy induced peripheral neuropathy (CIPN) has been described with many commonly used chemotherapy agents. This article provides a critical overview of pediatric CIPN, its incidence, clinical manifestations, late effects, and recent advances in understanding of risk factors and pharmacogenomics as well as evaluating current assessment strategies and treatment approaches.MethodsNeurotoxicity data was systematically collated from Medline, Embase and Pubmed and analysed for quality, relevance and originality in three stages prior to inclusion. Quality scoring was done using the QUALSYST assessment tool.ResultsA total of 61 studies met inclusion criteria. Peripheral neuropathy is common and may be long lasting with characteristics specific to each chemotherapy agent. There is significant variability in reported incidence and natural history, related to challenges in clinical assessment and diagnosis. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication and patient factors such as age and inherited susceptibilities. Recent identification of individual genetic variations has advanced understanding of pathomechanisms and may direct future treatment approaches.ConclusionWhile these studies guide suggestions for current clinical practice, further systematic research with development of strategies for amelioration and prevention of CIPN is necessary. Standardised assessment protocols and objective outcomes measures of CIPN applicable to patients of different ages are critical to enabling the development of novel treatments and facilitation of future clinical trials and treatment individualisation.     

Bortezomib in multiple myeloma: systematic review and clinical considerations

We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects.Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016).In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001).In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.     

30例自体外周造血干细胞移植治疗多发性骨髓瘤的疗效及预后因素评价

目的：对30例多发性骨髓瘤（multiple myeloma,MM）患者经自体外周造血干细胞移植（autologous hematopoietic stem cell transplantation ,APBSCT）治疗后的临床疗效进行评估,并分析可能影响预后的因素。方法：30例MM患者有2 例复发行2 次APBSCT,因此共计移植32例次。移植前予常规联合化疗（11例含万珂）,化疗联合G-CSF 动员APBSC ,选择以马法兰为基础的预处理方案,d0 天回输。结果：动员后患者采集的单个核细胞（MNC）中位数为6.41× 10⁸/kg,CD34+细胞4.75× 10⁶
/kg。APBSCT后中位中性粒细胞和血小板重建时间分别为9.5 天和11天。APBSCT后CR和VGPR 率分别为37.5% 和34.4% ,中位生存期（overallsurvival ,OS）为67.27个月,中位无进展生存期（progression-freesurvival ,PFS）为29.77个月,其中CR组、PR组中位PFS 分别为29个月、20个月,VGPR 组中位PFS 未达到,CR+VGPR组与PR组PFS 比较P=0.025。万珂组和非万珂组CR率分别为63.6% 和23.8%（P=0.034）,万珂组中位OS及PFS 均未达到,非万珂组中位PFS 为22个月（P=0.045）。 结论：硼替佐米诱导序贯APBSCT可获得更长的无病生存。APBSCT作为MM诱导缓解后的强化治疗,缓解率高,且移植后获得VGPR 以上反应的患者PFS 获益。     

HLA genotyping in Japanese patients with multiple myeloma receiving bortezomib: An exploratory biomarker study of JCOG1105 (JCOG1105A1)

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.     

Bortezomib‐induced peripheral neuropathy: A genome‐wide association study on multiple myeloma patients

The proteasome‐inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome‐wide association study on 646 bortezomib‐treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment. We identified 4 new promising loci for bortezomib‐induced PNP at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074). Even though the results did not reach genome‐wide significance level, they support the idea of previous studies, suggesting a genetic basis for neurotoxicity. The identified single nucleotide polymorphisms map to genes or next to genes involved in the development and function of the nervous system (CDH13, DCC, and TENM3). As possible functional clues, 2 of the variants, rs12521798 and rs17748074, affect enhancer histone marks in the brain. The rs12521798 may also impact expression of THBS4, which affects specific signal trasduction pathways in the nervous system. Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug‐induced PNP and to functionally validate our in silico predictions.     

