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Background: In England, 'fast-track' (also known as 'two-week wait') general practitioner referrals for suspected cancer in symptomatic patients are used to shorten diagnostic intervals and are supported by clinical guidelines. However, the use of the fast-track pathway may vary for different patient groups.Methods: We examined data from 669 220 patients with 35 cancers diagnosed in 2006-2010 following either fast-track or 'routine' primary-to-secondary care referrals using 'Routes to Diagnosis' data. We estimated the proportion of fast-track referrals by sociodemographic characteristic and cancer site and used logistic regression to estimate respective crude and adjusted odds ratios. We additionally explored whether sociodemographic associations varied by cancer.Results: There were large variations in the odds of fast-track referral by cancer (P<0.001). Patients with testicular and breast cancer were most likely to have been diagnosed after a fast-track referral (adjusted odds ratios 2.73 and 2.35, respectively, using rectal cancer as reference); whereas patients with brain cancer and leukaemias least likely (adjusted odds ratios 0.05 and 0.09, respectively, for brain cancer and acute myeloid leukaemia). There were sex, age and deprivation differences in the odds of fast-track referral (P<0.013) that varied in their size and direction for patients with different cancers (P<0.001). For example, fast-track referrals were least likely in younger women with endometrial cancer and in older men with testicular cancer.Conclusions: Fast-track referrals are less likely for cancers characterised by nonspecific presenting symptoms and patients belonging to low cancer incidence demographic groups. Interventions beyond clinical guidelines for 'alarm' symptoms are needed to improve diagnostic timeliness. [ABSTRACT FROM AUTHOR]

Background:Chinese women tend to have small and dense breasts and ultrasound is a common method for breast cancer screening in China. However, its efficacy and cost comparing with mammography has not been evaluated in randomised trials.Methods:At 14 breast centres across China during 2008-2010, 13 339 high-risk women aged 30-65 years were randomised to be screened by mammography alone, ultrasound alone, or by both methods at enrolment and 1-year follow-up.Results:A total of 12 519 and 8692 women underwent the initial and second screenings, respectively. Among the 30 cancers (of which 15 were stage 0/I) detected, 5 (0.72/1000) were in the mammography group, 11 (1.51/1000) in the ultrasound group, and 14 (2.02/1000) in the combined group (P=0.12). In the combined group, ultrasound detected all the 14 cancers, whereas mammography detected 8, making ultrasound more sensitive (100 vs 57.1%, P=0.04) with a better diagnostic accuracy (0.999 vs 0.766, P=0.01). There was no difference between mammography and ultrasound in specificity (100 vs 99.9%, P=0.51) and positive predictive value (72.7 vs 70.0%; P=0.87). To detect one cancer, the costs of ultrasound, mammography, and combined modality were $7876, $45 253, and $21 599, respectively.Conclusions:Ultrasound is superior to mammography for breast cancer screening in high-risk Chinese women. [ABSTRACT FROM AUTHOR]

Background: Chinese women tend to have small and dense breasts and ultrasound is a common method for breast cancer screening in China. However, its efficacy and cost comparing with mammography has not been evaluated in randomised trials.Methods: At 14 breast centres across China during 2008-2010, 13 339 high-risk women aged 30-65 years were randomised to be screened by mammography alone, ultrasound alone, or by both methods at enrollment and 1-year follow-up.Results: A total of 12 519 and 8692 women underwent the initial and second screenings, respectively. Among the 30 cancers (of which 15 were stage 0/I) detected, 5 (0.72/1000) were in the mammography group, 11 (1.51/1000) in the ultrasound group, and 14 (2.02/1000) in the combined group (P=0.12). In the combined group, ultrasound detected all the 14 cancers, whereas mammography detected 8, making ultrasound more sensitive (100 vs 57.1%, P=0.04) with a better diagnostic accuracy (0.999 vs 0.766, P=0.01). There was no difference between mammography and ultrasound in specificity (100 vs 99.9%, P=0.51) and positive predictive value (72.7 vs 70.0%; P=0.87). To detect one cancer, the costs of ultrasound, mammography, and combined modality were $7876, $45 253, and $21 599, respectively.Conclusions: Ultrasound is superior to mammography for breast cancer screening in high-risk Chinese women. [ABSTRACT FROM AUTHOR]

