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PubMed2005

Efficacy and safety of mycophenolate mofetil as part of induction therapy in liver transplantation.

AIMS: To report our experience with mycophenolate mofetil (MMF) for induction and maintenance therapy to prevent acute liver transplant rejection. METHODS: A retrospective analysis of 66 elective, noncombined liver transplant patients treated beginning de novo MMF and follow for a minimum of 2 years. Thirty-nine of the 66 cases received MMF, calcineurin inhibitors, and steroids. In 11 cases daclizumab was added; in 16 daclizumab was added without steroids. RESULTS: The global survival rate was 91% at 6 months, 89.4% at 1 year, and 87.9% after 2 years. Acute rejection episodes were observed in six patients (9.1%). All episodes responded to corticoids. Toxicity possibly, probably, or partially related to MMF was observed in 35 patients (53%) with definitive suspension required in 13 cases (20%), with dose reduction or temporary suspension in 22 (33%). Hematological toxicity associated with MMF was observed in 12 patients (18%), leading to definitive suspension in two patients (3.03%), temporary suspension in two cases (3.03%), and dose reduction in eight cases (12%). Opportunistic infection was observed in seven cases (10%). Gastrointestinal toxicity was mild and infrequent (five cases, 7.5%). CONCLUSION: Regimens containing MMF reduce rejection episodes with high survival rates and low toxicity.

Adult↗
PubMed2005

High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma.

BACKGROUND: The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. PATIENTS AND METHODS: One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m(2) HDMTX followed by leucovorin rescue. RESULTS: Toxicity was generally mild with toxicities of WHO grade > or =3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and < or =60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients < or =60 years and those >60 years old (18% versus 44%; P = 0.001). CONCLUSIONS: HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.

Adult↗
PubMed2002

Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer.

PURPOSE: To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS: The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m(2) at an initial dose of 1,250 mg/m(2) bid in nonpretreated patients and at a dose of 1,000 mg/m(2) bid in pretreated patients.

Adenocarcinoma↗
PubMed1984

On the sensitisation of skin radionecrosis in mice by misonidazole at low doses.

The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different states of oxygenation affecting sensitivity. The levels of sensitisation after different injected doses of misonidazole could be described reasonably well by the Alper -Howard-Flanders relationship, originally applied to the sensitisation of cells by oxygen, and hence the relationship could be used for interpolation. With clamped tails gassed with nitrogen at room temperature, 21-25 degrees C, the injected dose giving half the maximum sensitisation (defined as K inj ) was about 0.12-0.17 mg g-1 (0.6-0.8 mM). Unclamped tails in air demonstrated a value for K inj of about 0.14 mg g-1, indicating that the background level of oxygen and the injected misonidazole were not additive regarding sensitisation. With clamped tails gassed with nitrogen warmed to 37 degrees C (near body-core temperature) the sensitivity was slightly increased compared with clamped tails at 21-25 degrees C, and the additional increase in sensitivity following injections of misonidazole ( K inj of about 0.22 mg g-1) was less than at 21-25 degrees. With tails in air at 37 degrees C the increase in sensitivity following misonidazole was much more marked ( K inj of about 0.05 mg g-1) than expected. When eight "daily" fractions were given using 0.67 mg g-1 misonidazole and with the target cells well oxygenated at 37 degrees C (effective OER of about 2.0), the amount of sensitisation was less than for single doses, but it was similar (i.e. dose-modifying) for radiation doses per fraction between 2.6 and 6.3 Gy. At a dose of 0.1 mg g-1, giving a serum level corresponding to about the maximum tolerable in humans, the dose reduction factor would be only about 1.03 which corresponds roughly to a doubling in the tail necrosis rate from 5% to 10%. With future less neurotoxic drugs, higher serum levels may be expected to be tolerated and hence the dose reduction factor could be greater. This aspect, applicable to some but not all tissues tested in mice, should not be neglected in the design of future clinical trials with hypoxic-cell radiosensitisers .

Animals↗
PubMed2000

Pergolide versus bromocriptine for levodopa-induced motor complications in Parkinson's disease.

