The Association between Tumour Markers and Meta-iodobenzylguanidine Scans in South African Children with High-risk Neuroblastoma

AimsDiagnostic and post-induction ¹²³I-meta-iodobenzylguanidine (¹²³I-mIBG) scans have prognostic significance in the treatment of neuroblastoma, but data from low- and middle-income countries are limited due to resource constraints. The aim of this study was to determine the association between neuroblastoma-associated tumour markers (lactate dehydrogenase [LDH], ferritin and MYCN amplification) and ¹²³I-mIBG scans (modified Curie scores and metastatic disease patterns) in predicting complete metastatic response rates (mCR) and overall survival.Materials and methodsTwo hundred and ninety patients diagnosed with high-risk neuroblastoma in South Africa between January 2000 and May 2018 and a subanalysis of 78 patients with diagnostic ¹²³I-mIBG scans were included. Data collection included LDH, ferritin and MYCN amplification at diagnosis. Two nuclear physicians independently determined the modified Curie scores and pattern of distribution for each diagnostic and post-induction ¹²³I-mIBG scans with high inter-rater agreement (r = 0.952) and reliability (K = 0.805). The cut-off values for the diagnostic and post-induction modified Curie scores of ≥7.0 (P = 0.026) and 3 (P = 0.009), respectively, were generated. The association between the tumour markers and the modified Curie score of the ¹²³I-mIBG scans was determined using post-induction mCR and 2-year overall survival.ResultsDiagnostic LDH (P < 0.001), ferritin (P < 0.001) and the diagnostic modified Curie scores (P = 0.019) significantly predicted mCR. Only ferritin correlated with diagnostic modified Curie scores (P = 0.003) but had a low correlation coefficient of 0.353. On multivariable analysis, the only significant covariate for 2-year overall survival at diagnosis was LDH <750 U/l (P = 0.024). A post-induction chemotherapy modified Curie score ≤3.0 had a 2-year overall survival of 46.2% compared with 30.8% for a score >3.0 (P = 0.484).ConclusionLDH, ferritin and the diagnostic ¹²³I-mIBG scans significantly predicted mCR, but only LDH predicted 2-year overall survival. Ferritin and the modified Curie scores correlated with each other. MYCN amplification neither correlated with any aspect of the ¹²³I-mIBG scans nor significantly predicted mCR or 2-year overall survival. LDH and ferritin are therefore appropriate neuroblastoma tumour markers to be used in low- and middle-income countries with limited or no access to mIBG scans and/or MYCN amplification studies.     

Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: Report of CALGB 361006 (Alliance)

ObjectiveTo demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance.Materials and methodsWe conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests.ResultsThe recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction.ConclusionGA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health.     

Outcomes of Autologous Hematopoietic Cell Transplantation Compared With Chemotherapy Consolidation Alone for Non–High-Risk Acute Myeloid Leukemia in First Complete Remission in a Minority-Rich Inner-City Cohort With Limited Access to Allografts

IntroductionIn the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non–high-risk acute myeloid leukemia (AML) when allogeneic hematopoietic cell transplantation (alloHCT) is unfeasible, which is common in racial minorities because of donor registry under-representation and socioeconomic challenges. We compared autoHCT consolidation outcomes with chemotherapy alone in a minority-rich cohort in the Bronx.Patients and MethodsWe identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 patients who received consolidation with ≥2 cycles of chemotherapy, of whom 28 received autoHCT.ResultsThe cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count, and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS; 43 vs. 11 months; P = .003) and overall (OS) survival (not reached vs. 36 months; P = .043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37-0.75; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.95; P = .027).ConclusionIn this inner-city non–high-risk AML cohort, autoHCT provided OS and RFS benefit compared with chemotherapy alone. AutoHCT might constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, whereas integration of measurable residual disease can help select patients more likely to benefit.     

Chronic inflammation and risk of lung cancer in older adults in the health,aging and body composition cohort study

Objectives

We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults.

Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist,Sant 7, in breast tissue-derived fibroblasts

Interleukin 6 (IL-6) and its soluble receptor (IL-6sR) can markedly stimulate aromatase activity in cultured fibroblasts derived from normal or malignant breast tissues. IL-6 acts by binding to a low-affinity membrane-spanning receptor (IL-6R), which must associate with a high-affinity receptor (gp130) for signal transduction to occur. Sant 7 is a mutated form of IL-6 that can bind to the IL-6R, but inhibits its ability to interact with the gp130 signal transducing protein. In this study, we have used Sant 7 to examine its ability to inhibit IL-6+IL-6 soluble receptor (IL-6sR)-stimulated aromatase activity in breast tissue-derived fibroblasts. As previously observed, IL-6+IL-6sR markedly stimulated aromatase activity (7.7-20.8-fold) in fibroblasts derived from reduction mammoplasty tissue, tissue proximal to tumours and breast tumours. Sant 7 inhibited basal aromatase activity in some fibroblasts by 25-30% that had a high basal activity, but almost completely blocked the ability of IL-6+IL-6sR to stimulate aromatase activity. The IC(50) for the inhibition of IL-6+IL-6sR-stimulated aromatase activity by Sant 7 was 60 ng ml(-1). A comparison of the effects of prostaglandin E(2) (PGE(2)), which can also regulate aromatase activity, and IL-6+IL-6sR revealed a greater degree of aromatase stimulation by IL-6+IL-6sR. Sant 7, however, inhibited PGE(2)-stimulated aromatase activity by 70% suggesting that PGE(2) acts, in part, by stimulating IL-6 production. Much of the IL-6 and IL-6sR available to stimulate breast tumour aromatase activity may originate from infiltrating macrophages and lymphocytes. The ability to block aromatase stimulation by these factors may offer a novel therapeutic strategy for reducing oestrogen synthesis in breast tumours.     

Oncogenic Ras modulates p38 MAPK-mediated inflammatory cytokine production in glioblastoma cells

Inflammation is an important factor promoting the progression of glioblastoma. In the present study we examined the contribution of Ras signaling and TNFα/IL-1β cytokines to the development of the glioblastoma inflammatory microenvironment. Enhanced activation of Ras through de-regulated activation of receptor tyrosine kinases, such as EGFR, PDGFR and cMet, is a hallmark of the majority of glioblastomas. Glioblastoma microenvironment contains high levels of TNFα and IL-1β, which mediate inflammation through induction of a local network of cytokines and chemokines. While many studies have focused on Ras- and TNFα/IL-1β-driven inflammation in isolation, little is known about the co-operation between these oncogenic and microenvironment-derived stimuli. Using constitutively active HRasG12V that mimics enhanced Ras activation, we demonstrate that elevated Ras activity in glioblastoma cells leads to up-regulation of IL-6 and IL-8. Furthermore, Ras synergizes with the microenvironment-derived TNFα and IL-1β resulting in amplified IL-6/IL-8 secretion. IL-8 secretion induced by Ras and TNFα/IL-1β is attenuated by inhibitors targeting Erk, JNK and p38 MAPK pathways. IL-6 secretion significantly decreased upon inhibition of JNK and p38 MAPK pathways. Interestingly, although constitutively active HRasG12V does not increase basal or TNFα/IL-1β stimulated p38 MAPK activity, HRasG12V increased the efficacy of the p38 MAPK inhibitor SB203580 to inhibit IL-1β-induced IL-6 secretion. In summary, oncogenic Ras co-operates with the microenvironment-derived TNFα/IL-1β to sustain inflammatory microenvironment, which was effectively attenuated via inhibition of p38 MAPK signaling.     