硼替佐米联合不同化疗药物治疗多发性骨髓瘤疗效和安全性的Meta分析

目的:评价硼替佐米联合不同化疗药物治疗多发性骨髓瘤的疗效与安全性。方法:计算机检索PubMed数据库,Cochrane图书馆临床对照试验数据库,中国期刊全文数据库和中国生物医学文献数据库,进一步对纳入文献的参考文献进行扩大搜索。采用RevMan 5.3软件进行Meta分析。结果:共纳入8篇文献,包括1 627例患者。Meta分析显示硼替佐米联合地塞米松和沙利度胺(BTD)组较硼替佐米联合地塞米松(BD)组缓解率好［OR=1.70,95%CI（1.18,2.44）,P=0.005］,感染率［OR=1.19,95%CI（0.73,1.94）,P=0.48］和3-4级血小板减少率［OR=2.17,95%CI（0.91,5.19）,P=0.08］无统计学差异。硼替佐米联合地塞米松和阿霉素（BAD）组较BD组缓解率高［OR=3.79,95%CI（1.28,11.22）,P=0.01］。BTD组和硼替佐米联合马法兰和泼尼松（BMP）组缓解率无统计学差异［OR=1.42,95%CI（0.96,2.09）,P=0.08］。3-4级不良事件发生率无统计学差异［OR=1.55,95%CI（0.61,3.90）,P=0.35］。BAD组和硼替佐米联合地塞米松和环磷酰胺（BCD）组缓解率无统计学差异［OR=0.99,95%CI（0.61,1.59）,P=0.96］,BCD组疗效好于BAD组。结论:硼替佐米三药联合较硼替佐米二药联合效果好,毒副反应基本相同。不同的三药联合方案效果也不同,在BTD、BAD、BCD、BMP这几个方案中,BCD效果最好。     

A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors

The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12–16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27–42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51–59) of patients on CPI combinations and 46% (95% CI 40–53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.     

肺癌骨转移及骨相关事件危险因素分析：系统综述

骨转移及骨相关事件严重影响肺癌患者的生活质量及预后疗效。本研究运用已设定的研究方案,对已发表的肺癌骨转移／骨相关事件的危险因素进行系统分析,从而认识其相关危险因素。分析发现,T4分期、N3分期及 BSP 阳性表达的原发性肺癌患者发生骨转移的风险较对照组患者有所增加。低血钙和 CEA升高的肺癌患者发生骨转移的可能性较大,但尚未排除其他混杂因素的干扰。在肺癌骨转移患者中,长期吸烟和多重骨转移的患者组发生骨相关事件的风险较对照组人群有所增加。     

Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline

Questions

1. In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?
2. What is the toxicity associated with the use of bortezomib?
3. Which patients are more or less likely to benefit from treatment with bortezomib?

Perspectives

Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback.

Outcomes

Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events.

Methodology

A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc.

Results

The literature review found one randomized controlled trial (rct)—the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma.The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation.

Practice Guideline

This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status.

Recommendations

Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations:

• For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.
• Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.
• For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent–based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent–based chemotherapy is recommended.
• Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials.

Qualifying Statements

Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg.For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes.

Dosage

Bortezomib 1.3,g/m² is given as a rapid intravenous bolus over 3–5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed.

Response to Treatment

Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone.The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent–based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.     

Surviving childhood cancer: a systematic review of studies on risk and determinants of adverse socioeconomic outcomes

