• Do traditional BMI categories capture future obesity? A comparison with trajectories of BMI and incidence of cancer

      Watson, Charlotte; Geifman, D. N.; Manchester Cancer Research Centre & NIHR Manchester Biomedical Research Centre, Manchester, UK (2020)
      In 2016, 13 specific obesity related cancers were identified by IARC. Here, using baseline WHO BMI categories, latent profile analysis (LPA) and latent class trajectory modelling (LCTM) we evaluated the usefulness of one-off measures when predicting cancer risk vs life-course changes. Our results in LPA broadly concurred with the three basic WHO BMI categories, with similar stepwise increase in cancer risk observed. In LCTM, we identified 5 specific trajectories in men and women. Compared to the leanest class, a stepwise increase in risk for obesity related cancer was observed for all classes. When latent class membership was compared to baseline BMI, we found that the trajectories were composed of a range of BMI (baseline) categories. All methods reveal a link between obesity and the 13 cancers identified by IARC. However, the additional information included by LCTM indicates that lifetime BMI may highlight additional group of people that are at risk.
    • Does (124)Iodo-deoxyuridine measure cell proliferation in NSCLC? Initial investigations with PET imaging and radio-metabolite analysis.

      Williams, Heather; Julyan, Peter J; Ranson, Malcolm R; Zweit, Jamal; Gillies, James M; Hastings, David L (2007-02)
    • Does HLA type predispose some individuals to cancer?

      Little, Ann-Margaret; Stern, Peter L; The Anthony Nolan Bone Marrow Trust, The Royal Free Hospital, Hampstead, London, UK NW3 2QG. (1999-08)
      Polymorphic human major histocompatibility complex (MHC) genes are pivotal to the functioning immune system, and strong autoimmune disease associations with human leukocyte antigens (HLAs) have been established, although the precise mechanisms of these associations are not fully defined. There is now clear evidence of immunosurveillance in cancer, thus it seems reasonable to hypothesize that HLA types might predispose some individuals to particular malignancies. In addition, HLAs could influence the susceptibility or progression of a malignancy, and this might be most apparent in virally associated cancers. This article discusses the results and problems of searching for such HLAs and cancer associations. To date, it appears that no strong associations between HLAs and cancer risk exist.
    • Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis

      Olsen, CM; Pandeya, N; Law, MH; MacGregor, S; Iles, MM; Thompson, BS; Green, Adèle C; Neale, RE; Whiteman, DC; Department of Population Health, QIMR Berghofer Medical Research Institute, Queensland, Australia (2019)
      BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2á7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4á4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3á16, 95% confidence interval 1á39-7á22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development.
    • Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence

      Clifford, RE; Bowden, D; Blower, E; Kirwan, Cliona C; Vimalachandran, D; Institute of Cancer Medicine, The University of Liverpool, UK. (2020)
      Introduction: Tamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel 'off-target' effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies. Method: A qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references. Results: A total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC). Conclusions: With increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.
    • Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.

      Viviano, Beth L; Paine-Saunders, Stephenie; Gasiunas, Nijole; Gallagher, John T; Saunders, Scott; Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA. (2004-02-13)
      We have reported previously that Noggin is a heparin-binding protein and associates with the cell surface through heparan sulfate proteoglycans, where it remains functional for the binding of bone morphogenetic proteins (BMPs). Here we report that the binding of Noggin to the cell surface is highly selective for heparan sulfate and that specific structural features are required for the interaction. Noggin binds most efficiently to heparin sequences composed of 10 or more monosaccharides; N-, 6-O-, and 2-O-sulfates contribute to this interaction. In addition, we have shown that the developmentally regulated endosulfatase Qsulf1 selectively removes sulfate groups from the 6-O position of sugars within the most highly sulfated S domains of heparan sulfate, whereas 6-O-sulfates in the NA/NS domains are not substrates for the enzyme. The activity of Qsulf1 in cells in culture results in the release of Noggin from the cell surface and a restoration of BMP responsiveness to the cells. This shows that Noggin binds to the S domains of heparan sulfate and provides evidence that, in addition to modulating Wnt signaling in vivo by the release of heparan sulfate bound Wnt, Qsulf1 also modulates BMP signaling by the release of surface-bound Noggin.
    • Dominance of a repair function for X-ray-, U.V.- and alkylating agent-induced damage in hybrids between mouse lymphoma cells of different sensitivity.

