异基因造血干细胞移植治疗耳道复发的急性早幼粒细胞白血病一例并文献复习

目的:探讨急性早幼粒细胞白血病(APL)髓外复发的相关因素及治疗。方法:对1例APL缓解后耳道复发患者的临床资料进行回顾性分析,并复习相关文献。结果:患者2015年8月诊断为APL(低危型),经诱导后达完全缓解,随后进行巩固、维持治疗,并多次行腰椎穿刺术及椎管内注射化疗药物预防中枢神经系统白血病。2017年3月发现左外耳道新生物,活检确诊外耳道髓系肉瘤,示髓外复发。随后出现骨髓复发。经诱导巩固化疗后行异基因造血干细胞移植,存活至今。结论:对于髓外复发的急性早幼粒细胞白血病,其预后较差,异基因造血干细胞移植治疗有较好疗效。     

Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis

Information of myeloid lineage-related antigen on hematopoietic stem/progenitor cells (HSPCs) is important to clarify the mechanisms regulating hematopoiesis, as well as for the diagnosis and treatment of myeloid malignancies. We previously reported that special AT-rich sequence binding protein 1 (SATB1), a global chromatin organizer, promotes lymphoid differentiation from HSPCs. To search a novel cell surface molecule discriminating early myeloid and lymphoid differentiation, we performed microarray analyses comparing SATB1-overexpressed HSPCs with mock-transduced HSPCs. The results drew our attention to membrane-spanning 4-domains, subfamily A, member 3 (Ms4a3) as the most downregulated molecule in HSPCs with forced overexpression of SATB1. Ms4a3 expression was undetectable in hematopoietic stem cells, but showed a concomitant increase with progressive myeloid differentiation, whereas not only lymphoid but also megakaryocytic-erythrocytic progenitors were entirely devoid of Ms4a3 expression. Further analysis revealed that a subset of CD34⁺CD38⁺CD33⁺ progenitor population in human adult bone marrow expressed MS4A3, and those MS4A3⁺ progenitors only produced granulocyte/macrophage colonies, losing erythroid colony- and mixed colony-forming capacity. These results suggest that cell surface expression of MS4A3 is useful to distinguish granulocyte/macrophage lineage-committed progenitors from other lineage-related ones in early human hematopoiesis. In conclusion, MS4A3 is useful to monitor early stage of myeloid differentiation in human hematopoiesis.     

Metabolic Syndrome in Primary Gout

Background and Objectives. Primary gout has traditionally been associated with obesity, arterial hypertension, and abnormal lipid and glucose homeostasis, but we do not know the prevalence of these vascular risk factors in patients with primary gout from a Mediterranean country. Patients and Method. All patients with primary gout and 2 or more acute arthritis episodes documented by a physician were selected for the study. The diagnosis of MS required ≥3 criteria (ATP III). Patients were classified in two groups: decreased (underexcretors) and normal (normoexcretors) uric acid excretion related to serum urate levels. Results. One hundred and four patients (mean age, 59 years; 100 males) with primary gout were included in the study. MS was diagnosed in 38 subjects (37%). The most frequent triad defining MS was an increased waist circumference, blood pressure, and trygliceride levels. The prevalence of type 2 diabetes mellitus (T2D) was significantly higher in patients with the MS (21/38, 55%) as compared with subjects without the MS (3/66, 5%; p < 0.001). Mean serum urate level in patients with and without MS was identical (8.1 mg/dL), but mean 24-hour uric acid excretion was significantly lower in the former than in the latter (444 ± 110 mg/24-hour/1,73 m² versus 546 ± 221 mg/day/1,73 m²; p = 0.009). Conclusions. The condition of the MS occurs in about one-third of the patients with primary gout. Increased waist circumference, blood pressure, and triglycerides levels is the most frequent MS triad. Diminished urinary uric acid excretion is more severe in gout patients with the MS.     

XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34<Superscript>+</Superscript>38<Superscript>−</Superscript> cells in a phase 1/2 study of patients with relapsed/refractory AML

XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12–350 mg/m² AEG35156) and eight in phase 2 (350 mg/m² AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28–35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42–100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34 ⁺ 38 ⁻ AML stem cells and all phase 2 patients showing apoptosis induction in CD34 ⁺ 38 ⁻ cells achieved response. We conclude that at 350 mg/m², AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34 ⁺ 38 ⁻ AML stem cells.     

Establishment of a Humanized APL Model via the Transplantation of PML-RARA-Transduced Human Common Myeloid Progenitors into Immunodeficient Mice

Recent advances in cancer biology have revealed that many malignancies possess a hierarchal system, and leukemic stem cells (LSC) or leukemia-initiating cells (LIC) appear to be obligatory for disease progression. Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized by the formation of a PML-RARα fusion protein, leads to the accumulation of abnormal promyelocytes. In order to understand the precise mechanisms involved in human APL leukemogenesis, we established a humanized in vivo APL model involving retroviral transduction of PML-RARA into CD34⁺ hematopoietic cells from human cord blood and transplantation of these cells into immunodeficient mice. The leukemia well recapitulated human APL, consisting of leukemic cells with abundant azurophilic abnormal granules in the cytoplasm, which expressed CD13, CD33 and CD117, but not HLA-DR and CD34, were clustered in the same category as human APL samples in the gene expression analysis, and demonstrated sensitivity to ATRA. As seen in human APL, the induced APL cells showed a low transplantation efficiency in the secondary recipients, which was also exhibited in the transplantations that were carried out using the sorted CD34⁻ fraction. In order to analyze the mechanisms underlying APL initiation and development, fractionated human cord blood was transduced with PML-RARA. Common myeloid progenitors (CMP) from CD34⁺/CD38⁺ cells developed APL. These findings demonstrate that CMP are a target fraction for PML-RARA in APL, whereas the resultant CD34⁻ APL cells may share the ability to maintain the tumor.     

The role of neoadjuvant and adjuvant chemotherapy regimens consisting of different combinations of drugs in the treatment of advanced oral cancer

We performed a retrospective analysis on the effect of neoadjuvant chemotherapy with three cycles of methotrexate (100 mg/m² on day 1), cisplatin (90 mg/m² on day 1) and bleomycin (20 mg/m² on day 1–5) with 21 d gap between each cycle in 44 patients with advanced squamous cell carcinoma of the cheek, lip and tongue followed by surgery and adjuvant chemotherapy consisting of cisplatin (90 mg/m² on day 1), Mitomycin C (6 mg/m² on day 1) and 5-fluorouracil (1000 mg/m² 120 h continuous infusion from day 1) repeated every 3 weeks for three cycles. Following induction chemotherapy, complete response was observed in 11 out of 44 patients (25%), and a partial response in a further 28 patients (64%). The overall median survival of all patients was 29 months and those in stage III and stage IV were 30 and 15 months respectively (P<0.001). The median duration of the time to relapse in patients who responded to adjuvant chemotherapy was 28 months. The main toxic effect was vomiting followed by hematological toxicity. No treatment-related deaths occurred. The regimen showed a significant response, encouraging median survival and a good tolerability profile.     

Identification of biomarkers for early diagnosis of Parkinson's disease by multi-omics joint analysis