HPV16 E6 interacts with and degrades tumour suppressor protein TSC2 leading to the phosphorylation of p70 S6 kinase. We studied the association of S6 kinase phosphorylation and HPV16 infection in cervical cancer and esophageal cancer. Immunohistochemistry was used to assess phosphorylated S6 kinase (Thr 389) and phosphorylated S6 (Ser235/236) in 140 cervical cancer and 161 esophageal cancer specimens. Immunohistochemical staining for pS6 kinase and pS6 was significantly more frequent in the HPV16-infected cervical cancer specimens than the HPV16-negative specimens. In contrast, the expression of S6 kinase was similar in both HPV16-positive and -negative samples. The phosphorylation of Akt, the key regulator of S6 kinase, was also detected. Our analysis showed that Akt phosphorylation was unaffected by HPV16 infection. These results together with our previous study suggest that HPV16 modifies S6 kinase activation via mechanism, which activates S6 kinase downstream of Akt function.British Journal of Cancer (2007) 97, 218–222. doi:10.1038/sj.bjc.6603838 www.bjcancer.com Published online 10 July 2007 [ABSTRACT FROM AUTHOR]

To obtain functional evidence for DCC as a tumour suppressor associated with endometrial cancer, the human DCC cDNA encoding a complete open reading frame (ORF) was transfected into highly tumorigenic human endometrial carcinoma cells, HHUA and Ishikawa in which DCC expression was completely deleted. Reconstituted expression of DCC in HHUA had little effect on in vitro growth, but suppressed tumour formation in mice completely. The clones from Ishikawa had abundant DCC expression similar to that in normal endometrium. Their growth in vitro was suppressed and showed apoptotic phenotype. Lower levels of DCC expression in the prolonged passaged clones did not induce apoptosis, but still had the potential to suppress tumorigenicity. These observations imply a role of DCC in regulation of normal endometrial cell growth, and categorize DCC as the tumour suppressor gene for endometrial cancer. [ABSTRACT FROM AUTHOR]

Background:Axl plays multiple roles in tumourigenesis in several cancers. Here we evaluated the expression and biological function of Axl in renal cell carcinoma (RCC).Methods:Axl expression was analysed in a tissue microarray of 174 RCC samples by immunostaining and a panel of 11 normal tumour pairs of human RCC tissues by western blot, as well as in RCC cell lines by both western blot and quantitative PCR. The effects of Axl knockdown in RCC cells on cell growth and signalling were investigated. The efficacy of a humanised Axl targeting monoclonal antibody hMAb173 was tested in histoculture and tumour xenograft.Results:We have determined by immunohistochemistry (IHC) that Axl is expressed in 59% of RCC array samples with moderate to high in 20% but not expressed in normal kidney tissue. Western blot analysis of 11 pairs of tumour and adjacent normal tissue show high Axl expression in 73% of the tumours but not normal tissue. Axl is also expressed in RCC cell lines in which Axl knockdown reduces cell viability and PI3K/Akt signalling. The Axl antibody hMAb173 significantly induced RCC cell apoptosis in histoculture and inhibited the growth of RCC tumour in vivo by 78%. The hMAb173-treated tumours also had significantly reduced Axl protein levels, inhibited PI3K signalling, decreased proliferation, and induced apoptosis.Conclusions:Axl is highly expressed in RCC and critical for RCC cell survival. Targeting Axl is a potential approach for RCC treatment. [ABSTRACT FROM AUTHOR]

Background:Isolation of colorectal cancer (CRC) cell populations enriched for cancer stem cells (CSCs) may facilitate target identification. There is no consensus regarding the best methods for isolating CRC stem cells (CRC-SCs). We determined the suitability of various cellular models and various stem cell markers for the isolation of CRC-SCs.Methods:Established human CRC cell lines, established CRC cell lines passaged through mice, patient-derived xenograft (PDX)-derived cells, early passage/newly established cell lines, and cells directly from clinical specimens were studied. Cells were FAC-sorted for the CRC-SC markers CD44, CD133, and aldehyde dehydrogenase (ALDH). Sphere formation and in vivo tumorigenicity studies were used to validate CRC-SC enrichment.Results:None of the markers studied in established cell lines, grown either in vitro or in vivo, consistently enriched for CRC-SCs. In the three other cellular models, CD44 and CD133 did not reliably enrich for stemness. In contrast, freshly isolated PDX-derived cells or early passage/newly established CRC cell lines with high ALDH activity formed spheres in vitro and enhanced tumorigenicity in vivo, whereas cells with low ALDH activity did not.Conclusions:PDX-derived cells, early passages/newly established CRC cell lines and cells from clinical specimen with high ALDH activity can be used to identify CRC-SC-enriched populations. Established CRC cell lines should not be used to isolate CSCs. [ABSTRACT FROM AUTHOR]

