Exposure to household air pollution from biomass-burning cookstoves and HbA1c and diabetic status among Honduran women.

Household air pollution from biomass cookstoves is estimated to be responsible for more than two and a half million premature deaths annually, primarily in low and middle-income countries where cardiometabolic disorders, such as Type II Diabetes, are increasing. Growing evidence supports a link between ambient air pollution and diabetes, but evidence for household air pollution is limited. This cross-sectional study of 142 women (72 with traditional stoves and 70 with cleaner-burning Justa stoves) in rural Honduras evaluated the association of exposure to household air pollution (stove type, 24-hour average kitchen and personal fine particulate matter [PM2.5 ] mass and black carbon) with glycated hemoglobin (HbA1c) levels and diabetic status based on HbA1c levels. The prevalence ratio (PR) per interquartile range increase in pollution concentration indicated higher prevalence of prediabetes/diabetes (vs normal HbA1c) for all pollutant measures (eg, PR per 84 µg/m3 increase in personal PM2.5 , 1.49; 95% confidence interval [CI], 1.11-2.01). Results for HbA1c as a continuous variable were generally in the hypothesized direction. These results provide some evidence linking household air pollution with the prevalence of prediabetes/diabetes, and, if confirmed, suggest that the global public health impact of household air pollution may be broader than currently estimated.

Quantifying the Contribution to Uncertainty in Mortality Attributed to Household, Ambient, and Joint Exposure to PM2.5 From Residential Solid Fuel Use.

While there have been substantial efforts to quantify the health burden of exposure to PM2.5 from solid fuel use (SFU), the sensitivity of mortality estimates to uncertainties in input parameters has not been quantified. Moreover, previous studies separate mortality from household and ambient air pollution. In this study, we develop a new estimate of mortality attributable to SFU due to the joint exposure from household and ambient PM2.5 pollution and perform a variance-based sensitivity analysis on mortality attributable to SFU. In the joint exposure calculation, we estimate 2.81 (95% confidence interval: 2.48-3.28) million premature deaths in 2015 attributed to PM2.5 from SFU, which is 580,000 (18%) fewer deaths than would be calculated by summing separate household and ambient mortality calculations. Regarding the sources of uncertainties in these estimates, in China, India, and Latin America, we find that 53-56% of the uncertainty in mortality attributable to SFU is due to uncertainty in the percent of the population using solid fuels and 42-50% from the concentration-response function. In sub-Saharan Africa, baseline mortality rate (72%) and the concentration-response function (33%) dominate the uncertainty space. Conversely, the sum of the variance contributed by ambient and household PM2.5 exposure ranges between 15 and 38% across all regions (the percentages do not sum to 100% as some uncertainty is shared between parameters). Our findings suggest that future studies should focus on more precise quantification of solid fuel use and the concentration-response relationship to PM2.5, as well as mortality rates in Africa.

Vectorized gene therapy of liver tumors: proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine.

Background: TG4023 is a modified vaccinia virus Ankara (MVA) containing the yeast-originated transgene FCU1, expressing cytosine deaminase and uracil phosphoribosyltransferase enzymes that transform the prodrug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5'-monophosphate, respectively. This first-in-human study aimed to assess the maximum tolerated dose (MTD) of intratumoral (IT) TG4023 and the safety, feasibility, and proof-of-concept (PoC) of TG4023/5-FC combination to deliver high 5-FU concentrations in tumors. Patients and Methods: Cancer patients without further therapeutic option and with at least one injectable primary or metastatic liver tumor underwent on day 1 a percutaneous IT injection of TG4023 at doses of 107, 108, or 4.108 plaque forming units (p.f.u.) using ultrasound imaging guidance, after a dose-limiting toxicities (DLTs)-driven 3 + 3 dose-escalating design. On day 2, patients were given intravenous and/or oral 5-FC at a dose of 200 mg/kg/day for 14 days and were followed for safety through day 43. Tumor response was assessed at week 6, according to RECIST. Plasma and tumor 5-FU concentrations were measured to establish the PoC. Results: In total, 16 patients completed treatment with TG4023 and 5-FC. One DLT/7 patients (ALT/aspartate aminotransferase transient increase) was observed at 4 × 108 p.f.u.; MTD was therefore not reached. The most frequent adverse events were pyrexia, asthenia, vomiting, and decreased appetite. Eight of 16 patients had stable disease. Mean 5-FU concentrations in plasma were 1.9 ± 2.6 ng/ml and 56 ± 30 ng/g in tumors. Seroconversion for anti-FCU1 antibodies was found for one patient from each cohort (16%, overall). Conclusions: This phase I study demonstrated that IT injections of TG4023 were feasible and well tolerated; MTD was defined as 4 × 108 p.f.u. Therapeutic 5-FU concentrations in tumors established the virus-directed enzyme-prodrug therapy PoC. Clinicaltrials.gov Number: NCT00978107.