ObjectiveThe purpose of this study is to identify the biomarkers for early diagnosis of Parkinson's disease (PD) by multi-omics joint analysis, so as to identify the biomarkers for early diagnosis of PD, and to help clinicians make early diagnosis and treatment.MethodsIn this study, mice are taken as the study subjects. The model of PD mice is established, and then lymphocyte, striatum, substantia nigra protein and proteolysis are extracted. After that, the experiments of protein imprinting and 4¹⁸O labeling are carried out. Mass Spectrometry (MS) analysis technology is mainly used to study proteomics and to analyze the quantitative and qualitative situation of differential proteins in striatum, substantia nigra protein and lymphocyte. By this method, biomarkers for early diagnosis of PD are analyzed and identified.ResultsThe biomarkers of Parkinson's early onset are related to the same quantitative differential expression of lymphocyte, striatum, substantia nigra protein, lymphocyte and substantia nigra.ConclusionThis experimental method can analyze and identify the biomarkers of early diagnosis of PD, help to explore the pathophysiology and pathogenesis of PD, effectively help clinicians make timely diagnosis in advance, and improve the prevention and treatment effect of the disease.     

Detection of circulating tumor-derived material in peripheral blood of pediatric sarcoma patients: A systematic review

BackgroundDetection of circulating tumor-derived material (cTM) in the peripheral blood (PB) of cancer patients has been shown to be useful in early diagnosis, prediction of prognosis, and disease monitoring. However, it has not yet been thoroughly evaluated for pediatric sarcoma patients.MethodsWe searched the PubMed and EMBASE databases for studies reporting the detection of circulating tumor cells, circulating tumor DNA, and circulating RNA in PB of pediatric sarcoma patients. Data on performance in identifying cTM and its applicability in diagnosis, and evaluation of tumor characteristics, prognostic factors, and treatment response was extracted from publications.ResultsA total of 79 studies were assigned for the present systematic review, including detection of circulating tumor cells (116 patients), circulating tumor DNA (716 patients), and circulating RNA (2887 patients). Circulating tumor cells were detected in 76% of patients. Circulating DNA was detected in 63% by targeted NGS, 66% by shallow WGS, and 79% by digital droplet PCR. Circulating RNA was detected in 37% of patients.ConclusionOf the cTM from Ewing's sarcoma and rhabdomyosarcoma ctDNA proved to be the best target for clinical application including diagnosis, tumor characterization, prognosis, and monitoring of disease progression and treatment response. For osteosarcoma the most promising targets are copy number alterations or patient specific micro RNAs, however, further investigations are needed to obtain consensus on clinical utility.     

Étude clinique de phase I avec bénéfice individuel direct de radioimmunothérapie du myélome multiple utilisant l’anticorps anti-CD138 marqué à l’iode 131 (131I-B-B4)

PurposeThe objective of this study was to evaluate the toxicity, the absorbed dose to critical organs and tumour of B-B4 monoclonal antibody labeled with Iodine 131 in patients with multiple myeloma (MM) enrolled in a phase I study.Patients and methodFour patients with MM were enrolled and received for dosimetric study an injection of 20 mg/m² of B-B4 coupled with 370 MBq of Iodine 131. During the treatment phase, after viewing the target, three patients received a fixed dose of 20 mg/m² of ¹³¹I-B-B4 with an initial activity of 555 MBq/m², corresponding to level 1.ResultsImmunoscintigraphy showed an early and intensive uptake of the axial skeleton confirming the targeting of the disease by the antibody. Grade 3/4 haematological toxicity was observed in two patients with a trend to tally with the estimated average dose received by the bone marrow, calculated in the dosimetric study (blood method and imaging method). No other toxicity was observed. No complete or partial response was observed.ConclusionThe dose of 555 MBq/m² of ¹³¹I-B-B4 has shown encouraging results in terms of dosimetry and toxicity of RIT in MM. Other developments are possible with the use of humanized monoclonal antibody and the labeling with an alpha particle emitter.     