Background: Resistance to chemotherapeutic agents is a major obstacle to cancer treatment. A group of ABC efflux pumps, the Multidrug Resistance Proteins, is a source of resistance. Herein, we investigated the role of ABCC10 in mammary tumours, given the important role we have defined for ABCC10 in transporting taxanes, and the recognition that some ABCC proteins have roles in tumour growth.Methods: ABCC10 expression was correlated to human breast cancer subtype using breast tissue microarrays. Real-time quantitative PCR and western blot analysis were used to examine ABCC10 expression in human breast cancer lines. Abcc10(-/-) mice were crossed to MMTV-PyVmT mice to produce Abcc10(-/-) vs Abcc10(+/+) mammary tumours and derivative cell lines. We used allograft and cellular assays to perform baseline and drug sensitization analysis of tumours and cell lines.Results: Clinical sample analyses indicated that ABCC10 was more highly expressed in Her2+ and ER+ than in Her2-, ER-, and triple-negative breast cancer. Unexpectedly, PyVmT; Abcc10(-/-) tumours grew more rapidly than PyVmT; Abcc10(+/+) tumours and were associated with significantly reduced apoptosis and metastasis. PyVmT; Abcc10(-/-) lines were less migratory than PyVmT; Abcc10(+/+) lines. Finally, we showed increased survival of docetaxel-treated MMTV-PyVmT; Abcc10(-/-) mice compared with wild-type mice.Conclusions: These data identify roles for Abcc10 in breast cancer pathogenesis and in vivo docetaxel resistance. [ABSTRACT FROM AUTHOR]

Background:Resistance to chemotherapeutic agents is a major obstacle to cancer treatment. A group of ABC efflux pumps, the Multidrug Resistance Proteins, is a source of resistance. Herein, we investigated the role of ABCC10 in mammary tumours, given the important role we have defined for ABCC10 in transporting taxanes, and the recognition that some ABCC proteins have roles in tumour growth.Methods:ABCC10 expression was correlated to human breast cancer subtype using breast tissue microarrays. Real-time quantitative PCR and western blot analysis were used to examine ABCC10 expression in human breast cancer lines. Abcc10−/− mice were crossed to MMTV-PyVmT mice to produce Abcc10−/− vs Abcc10+/+ mammary tumours and derivative cell lines. We used allograft and cellular assays to perform baseline and drug sensitization analysis of tumours and cell lines.Results:Clinical sample analyses indicated that ABCC10 was more highly expressed in Her2+ and ER+ than in Her2−, ER−, and triple-negative breast cancer. Unexpectedly, PyVmT; Abcc10−/− tumours grew more rapidly than PyVmT; Abcc10+/+ tumours and were associated with significantly reduced apoptosis and metastasis. PyVmT; Abcc10−/− lines were less migratory than PyVmT; Abcc10+/+ lines. Finally, we showed increased survival of docetaxel-treated MMTV-PyVmT; Abcc10−/− mice compared with wild-type mice.Conclusions:These data identify roles for Abcc10 in breast cancer pathogenesis and in vivo docetaxel resistance. [ABSTRACT FROM AUTHOR]

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies.Methods: Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied.Results: GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells. Mechanistically, GUT-70 showed binding affinity to heat-shock protein 90 (Hsp90) and ubiquitin-dependent proteasomal degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53. Depletion of constitutively overexpressed cyclin D1 by GUT-70 was accompanied by p27 accumulation and decreased Rb phosphorylation. GUT-70 induced mitochondrial apoptosis with Noxa upregulation and Mcl-1 downregulation in mt-p53 cells, but Mcl-1 accumulation in wt-p53 cells. Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK. Treatment with a combination of GUT-70 and bortezomib or doxorubicin had synergistic antiproliferative effects in MCL cells that were independent of p53 status.Conclusion: GUT-70 has pronounced antiproliferative effects in MCL with mt-p53, a known negative prognostic factor for MCL, through Hsp90 inhibition. These findings suggest that GUT-70 has potential utility for the treatment of MCL. [ABSTRACT FROM AUTHOR]

Granzyme B (GrB) is the prototypic member of a serine protease family primarily used by cytotoxic lymphocytes to kill target cells. We report here that, by immunohistochemical staining of paraffin-embedded tumour sections, GrB protein was unexpectedly detected in malignant cells of a subset of breast cancers and their adjacent reactive endothelial and mesenchymal cells in which endogenous retinoblastoma protein (pRB) is overexpressed. The identity of the endogenous GrB was further confirmed experimentally in RB-deficient breast carcinoma cell culture upon overexpression of ectopic pRB. Our finding extends the recent paradigm-shifting trend for a more diverse biological role of granzyme B, and might provide a rational basis for exploring its potential prognostic value in a variety of human cancers. [ABSTRACT FROM AUTHOR]