BMC Cancer (BMC CANCER)

Publications in this journal

• Article: The modified Glasgow prognostic score in prostate cancer: results from a retrospective clinical series of 744 patients.

  Kashif Shafique, Michael J Proctor, Donald C McMillan, Hing Leung, Karen Smith, Billy Sloan, David S Morrison
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  ABSTRACT: BACKGROUND: As the incidence of prostate cancer continues to rise steeply, there is an increasing need to identify more accurate prognostic markers for the disease. There is some evidence that a higher modified Glasgow Prognostic Score (mGPS) may be associated with poorer survival in patients with prostate cancer but it is not known whether this is independent of other established prognostic factors. Therefore the aim of this study was to describe the relationship between mGPS and survival in patients with prostate cancer after adjustment for other prognostic factors. METHODS: Retrospective clinical series on patients in Glasgow, Scotland, for whom data from the Scottish Cancer Registry, including Gleason score, Prostate Specific Antigen (PSA), C-reactive protein (CRP) and albumin, six months prior to or following the diagnosis, were included in this study.The mGPS was constructed by combining CRP and albumin. Five-year and ten-year relative survival and relative excess risk of death were estimated by mGPS categories after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days. RESULTS: Seven hundred and forty four prostate cancer patients were identified; of these, 497 (66.8%) died during a maximum follow up of 11.9 years. Patients with mGPS of 2 had poorest 5-year and 10-year relative survival, of 32.6% and 18.8%, respectively. Raised mGPS also had a significant association with excess risk of death at five years (mGPS 2: Relative Excess Risk = 3.57, 95% CI 2.31-5.52) and ten years (mGPS 2: Relative Excess Risk = 3.42, 95% CI 2.25-5.21) after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days. CONCLUSIONS: The mGPS is an independent and objective prognostic indicator for survival of patients with prostate cancer. It may be useful in determining the clinical management of patients with prostate cancer in addition to established prognostic markers.
  BMC Cancer 06/2013; 13(1):292.
• Article: ID3 contributes to cerebrospinal fluid seeding and poor prognosis in medulloblastoma.

  Ji Hoon Phi, Seung Ah Choi, Sang-Hee Lim, Joongyub Lee, Kyu-Chang Wang, Sung-Hye Park, Seung-Ki Kim
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  ABSTRACT: BACKGROUND: The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma. METHODS: ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels. RESULTS: Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas. CONCLUSIONS: High ID3 expression is associated with medullolbastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma.
  BMC Cancer 06/2013; 13(1):291.
• Article: Cancer survivors in Switzerland: a rapidly growing population to care for.

  Christian Herrmann, Thomas Cerny, Anita Savidan, Penelope Vounatsou, Isabelle Konzelmann, Christine Bouchardy, Harald Frick, Silvia Ess
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  ABSTRACT: BACKGROUND: Cancer survivors are a heterogeneous group with complex health problems. Data concerning its total number and growing dynamics for Switzerland are scarce and outdated. METHODS: Population and mortality data were retrieved from the Swiss Federal Statistical Office (FSO). Incidence and relative survival for invasive cancers were computed using data from the cancer registries Geneva (1970--2009), St. Gallen - Appenzell (1980--2010), Grisons & Glarus (1989--2010), and Valais (1989--2010). We estimated prevalence for 1990--2010 using the Prevalence, Incidence Approach MODel (PIAMOD) method. We calculated trends in prevalence estimates by Joinpoint analysis. Projections were extrapolated using the above models and based on time trends of the period 2007--2010. RESULTS: The estimated number of cancer survivors increased from 139[prime]717 in 1990 (2.08% of the population) to 289[prime]797 persons in 2010 (3.70%). The growth rate shows an exponential shape and was 3.3% per year in the period 2008 to 2010. Almost half of the survivors have a history of breast, prostate or colorectal cancer. Among cancer survivors, 55% are women but the increases have been more marked in men (p < 0.01, 3.9% annual increase in men vs. 2.7% in women since 2008). By the end of 2020 372[prime]000 cancer survivors are expected to live in Switzerland. CONCLUSIONS: There is a rapidly growing population of cancer survivors in Switzerland whose needs and concerns are largely unknown.
  BMC Cancer 06/2013; 13(1):287.
• Article: The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells

  Kornelius Kerl, David Ries, Rebecca Unland, Christiane Borchert, Natalia Moreno, Martin Hasselblatt, Heribert Jürgens, Marcel Kool, Dennis Görlich, Maria Eveslage, Manfred Jung, Michael Meisterernst, Michael Frühwald
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  ABSTRACT: Background Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.
  BMC Cancer 06/2013;
• Article: Profiling of normal and malignant breast tissue show CD44high/CD24low phenotype as a predominant stem/progenitor marker when used in combination with Ep-CAM/CD49f markers.