Neutrophil elastase is important for PML-retinoic acid receptor alpha activities in early myeloid cells

Expression of the PML-retinoic acid receptor alpha (PML-RARalpha) fusion protein is the initiating genetic event for acute promyelocytic leukemia (APL), but the molecular mechanisms responsible for disease initiation are not yet clear. Several observations have suggested that early myeloid cells are uniquely susceptible to transformation by PML-RARalpha. Recently, we have shown that the early myeloid-specific protease neutrophil elastase is important for APL development in the mouse. To better understand the role of neutrophil elastase for the pathogenesis of APL, we examined the consequences of PML-RARalpha expression in early myeloid cells with or without neutrophil elastase. We found that high-level PML-RARalpha expression was associated with cellular toxicity that was dependent on the expression of neutrophil elastase; a mutant form of PML-RARalpha that resisted neutrophil elastase cleavage was not toxic. When PML-RARalpha was expressed at very low levels in the early myeloid cells of mice, it induced myeloid expansion and delayed myeloid maturation; neutrophil elastase was also required for these activities. The activities of PML-RARalpha in early myeloid cells are therefore strongly influenced by the presence of neutrophil elastase. To assure physiologic relevance, PML-RARalpha functions should be evaluated in neutrophil elastase-expressing early myeloid cells.     

Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation

Autophagy is an intracellular bulk degradation process involved in cell survival upon stress induction, but also with a newly identified function in myeloid differentiation. The autophagy-related (ATG)8 protein family, including the GABARAP and LC3 subfamilies, is crucial for autophagosome biogenesis. In order to evaluate the significance of the GABARAPs in the pathogenesis of acute myeloid leukemia (AML), we compared their expression in primary AML patient samples, CD34⁺ progenitor cells and in granulocytes from healthy donors. GABARAPL1 and GABARAPL2/GATE-16, but not GABARAP, were significantly downregulated in particular AML subtypes compared to normal granulocytes. Moreover, the expression of GABARAPL1 and GATE-16 was significantly induced during ATRA-induced neutrophil differentiation of acute promyelocytic leukemia cells (APL). Lastly, knocking down GABARAPL2/GATE-16 in APL cells attenuatedneutrophil differentiation and decreased autophagic flux. In conclusion, low GABARAPL2/GATE-16 expression is associated with an immature myeloid leukemic phenotype and these proteins are necessary for neutrophil differentiation of APL cells.     

CHLOROPHYLL-a CONCENTRATION IN THE LOWER KAFUE RIVER AND CHONGWE RIVER BASINS

SUMMARY

The concentration of chlorophyll a was measured in the warm monomictic impoundment, Itezhi-tezhi Lake ([xbar] = 2,00 mg m^?3); in the small, slightly polluted Chongwe Dam ([xbar] = 11,0 mg m^?3); and in the temporary Mungasiya River ([xbar] = 53,4 mg m^?3). The average standing crop of the periphyton of green filamentous algae in the Chongwe River reached 28,3 mg m^?2. The highest concentrations of chlorophyll ([xbar] = 69,6 mg m^?2) were found in the Cyanophyta community of the extreme biotope of Longola Hot Springs.     

Daunoxome® Treatment of Solid Tumors: Preclinical and Clinical Investigations

Abstract

Daunorubicin has been entrapped into small unilamellar vesicles (50-80 nm dia) composed of a 2:1 mole ratio of highly purified DSPC:cholesterol. In earlier studies, liposomes of this size and composition had been demonstrated to deliver their entrapped contents selectively to a wide range of solid tumors in vivo. Preclinical and initial clinical investigations of these daunorubicin liposomes (DaunoXome) are discussed. In one murine solid tumor model (P1798 lymphosarcoma), a ten-fold increased delivery of entrapped daunorubicin to tumor tissue was observed. Efficacy studies in the same model indicated improved tumor regression and extended life spans that correlated with the observed degree of enhanced tumor drug delivery. In a second tumor model (MA16C mammary adenocarcinoma), a ten-fold enhancement in efficacy again was demonstrated. In terms of median survival times and long term survival rate, DaunoXome dosed at 2 mg/kg (daunorubicin) demonstrated an efficacy comparable to free drug at 20 mg/kg. Clinical pharmacokinetics paralleled findings from animal studies. In humans, DaunoXome produced daunorubicin plasma AUC levels that were more than 35-fold greater than those reported for comparable doses of free drug at 80 mg/m². Response rates above 50% have been shown for treatment of Kaposi's sarcoma. A low incidence of side effects has been observed and HIV positive patients have been able to continue antiviral therapy during DaunoXome treatments. Cardiotoxicity has not manifested clinically even for patients receiving in excess of 1 gram/m² cumulative daunorubicin.     