OBJECTIVES: To compare the efficacy and safety of adjunct pergolide therapy versus bromocriptine in patients with Parkinson's disease, already established on levodopa and suffering the long-term complications of therapy. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Eli Lilly Company and Sandoz Limited. SELECTION CRITERIA: Randomised controlled trials of pergolide versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by each author and differences settled by discussion. MAIN RESULTS: Three short-term trials fulfilled the inclusion criteria for the review. Pergolide was superior to bromocriptine regarding UPDRS and NYPDS motor and NYPDS ADL scores in two trials. More patients recorded a 'marked' or 'moderate improvement' in clinician's global impression score with pergolide than bromocriptine in two studies. Insufficient evidence on fluctuations and dyskinesia was available to draw any conclusions. No significant differences between the agonists were seen in levodopa dose reduction, drop outs or adverse events. REVIEWER'S CONCLUSIONS: Although pergolide is superior to bromocriptine in reducing motor impairments and disability, no firm conclusions regarding levodopa-induced motor complications can be reached. Levodopa dose reduction, adverse events and withdrawals from treatment are similar for the two agonists. The small advantage of pergolide in efficacy does not take into account its additional cost compared with bromocriptine.

Antiparkinson Agents↗
PubMed2004

Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon alpha-2b+ full-course vs. 16-week delayed ribavirin.

Human immunodeficiency virus (HIV)-infected patients increasingly experience the consequences of chronic hepatitis C virus (HCV) coinfection. This trial randomized 107 patients coinfected with HIV and HCV to receive 48 weeks of interferon alfa-2b (IFN) 3 million units three times weekly plus either a full course of ribavirin (RBV) at 800 mg/day (group A; n = 53) or 16 weeks of placebo, followed by RBV (group B; n = 54). The primary endpoint of sustained viral response (SVR) rate (undetectable HCV RNA at posttreatment week 24) was not different between groups A (11.3%) and B (5.6%; P =.32). Within group A, the SVR rate was lower in genotype 1 (2.5%) than in genotypes 2 through 4 (41.7%; P =.002). Fifty-five patients discontinued therapy prematurely, mostly because of adverse events or patient decisions. At treatment week 12, the percentage of CD4+ cells rose in group A (+4.1%; P <.001), but not in group B (-0.3%). A significant proportion (22%) of patients who were HIV viremic at baseline had undetectable HIV RNA at week 12. By week 16, the hemoglobin level decreased more in group A (-2,52 g/dL) than in group B (-1.02 g/dL; P <.001). In group A, the hemoglobin decline was steeper in patients receiving zidovudine (azidothymidine [AZT], -3.64 g/dL vs. no AZT, -2.08 g/dL), and patients receiving zidovudine had more anemia-related RBV dose reductions (AZT, 60% vs. no AZT, 16%). In conclusion, HCV therapy with IFN plus RBV is relatively safe in patients coinfected with HIV and HCV, but frequent treatment discontinuations and anemia-related RBV dose reductions contribute to a poor SVR rate. Control of HIV infection improves rather than worsens during therapy.

Adult↗
PubMed1995

[A bimetal anode with tungsten or rhodium? Comparative studies on image quality and dosage requirement in mammography].

PURPOSE: The impact of different anode materials (tungsten and rhodium) on spatial resolution, image contrast and radiation exposure was studied. MATERIALS AND METHODS: Two mammographic systems providing bimetal x-ray tubes (Mo/W and Mo/Rh) were compared by imaging a breast radiography phantom with additional acrylic plates from 3 to 8 cm thickness. Spatial resolution was evaluated using a line bar pattern. Image contrast was assessed by measuring the ratio of optical densities in a acrylic step-wedge. The entrance dose was measured with a low energy ionisation chamber. RESULTS: The spatial resolution was about 13 lp/mm regardless of the beam quality. The image contrast depended substantially on the thickness. A similar image contrast was found with Mo/Mo, Mo/Rh and Rh/Rh for simulated breast thicknesses of 4 to 6 cm and with Rh/Rh and W/Rh for 7 cm. In comparison to Mo/Mo the dose reduction was significant for Mo/Rh (35%), Rh/Rh (50%) and W/Rh (60%). CONCLUSIONS: Bimetal x-ray tubes provide optimal conditions for screen film mammography of both normal and dense breasts, allowing good contrast and dose reduction by using the adequate anode/filter-combination.

Electrodes↗
PubMed1980

[Investigations on combined injuries, 29th communication. Protective effect of aminopropylamino-ethylthiophosphate (WR 2721) in mice with radiation and combined injuries (irradiation and skin wound or burn) (author's transl)].