Methanol-based fixation is superior to buffered formalin for next-generation sequencing of DNA from clinical cancer samples.

BACKGROUND: Next-generation sequencing (NGS) of tumour samples is a critical component of personalised cancer treatment, but it requires high-quality DNA samples. Routine neutral-buffered formalin (NBF) fixation has detrimental effects on nucleic acids, causing low yields, as well as fragmentation and DNA base changes, leading to significant artefacts. PATIENTS AND METHODS: We have carried out a detailed comparison of DNA quality from matched samples isolated from high-grade serous ovarian cancers from 16 patients fixed in methanol and NBF. These experiments use tumour fragments and mock biopsies to simulate routine practice, ensuring that results are applicable to standard clinical biopsies. RESULTS: Using matched snap-frozen tissue as gold standard comparator, we show that methanol-based fixation has significant benefits over NBF, with greater DNA yield, longer fragment size and more accurate copy-number calling using shallow whole-genome sequencing (WGS). These data also provide a new approach to understand and quantify artefactual effects of fixation using non-negative matrix factorisation to analyse mutational spectra from targeted and WGS data. CONCLUSION: We strongly recommend the adoption of methanol fixation for sample collection strategies in new clinical trials. This approach is immediately available, is logistically simple and can offer cheaper and more reliable mutation calling than traditional NBF fixation.

Comparison of visual and automated assessment of tumour inflammatory infiltrates in patients with colorectal cancer.

BACKGROUND: Cancer-associated inflammation is increasingly recognised to be an important determinant of oncological outcome. In colorectal cancer, the presence of peri-tumoural inflammatory/lymphocytic infiltrates predicts improved survival. To date, these infiltrates, assessed visually on haematoxylin and eosin (H&E) stained sections, have failed to enter routine clinical practice, partly due to their subjective assessment and considerable inter-observer variation. The present study aims to develop an automated scoring method to enable consistent and reproducible assessment of tumour inflammatory infiltrates in colorectal cancer. METHODS: 154 colorectal cancer patients who underwent curative resection were included in the study. The local inflammatory infiltrate was assessed using the method described by Klintrup-Makinen. H&E tumour sections were uploaded to an image analysis programme (Slidepath, Leica Biosystems). An image analysis algorithm was developed to count the inflammatory cells at the invasive margin. The manual and automated assessments of the tumour inflammatory infiltrates were then compared. RESULTS: The automated inflammatory cell counts assessed using the freehand annotation method (p<0.001) and the rectangular box method (p<0.001) were significantly associated with both K-M score (p<0.001) and K-M grade (p<0.001). The inflammatory cell counts were divided using quartiles to group tumours with similar inflammatory cell densities. There was good agreement between the manual and automated scoring methods (intraclass correlation coefficient (ICC)=0.82). Similar to the visual K-M scoring system, the automated K-M classification of the inflammatory cell counts, using quartiles, was significantly associated with venous invasion (p<0.05) and modified Glasgow Prognostic Score (mGPS) (p⩽0.05). On univariate survival analysis, both automated K-M category (p<0.05) and automated K-M grade (p<0.005) were associated with cancer-specific survival. CONCLUSION: The results of the present study demonstrate that automated assessment effectively recapitulates the clinical value of visual assessment of the local inflammatory cell infiltrate at the invasive margin of colorectal tumours. In addition, it is possible to obtain an objective assessment of tumour inflammatory infiltrates using routinely stained H&E sections. An automated, computer-based scoring method is therefore a workable and cost-effective approach to clinical assessment of local immune cell infiltrates in colorectal cancer.