Release of soluble IL-6 receptor (IL-6sR) in comparison with release of soluble TNF receptors (sTNF-Rs) by PMNs and WBC derived from breast cancer patients

Soluble cytokine receptors are more general phenomena and play a wider physiological role in the regulation of the immune system than previously recognized. Soluble IL-6 receptor (IL-6sR) and soluble TNF receptors (sTNF-Rs) might play a regulatory role in a variety of normal and abnormal reactions mediated by IL-6 and TNF-alpha. The release of IL-6sR and sTNF-Rs by polymorphonuclear cells (PMNs) of breast cancer patients in vitro was measured. The results obtained were compared to the secretion of these soluble receptors by whole blood cells (WBC). We found that PMNs of patients examined secreted the concentrations of IL-6sR as in healthy subjects. Simultaneously, significantly higher values of sTNF-RI and sTNF-RII released by PMNs of patients were measured in comparison with the values of the control group. The mean concentrations of IL-6sR and sTNF-Rs secreted by WBC of control and cancer groups were higher than those released by PMNs. Altered secretion of sTNF-Rs and no altered secretion of IL-6sR by PMNs of breast cancer patients may have various implications for response to malignancy.     

Impact of Time Between Induction Chemotherapy and Complete Remission on Survival Outcomes in Patients With Acute Myeloid Leukemia

BackgroundThe majority of patients with acute myeloid leukemia (AML) receive intensive induction chemotherapy for obtaining a complete remission (CR). Despite consolidation chemotherapy and advances in allogeneic hematopoietic stem cell transplantation, most of these patients finally relapse and die from AML. The aim of this study is to determine the impact of duration of remission achievement on survival of patients with newly diagnosed AML who achieve CR after induction chemotherapy.Materials and MethodsWe retrospectively analyzed patients with AML who received first induction chemotherapy between 2001 and 2018.ResultsThe 5-year overall survival for patients who had early remission after induction chemotherapy and patients who had delayed remission after induction chemotherapy were 83% (95% confidence interval [CI], 0.79-0.87) and 35% (95% CI, 0.31-0.39), respectively (P < .001). The 5-year disease-free survival for patients who had early remission after induction chemotherapy and patients who had delayed remission after induction chemotherapy were 81% (95% CI, 0.75-0.87) and 28% (95% CI, 0.21-0.35), respectively (P < .001).ConclusionIn conclusion, time to entering CR is a predictor factor of overall survival and disease-free survival for patients with newly diagnosed AML who achieve CR after first induction chemotherapy. Patients achieving CR only after a lengthy time (eg, more than 29 days) should be considered to have high relapse rate and should undergo allogeneic hematopoietic stem cell transplantation.     

In Vitro Effects of Lithium Chloride on TNFα and IL-6 Production by Monocytes from Breast Cancer Patients

Abstract

It is well known that lithium chloride (LiCI) is able to trigger human monocytes to release tumor necrosis factor alpha (TNFα). In this study we have evaluated the In Vitro effect of LiCI on TNFα and interleukin-6 (IL-6) release by monocytes from patients affected by non-metastatic (BCa/M0) and metastatic breast cancer (BCa/M1), preincubated with autologous serum (sPt). Our data demonstrate that monocytes from cancer patients (BCa) treated with LiCI released lower amounts of TNFα compared to those from healthy donors (HD). Preincubation in autologous serum (sPt) impaired TNFα production by monocytes treated with LiCI. On the contrary, our data indicate that IL-6 production by monocytes from BCa was not impaired. Moreover, the results obtained from the same cells, preincubated in sPt and treated with LiCl, indicate that serum factors may synergize with LiCI treatment in releasing IL-6.     