  Hazem Ghebeh, Ghida Majed Sleiman, Pulicat S Manogaran, Amer Al-Mazrou, Eman Barhoush, Falah H Al-Mohanna, Asma Tulbah, Khalid Al-Faqeeh, Chaker N Adra
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  ABSTRACT: BACKGROUND: Accumulating evidence supports cancer to initiate and develop from a small population of stem-like cells termed as cancer stem cells (CSC). The exact phenotype of CSC and their counterparts in normal mammary gland is not well characterized. In this study our aim was to evaluate the phenotype and function of stem/progenitor cells in normal mammary epithelial cell populations and their malignant counterparts. METHODS: Freshly isolated cells from both normal and malignant human breasts were sorted using 13 widely used stem/progenitor cell markers individually or in combination by multi-parametric (up to 9 colors) cell sorting. The sorted populations were functionally evaluated by their ability to form colonies and mammospheres, in vitro. RESULTS: We have compared, for the first time, the stem/progenitor markers of normal and malignant breasts side-by-side. Amongst all markers tested, we found CD44high/CD24low cell surface marker combination to be the most efficient at selecting normal epithelial progenitors. Further fractionation of CD44high/CD24low positive cells showed that this phenotype selects for luminal progenitors within Ep-CAMhigh/CD49f + cells, and enriches for basal progenitors within Ep-CAM-/low/CD49f + cells. On the other hand, primary breast cancer samples, which were mainly luminal Ep-CAMhigh, had CD44high/CD24low cells among both CD49fneg and CD49f + cancer cell fractions. However, functionally, CSC were predominantly CD49f + proposing the use of CD44high/CD24low in combination with Ep-CAM/CD49f cell surface markers to further enrich for CSC. CONCLUSION: Our study clearly demonstrates that both normal and malignant breast cells with the CD44high/CD24low phenotype have the highest stem/progenitor cell ability when used in combination with Ep-CAM/CD49f reference markers. We believe that this extensive characterization study will help in understanding breast cancer carcinogenesis, heterogeneity and drug resistance.
  BMC Cancer 06/2013; 13(1):289.
• Article: The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells.

  Kornelius Kerl, David Ries, Rebecca Unland, Christiane Borchert, Natalia Moreno, Martin Hasselblatt, Heribert Jürgens, Marcel Kool, Dennis Görlich, Maria Eveslage, Manfred Jung, Michael Meisterernst, Michael Frühwald
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND: Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. METHODS: Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. RESULTS: HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. CONCLUSION: Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.
  BMC Cancer 06/2013; 13(1):286.
• Article: Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promotes cell death.

  Gang Cheng, Jacek Zielonka, Donna M McAllister, A Craig Mackinnon, Joy Joseph, Michael B Dwinell, Balaraman Kalyanaraman
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  ABSTRACT: BACKGROUND: Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells. METHODS: In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed. RESULTS: Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer. CONCLUSIONS: We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.
  BMC Cancer 06/2013; 13(1):285.
• Article: CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients.