Because of the crucial practical importance of combined injuries, investigations of the efficacy of the radioprotective agent aminopropylamino-ethylthiophosphate (WR 2721) were performed on mice which were whole-body X-irradiated and stressed with a second trauma either as an open wound or as burn wounds on the skin. In cases of sole whole-body irradiation, probit analyses of our data yielded the dose reduction factors (DRF) of 2.42 (NMRI-Hannover) and 2.12 (NMRI-Kisslegg). In case of a combination of an open skin wound (SW) with irradiation in mice of the Hannover breed the following dose reduction factors have been obtained: for irradiation+SDW 10 min p. r. the DRF 2.22, for irradiation+SW 2 d p. r. the DRF 2.30, and for irradiation+SW 8 d p. R.. the DRF 2.29. In cases of combined injuries with two burn wounds (BW) as second trauma in mice of the Kissblegg breed yielded: the DRF 2.01 for irradiation+BW 10 min p. r., and the DRF 1.91 for irradiation+BW 2 d p. r. The protective effect of WR 2721 is apparently similar in the various groups with combined injuries as compared to the animals exposed to whole-body irradiation only. The mechanisms of action of the sulphur-containing radioprotective agents are discussed.

Amifostine↗
PubMed1997

Paclitaxel and epirubicin as first-line therapy for patients with metastatic breast cancer.

Paclitaxel (Taxol), has aroused considerable interest for its high single-agent activity in breast cancer and novel mechanism of action. Epirubicin (Farmorubicin), the 4'epimer of doxorubicin (Adriamycin), also has high activity in breast cancer, with the advantage of a lower rate of toxic side effects-especially cardiac effects-compared with its parent compound. The combination of paclitaxel and doxorubicin has yielded response rates between 63% and 94% in phase I/II studies, but authors reported severe cardiac toxic events. The goal for the current study was to evaluate the combination of paclitaxel and epirubicin, focusing mainly on cardiac toxicity. Of a total of 85 patients entered, 68 patients with metastatic breast cancer were evaluable. Nearly 20% had primary metastatic breast cancer with large tumors. Half had received adjuvant chemotherapy. Study medication in Group A consisted of 60 mg/m2 epirubicin given over 1 hour, followed by paclitaxel 175 mg/m2 as a 3-hour IV infusion. In Group B, 90 mg/m2 epirubicin was combined with 175 mg/m2 paclitaxel, delivered as for Group A. The main toxicity in both groups was neutropenia. In Group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in 7 patients; dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac adverse events were reported in Group A. In Group B, only one patient could be escalated to 200 mg/m2 but three patients required a dose reduction. In this group, one patient had a decrease of left ventricular ejection fraction of more than 10% without any clinical signs. Of 43 patients in Group A and 25 in Group B, the response rate was 67% in Group A and 68% in Group B. The duration of response was 8.2 months in both groups. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 or 90 mg/m2 can be safely administered. The response data were encouraging and further evaluation is warranted.

Antibiotics, Antineoplastic↗
PubMed2002

Rat strain differences in nicotine self-administration using an unlimited access paradigm.

An effective animal model for elucidating the neurobiological basis of human smoking should simulate important aspects of this behavior. Therefore, a 23 h unlimited access nicotine self-administration model was used to compare inbred Lewis rats, which have a propensity to self-administer drugs of abuse, to inbred Fisher 344 rats and to the outbred Holtzman strain. Using this unlimited access model, 88.8% of Lewis vs. 57.1% of Holtzman rats achieved maintenance self-administration at a fixed ratio 1 (FR 1) at 0.03 mg/kg IV nicotine (P<0.05). In contrast, Fisher rats did not acquire self-administration under these conditions. Of the Lewis and Holtzman rats that achieved maintenance self-administration on an FR 1 schedule, a greater percentage of Lewis rats acquired nicotine self-administration at FR 2 (P<0.05) and progressed to FR 4 (P<0.05). Using naïve cohorts in a progressive dose reduction study, 83.3% of Lewis rats achieved maintenance at 0.0075 mg/kg nicotine as compared to 31.8% of Holtzman rats (P<0.05). Furthermore, only Lewis rats showed differences in active vs. inactive bar presses during maintenance at sequential dose reductions (P<0.001). Thus, in this unlimited access model, inbred Lewis rats will more reliably acquire nicotine self-administration than outbred Holtzman rats. Moreover, Lewis rats showed a significantly higher likelihood of continuing to self-administer nicotine in face of both increasing work requirements and decreasing drug reinforcement. Therefore, it is likely that Lewis rats would be genetically susceptible to nicotine addiction.