消化道肿瘤患者癌因性疲乏与血清炎性因子及下丘脑-垂体-肾上腺素轴水平的相关性

目的 了解消化道肿瘤患者的疲乏水平,探讨癌因性疲乏(CRF)与血清炎性因子及下丘脑-垂体-肾上腺素(HPA)轴水平的相关性.方法 采用简易疲乏量表评估患者的疲乏水平,采用免疫比浊法测定血清C反应蛋白(CRP)水平,免疫微粒电发光法测定皮质醇水平,酶联免疫吸附试验(ELISA)测量血清中白细胞介素(IL)-6、IL-1β、肿瘤坏死因子-α(TNF-α)、促肾上腺皮质激素(ACTH)和去甲肾上腺素(NE)的水平.结果 消化道肿瘤患者CRF平均总体得分为(3.15±1.93)分,疲乏程度为轻中度,疲乏水平与血清中CRP、TNF-α水平呈明显正相关(r=0.321,P=0.000;r=0.265,P=0.000),与HPA轴中的NE、ACTH水平呈明显正相关(r=0.174,P=0.015;r=0.257,P=0.000),与皮质醇水平无关(r=0.033,P=0.652).美国东部肿瘤协作组(ECOG)得分(t=8.081,P=0.000)、文化程度(t=-4.244,P=0.000)、正在接受的治疗(t=4.563,P=0.000)、自诊断至采血日时间(t=3.453,P=0.001)、CRP(t=2.837,P=0.006)是CRF的重要影响因素.结论 消化道肿瘤患者CRF状况普遍存在,CRF与HPA轴中的NE、ACTH水平呈正相关.医务人员应重视对患者血清中炎性因子及激素水平的测定,改善患者的疲乏状况,提高生命质量.     

急性髓系白血病患者化疗后血清IL-8、IL-6水平与感染的关系

目的：探讨急性髓系白血病(AML)患者化疗后粒细胞缺乏发热时血清白细胞介素8(IL-8)和白细胞介素6(IL-6)水平与感染的关系。方法：采用双抗体夹心酶联免疫吸附法(ELISA)检测42例AML患者和20名正常对照者血清IL-8、IL-6水平。结果：血清IL-8和IL-6水平在AML患者发热第1天均升高，其中病原学检查阳性组显著高于原因不明发热组(P均＜0.002)和仅有临床感染证据组(P均＜0.05)，仅有临床感染证据组也较原因不明发热组增高(P均＜0.02)，且革兰氏阴性菌感染者较革兰氏阳性菌感染者增高明显(P均＜0.01)；IL-8和IL-6呈显著正相关(r=0.841，P＜0.001)，并均与体温呈正相关(r=0.447和0.570，P＜0.005和P＜0.001)；并发败血症死亡患者的血清IL-8、IL-6水平呈持续增高。结论：应用夹心法ELISA联合检测血清IL-8、IL-6水平，将有助于确定AML患者化疗后粒细胞缺乏发热时的早期感染及其严重性。     

Serum biomarkers for predicting overall survival and early mortality in older patients with metastatic solid tumors

ObjectivesWe aimed to explore serum biomarkers for predicting survival of older patients with metastatic solid tumors who received first line palliative chemotherapy.Materials and MethodsSerum samples were prospectively collected before first-line chemotherapy at 11 academic centers in Korea. All patients were participants in a prospective cohort study of older patients with metastatic solid tumors. Serum levels of C-reactive protein (CRP), CXCL10, SIRT1, VEGF-A, activin A, C-terminal telopeptide of type I collagen (CTx), total 25-hydroxyvitamin D were measured by ELISA and interleukin-6 (IL-6), myostatin, irisin, FGF-19, FGF-21, FGF-23 by Luminex multiplex assay. Overall survival (OS) was determined.ResultsSerum samples from 138 patients (median age: 75 years, range: 70–92 years) were collected from February 2014 to December 2016. During a median follow up time of 13.8 months, 73 (52.9%) patients died. Among 13 serum markers, CRP (log-rank, P = 0.009), activin A (P = 0.007), and myostatin (P = 0.047) were significantly correlated with OS in univariate analyses. Activin A (hazard ratio [HR] 2.22, 95% confidence interval [CI] 1.32–3.72; P = 0.003) and myostatin (HR 3.02, 95% CI 1.39–6.57; P = 0.005) were significantly associated with OS after adjustment for other clinical factors. In predicting early (6-month) mortality, two inflammatory markers, IL-6 and CRP, were included in the decision-tree model.ConclusionIn older patients with cancer, high serum concentrations of activin A and myostatin were predictive of poor OS. IL-6 and CRP might be useful to select older patients at risk of early mortality. These markers could be incorporated into predictive tools for clinical decision-making and warrant further investigation.     