Uric Acid Metabolism in Patients with Primary Gout and the Metabolic Syndrome

Forty-four patients (40 males) with a mean age of 58 years were included in this pilot study. Mean serum urate concentration in patients with and without the metabolic syndrome (MS) was 8.8 mg/dL and 8.1 mg/dL, respectively. Urinary uric acid excretion was 543 mg/day/1.73m² in the former and 609 mg/day/1.73m² in the latter. Uric acid to creatinine ratio was 0.37 mg/mg in patients with the MS and 0.42 mg/mg in those without the MS. Mean serum urate increased from 8.6 mg/dL in subjects with three or more MS components to 10.3 mg/dL in those with five MS components. Serum urate was markedly lower in patients with mild MS (9 patients, 8.6 mg/dL) as compared to severe MS (10 patients, 9.2 mg/dL). In contrast, urinary uric acid to creatinine ratio was 0.42 mg/mg in patients with gout and mild MS and 0.33 mg/mg in gout patients with severe MS. Uric acid underexcretion appears to be more severe in gout patients with the MS. This disturbance appears to be related to the severity of the MS.     

NLS-RARα contributes to differentiation block and increased leukemogenic potential in vivo

The fusion oncogene, promyelocytic leukemia (PML)-retinoic acid receptor-α (RARα), is crucial for acute promyelocytic leukemia (APL) pathogenesis. Previous studies have reported that PML-RARα is cleaved by neutrophil elastase (NE), an early myeloid-specific serine protease, leading to translocation of the nuclear localization signal (NLS) of the PML protein to the N-terminal of RARα. This study was designed to evaluate the value of NLS-RARα in the early diagnosis of APL. To investigate the potential functional role of NLS-RARα in leukemogenesis, HL-60 and U937 cell lines were transfected with NLS-RARα lentivirus and negative control (LVNC). The results showed that the induced expression of NLS-RARα down-regulated expressions of CD11b, CD11c, and CD14 compared to the LVNC group induced by 1α, 25-dihydroxyvitamin D₃(1,25(OH)₂D₃). This suggested that NLS-RARα overexpression inhibited granulocytic and monocytic differentiation of myeloid leukemia cells. In addition, Wright-Giemsa staining, flow cytometry, respiratory burst assay, and NBT reduction assay all confirmed the importance of NLS-RARα in differentiation. The mechanistic investigations revealed that induced NLS-RARα expression inhibited 1,25(OH)₂D₃-induced granulocytic differentiation by regulating the cell cycle regulators p19^INK4D, p21^WAF1/CIP1, cyclinD1, cyclin E1, and pRB. Furthermore, the cleaved protein NLS-RARα enhanced the oncogenicity of U937 cells in NOD/SCID mice. These findings collectively demonstrated that NLS-RARα blocked granulocytic and monocytic differentiation of myeloid leukemia cells by inhibiting the downstream targets of the RARα signal pathway and the cell cycle. This may provide a promising new target and method for diagnosing and treating APL.     