  Agnes Yy Lee, Rupert Bauersachs, Mette S Janas, Mikala F Jarner, Pieter W Kamphuisen, Guy Meyer, Alok A Khorana
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  ABSTRACT: BACKGROUND: Low-molecular-weight heparin (LMWH) is recommended and commonly used for extended treatment of cancer-associated thrombosis (CAT), but its superiority over warfarin has been demonstrated in only one randomised study. We report here the rationale, design and a priori analysis plans of Comparison of Acute Treatments in Cancer Haemostasis (CATCH; NCT01130025), a multinational, Phase III, open-label, randomised controlled trial comparing tinzaparin with warfarin for extended treatment of CAT. METHODS: The primary objective is to assess the efficacy of tinzaparin in preventing recurrent venous thromboembolism (VTE) in patients with active cancer and acute, symptomatic proximal deep vein thrombosis and/or pulmonary embolism. The secondary objectives are to determine: safety of tinzaparin given over 6 months; clinical and laboratory markers for recurrent VTE and/or major bleeding; 6-month overall mortality; incidence and severity of post-thrombotic syndrome; patient-reported quality of life; and healthcare resource utilisation. Nine hundred patients are randomised to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5--10 days and dose-adjusted warfarin (target INR 2.0--3.0) for 6 months. The primary composite outcome is time to recurrent VTE, including incidental VTE and fatal pulmonary embolism. All patients are followed up to 6 months or death, whichever comes sooner. Blinded adjudication will be performed for all reported VTE, bleeding events and causes of death. Efficacy will be analysed using centrally adjudicated results of all patients according to intention-to-treat analysis. An independent Data Safety Monitoring Board is reviewing data at regular intervals and an interim analysis is planned after 450 patients have completed the study. DISCUSSION: The results will add significantly to the knowledge of the efficacy, safety and cost effectiveness of tinzaparin in the prevention of recurrent VTE in patients with cancer and thrombosis. Prospective data will emerge on the clinical significance of incidental VTE and risk stratification in patients with CAT. Results on post-thrombotic syndrome, quality of life and healthcare resource utilisation will inform decision makers on how to secure better patient care. If tinzaparin is shown to be more effective than warfarin, CATCH will provide valuable confirmatory data to support the use of the LMWH tinzaparin for extended treatment of CAT.
  BMC Cancer 06/2013; 13(1):284.
• Article: Detection of cancer before distant metastasis.

  Frank Aw Coumans, Sabine Siesling, Leon Wmm Terstappen
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  ABSTRACT: BACKGROUND: To establish a distant metastasis (DM) cells must disseminate from the primary tumor and overcome a series of obstacles, the metastatic cascade. In this study we develop a mathematical model for this cascade to estimate the tumor size and the circulating tumor cell (CTC) load before the first metastasis has formed from a primary breast cancer tumor. METHODS: The metastatic cascade is described in discrete steps: 1. local tumor growth; 2. dissemination into circulation; 3. survival in circulation; 4. extravasation into tissue; and 5. growth into a metastasis. The model was built using data and relationships described in the literature to predict the relationship between tumor size and probability of distant metastasis for 38715 patients with surgically removed TXNXM0 primary breast cancer from the Netherlands Cancer Registry. The model was calibrated using primary tumor size, probability of distant metastasis and time to distant metastasis for 1489 patients with stage T1BNXM0 (25% of total patients with T1BNXM0). Validation of the model was done with data for all patients. RESULTS: From the time to distant metastasis of these 38715 breast cancer patients, we determined a tumor doubling time of 1.7 +/- 0.9 months. Fitting the data for 25% of T1B patients estimates a metastatic efficiency of 1 metastasis formed per 60 million disseminated tumor cells. Validation of the model to data of patients in all T-stages shows good agreement between model and epidemiological data. To reduce the 5-year risk of distant metastasis for TXNXM0 from 9.2% to 1.0%, the primary tumor needs to be detected and removed before it reaches a diameter of 2.7 +/- 1.6 mm. At this size, the model predicts that there will be 9 +/- 6 CTC/L blood. CONCLUSIONS: To reduce the rate of distant metastasis in surgically treated TXNXM0 breast cancer to 1%, imaging technology will need to be able to detect lesions of 2.7 mm in diameter or smaller. Before CTC detection can be applied in the early disease setting, sensitivity will need to be improved by at least 15-fold and combined with technology that minimizes false positives.
  BMC Cancer 06/2013; 13(1):283.
• Article: Polycyclic aromatic hydrocarbons: Determinants of urinary 1-hydroxypyrene glucuronide concentration and risk of colorectal cancer in the Shanghai Women's Health Study.