Substantial improvements in childhood cancer survival have resulted in a steadily increasing population of childhood cancer survivors. Whereas somatic late effects have been assessed in many studies, less is known about the impact of childhood cancer on socioeconomic outcomes in survivors. The aim of this article was to evaluate and summarise the evidence on the socioeconomic conditions of childhood cancer survivors and to identify survivors at particular risk of adverse socioeconomic outcomes. An extensive literature search of three electronic databases was conducted. Of 419 articles identified, 52 met the inclusion criteria. All the selected articles were appraised for quality, and findings were summarised in a narrative synthesis. Childhood cancer survivors were at higher risk of adverse socioeconomic outcomes with regard to educational achievement, income and social security benefits than the general population or a sibling comparison group. The risks for unemployment and a lower occupational position were significantly increased only for survivors of a central nervous system tumour. Notably, survivors of central nervous system tumours, survivors treated with cranial radiotherapy and those diagnosed at younger age independent of cancer type were determinants of particular adverse socioeconomic outcomes. Given the increasing population of childhood cancer survivors, targeted follow-up interventions and support strategies addressing not only the somatic and psychiatric late effects but also the socioeconomic difficulties that some childhood cancer survivors face is of high importance to reduce social inequity, and ensure a high quality of life after childhood cancer.     

Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review.

BACKGROUND: Anthracyclines are essential for the treatment of the children with cancer. We performed a systematic review to evaluate the existing evidence of the frequency and risk factors of anthracycline-induced clinical heart failure (A-CHF) in children. DESIGN: Medline was searched for articles reporting the frequency of A-CHF, published from 1966 to December 2000. Information about study features, risk factors and frequency were abstracted, and a validity score was given for each study. The potential predictive factors of A-CHF were analysed both within and across the studies. RESULTS: The frequency of A-CHF in children was estimated in 30 studies described in 25 articles. All studies have serious methodological limitations. The frequency varied between 0% and 16%. In the analysis across the studies the type of anthracyclines and the maximal dose in 1 week explain a considerable part of the variation of the frequency of A-CHF. CONCLUSIONS: Doxorubicin and a dose above 45 mg/m2 within 1 week seemed to increase the frequency of A-CHF. Well designed and executed studies are needed to accurately estimate the frequency of A-CHF and reliably assess the importance of potential risk factors.     

Efficacy and tolerability of bendamustine,bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.     

Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review.

BACKGROUND: The aim of this systematic review was to summarise and appraise the published evidence with regard to the frequency and risk factors of subclinical cardiotoxicity in apparently healthy survivors of childhood cancer after anthracycline therapy. PATIENTS AND METHODS: A search was made in Medline for studies published between 1966 and May 2001 that included >50 children and reported on the frequency of measures of subclinical cardiotoxicity. Information about the studies was abstracted by two reviewers and a validity score was calculated for each study. RESULTS: The reported frequency of subclinical cardiotoxicity varied between 0% and 57% in the 25 studies included. Differences in outcome definitions of subclinical cardiotoxicity and differences in study patients with respect to the dose of anthracycline seemed to explain part of the wide variance of the frequency of subclinical cardiotoxicity. Fourteen of the 25 studies showed serious methodological limitations. CONCLUSIONS: The reported frequency of subclinical cardiotoxicity shows a wide variation. Well designed studies with accurate and precise outcome measurements in well described groups of patients, after a sufficiently long follow-up period, are needed to obtain more insight into the frequency and importance of risk factors, and the clinical consequences of anthracycline-related subclinical cardiotoxicity.     