      Fox, Margaret; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1979-10)
      Cell lines resistant to IUdR and 6-thioguanine were isolated from a radiosensitive mouse lymphoma line LS and its radioresistant derivative AII respectively. Their biological and biochemical characteristics, as measured by plating in HAT medium IUdR and TG and by (14C) hypoxanthine and (3H) thymidine uptake were measured and found to be consistent with those expected for drug resistant cell lines. Two hybrid cell lines were isolated from crosses between the LS IUdRr line and AII TGr line and their radiosensitivity measured relative to that of the parental lines. Radioresistance was found to be dominant in both the hybrid lines as was resistance to EMS and U.V. to which the parental lines also show differential sensitivity. The ability to recover from sublethal damage after X-irradiation was found to be temperature sensitive in radiosensitive cells, an inverse effect being seen when LS cells were irradiated at 20 degrees C and held at 20 degrees C between dose fractions. Hybrid cells showed a normal amount of recovery from sub-lethal damage when compared with that in AII cells but this occurred at t slightly slower rate at 20 degrees "c than at 37 degrees C. Recovery from sub-lethal damage in AII cells was unaffected by lowering the temperature. These findings suggest that the radiosensitive cells may be temperature sensitive, in some step or steps in the ligation process.
    • The dominant lethal assay in the mouse.

      Bateman, A J; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester M20 9BX United Kingdom (1973-06)
    • Dominant selection of hematopoietic progenitor cells with retroviral MDR1 co-expression vectors.

      Hildinger, M; Fehse, B; Hegewisch-Becker, S; John, J; Rafferty, Joseph A; Ostertag, W; Baum, C; Department of Cell and Virus Genetics, Heinrich-Pette-Institute for Experimental Virology and Immunology at the University of Hamburg, University Hospital Hamburg-Eppendorf, Germany. (1998-01-01)
      When transferring the human multidrug resistance 1 (MDR1) cDNA, FMEV retroviral vectors mediate high-dose multidrug resistance and, thus, background-free selection in primary human hematopoietic progenitor cells. Here, we analyzed strategies for co-expression of a second gene from an FMEV:MDR1 vector. When linking the cDNAs with the internal ribosomal entry site (IRES) of poliovirus or retroviral splice signals, almost all multidrug-resistant hematopoietic colonies simultaneously coexpressed the 3' positioned second gene, neomycin-phosphotransferase (neoR). The IRES strategy allowed functional co-transfer of a 4.2-kb lacZ-neoR fusion gene, resulting in a total proviral genome size of 11 kb, corresponding to the packaging limit of retroviral vectors. Preselection based on multidrug resistance elevated the expression of the second gene in IRES constructs, but not in splice vectors. Moreover, three intriguing observations were made. First, up to 30% of cells preselected for functional transfer of the 3' positioned cDNA (neoR) showed infunctional MDR1; this occurred irrespective of the linking principle and was associated with instability of the MDR1 transcription unit. Second, the levels of multidrug resistance achieved with the co-expression vectors were moderately lower (15-30% reduced) than those mediated by the monocistronic counterpart. Third, transduction with FMEV:MDR1 co-expression vectors still resulted in high-dose cancer drug resistance and background-free selection of hematopoietic progenitor cells (including primary human CD34+ colony-forming units). Thus, for the first time, we describe MDR1 co-expression vectors that maintain their desired function in early and primary human hematopoietic cells. However, careful interpretation of the data reveals that further vector improvements are required to obtain clinically useful MDR1 co-expression vectors.
    • Donor stromal cells from human blood engraft in NOD/SCID mice.