  Jonathan N Hofmann, Linda M Liao, Paul T Strickland, Xiao-Ou Shu, Gong Yang, Bu-Tian Ji, Hong-Lan Li, Nathaniel Rothman, Farin Kamangar, Yu-Tang Gao, Wei Zheng, Wong-Ho Chow
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  ABSTRACT: BACKGROUND: Associations between polycyclic aromatic hydrocarbons (PAHs) and colorectal cancer have been reported previously but few studies have characterized PAH exposure using biological measurements. We evaluated colorectal cancer risk in relation to urinary concentration of 1-hydroxypyrene glucuronide (1-OHPG), a polycyclic aromatic hydrocarbon (PAH) metabolite, and assessed determinants of PAH exposure among controls in the Shanghai Women's Health Study (SWHS). METHODS: Concentrations of 1-OHPG were measured in spot urine samples collected from 343 colorectal cancer cases and 343 individually matched controls. Questionnaires were administered to collect information on demographic characteristics and reported exposures. Odds ratios were calculated for risk of colorectal cancer in relation to quartiles of urinary 1-OHPG concentration. Potential determinants of natural log-transformed urinary 1-OHPG concentration were evaluated among a combined sample of controls from this study and another nested case--control study in the SWHS (Ntotal=652). RESULTS: No statistically significant differences in risk of colorectal cancer by urinary 1-OHPG levels were observed. Among controls, the median (interquartile range) urinary 1-OHPG concentration was 2.01 pmol/mL (0.95-4.09). Active and passive smoking, using coal as a cooking fuel, eating foods that were cooked well done, and recent consumption of fried dough (e.g., youtiao) were associated with elevated levels of 1-OHPG, though only active smoking and fried dough consumption achieved statistical significance in multivariate analyses. CONCLUSIONS: This study does not provide evidence of an association between urinary levels of 1-OHPG and risk of colorectal cancer among women. Several environmental and dietary sources of PAH exposure were identified. Overall, the levels of 1-OHPG in this population of predominantly non-smoking women were considerably higher than levels typically observed among non-smokers in Europe, North America, and other developed regions.
  BMC Cancer 06/2013; 13(1):282.
• Article: Phase II/III multicentre randomised controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus peri-operative chemotherapy for resectable gastric signet ring cell adenocarcinomas -- PRODIGE 19 -- FFCD1103 -- ADCI002.

  Guillaume Piessen, Mathieu Messager, Karine Le Malicot, William B Robb, Frédéric Di Fiore, Marie Guilbert, Marie Moreau, Véronique Christophe, Antoine Adenis, Christophe Mariette
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  ABSTRACT: BACKGROUND: A dramatic increase in the incidence of the diffuse form of gastric adenocarcinomas and particularly signet ring cell carcinomas has been observed in Western countries. Evidence is accruing that signet ring cell carcinomas may have inherent chemo resistance leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach.Methods/design: PRODIGE-19-FFCD1103-ADCI002 is a prospective multicentre controlled randomised phase II/III trial comparing current standard of care of perioperative chemotherapy (2x3 cycles of Epirubicin, cisplatin, 5-fluorouracil) with a strategy of primary surgery followed by adjuvant chemotherapy (6 cycles of Epirubicin, cisplatin, 5-fluorouracil) in patients with a stage IB-III gastric signet ring cell tumour. The principal objective of the phase II study (84 patients) is to determine if the experimental arm (primary surgery followed by adjuvant chemotherapy) has sufficient interest in terms of percentage of living patients at 24 months to be evaluated in a phase III trial. If 7 or less patients in the experimental arm are alive at 24 months, phase III will not be initiated. The primary objective of phase III (230 additional patients) is to demonstrate superiority of the experimental arm in terms of overall survival. Secondary endpoints include overall survival at 36 months, disease free survival at 24 and 36 months, R0 resection rates, treatment tolerance, postoperative mortality and morbidity evaluated by Clavien-Dindo severity index, the prognostic impact of positive peritoneal cytology and the assessment of quality of life. An ancillary study will assess the emotional and cognitive impact of surgery and perioperative chemotherapy for both the patient and their partner. DISCUSSION: As inherent chemo resistance of signet ring cell tumours and delay in definitive surgery may favour tumour progression we hypothesise that a policy of primary surgery followed by adjuvant chemotherapy will improve overall survival compared to a standard perioperative chemotherapeutic strategy. This randomised phase II/III trial is the first dedicated to this histological subtype. Whilst the development of new biomarkers and targeted therapies are awaited, the results of this trial should further help in devising individualised protocols of patient care in a tumour group whose diversity increasingly demands assessment of alternative strategies.Trial registration: NCT01717924 (ClinicalTrials.gov).
  BMC Cancer 06/2013; 13(1):281.
• Article: Potentiality of a triple microRNA classifier: miR-193a-3p, miR-23a and miR-338-5p for early detection of colorectal cancer.