NFκB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression.

BACKGROUND: Cell line models suggest that activation of NFκB is associated with progression of prostate cancer. This pathway may be a therapeutic target if these observations translate to clinical specimens. METHODS: Immunohistochemistry measured NFκBp65 (p65), NFκBp65 nuclear localisation signal (NLS), NFκBp65 phosphorylated at ser 276 (p65(ser276)), NFκBp65 phosphorylated at ser 536 (p65(ser536)), IκBα phosphorylated at ser 32/36 (pIκBα(ser32/36)) and MMP-9 protein expression in 61 matched hormone naive prostate cancer (HNPC) and castrate-resistant prostate cancer (CRPC) tumours. Animal and cell models were used to investigate the role of NFκB inhibition in prostate carcinogenesis. RESULTS: In HNPC tumours, NLS expression significantly associated with a shorter time to disease recurrence and disease-specific death. In CRPC tumours p65, pIκBα(ser32/36) and MMP-9 expression significantly associated with shorter time to death from disease recurrence and shorter disease-specific death. MMP-9 and pIκBα(ser32/36) expression significantly associated with metastases at recurrence and were independent of Gleason sum and prostate-specific antigen at recurrence. Expression of phosphorylated Akt was associated with increased p65 activation in mouse models and inhibition of NFκB in LNCaP cells significantly reduced cellular proliferation and induced apoptosis. CONCLUSION: These results provide further evidence that the NFκB pathway could be exploited as a target for CRPC.

Expression and prognostic significance of Src family members in renal clear cell carcinoma.

BACKGROUND: The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance. METHODS: mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y(530) (SrcY(530)), phosphorylated Src at Y(419) (SrcY(419)) and the downstream focal adhesion kinase (FAK) marker at the Y(861) site (FAK Y(861)) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method. RESULTS: Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY(530) and SrcY(419) were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y(861) was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y(861) was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40-7.98, P=0.006). CONCLUSION: We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y(861), a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.

Prospective study of the role of inflammation in renal cancer.

BACKGROUND: The local and systemic inflammatory responses provide prognostic information in cancer. The modified Glasgow Prognostic Score (mGPS) provides additional prognostic information than C-reactive protein (CRP) alone when assessing the systemic inflammation in cancer. The aim of this study was to determine the role of local and systemic inflammation in renal cancer. METHODS: The cohort consisted of 79 patients who had undergone potential curative resection. Systemic inflammation, mGPS, was constructed by measuring preoperative CRP and albumin concentrations and the Klintrup-Makinen score was evaluated histologically for the local inflammatory response. Pathological parameters such as T stage, grade and tumour necrosis were also assessed. The local inflammatory response was assessed by examining all inflammatory cells at the tumour edge on diagnostic haematoxylin and eosin slides. RESULTS: On univariate analysis, T stage (p < 0.001), grade (p = 0.044) and mGPS (p < 0.001) were significant predictors of cancer-specific survival. On multivariate analysis, mGPS (hazard ratio 8.64, 95% confidence interval 3.5-21.29, p < 0.001) was the only significant independent predictor of cancer-specific survival. CONCLUSION: A preoperative systemic inflammatory response as measured by the mGPS is an independent predictor of poor cancer-specific survival in renal cancer in patients undergoing potential curative resection.

Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer.