Survivin和Cox-2蛋白与非小细胞肺癌危险因素的系统评价

目的:系统评价存活蛋白(Survivin)、环氧化酶2(cyclooxygenase 2,Cox-2)表达水平与非小细胞肺癌non-small cell lungcancer,NSCLC)危险因素的关系。方法:计算机检索Cochrane Library(2011年第1期),PubMed、CNKI等数据库,并辅以手工检索,按照纳入与排除标准选择病例对照试验。评价质量及提取资料后,采用RevMan 4.2.10软件对数据库进行系统评价。结果:对于Survivin,共纳入15个研究,其中1 222例NSCLC患者,447例正常对照。Meta分析结果显示:Survivin在NSCLC组及正常对照组[比值比(odds ratio,OR)=11.11,95%可信区间(confidenceinterval,CI)为5.92～20.83]的表达差异具有统计学意义(P0.05)。临床病理检查结果显示:Survivin在TNM分期T3～T4期与T1～T2期,临床分期Ⅲ～Ⅳ期与Ⅰ～Ⅱ期,淋巴结转移组与非淋巴结转移组,低分化组与中高分化组间的表达差异均具有统计学意义(P均0.05)。对于Cox-2,共纳入12个研究,其中975例NSCLC患者,209例正常对照。Meta分析结果显示:Cox-2在NSCLC组及正常对照组(OR=29.46,95%CI=15.91～54.56)的表达差异具有统计学意义(P0.05)。临床病理检查结果显示:Cox-2在TNM分期T3～T4期与T1～T2期的表达差异无统计学意义(P0.05)。Cox-2在临床分期Ⅲ～Ⅳ期与Ⅰ～Ⅱ期,淋巴结转移组与非淋巴结转移组,低分化组与中高分化组间的表达差异均具有统计学意义(P均0.05)。Spearman等级相关分析显示,Survivin与Cox-2蛋白阳性率在NSCLC中的表达具有相关性(r=0.514,P0.05)。结论:Survivin、Cox-2在NSCLC中高表达,增加了其恶性行为的发生危险,同时Survivin与Cox-2在NSCLC表达也有一定的相关性。     

Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients

BACKGROUND:

Intracranial involvement in multiple myeloma is extremely rare. The effect of new drugs (eg, thalidomide, bortezomib, lenalidomide) with respect to old drugs (eg, alkylators, steroids) has not been reported.

METHODS:

We collected clinical and biological data of patients presenting with an osteo‐dural or primary dural multiple myeloma (OD‐DMM) or a central nervous system myelomatosis (CNS‐MM) by sending a questionnaire to the centers of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA).

RESULTS:

A total of 50 patients were registered. New therapies were used in 35 patients, whereas 15 patients received old treatments. Twenty‐five out of 50 patients obtained a complete remission or a very good partial remission (CR+VGPR). Overall survival (OS) for CNS‐MM was 6 months, for OD‐DMM 25 months. OS was 25 months for patients treated with new agents versus 8 months with old agents. Improved OS and progression‐free survival were predicted by response (CR+VGPR) and by patients who underwent stem cell transplantation versus chemotherapy. β2‐Microglobulin >5 mmol/L was a poor prognostic factor. Multivariate analysis showed poor survival for patients with β2‐microglobulin >5 mmol/L and better survival for patients achieving CR+VGPR.

CONCLUSIONS:

The overall data highlight the relevance of therapy with new drugs in intracranial myeloma, providing a framework for future clinical trials. Cancer 2011;. © 2011 American Cancer Society.     

Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: A systematic review

There has been conflicting evidence concerning the possible association between tuberculosis (TB) and subsequent risk of lung cancer. To investigate whether currently published epidemiological studies can clarify this association, we performed a systematic review of 37 case‐control and 4 cohort studies (published between January 1966 and January 2009) and a meta‐analysis of risk estimates, with particular attention to the role of smoking, passive smoking and the timing of diagnosis of TB on this relationship. Data for the review show a significantly increased lung cancer risk associated with preexisting TB. Importantly, the association was not due to confounding by the effects of tobacco use (RR = 1.8, 95% confidence interval (CI) = 1.4–2.2, among never smoking individuals), lifetime environmental tobacco smoke exposure (RR = 2.9, 95%CI = 1.6–5.3, after controlling) or the timing of diagnosis of TB (the increased lung cancer risk remained 2‐fold elevated for more than 20 years after TB diagnosis). Interestingly, the association was significant with adenocarcinoma (RR = 1.6, 95%CI = 1.2–2.1), but no significant associations with squamous and small cell type of lung cancer were observed. Although no causal mechanism has been demonstrated for such an association, present study supports a direct relation between TB and lung cancer, especially adenocarcinomas. © 2009 UICC