  Fung Lin Yong, Chee Wei Law, Chee Woon Wang
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  ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are short, non-coding RNA molecules that act as regulators of gene expression. Circulating blood miRNAs offer great potential as cancer biomarkers. The objective of this study was to correlate the differential expression of miRNAs in tissue and blood in the identification of biomarkers for early detection of colorectal cancer (CRC). METHODS: The study was divided into two phases: (I) Marker discovery by miRNA microarray using paired cancer tissues (n = 30) and blood samples (CRC, n = 42; control, n = 18). (II) Marker validation by stem-loop reverse transcription real time PCR using an independent set of paired cancer tissues (n = 30) and blood samples (CRC, n = 70; control, n = 32). Correlation analysis was determined by Pearson's test. Logistic regression and receiver operating characteristics curve analyses were applied to obtain diagnostic utility of the miRNAs. RESULTS: Seven miRNAs (miR-150, miR-193a-3p, miR-23a, miR-23b, miR-338-5p, miR-342-3p and miR-483-3p) have been found to be differentially expressed in both tissue and blood samples. Significant positive correlations were observed in the tissue and blood levels of miR-193a-3p, miR-23a and miR-338-5p. Moreover, increased expressions of these miRNAs were detected in the more advanced stages. MiR-193a-3p, miR-23a and miR-338-5p were demonstrated as a classifier for CRC detection, yielding a receiver operating characteristic curve area of 0.887 (80.0% sensitivity, 84.4% specificity and 83.3% accuracy). CONCLUSION: Dysregulations in circulating blood miRNAs are reflective of those in colorectal tissues. The triple miRNA classifier of miR-193a-3p, miR-23a and miR-338-5p appears to be a potential blood biomarker for early detection of CRC.
  BMC Cancer 06/2013; 13(1):280.
• Article: Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer -- the RAPIDO trial.

  Per J Nilsson, Boudewijin van Etten, Geke Ap Hospers, Lars Påhlman, Cornelis Jh van de Velde, Regina Gh Beets-Tan, Lennart Blomqvist, Jannet C Beukema, Ellen Kapiteijn, Corrie Am Marijnen, Iris D Nagtegaal, Theo Wiggers, Bengt Glimelius
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  ABSTRACT: BACKGROUND: Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.Methods and design: Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life. DISCUSSION: Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer.Trial registration: ClinicalTrials.gov NCT01558921.
  BMC Cancer 06/2013; 13(1):279.
• Article: Integral analysis of p53 and its value as prognostic factor in sporadic colon cancer.

  Arantza Fariña Sarasqueta, Giusi Forte, Wim E Corver, Noel F de Miranda, Dina Ruano, Ronald van Eijk, Jan Oosting, Rob Aem Tollenaar, Tom van Wezel, Hans Morreau
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  ABSTRACT: BACKGROUND: p53 (encoded by TP53) is involved in DNA damage repair, cell cycle regulation, apoptosis, aging and cellular senescence. TP53 is mutated in around 50% of human cancers. Nevertheless, the consequences of p53 inactivation in colon cancer outcome remain unclear. Recently, a new role of p53 together with CSNK1A1 in colon cancer invasiveness has been described in mice. METHODS: By combining data on different levels of p53 inactivation, we aimed to predict p53 functionality and to determine its effects on colon cancer outcome. Moreover, survival effects of CSNK1A1 together with p53 were also studied.Eighty-three formalin fixed paraffin embedded colon tumors were enriched for tumor cells using flow sorting, the extracted DNA was used in a custom SNP array to determine chr17p13-11 allelic state; p53 immunostaining, TP53 exons 5, 6, 7 and 8 mutations were determined in combination with mRNA expression analysis on frozen tissue. RESULTS: Patients with a predicted functional p53 had a better prognosis than patients with non functional p53 (Log Rank p=0.009). Expression of CSNK1A1 modified p53 survival effects. Patients with low CSNK1A1 expression and non-functional p53 had a very poor survival both in the univariate (Log Rank p<0.001) and in the multivariate survival analysis (HR=4.74 95% CI 1.45 -- 15.3 p=0.009). CONCLUSION: The combination of mutational, genomic, protein and downstream transcriptional activity data predicted p53 functionality which is shown to have a prognostic effect on colon cancer patients. This effect was specifically modified by CSKN1A1 expression.
  BMC Cancer 06/2013; 13(1):277.
• Article: Infections in pediatric acute promyelocytic leukemia: from the canadian infections in acute myeloid leukemia research group.