肺癌患者血清趋化因子的表达水平及临床意义

目的 检测干扰素诱导的T细胞趋化因子(ITAC)、Fractalkine、巨噬细胞炎性蛋白(MIP)-3α、白细胞介素8(IL-8)、MIP-1α和MIP-1β在肺癌患者血清的表达水平,分析其与肺癌临床特征之间的关系及各趋化因子间相关性.方法 采用液相芯片技术联合检测40例初诊肺癌患者和30例正常人血清中上述6种趋化因子的表达情况,采用SPSS 17.0软件分析其与肺癌临床特征的关系及各趋化因子之间的相关性.结果 肺癌患者血清IL-8、Fractalkine、MIP-3α表达量中位数(四分位数间距)分别为5.16(4.74)、128.45 (141.89)、10.31(8.88),正常人分别为2.01(0.95)、61.46(74.81)、8.08(5.87),组间差异均有统计学意义(Z=-4.783,P ＜0.001;Z=-4.046,P＜0.001;Z=-3.105,P=0.002).肺腺癌组MIP-1β水平显著高于鳞状细胞癌组[18.32(12.27)∶13.72(7.31),Z=-2.212,P =0.027],而鳞状细胞癌组ITAC水平显著高于小细胞肺癌组[24.51(22.48)∶9.28(4.85),Z=-2.460,P=0.014];在肺癌患者和正常人中,MIP-3α与Fractalkine均呈正相关(r=0.619,P ＜0.001;r=0.766,P ＜0.001).结论 IL-8 、Fractalkine、MIP-3α在肺癌患者中的表达明显升高,可能在肺癌的转移中发挥重要作用.     

Cytokine serum levels in soft tissue sarcoma patients: correlations with clinico-pathological features and prognosis

We investigated the correlations between serum levels of selected proinflammatory, hematopoietic and angiogenic cytokines and soluble cytokine receptors with the clinico-pathological features and prognosis in soft tissue sarcoma patients. Serum levels of 9 cytokines (TNFalpha, IL-1ra, IL-6, IL-8, IL-10, M-CSF, G-CSF, VEGF, bFGF) and 4 free cytokine receptors (sIL-2R alpha, sIL-6R, TNFRI, TNFRII) were measured by means of an enzyme-linked immunoadsorbent assay kit in 156 soft tissue sarcoma patients before the treatment and in 50 healthy controls. Serum levels of 10 cytokines and cytokine receptors were also assayed during patients' follow-up after the treatment. Significantly elevated pretreatment serum levels of 11/13 cytokines and cytokine receptors were found in sarcoma patients, as compared to healthy controls. In 40.4% of patients 6 or more cytokines and cytokine receptors (most frequently: TNF RI, IL-6, IL-8) were elevated in parallel. Serum levels of IL-6, sIL-2R, VEGF, M-CSF and TNF RI correlated significantly with tumor size and serum levels of IL-8 and IL-6 were significantly higher in patients with Grade 2/3 vs. Grade 1 tumors. We did not observe any significant differences in cytokine serum levels between patients with primary and recurrent tumors and patients with and without distant metastases. Using univariate analysis, overall survival (OS) in all patients was affected by tumor size (<5 cm vs. 5-10 cm vs. >10 cm), tumor grade (G1 vs. G2/3), presence of metastases, pretreatment serum levels of 8 cytokines (IL-6, IL-8, IL-10, sIL-2R, TNF RI, TNF RII, M-CSF, VEGF) and the number of cytokines increased (0-1 vs. 2-5 vs. < or = 6). Elevated serum levels of IL-6, IL-8, IL-10 and sIL-2R alpha, high tumor grade and larger tumor size strongly correlated with shorter disease-free survival (DFS). Multivariate analysis identified G2/3 tumor grade (p = 0.001), the presence of metastases (p = 0.004), elevated IL-6 serum level (p = 0.02), elevated IL-8 serum level (p = 0.048) and the number of cytokine serum levels above upper cut-off values (p = 0.01) as the independent prognostic factors related to OS, and G2/3 tumor grade (p = 0.005) and increased IL-6 serum level (p = 0.035) as independent prognostic factors related to DFS. In a group of patients without metastases (M0) higher tumor grade, elevated serum level of IL-6 and TNF RII, and the number of elevated cytokine serum levels correlated independently with poor survival. We found a significant decrease of several cytokine serum levels in patients after treatment (IL-1ra, IL-6, IL-8, IL-10, TNF RII, M-CSF) [p < 0.05]. Persistently elevated serum level of IL-6 after the treatment has also shown negative prognostic significance for OS (univariate analysis). Serum levels of some proinflammatory, hematopoietic and angiogenic cytokines and cytokine receptors are elevated, frequently in parallel, in a large percentage of soft tissue sarcoma patients. Significant correlations of serum cytokine levels with tumor size and grade suggest that some of these cytokines may be directly or indirectly involved in the progression of soft tissue sarcomas. Serum assays of IL-6, IL-8 and TNF RII before or after the treatment may be useful in establishing soft tissue sarcoma patients prognosis.     