      Goan, Silvia-Renate; Junghahn, Ilse; Wissler, Manuela; Becker, Michael; Aumann, Jutta; Just, Ursula; Martiny-Baron, Georg; Fichtner, Iduna; Henschler, Reinhard; Max Delbrück Center for Molecular Medicine, Berlin, Germany. (2000-12-01)
      Little is known about the presence, frequency, and in vivo proliferative potential of stromal cells within blood-derived hematopoietic transplants. In this study, nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice were injected with human CD34(+) peripheral blood cells (PBCs) or cord blood cells (CBCs, either enriched for CD34 or density-gradient separated mononuclear cells). Flow cytometric analysis 5 to 11 weeks after transplantation revealed the presence of a human lymphomyeloid hematopoiesis within the murine bone marrow. Immunohistochemical staining of bone marrow cell suspensions using human-specific antibodies showed human cells staining positive for human fibroblast markers, human von Willebrand factor (vWF) and human KDR (vascular endothelial growth factor receptor-2) in mice transplanted with CD34(+) PBCs or CBCs, with mean frequencies between 0.6% and 2.4%. In stromal layers of bone marrow cultures established from the mice, immunohistochemical staining using human-specific antibodies revealed flattened reticular cells or spindle-shaped cells staining positive with human-specific antifibroblast antibodies (mean frequency, 2.2%). Cell populations of more rounded cells stained positive with human-specific antibodies recognizing CD34 (1.5%), vWF (2.2%), and KDR (1.6%). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and subsequent complementary DNA sequencing detected transcripts of human KDR (endothelial specific) and human proline hydroxylase-alpha (fibroblast specific) within the bone marrow and spleen of transplanted mice. Analysis of nontransplanted control mice yielded negative results in immunocytochemistry and RT-PCR. Cells expressing endothelial and fibroblast markers were also detected in the grafts before transplantation, and their numbers increased up to 3 log in vivo after transplantation. These results indicate that stromal progenitor cells are present in human cytokine-mobilized peripheral blood or cord blood that engraft in NOD/SCID mice. (Blood. 2000;96:3971-3978)
    • Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells.

      Lee, Siow Ming; Thatcher, Nick; Dougal, Mark; Margison, Geoffrey P; CRC Dept of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. (1993-02)
      There is increasing experimental evidence to suggest that endogenous expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in cellular resistance to certain chemotherapeutic agents including dacarbazine (DTIC). We have recently shown wide interindividual variation in the depletion and subsequent regeneration of ATase in peripheral blood mononuclear cells (PMCs) following DTIC and this has now been extended to ascertain whether or not depletion is related to dosage of DTIC used and repeated treatment cycles of chemotherapy. ATase levels were measured in three groups of 25 patients (pts) up to 24 h after receiving DTIC at 400 mg m-2, 500 mg m-2 or 800 mg m-2. Each group also received fotemustine (100 mg m-2), 4 h after DTIC. The lowest extent of ATase depletion (highest nadir ATase) was seen in patients receiving 400 mg m-2. The mean nadir ATase, expressed as a percentage of pre-treatment ATase, was respectively 56.3%, 26.4% and 23.9% for 400 mg m-2, 500 mg m-2 and 800 mg m-2. The median nadir of ATase activity for pts receiving 800 mg m-2 pts was at 4-6 h and for pts given lower doses it was at 2-3 h. In addition, repeated measures analysis of variance of observations before chemotherapy, then at 2, 3, 4, 6 and 18 h after chemotherapy provides some evidence that ATase was depleted to a lesser extent after cycle 1 than after subsequent cycles (P = 0.025). It also provides evidence that the change in ATase activity over time varied with dose and cycle. The findings can be interpreted on the basis of a dosage-dependent metabolism of DTIC to an agent capable of methylation of DNA and subsequent depletion of PMC ATase: with higher DTIC doses, the extent of ATase depletion may be limited by the pharmacokinetics of DTIC metabolism. PMC ATase was measured in another group of 8 pts at various times after receiving only fotemustine (100 mg m-2) and in contrast to DTIC, no ATase depletion was seen suggesting that insufficient concentrations of fotemustine and/or its metabolites were available to react with DNA to produce a depletion of PMC ATase activity.
    • Dose and time related responses of the irradiated prepubertal rat testis. I. Leydig cell function.