  Sonia Cellot, Donna Johnston, David Dix, Marie-Chantal Ethier, Biljana Gillmeister, David Mitchell, Rochelle Yanofsky, Victor Lewis, Carol Portwine, Victoria Price, Shayna Zelcer, Mariana Silva, Lynette Bowes, Bruno Michon, Kent Stobart, Josee Brossard, Joseph Beyene, Lillian Sung
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  ABSTRACT: BACKGROUND: It is not known whether children with acute promyelocytic leukemia (APL) have an infection risk similar to non- APL acute myeloid leukemia. The objective was to describe infectious risk in children with newly diagnosed APL and to describe factors associated with these infections. METHODS: We conducted a retrospective, population-based cohort study that included children <= 18 years of age with de novo APL treated at 15 Canadian centers. Thirty-three children with APL were included; 78.8% were treated with APL -specific protocols. RESULTS: Bacterial sterile site infection occurred in 12 (36.4%) and fungal sterile site infection occurred in 2 (6.1%) children. Of the 127 chemotherapy courses, 101 (79.5%) were classified as intensive and among these, the proportion in which a sterile site microbiologically documented infection occurred was 14/101 (13.9%). There was one infection-related death. CONCLUSIONS: One third of children with APL experienced at least one sterile site bacterial infection throughout treatment and 14% of intensive chemotherapy courses were associated with a microbiologically documented sterile site infection. Infection rates in pediatric APL may be lower compared to non- APL acute myeloid leukemia although these children may still benefit from aggressive supportive care during intensive chemotherapy.
  BMC Cancer 06/2013; 13(1):276.
• Article: NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients.

  Kerstin Willander, Ravi Kumar Dutta, Jonas Ungerbäck, Rebeqa Gunnarsson, Gunnar Juliusson, Mats Fredrikson, Mats Linderholm, Peter Söderkvist
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  ABSTRACT: BACKGROUND: NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors. METHODS: In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios. RESULTS: In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002). CONCLUSIONS: Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.
  BMC Cancer 06/2013; 13(1):274.
• Article: Diagnostic markers of urothelial cancer based on DNA methylation analysis.

  Yoshitomo Chihara, Yae Kanai, Hiroyuki Fujimoto, Kokichi Sugano, Kiyotaka Kawashima, Gangning Liang, Peter A Jones, Kiyohide Fujimoto, Hiroki Kuniyasu, Yoshihiko Hirao
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  ABSTRACT: BACKGROUND: Early detection and risk assessment are crucial for treating urothelial cancer (UC), which is characterized by a high recurrence rate, and necessitates frequent and invasive monitoring. We aimed to establish diagnostic markers for UC based on DNA methylation. METHODS: In this multi-center study, three independent sample sets were prepared. First, DNA methylation levels at CpG loci were measured in the training sets (tumor samples from 91 UC patients, corresponding normal-appearing tissue from these patients, and 12 normal tissues from age-matched bladder cancer-free patients) using the Illumina Golden Gate methylation assay to identify differentially methylated loci. Next, these methylated loci were validated by quantitative DNA methylation by pyrosequencing, using another cohort of tissue samples (Tissue validation set). Lastly, methylation of these markers was analyzed in the independent urine samples (Urine validation set). ROC analysis was performed to evaluate the diagnostic accuracy of these 12 selected markers. RESULTS: Of the 1303 CpG sites, 158 were hyper ethylated and 356 were hypo ethylated in tumor tissues compared to normal tissues. In the panel analysis, 12 loci showed remarkable alterations between tumor and normal samples, with 94.3% sensitivity and 97.8% specificity. Similarly, corresponding normal tissue could be distinguished from normal tissues with 76.0% sensitivity and 100% specificity. Furthermore, the diagnostic accuracy for UC of these markers determined in urine samples was high, with 100% sensitivity and 100% specificity. CONCLUSION: Based on these preliminary findings, diagnostic markers based on differential DNA methylation at specific loci can be useful for non-invasive and reliable detection of UC and epigenetic field defect.
  BMC Cancer 06/2013; 13(1):275.
• Article: Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prognostic and therapeutic implications.