Cytokines and angiogenic factors in patients with metastatic renal cell carcinoma treated with interferon-α: association of pretreatment serum levels with survival

BackgroundTo correlate serum cytokine and angiogenic factor (CAF) levels with overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with interferon-α (IFN-α).Patients and methodsSerum CAF levels were measured in 103 patients treated on a randomized trial with IFN-α 0.5 million units (MU) twice daily or 5 MU daily. Concentrations of 17 analytes were determined by multiplex bead immunoassays [vascular endothelial growth factor A (VEGF_A) and several cytokines] or enzyme-linked immunosorbent assay (basic fibroblast growth factor). We used proportional hazards models to evaluate the effect of CAF levels and clinical factors on OS.ResultsPretreatment serum interleukin (IL) 5, IL-12 p40, VEGF_A, and IL-6 levels and Memorial Sloan-Kettering Cancer Center risk grouping independently correlated with OS, with hazard ratios of 2.33, 2.00, 2.07, 1.82, and 0.39, respectively (concordance index = 0.69 for the combined model versus 0.60 for the CAF model versus 0.52 for the clinical model). Based on an index derived from these five risk factors (RFs), patients with 0–2 RF had a median OS time of 32 months versus 9 months for patients with 3–5 RF (P < 0.0001).ConclusionsSerum CAF profiling contributes to prognostic evaluation in mRCC and helps to identify a subset of patients with 20% 5-year OS.     

The role of grip strength and short physical performance battery test in predicting chemotherapy-related outcomes in older adults with cancer

BackgroundGrip strength (GS) and the Short Physical Performance Battery (SPPB) are brief objective tests used during a comprehensive geriatric assessment (CGA) to assess physical performance. Abnormal GS and SPPB scores are associated with greater morbidity and mortality in older adults with cancer but their relationship with chemotherapy tolerability is unclear. We explored the performance of GS and SPPB in predicting therapy delay, dose reduction, and treatment completion in older adults undergoing chemotherapy or chemoradiation. Additionally, we examined associations between GS, SPPB, and instrumental activities of daily living (IADLs).MethodsRetrospective review of patients ≥65 years old who had undergone a pre-treatment CGA in a geriatric oncology clinic were retrieved from electronic charts and institutional databases. Abnormal GS was defined as <26 kg and < 16 kg for men and women, respectively. Abnormal SPPB was defined as ≤9 points. Logistic regression was used to examine the associations between abnormal GS or SPPB alone or combined with chemotherapy-related outcomes (e.g., delay, dose reduction, completion). Chi-squared tests were used to determine associations between physical performance measures (GS and SPPB) and IADLs.ResultsA total of 85 participants (mean age 79.1 years old) with mixed cancer diagnoses were included. Approximately 67% of participants exhibited abnormal GS or SPPB prior to treatment. Abnormal GS or SPPB (combined) was associated with treatment delay (odds ratio (OR) = 7.58, 95% confidence interval (CI) = 1.77, 32.43, P = 0.006). When physical performance measures were examined separately, only SPPB predicted treatment delay (OR = 3.26, 95%CI = 1.04, 10.21, P = 0.043). Abnormal GS or SPPB were not associated with dose reduction or treatment completion. Abnormal GS and SPPB alone or combined demonstrated only modest sensitivity (41.9–76.7%) and negative predictive value (57.9–64.2%) in identifying IADLs dependence.ConclusionGS and SPPB may be used to predict treatment delay in older adults prior to chemotherapy and chemoradiation. Additional studies are warranted to examine whether GS and/or SPPB can predict dose reduction and treatment completion in older adults prior to receiving chemotherapy or chemoradiation.     

Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration.

PURPOSE: A phase II trial that uses liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in patients with relapsed osteosarcoma is underway. To determine if in vivo cytokine induction plays a role in the mechanism of action of L-MTP-PE, we investigated the circulating cytokine levels of 16 patients who were undergoing therapy. PATIENTS AND METHODS: Patients had histologically proven osteosarcoma and pulmonary metastases that developed either during adjuvant chemotherapy or that were present at diagnosis and persisted despite chemotherapy. Patients were rendered disease-free by surgery. The major goal of the study was to improve the disease-free interval in this high-risk group. L-MTP-PE 2 mg/m2 was infused during a 1-hour period twice a week for 12 weeks, then once a week for 12 weeks. Serial blood samples were collected after L-MTP-PE administration and were assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha] interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-6, interferon-gamma [IFN-gamma], neopterin, C-reactive protein). RESULTS: After the infusion of L-MTP-PE, there was rapid induction of circulating TNF alpha and IL-6. TNF alpha levels peaked 1 to 2 hours after infusion in 10 of 16 patients, whereas peak IL-6 levels were detected at 2 to 3 hours in all patients. Induction of circulating TNF alpha and IL-6 was evident only after the first dose of L-MTP-PE. Neither IL-1 alpha nor IL-1 beta was detected in the plasma. Neopterin levels increased at 24 hours postinfusion, which indicated macrophage activation, and were not related to the induction of circulating IFN-gamma. C-reactive protein was elevated in all patients at 24 hours and decreased by 72 hours. Unlike circulating TNF alpha and IL-6, elevations in C-reactive protein and neopterin could be detected throughout the treatment course. CONCLUSION: It is concluded that L-MTP-PE has specific biologic effects in patients with osteosarcoma that may be important to the drug's immunostimulatory capacity and its effectiveness as an antitumor agent.     

The effects of IL-1 beta and IL-4 on the proliferation and endogenous secretion of growth factors by acute myeloblastic leukemic cells.

The effects of interleukin-1 beta (IL-1) and IL-4 were studied on the proliferation of acute myeloid leukemia (AML) cells. IL-1 stimulated tritiated thymidine (3H-TdR) uptake of AML cells in 8/12 cases, whereas IL-4 enhanced 3H-TdR uptake in 5/12. Combination of both factors resulted in an additive effect in 6/12 cases which could be abrogated by the addition of anti-granulocyte-macrophage colony stimulating factor (GM-CSF). To study whether IL-1, IL-4, or IL-1 plus IL-4 affects the AML progenitor cell directly or indirectly by the release of endogenous factors, supernatants of stimulated AML cells (n = 6) were analyzed for GM-CSF, IL-6, and tumor necrosis factor-alpha (TNF) production. IL-1 induced the endogenous secretion of GM-CSF, IL-6, and TNF in most cases. In contrast, no secretion of growth factors was induced by IL-4, whereas in 2 cases IL-4 suppressed the IL-1-induced secretion of GM-CSF, TNF, and IL-6. This was associated with a decline in the proliferative response to IL-1 measured in a clonogenic assay. In addition it was shown that exogenous supplied GM-CSF and TNF could raise the suppressive effects of IL-4 on the IL-1-supported proliferation. In summary these data indicate that the IL-4-supported proliferation is not caused by the endogenous secretion of GM-CSF, IL-6, and TNF. Furthermore the suppressive effect of IL-4 on the IL-1-induced proliferation in some cases may be caused by a reduced secretion of GM-CSF, TNF, and IL-6.     