Prevalencia de hiperandrogenismo y síndrome de ovario poliquístico en transexuales de mujer a hombre

IntroductionPrevalence of hyperandrogenism (HA), including the polycystic ovary syndrome (PCOS), in female-to-male transsexuals (FMT) is high. This has been related to metabolic syndrome (MS), which appears to increase cardiovascular morbidity and mortality throughout cross-sex hormone (CSH) therapy.ObjectivesTo assess the prevalence of HA and PCOS in FMT patients before the start of CSH therapy, and their association to MS and its components, insulin resistance (IR) and other cardiovascular risk (CVR) factors.Materials and methodsSeventy-seven FMTs underwent clinical and biochemical assessment for HA before the start of CSH therapy. CVR, IR, and other MS parameters were also assessed.ResultsPrevalence of HA was 49.4% (73.7% were cases of PCOS [Rotterdam criteria]), and prevalence of PCOS in the overall sample was 36.4%. Prevalence of MS was 38.4% and 51.7% according to ATP-III and IDF criteria respectively). MS (according to ATP-III and IDF criteria respectively) was found in 36.8% and 57.9% as compared to 25.6% and 41% of patients with and without HA respectively (p < 0.0001 and P < 0.01 respectively). Of total patients, 54.5% had normal weight (body mass index [BMI] 18.5-24.9 kg.m^-2), 26% were overweight (BMI 25-29.9 kg.m^-2), and 19.5% were obese (BMI ≥ 30 kg.m^-2). After adjusting for BMI, the comparison of hormonal, metabolic, and anthropometric parameters showed statistically significant differences in plasma glucose, HOMA-IR, and abdominal circumference (P < 0.001 for all), as well as HDL cholesterol (HDL) (P = 0.033), but not in total testosterone or calculated free testosterone levels. In the total sample, 27.3% had HDL levels less than 50 mg/dL.ConclusionsOverall HA, and PCOS in particular, are highly prevalent in FMTs. HA and PCOS are related to early development of SM, IR, and other CVR factors with unknown consequences in adulthood.     

Efficacy and safety of Abelmoschus manihot for IgA nephropathy: A multicenter randomized clinical trial

Rationale and ObjectiveIgA nephropathy (IgAN) is an important cause for end-stage renal disease worldwide. The treatment for IgAN remains challenging, and few randomized and controlled clinical trials have been conducted to evaluate new therapies. The present study assesses the efficacy and safety of Abelmoschus manihot (AM) in IgAN patients.Study DesignRandomized, non-inferiority, double-blind, double-dummy multicenter trial.Setting and ParticipantsThis trial was designed to recruit 1,600 biopsy-proven IgAN patients (proteinuria between 0.5-3.0 g/d and estimated glomerular filtration rate [eGFR] of ≥ 45 ml/min/1.73 m²) across China.InterventionsThe participants were randomized at 1:1 to AM (2.5 g for three times per day) or losartan potassium (100 mg per day) for 48 weeks.OutcomesThe primary outcome was the change in 24-hour proteinuria from baseline to week 48. The secondary outcomes were the change in eGFR from baseline to week 48, and the incidents of endpoint events (proteinuria ≥ 3.5 g/24 h, doubling of serum creatinine, or receiving renal replacement treatment).ResultsAmong 1,470 randomized patients (mean age, 37.4 [SD, 10.6] years old; 777 [52.9%] were female; mean eGFR, 95.0 [SD, 24.3] mL/min/1.73 m²; mean 24-hour proteinuria, 1.2 [SD, 0.7] g/d), the mean decline in 24-h proteinuria at week 48 was 230 mg and 253 mg in the AM and losartan potassium groups, respectively (P = 0.676). The mean difference in the change in 24-h proteinuria between these two groups was -23.32 mg (95% confident interval: -123.2 to 76.6, p = 0.647). The mean decline in eGFR was 0.41 ml/min/1.73 m² and 0.76 ml/min/1.73 m² in the AM and losartan potassium groups, respectively (p = 0.661). The mean difference in the change in eGFR between these two groups was -0.43 ml/min/1.73 m² (95% confident interval: -1.99 to 1.13, p = 0.589). The incidence of endpoint events was 8.6% in the AM group and 8.2% in the losartan group (p = 0.851).LimitationsThe results of the trial may not be generalized to IgAN patients with a proteinuria of > 3.0 g/d and an eGFR of < 45 ml/min/1.73 m². The long-term benefits of AM in reducing the risk of progressive renal dysfunction remains unclear, based on this 48-week observation.ConclusionAM can be recommended as a promising treatment for IgAN patients.     