Animals↗
PubMed2005

Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group.

PURPOSE: The synergic combination of oxaliplatin and capecitabine has demonstrated activity against various gastrointestinal cancers, including colon cancer. We therefore undertook this phase II study to test this first-line combination in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia. PATIENTS AND METHODS: Forty-three patients with histologic or cytologic confirmation of the above malignancy were recruited. The cohort had Eastern Cooperative Oncology Group performance statuses of 0, 1 and 2 in 47%, 51%, and 2%, respectively. Median age was 61 years (range 32-80). All had adequate organ function. Initially, patients were prescribed 130 mg/m2 intravenously on day 1 and capecitabine 1000 mg/m2 orally twice a day, on days 1-14 of a 21-day cycle. Four treatment-related deaths in the first 24 patients led to a reduction in capecitabine to 850 mg/m2 orally twice a day, days 1-14, for the remainder of the cohort. RESULTS: The tumor response rate was 35% [95% confidence intervals (CI) 23% to 50%]. All responses were partial; seven of 24 occurred before the capecitabine dose reduction, and eight of 19 after. Median time to tumor progression was 4 months (95% CI 3.1-4.6), and median survival 6.4 months (95% CI 4.6-10). To date, there have been 36 deaths. Four were treatment-related (one infection, two myocardial infarctions, one respiratory failure), and all occurred before the capecitabine dose reduction. Notable grade 4 events from the entire cohort included diarrhea (two patients), vomiting (three), dyspnea (one), thrombosis (two) and anorexia (two). Grade 3 events included nausea (12 patients), diarrhea (12), fatigue (10), abdominal pain (seven), vomiting (six), dyspnea (six), hypokalemia (six), dehydration (five), hypokalemia (five) and infection (four). CONCLUSIONS: Oxaliplatin and capecitabine in combination demonstrates activity in metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia. The lower dose (capecitabine 850 mg/m2 orally twice a day, days 1-14, and oxaliplatin 130 mg/m2 intravenously on day 1) yielded an acceptable toxicity profile and merits further study.

Adenocarcinoma↗
PubMed1994

Treatment of small cell lung cancer in the elderly.

OBJECTIVE: Since both the incidence of lung cancer and the proportion of the population over age 65 are increasing rapidly in North America, we undertook a retrospective review of elderly patients with small cell lung cancer (SCLC) in an attempt to assess the effect of age on treatment decisions, response, survival, and toxicity. DESIGN: Retrospective chart view. SETTING: Oncology Unit of a university-affiliated teaching hospital. PATIENTS: There were 123 patients age > 70 years treated from 1976-88. Chemotherapy consisted of either cyclophosphamide, doxorubicin, and vincristine, or etoposide and cisplatin. RESULTS: There were 74 patients aged 70-74, 35 aged 75-80, and 14 aged 80 years or older. No significant differences existed between the groups in sex, stage, performance status, or presence of co-morbid disease. Median survivals for patients with limited and extensive disease were 11.9 and 5.2 months, respectively (P = < 0.0001), with no significant difference for patients in any age group (P = 0.4). For both limited and extensive disease, survival correlated strongly with the treatment received. Twenty-five patients received no treatment (median survival 1.1 months), 20 had radiation only (median 7.8 months), and 27 patients had < 3 cycles of chemotherapy (median 3.9 months). Median survival for the 50 patients who had 4-6 cycles was 10.7 months (limited disease 15.0 months, extensive disease 8.61 months). In the Cox Model, survival correlated strongly with stage of disease and chemotherapy treatment (P < 0.0001), but only marginally with performance status (P < 0.077). Of the 77 patients who had chemotherapy, less than 50% in all age groups completed six cycles. Only two patients completed chemotherapy without a single dose reduction, and 76.7% required more than two reductions. CONCLUSIONS: Chemotherapy should not be withheld from elderly patients with SCLC on the basis of age. The survival of patients who receive chemotherapy is significantly longer than that of untreated patients even though frequent dose reductions for toxicity may be required. The survival benefit is due to treatment effect and is not due to a selection bias in the cohort of patients chosen for therapy.

Activities of Daily Living↗
PubMed1997

Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: rapid development of neurotoxicity is dose-limiting.

PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosuppression. PATIENTS AND METHODS: A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m2) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 micrograms/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/microL). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m2 (n = 6). RESULTS: At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m2), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m2, n = 1; 275 mg/m2, n = 2), neutropenia (225 mg/m2, n = 2), diarrhea (275 mg/m2, n = 2), and nephrotoxicity (225 mg/m2, n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m2, n = 1 each) physician request (275 mg/m2, n = 1), and death (275 mg/m2, n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/microL. CONCLUSION: The MTD of paclitaxel was determined to be 225 mg/m2 when administered as a 3-hour infusion and combined with cisplatin (75 mg/m2). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels.

Adult↗
PubMed1987

Dose response studies of gentamicin nephrotoxicity in rats with experimental renal dysfunction. III. Effects of dosage adjustment method.

Previous studies indicate that while Sprague-Dawley (SD) rats with pre-existing renal insufficiency were resistant to gentamicin nephrotoxicity, beagle dogs with renal dysfunction were sensitive. In this study the effects of gentamicin dose reduction method on nephrotoxicity were investigated in subtotally (approx. 65%) nephrectomized (Nx) SD rats. Thirty SD rats were assigned as controls (Ctrls, n = 10) or Nx (n = 20). All rats received gentamicin for 7 days. Nx rats received either a decreased dose, fixed interval (FI) or increased interval, fixed dose (FD) regimen to compensate for prior renal insufficiency. Pre- and post-dosing serum creatinine and urea nitrogen (SCr, SUN), adjusted SCr and SUN ([postdosing-predosing]/predosing), histopathologic scores and single-dose pharmacokinetic parameters were determined in all rats. Adjusted SCr and Sun values, as well as histopathology scores were consistently greater in FI rats than in FD rats. Additionally, FI rats had significantly greater predicted trough gentamicin levels than Ctrl or FD rats. The relatively lower nephrotoxicity in the FD regimen in rats agrees with results previously reported in dogs, thus indicating that the method of dose reduction in patients with compromised renal function may be a significant factor in lowering nephrotoxic potential. In addition, the subtotal Nx rat may thus be a valuable and economical model for assessing the nephrotoxicity of different drug dosage regimens in pre-existing renal disease.

Animals↗
PubMed2001

Ectopic expression of DREF induces DNA synthesis, apoptosis, and unusual morphogenesis in the Drosophila eye imaginal disc: possible interaction with Polycomb and trithorax group proteins.

The promoters of Drosophila genes encoding DNA replication-related proteins contain transcription regulatory element DRE (5'-TATCGATA) in addition to E2F recognition sites. A specific DRE-binding factor, DREF, positively regulates DRE-containing genes. In addition, it has been reported that DREF can bind to a sequence in the hsp70 scs' chromatin boundary element that is also recognized by boundary element-associated factor, and thus DREF may participate in regulating insulator activity. To examine DREF function in vivo, we established transgenic flies in which ectopic expression of DREF was targeted to the eye imaginal discs. Adult flies expressing DREF exhibited a severe rough eye phenotype. Expression of DREF induced ectopic DNA synthesis in the cells behind the morphogenetic furrow, which are normally postmitotic, and abolished photoreceptor specifications of R1, R6, and R7. Furthermore, DREF expression caused apoptosis in the imaginal disc cells in the region where commitment to R1/R6 cells takes place, suggesting that failure of differentiation of R1/R6 photoreceptor cells might cause apoptosis. The DREF-induced rough eye phenotype was suppressed by a half-dose reduction of the E2F gene, one of the genes regulated by DREF, indicating that the DREF overexpression phenotype is useful to screen for modifiers of DREF activity. Among Polycomb/trithorax group genes, we found that a half-dose reduction of some of the trithorax group genes involved in determining chromatin structure or chromatin remodeling (brahma, moira, and osa) significantly suppressed and that reduction of Distal-less enhanced the DREF-induced rough eye phenotype. The results suggest a possibility that DREF activity might be regulated by protein complexes that play a role in modulating chromatin structure. Genetic crosses of transgenic flies expressing DREF to a collection of Drosophila deficiency stocks allowed us to identify several genomic regions, deletions of which caused enhancement or suppression of the DREF-induced rough eye phenotype. These deletions should be useful to identify novel targets of DREF and its positive or negative regulators.

Animals↗
PubMed2005

Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques?