BACKGROUND: We previously reported that sphingosine 1-phosphate receptor 4 (S1P(4)) is expressed and stimulates the ERK-1/2 pathway via a human epidermal growth factor receptor 2 (HER2)-dependent mechanism in oestrogen receptor-negative (ER(-)) MDA-MB-453 breast cancer cells. METHODS: Clinical relevance of S1P(4) and sphingosine kinase 1 (SK1, which catalyses the formation of S1P) was assessed in a cohort of 140 ER(-) breast tumours by immunohistochemistry (IHC) and the weighted histoscore method. Additional evidence for a functional interaction between S1P(4) and SK1 and between HER2 and SK1 was obtained using MDA-MB-453 cells. RESULTS: High S1P(4) expression is associated with shorter disease-free (P=0.014) and disease-specific survival (P=0.004), and was independent on multivariate analysis. In addition, patients with tumours that contain high and low levels of SK1 and S1P(4), respectively, have a significantly shorter disease-free survival (P=0.043) and disease-specific survival (P=0.033) compared with patients whose tumours contain both low S1P(4) and SK1 levels. In addition, high tumour expression of SK1 was significantly associated with shorter disease-specific survival (P=0.0001) in patients with HER2-positive tumours. Treatment of MDA-MB-453 cells with the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) reduced the basal and S1P/S1P(4)-induced activation of ERK-1/2 and altered HER2 trafficking in these cells. CONCLUSION: These findings highlight an important role for S1P(4) and SK1 in ER(-) breast cancer progression.

The interrelationships between Src, Cav-1 and RhoGD12 in transitional cell carcinoma of the bladder.

BACKGROUND: The aim of this current study was to assess the expression and activity of Src family kinases, focal adhesion kinase (FAK), caveolin (Cav-1) and RhoGD12 in bladder cancer. METHODS: Fifty-eight patients with a new diagnosis of bladder cancer undergoing transurethral resection were included. Immunohistochemical staining was utilised to assess expression of c-Src, dephosphorylated (SrcY(530)), phosphorylated Src (Y(419)), phosphorylated FAK (FAK Y(861)), Cav-1 and RhoGD12. Expression was assessed using the weighted histoscore method. RESULTS: High expression of dephosphorylated Y(527), phosphorylated Y(416) and phosphorylated FAK Y(861) in the membrane were associated with increased cancer-specific survival (P=0. 01, P=0.001, P=0.008, respectively) and expression of Y(416) in the membrane was an independent factor on multivariate analysis when combined with known clinical parameters (P=0.008, HR 0.288, 95% CI 0.11-0.72). CONCLUSION: These results demonstrate that in contrast to other solid tumours, activation of the Src family members and downstream signalling proteins are associated with a good prognosis in transitional cell carcinoma of the bladder, and activated Src has a positive relationship with RhoGD12.

The relationship between tumour necrosis, tumour proliferation, local and systemic inflammation, microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma.

BACKGROUND: There is increasing evidence that the local and systemic inflammatory responses are associated with survival in oesophageal cancer. The aim of this study was to examine the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation and microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma. METHODS: The interrelationship between tumour necrosis, tumour proliferation, local inflammatory response (Klintrup-Makinen criteria, intra-tumoural CD8+ lymphocyte and macrophage infiltration), systemic inflammatory response (modified Glasgow Prognostic score (mGPS)), and microvessel density was examined in 121 patients undergoing potentially curative resection for oesophageal adenocarcinoma (including type I and II tumours of the gastro-oesophageal junction). RESULTS: Tumour necrosis was not significantly associated with any tumour measure other than the degree of differentiation. On multivariate analysis, only age (HR 1.93, 95% CI 1.23-3.04, P=0.004), mGPS (HR 2.91, 95% CI 1.51-5.62, P=0.001), positive to total lymph node ratio (HR 2.38, 95% CI 1.60-3.52, P<0.001) and macrophage infiltration (HR 1.49, 95% CI 1.02-2.18, P=0.041) were independently associated with cancer-specific survival in oesophageal adenocarcinoma. Intra-tumoural macrophages were associated with tumour proliferation (P<0.001) and CD8+ lymphocytes infiltration (P<0.01). CONCLUSION: The results of this study suggest that tumour necrosis does not link local and systemic inflammatory responses and is not significantly associated with survival. In contrast, tumour macrophage infiltration appears to have a central role in the proliferative activity and the coordination of the inflammatory cell infiltrate and is independently associated with poorer survival in patients with oesophageal adenocarcinoma.