      Delic, Julian I; Hendry, Jolyon H; Morris, Ian D; Shalet, Stephen M; Department of Radiobiology, Paterson Laboratories, Christie Hospital and Holt Radium Institute (1985-12)
      The testes of prepubertal rats were locally irradiated with 300 kVp x-rays to doses of between 1 and 15 Gy. Leydig cell function was assessed between 2 and 36 weeks post-irradiation. Dysfunction was observed at two weeks as evidenced by a reduction in serum levels of testosterone to between 40 and 70% of control, with a threshold dose of about 5 Gy. Endocrine deficiencies in the Leydig cell population were indicated at later times by increased serum levels of LH, although serum testosterone concentrations recovered to control levels. The elevations in serum LH increased with time suggesting progressive Leydig cell failure.
    • Dose and time related responses of the irradiated prepubertal rat testis. II. Seminiferous epithelial function.

      Delic, Julian I; Hendry, Jolyon H; Morris, Ian D; Shalet, Stephen M; Department of Radiobiology, Paterson Laboratories, CHristie Hospital and Holt Radium Institute (1985-12)
      Dose-related effects of radiation upon the seminiferous epithelium were examined in the prepubertal rat. Marked damage to the spermatogenic cell populations was produced by doses of 5 Gy and above. As a result serum levels of FSH were increased, maximum changes being observed at 2 weeks, but levels remaining high even at 36 weeks after irradiation. Serum levels of androgen binding protein (ABP) were inversely related to serum FSH. Above a threshold dose of 5 Gy, serum ABP levels were reduced to between 30-50% of control values, possibly indicating damage to the Sertoli cells. Progression in the degree of testicular failure was indicated at 36 weeks after a dose of 15 Gy by further increases in serum gonadotrophins when compared to earlier times and by the absence of spermatogenesis.
    • Dose and time relationships in the endocrine response of the irradiated adult rat testis.

      Delic, Julian I; Hendry, Jolyon H; Morris, Ian D; Shalet, Stephen M; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester, M20 9BX, UK. (1986)
      The dose- and time-dependent responses for the interstitial and tubular compartments in irradiated adult rat testes are described. Leydig cell dysfunction, as indicated by increased serum LH (to a maximum of 385% of control after 5 Gy) and decreased serum T (to a minimum of 30% of control after 10 Gy), was observed at 8 weeks postirradiation. Subsequent recovery of Leydig cell function was then observed, so that after 9 months serum T was normal but LH was still marginally elevated. The dysfunction, with a threshold of about 4 to 5 Gy, was associated with a loss of Leydig cells from the testis. Spermatogenic damage was observed; after doses of 3 Gy and above a marked dose-response was recorded as assessed by counts of tubule cross sections exhibiting spermatogenesis. Reduced serum levels of androgen binding protein indicated Sertoli cell dysfunction at 8 weeks after 3 Gy and above, with values of less than one half of those seen in the controls. Serum FSH also was elevated to between 150% and 200% of control, and after 9 months closely reflected androgen binding protein changes. Unlike the Leydig cell, no recovery with time was observed for this aspect of Sertoli cell function.
    • Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies.

      Geoerger, B; Vassal, G; Doz, F; O'Quigley, J; Wartelle, M; Watson, Amanda J; Raquin, M-A; Frappaz, D; Chastagner, P; Gentet, J-C; et al. (2005-09-05)
      Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.
    • Dose fractionation and hepatocyte clonogens: alpha/beta congruent to 1-2 Gy, and beta decreases with increasing delay before assay.

      Fisher, David R; Hendry, Jolyon H; Radiobiology Department, Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, United Kingdom. (1988-01)
      The sensitivity to X-ray dose fractionation was assessed for hepatocytes forming colonies in fat pads in mice. When the cells were assayed 1 day after the last irradiation the alpha/beta ratio was 1.0-1.6 depending on the method of analysis. The alpha/beta ratio describing the shape of the single-dose survival curve was much higher, and it did not predict the response to fractionation. When the assay was delayed for 10 months after the fractionated irradiation, the alpha/beta ratio was 1.9-2.1, and the beta component showed the greatest change with time. It is concluded that hepatocytes respond to dose fractionation in a manner expected of a late-responding tissue, even when the cells are assayed as early as 1 day after the last dose.
    • Dose to the coronary arteries is significantly associated with overall survival in non-small-cell-lung-cancer (NSCLC) patients treated with curative-intent radiotherapy.