PURPOSE: To calculate treatment plans and compare the dose distributions and dose-volume histograms (DVHs) for photon three-dimensional conformal radiation therapy (3D-CRT), electron therapy, intensity-modulated radiation therapy (IMRT), and standard (nonintensity modulated) proton therapy in three pediatric disease sites. METHODS AND MATERIALS: The tumor volumes from 8 patients (3 retinoblastomas, 2 medulloblastomas, and 3 pelvic sarcomas) were studied retrospectively to compare DVHs from proton therapy with 3D-CRT, electron therapy, and IMRT. In retinoblastoma, several planning techniques were analyzed: A single electron appositional beam was compared with a single 3D-CRT lateral beam, a 3D-CRT anterior beam paired with a lateral beam, IMRT, and protons. In medulloblastoma, three posterior fossa irradiation techniques were analyzed: 3D-CRT, IMRT, and protons. Craniospinal irradiation (which consisted of composite plans of both the posterior fossa and craniospinal components) was also evaluated, primarily comparing spinal irradiation using 3D-CRT electrons, 3D-CRT photons, and protons. Lastly, in pelvic sarcoma, 3D-CRT, IMRT, and proton plans were assessed. RESULTS: In retinoblastoma, protons resulted in the best target coverage combined with the most orbital bone sparing (10% was the mean orbital bone volume irradiated at > or =5 Gy for protons vs. 25% for 3D-CRT electrons, 69% for IMRT, 41% for a single 3D lateral beam, 51% for a 3D anterolateral beam with a lens block, and 65% for a 3D anterolateral beam without a lens block). A single appositional electron field was the next best technique followed by other planning approaches. In medulloblastoma, for posterior fossa and craniospinal irradiation, protons resulted in the least dose to the cochlea (for only posterior fossa irradiation at > or =20 Gy, 34% was the mean cochlear volume irradiated for protons, 87% for IMRT, 89% for 3D-CRT) and hypothalamus-pituitary axis (for only posterior fossa irradiation at > or =10 Gy, 21% was the mean hypothalamus-pituitary volume irradiated for protons, 81% for IMRT, 91% for 3D-CRT); additional dose reductions to the optic chiasm, eyes, vertebrae, mandible, thyroid, lung, kidneys, heart, and liver were seen. Intensity-modulated radiotherapy appeared to be the second best technique for posterior fossa irradiation. For spinal irradiation 3D-CRT electrons were better than 3D-CRT photons in sparing dose to the thyroid, heart, lung, kidney, and liver. With pelvic sarcoma, protons were superior in eliminating any dose to the ovaries (0% of mean ovarian volume was irradiated at > or =2 Gy with protons) and to some extent, the pelvic bones and vertebrae. Intensity-modulated radiotherapy did show more bladder dose reduction than the other techniques in pelvic sarcoma irradiation. CONCLUSIONS: In the diseases studied, using various techniques of 3D-CRT, electrons, IMRT, and protons, protons are most optimal in treating retinoblastomas, medulloblastomas (posterior fossa and craniospinal), and pelvic sarcomas. Protons delivered superior target dose coverage and sparing of normal structures. As dose-volume parameters are expected to correlate with acute and late toxicity, proton therapy should receive serious consideration as the preferred technique for the treatment of pediatric tumors.

Adolescent↗
PubMed2006

Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

PURPOSE: To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS: Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS: Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION: Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Adult↗
PubMed2006

Managing thyroid cancer without thyroxine withdrawal.

Thyroxine (T4) withdrawal or recombinant TSH is used for the stimulation of thyroglobulin (Tg), whole-body scanning (WBS) and iodine-131 treatment in patients with thyroid carcinoma. This study evaluated the T4 dose reduction protocol as an alternative for patients' preparation. Fifty-one patients were submitted to total T4 withdrawal for WBS and Tg measurement. T4 treatment was then resumed and maintained until TSH reached levels < 0.3 mIU/l. The T4 dose was then decreased to 0.8 microg/kg/day and TSH was measured weekly. Tg was assayed when TSH was > 30 mIU/l. Patients diagnosed with the disease upon initial evaluation were treated. We also evaluated the clinical and laboratory changes observed for both preparations. Using the reduced dose protocol, TSH levels > 30 mIU/l were reached within 6 and 8 weeks in 84.6 and 100% of the patients, respectively. T4 withdrawal was associated with more common symptoms of hypothyroidism and elevation of creatine kinase (CK) and LDL cholesterol. The T4 dose reduction protocol proved to be useful for Tg stimulation and ablative therapy, without the complication of severe hypothyroidism or the cost of recombinant TSH.

Adult↗