  Dimitrios Balafoutas, Axel Zur Hausen, Sebastian Mayer, Marc Hirschfeld, Markus Jaeger, Dominik Denschlag, Gerald Gitsch, Achim Jungbluth, Elmar Stickeler
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  ABSTRACT: BACKGROUND: Cancer--testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors. METHODS: The reactivity pattern of various mAbs (6C1, MA454, M3H67, 57B, E978, GAGE #26 and NY-BR-1 #5) were assessed by immunohistochemistry in a tissue micro array series of 210 randomly selected primary invasive breast cancers in order to study the diversity of different CTAs (e.g. MAGE-A, NY-ESO-1, GAGE) and NY-BR-1. These expression data were correlated to clinico-pathological parameters and outcome data including disease-free and overall survival. RESULTS: Expression of at least one CTA was detectable in the cytoplasm of tumor cells in 37.2% of the cases. NY-BR-1 expression was found in 46.6% of tumors, respectively. Overall, CTA expression seemed to be linked to adverse prognosis and M3H67 immunoreactivity specifically was significantly correlated to shorter overall and disease-free survival (p=0.000 and 0.024, respectively). CONCLUSIONS: Our findings suggest that M3H67 immunoreactivity could serve as potential prognostic marker in primary breast cancer patients. The exclusive expression of CTAs in tumor tissues as well as the frequent expression of NY-BR-1 could define new targets for specific breast cancer therapies.
  BMC Cancer 06/2013; 13(1):271.
• Article: Influence of a six month endurance exercise program on the immune function of prostate cancer patients undergoing Antiandrogen- or Chemotherapy: design and rationale of the ProImmun study.

  Philipp Zimmer, Elke Jäger, Wilhelm Bloch, Eva Maria Zopf, Freerk T Baumann
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  ABSTRACT: BACKGROUND: Exercise seems to minimize prostate cancer specific mortality risk and treatment related side effects like fatigue and incontinence. However the influence of physical activity on the immunological level remains uncertain. Even prostate cancer patients undergoing palliative treatment often have a relatively long life span compared to other cancer entities. To optimize exercise programs and their outcomes it is essential to investigate the underlying mechanisms. Further, it is important to discriminate between different exercise protocols and therapy regimes. METHODS: The ProImmun study is a prospective multicenter patient preference randomized controlled trial investigating the influence of a 24 week endurance exercise program in 80--100 prostate cancer patients by comparing patients undergoing Antiandrogen therapy combined with exercise (AE), Antiandrogen therapy without exercise (A), Chemotherapy with exercise(CE) or Chemotherapy without exercise (C). The primary outcome of the study is a change in prostate cancer relevant cytokines and hormones (IL-6, MIF, IGF-1, Testosterone). Secondary endpoints are immune cell ratios, oxidative stress and antioxidative capacity levels, VO2 peak, fatigue and quality of life. Patients of the intervention group exercise five times per week, while two sessions are supervised. During the supervised sessions patients (AE and CE) exercise for 33 minutes on a bicycle ergometer at 70-75% of their VO2 peak. To assess long term effects and sustainability of the intervention two follow-up assessments are arranged 12 and 18 month after the intervention. DISCUSSION: The ProImmun study is the first trial which primarily investigates immunological effects of a six month endurance exercise program in prostate cancer patients during palliative care. Separating patients treated with Antiandrogen therapy from those who are additionally treated with Chemotherapy might allow a more specific view on the influence of endurance training interventions and the impact of different therapy protocols on the immune function.Trial registrationGerman Clinical Trials Register: DRKS00004739.
  BMC Cancer 06/2013; 13(1):272.