Comparison of visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer.

BACKGROUND: Immunohistochemistry of Ki-67 protein is widely used to assess tumour proliferation, and is an established prognostic factor in breast cancer. There is interest in automating the assessment of Ki-67 labelling index (LI) with possible benefits in handling increased workload, with improved accuracy and precision. PATIENTS AND METHODS: Visual and automated assessment of Ki-67 LI and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microarrays (n=379 patients) immunostained for Ki-67 were scored visually and automatically with the Slidepath Tissue IA system. RESULTS: Visual and automated Ki-67 LI were in excellent agreement (ICCC=0.96, P<0.001). On univariate analysis, visual (P<0.001) and automated Ki67 LI (P<0.05) were associated with cancer-specific survival in patients with invasive ductal breast cancer overall and in patients who received endocrine therapy (Tamoxifen) (P<0.01 for visual and P<0.05 for automated scoring). CONCLUSION: Automated assessment of Ki-67 LI would appear to be comparable to visual Ki-67 LI. However, automated Ki-67 LI assessment was inferior in predicting cancer survival in patients with breast cancer, including patients who received Tamoxifen.

Is the presence or absence of tumour necrosis a significant predictor of survival in renal cell cancer?

OBJECTIVE: Currently when renal cancer pathology is assessed the presence or absence of necrosis is simply reported. It has been suggested that a presence or absence response ignores heterogeneity and a classification based on the extent of necrosis involvement would aid prognostic value in cancer-specific survival. The aim of this study was to determine whether a quantitative assessment of tumour necrosis would provide additional prognostic information. METHODS: We studied the pathological features and cancer-specific survival of 47 patients with renal cancer undergoing surgery with curative intent. A quantitative assessment of tumour necrosis was compared to the presence or absence of necrosis. RESULTS: Tumour necrosis was present in 27 of 47 cases. A simple assessment of the presence or absence was not associated with cancer-specific survival (p = 0.052). When assessed quantitatively, tumour necrosis was associated with decreased cancer-specific survival (p < 0.001). A 2-tiered assessment, <25% and >25% involvement of necrosis, was further utilised and shown to predict cancer-specific survival (p < 0.001). On multivariate analysis, using this 2-tiered assessment of <25% and >25% involvement of necrosis was retained as a significant independent factor for cancer-specific survival (HR 11.84, 95% CI 3.81-36.75, p < 0.001). CONCLUSION: A simple assessment of the presence/absence of tumour necrosis is reported to be a prognostic factor in renal cell cancer. In this study, the presence/absence was not shown to be a significant prognostic marker of cancer-specific survival. However, a more accurate quantitative assessment of tumour necrosis, whereby a 2-tiered response is still utilised, but basing this on <25% and >25% involvement of necrosis was statistically significant and independent in predicting cancer-specific survival.

Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer.

BACKGROUND: Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC. METHODS: Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway. RESULTS: Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours. CONCLUSION: We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer.

The WASP/Las17p-interacting protein Bzz1p functions with Myo5p in an early stage of endocytosis.