The effect of silica exposure on the risk of lung cancer: A dose-response meta-analysis

BackgroundThe relationship between silica and the risk of developing lung cancer has been established in previous literature, but how much the level of exposure to silica can increase the risk of lung cancer is a question that has been addressed in this review.MethodsThree electronic databases, including MEDLINE, Scopus, and Web of Science were searched for relevant literature. For the dose-response relationship between exposure to silica and developing lung cancer, we performed a meta-analysis using the random-effects model. For each level of exposure, we calculated the overall risk ratio (RR) with 95% confidence intervals (CI).ResultsNineteen studies were included in the meta-analysis. There was a positive and significant increasing dose-response trend between silica exposure and the risk of developing lung cancer as follows: < 0.50 mg/m³ 1.14 (95% CI: 1.05, 1.23; I² = 79%), 0.50–0.99 mg/m³ 1.34 (95% CI: 1.05, 171; I² = 45%), 1.00–1.99 mg/m³ 1.14 (95% CI: 1.00, 1.30; I² = 70%), 2.00–2.99 mg/m³ 1.47 (95% CI: 1.05, 2.06; I² = 57%), 3.00–3.99 mg/m³ 1.44 (95% CI: 0.99, 2.11; I² = 58%), and ≥ 4.00 mg/m³ 1.64 (95% CI: 1.20, 2.24; I² = 88%). The heterogeneity across studies was mild to moderate.ConclusionsThe presence of a dose-response relationship favors the causal relationship between exposure to silica and developing lung cancer.     

Phase I trial of combined treatment with ch14.18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma

Purpose: We conducted a phase I trial of interleukin 2 (IL-2) in combination with chimeric 14.18 (ch14.18) and murine R24 antibodies to determine the maximal tolerated dose (MTD), immunological effects, and toxicity of this treatment combination. Experimental Design: Twenty-seven patients with either melanoma (23 patients) or sarcoma (4 patients) were enrolled to receive a combination therapy with ch14.18 and R24 antibodies together with continuous infusion of Roche IL-2 (1.5×10⁶ U/m²/day, 26 patients) or Chiron IL-2 (4.5×10⁶ U/m²/day, 1 patient) given 4 days/week for 3 weeks. The antibodies ch14.18 (2–7.5 mg/m²/day) and R24 (1–10 mg/m²/day) were scheduled to be administered for 5 days during the second week of IL-2 therapy. Results: When given in combination in this study, the MTD for ch14.18 was 5 mg/m²/day and the MTD for R24 was 5 mg/m²/day. Dose-limiting toxicities were severe allergic reactions to both ch14.18 and R24 as well as pain related to ch14.18. This ch14.18 MTD was lower than the 7.5 mg/m²/day MTD previously determined for ch14.18 given alone with the same dose and schedule of IL-2. Immunological effects included the induction of lymphokine-activated killer (LAK) activity and antibody-dependent cell-mediated cytoxicity (ADCC). Anti-idiotype response to ch14.18 was seen in six patients, including two melanoma patients who had a partial response to treatment. In addition to two partial responses, four patients had a stable disease and one patient remained without any evidence of disease. Conclusions: Immunotherapy with IL-2 in combination with ch14.18 and R24 antibodies augments LAK function and ADCC measured in vitro in all patients. While there exist theoretical advantages of combining these two antibodies, the MTD of ch14.18 and of R24 were lower than the MTD of each antibody in prior studies evaluating single antibody therapy with IL-2. As such, the combination of these two antibodies together with IL-2 therapy appeared to influence the MTD and toxicity of each of the administered antibodies. This work is supported by NIH grants M01-RR03186, R01-CA32685, and P30-CA14520