      Mahil, J; van Herk, Marcel; Faivre-Finn, Corinne; Choudhury, Ananya; McWilliam, Alan; Faculty of Biology, Medicine And Health, University of Manchester, (2018-01)
    • The dose-dependence of the split-dose response of marrow colony-forming units (CFU-S): similarity to other tissues.

      Hendry, Jolyon H; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1979-12)
      The split-dose effect for survival of colony-forming units (CFU-S) in mouse bone-marrow increases with increasing total dose. This is compatible with the shape of the survival curve, since detailed measurements at doses lower than 200 rad show the presence of a marked initial slope, followed by a tendency towards an increased sensitivity at higher doses. The magnitude of the increase in the split-dose effect is quantitatively similar to values observed by others at comparable low doses in skin, intestine and lung, as deduced from multifraction experiments. It is concluded that these cells do not differ markedly, as has been generally believed, from many other cell types in the ability to demonstrate split-dose effects, when the doses used in the experiments are strictly comparable.
    • Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial

      Nutting, C. M.; Griffin, C. L.; Sanghera, P.; Foran, B.; Beasley, M.; Bernstein, D.; Cosgrove, V.; Fisher, S.; West, Catharine M L; Sibtain, A.; et al. (2021)
      Background: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. Methods: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Findings: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. Conclusion: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer.
    • Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer. Selection of the most acceptable regimen to induce maximal tumor response and investigation of the optimal time to collect peripheral blood progenitor cells for haematological rescue after high-dose consolidation chemotherapy.

      Van Hoef, M E; Baumann, Irith; Lange, C; Luft, T; De Wynter, Erika A; Ranson, Malcolm R; Morgenstern, Godfrey R; Yvers, A; Dexter, T Michael; Testa, Nydia G; et al. (1994-03)
      BACKGROUND: In advanced breast cancer high-dose consolidation chemotherapy with haematological rescue has resulted in prolonged disease free and overall survival in a small percentage of patients. Maximal reduction of the tumor burden by intensive induction treatment preceding the high-dose chemotherapy may favor that outcome. The aims of this study were to find a rapid highly effective induction regimen with acceptable toxicity and to examine the optimal time for peripheral blood progenitor cell (PBPC) collection for haematological rescue. SUBJECTS AND METHODS: Twenty-four patients received 4 cycles of FAC chemotherapy (5-FU, adriamycin, cyclosphamide), each followed by 10 micrograms/kg/d of lenograstim (glycosylated rHuG-CSF) s.c. day 2 to 11. Chemotherapy was administered at 4 dose intensity levels with 6 patients including at each level (level 1: 500(F)/50(A)/500(C) mg/m2/3wk, level 2: 500/50/500 mg/m2/2wk, level 3: 500/75/500 mg/m2/2wk, m2/2wk, level 4: 500/75/1000 mg/m2/2wk d1 i.v.). In addition lenograstim (10 micrograms/kg/d s.c.) was administered for a period of 10 days before (period X) and after (period Y) chemotherapy. In 16 patients (4 at each dose intensity level) assessment of PBPC was performed during period X and Y as well as during cycle 1 and 4. A single apheresis to collect PBPC was planned during chemotherapy cycle 1. RESULTS: The best response was obtained at dose intensity level 3 (all 6 patients responded, 3 of them achieved CR) with acceptable toxicity. Peak circulating numbers of total CFC/ml blood were median 5819 (period X), 4635 (cycle 1), 3807 (cycle 4) and 3519 (period Y) and occurred concurrently with peak circulating numbers of CD34+ cells. The and median 3.76 x 10(6)/kg CD34+ cells. Three patients received high-dose consolidation chemotherapy with PBPC support. Recovery of ANC > 0.5 x 10(9)/l occurred on median day 11 and of platelets > 20 x 10(9)/l on median day 10. CONCLUSION: Dose intensity level 3 is the best usable induction regimen in this study. The optimal time for apheresis is either during lenograstim before chemotherapy treatment or during the first cycle of chemotherapy. Rapid haematological recovery was obtained by reinfusion of PBPC as sole source of support in the patients receiving high-dose consolidation chemotherapy.