Comprehensive serum cytokine analysis identifies IL-1RA and soluble IL-2Rα as predictors of event-free survival in T-cell lymphoma

BackgroundT-cell malignancies are heterogeneous in their clinical presentation and pathology, and have a poor prognosis. New biomarkers are needed to predict prognosis and to provide insights into signal pathways used by these cells. The goal of this study was to evaluate pretreatment serum cytokines in patients with newly diagnosed T-cell neoplasms and correlate with clinical outcome.Patients and methodsWe evaluated 30 cytokines in pretreatment serum from 68 untreated patients and 14 normal controls. Significantly elevated cytokines were correlated with patterns of abnormalities, event-free survival (EFS) and overall survival (OS).ResultsOur data demonstrated significantly elevated levels (versus controls) of seven cytokines—epidermal growth factor (EGF), IL-6, IL-12, interferon gamma-induced protein (IP)-10, soluble interleukin (sIL)-2Rα, monokine induced by gamma interferon (MIG), and IL-1RA—in all T-cell neoplasms (P < 0.05). In the angioimmunoblastic subset, all seven cytokines except IP-10 and in the peripheral T-cell lymphoma (TCL)-not otherwise specified subset, only IP-10, sIL-2Rα, MIG, and IL-8 were statistically elevated compared with control. Of these, elevated cytokines all but EGF were predictive of an inferior EFS; IL-1RA, sIL-2Rα, and MIG predicted an inferior OS. In a multivariate analysis, sIL-2Rα [hazard ratio (HR) = 3.95; 95% confidence interval (CI) 1.61–8.38] and IL-1RA (HR = 3.28; 95% CI 1.47–7.29) levels remained independent predictors of inferior EFS. TCL cell lines secreted high levels of sIL-2Rα and expressed the IL-2Rα surface receptor.ConclusionsThis report describes the cytokines relevant to prognosis in patients with untreated TCL and provides the rationale to include serum IL-1RA and sIL-2Rα as biomarkers in future trials. Inhibition of these cytokines may also be of therapeutic benefit.     

Effects of chemotherapy on aging white matter microstructure: A longitudinal diffusion tensor imaging study

ObjectiveWe aimed to use diffusion tensor imaging (DTI) to detect alterations in white matter microstructure in older patients with breast cancer receiving chemotherapy.MethodsWe recruited women age ≥60 years with stage I–III breast cancer (chemotherapy [CT] group; n = 19) to undergo two study assessments: at baseline and within one month after chemotherapy. Each assessment consisted of a brain magnetic resonance imaging scan with DTI and neuropsychological (NP) testing using the National Institutes of Health (NIH) Toolbox Cognition Battery. An age- and sex-matched group of healthy controls (HC, n = 14) underwent the same assessments at matched intervals. Four DTI parameters (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], and radial diffusivity [RD]) were calculated and correlated with NP testing scores.ResultsFor CT group but not HCs, we detected statistically significant increases in MD and RD in the genu of the corpus callosum from time point 1 to time point 2 at p < 0.01, effect size:0.3655 and 0.3173, and 95% confidence interval: from 0.1490 to 0.5821, and from 0.1554 to 0.4792, for MD and RD respectively. AD values increased for the CT group and decreased for the HC group over time, resulting in significant between-group differences (p = 0.0056, effect size:1.0215, 95% confidence interval: from 0.2773 to 1.7657). There were no significant correlations between DTI parameters and NP scores (p > 0.05).ConclusionsWe identified alterations in white matter microstructures in older women with breast cancer undergoing chemotherapy. These findings may potentially serve as neuroimaging biomarkers for identifying cognitive impairment in older adults with cancer.