The formation of actin filaments is crucial for endocytosis and other interrelated cellular phenomena such as motility, polarized morphogenesis, and cytokinesis. In this paper we have investigated the role of the WASP/Las17-interacting protein Bzz1p in endocytosis and trafficking to the vacuole. We and others have recently shown that Bzz1p is an actin patch protein that interacts directly with Las17p via a SH3-polyproline interaction. Bzz1p functions with type I myosins to restore polarity of the actin cytoskeleton after NaCl stress. In an in vitro bead assay, GST-Bzz1p fusion protein triggers a functional actin polymerization machinery through its two C-terminal SH3 domains. In this paper we implicate Bzz1p with the type I myosins both in fluid-phase and in the internalization step of receptor-mediated endocytosis. As deduced from their localization as GFP fusions, the vacuolar delivery of endocytic and biosynthetic cargoes as well as the multivesicular body pathway appear unaffected. We further elucidate Bzz1p direct participation in actin polymerization by demonstrating that each of the SH3 domains of Bzz1p individually is able to trigger actin polymerization in a cell-free system dependent on Arp2/3, Las17p, Vrp1p, and the type I myosins. Taken together, our results show that Bzz1p participates, essentially via its SH3 domains, in early steps of endocytosis together with known actin nucleation activators.

SH3 domain-containing proteins and the actin cytoskeleton in yeast.

SH3 (Src homology-3) domains are involved in protein-protein interactions through proline-rich domains. Many SH3-containing proteins are implicated in actin cytoskeleton organization. The aim of our ongoing work is to study the functions of the SH3-containing proteins in actin cytoskeleton regulation. The yeast Saccharomyces cerevisiae proteome includes 29 SH3 domains distributed in 25 proteins. We have examined the direct involvement of these SH3 domains in actin polymerization using an in vitro polymerization assay on GST (glutathione S-transferase)-SH3-coated beads. As expected, not all SH3 domains show polymerization activity, and many recruit distinct partners as assessed by microscopy and pull-down experiments. One such partner, Las17p, the yeast homologue of WASP (Wiskott-Aldrich syndrome protein), was assayed because it stimulates actin nucleation via the Arp2/3 (actin-related protein 2/3) complex. Ultimately, proteins involved in specific biological processes, such as membrane trafficking, may also be recruited by some of these SH3 domains, shedding light on the SH3-containing proteins and actin cytoskeleton functions in these processes.

TEL-AML1 fusion RNA as a new target to detect minimal residual disease in pediatric B-cell precursor acute lymphoblastic leukemia.

It has recently been shown that the t(12;21)(p13;q22) translocation fuses two genes, TEL on chromosome 12 and AML1 on chromosome 21. We have evaluated the frequency of this newly described translocation in acute lymphoblastic leukemia (ALL), and the feasibility of minimal residual disease (MRD) monitoring by polymerase chain reaction (PCR) amplification of TEL-AML1 transcripts. Thirty-nine adult- and 45 childhood-ALLs consecutively diagnosed in a single center were included in this study. TEL-AML1 fusion transcripts were searched for in the 39 adult- and 45 childhood-ALLs for which material was available. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were also studied by PCR in these cases. TEL-AML1 transcripts were found in 8 out of 35 (23%) childhood B-cell precursor ALLs (BCP-ALLs). TEL-AML1 transcripts were detected in only 1 of 31 adult BCP-ALLs (P = .04, Fisher's exact test). Nevertheless, in this adult case, TEL-AML1 transcripts were found at a low level in 2 of 3 different samples. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were found in 12, 3, and 1 cases of 31 adult BCP-ALLs, and in 1, 2, and 1 cases of 35 childhood BCP-ALLs, respectively. TEL-AML1 transcripts were never found associated with any other fusion transcripts. Taken together, the four types of chimeric transcripts were detected in 12 of 35 (34%) childhood BCP-ALL cases. No TEL-AML1 transcripts were detected in 11 T-cell ALLs (4 adults and 5 children), nor in 2 B-cell (slg+) ALLs. MRD was evaluated in 21 samples collected in 9 TEL-AML1+ childhood BCP-ALL cases during therapy (median follow-up = 200 days). Of 8 patients evaluated after induction therapy, 4 showed detectable but low levels of MRD. Of 7 patients serially evaluated, only one showed persistence of detectable MRD. This study shows that TEL-AML1 transcripts are frequently detected in pediatric BCP-ALLs and that these transcripts are molecular targets that will simplify the strategy of MRD monitoring in childhood BCP-ALL.