Interferon alpha for the treatment of superficial bladder cancer.
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Publications and source records attributed to J Franklin.
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The current phase-II trial was initiated to assess the efficacy and toxicity of the Ida-FLAG regimen in patients with poor-risk acute myeloid leukemia (AML). Three subgroups of patients with AML were eligible for the study: (a) refractory, (b) first relapse, or (c) secondary AML (i.e., signs of trilineage myelodysplasia at diagnosis or the history of a myelodysplasia or myeloproliferative disorder). Fifty-seven fully evaluable patients were included in the study. Twenty patients received a second course of Ida-FLAG. Complete remission was achieved by 1/14 patients with refractory AML, 12/15 patients with relapsed AML, and 17/28 patients with secondary AML. The median duration of ANC <1000/microl was 17 days (10-36); of platelets <30,000/microl 23 days (9-65); of days with fever >38.0 degrees C 6 days (1-33). Thirteen patients (22.8%) died within 42 days of severe infection or hemorrhage. Overall survival at 20 weeks in the subgroups was 24% for patients with refractory, 78% for patients with relapsed, and 55% for patients with secondary AML. The toxicity of the first cycle of Ida-FLAG is moderate. The feasibility and subjective tolerance of the Ida-FLAG regimen are acceptable. There is no evidence for an increase of atypical infections. The efficacy for patients with secondary AML and especially those with first relapse of AML is good, with a high rate of complete remissions. Remission duration seems to be short. Therefore, an intensified post-remission therapy seems necessary.
OBJECTIVE: We sought to compare our 5-year program of fragile X screening of high-risk gravid women with our program of fragile X testing of affected individuals (probands). STUDY DESIGN: All women referred to the prenatal genetics clinic from 1994 to 1998 who had a family history of unspecified mental retardation or learning or behavioral disorders (known fragile X families excluded) were offered fragile X screening. Results were compared with those of probands with the same diagnoses who underwent fragile X testing during the same time period. RESULTS: We counseled 12,349 prenatal patients from 1994-1998, of whom 263 (2.1%) had a positive family history and underwent fragile X screening. No mutations or premutations were identified. In contrast, 31 (1.9%) of 1637 affected probands who underwent fragile X testing during the same time period had positive results, which was a significant difference (0/263 vs 31/1637; P <.05). CONCLUSIONS: Testing the affected proband is superior to screening the pregnant relative of the proband for identification of families at risk for fragile X syndrome.
PURPOSE: Recent studies have suggested that lymphocyte-predominant Hodgkin's disease (LPHD) is both clinically and pathologically distinct from other forms of Hodgkin's disease, including classical Hodgkin's disease (CHD). However, large-scale clinical studies were lacking. This multicenter, retrospective study investigated the clinical characteristics and course of LPHD patients and lymphocyte-rich classical Hodgkin's disease (LRCHD) patients classified according to morphologic and immunophenotypic criteria. MATERIALS AND METHODS: Clinical data and biopsy material of all available cases initially submitted as LPHD were collected from 17 European and American centers, stained, and reclassified by expert pathologists. RESULTS: The 426 assessable cases were reclassified as LPHD (51%), LRCHD (27%), CHD (5%), non-Hodgkin's lymphoma (3%), and reactive lesion (3%); 11% of cases were not assessable. Patients with LPHD and LRCHD were predominantly male, with early-stage disease and few risk factors. Patients with LRCHD were significantly older. Survival and failure-free survival rates with adequate therapy were similar for patients with LPHD and LRCHD, and were stage-dependent and not significantly better than stage-comparable results for CHD (German trial data). Twenty-seven percent of relapsing LPHD patients had multiple relapses, which is significantly more than the 5% of relapsing LRCHD patients who had multiple relapses. Lymphocyte-predominant Hodgkin's disease patients had significantly superior survival after relapse compared with LRCHD or CHD patients; however, this was partly due to the younger average age of LPHD patients. CONCLUSION: The two subgroups of LPHD and LRCHD bore a close clinical resemblance that was distinct from CHD; the course was similar to that of comparable nodular sclerosis and mixed cellularity patients. Thorough staging is necessary to detect advanced disease in LPHD and LRCHD patients. The question of how to treat such patients, either by reducing treatment intensity or following a "watch and wait" approach, remains unanswered.
The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level.
Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RAS point mutations in these samples. We confirmed mutations of NF1 in three leukemias, one of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.
PURPOSE: We provide scientists and clinicians with an introduction to the basic principles and methods of positron emission tomography (PET) and summarize the recent research and clinical applications of PET in the urological field. Specifically, we introduce PET so that the reader can understand and objectively review current and future articles that involve this imaging technology. MATERIALS AND METHODS: The recent applications of PET in urology in the published literature were searched and reviewed. RESULTS: In prostate carcinoma preliminary studies using radiotracer 18-fluoro-2-deoxyglucose (FDG) demonstrated that PET cannot reliably differentiate between primary prostate cancer and benign prostatic hyperplasia, and that PET is not as sensitive as bone scintigraphy for the detection of osseous metastases. However, PET may have a role in the detection of lymph node metastases in patients with prostate specific antigen relapse after primary local therapy. In renal cell carcinoma recent studies have shown the ability of FDG PET to detect primary and metastatic lesions and to monitor response to therapy. In the staging of testicular cancer FDG PET has been used to differentiate viable carcinoma from benign teratomas and/or fibrotic or necrotic changes. CONCLUSIONS: Current developments in PET technology that accurately stage the extent of tumor before surgery as well as monitor effectiveness or ineffectiveness of new or current therapies may make PET a valuable tool in research and in the management of urological diseases.
Epidemiological data suggest long-term oxygen therapy (LTOT) delivered by oxygen concentrators in patients with severe hypoxic chronic obstructive pulmonary disease (COPD) is under-prescribed by General Practitioners (GPs) in England and Wales. One reason for this may be the unavailability to GPs of a measure of arterial oxygenation needed to fulfil the defined prescription criteria. Provision of a non-invasive measure of oxygenation may improve detection of hypoxic subjects and increase appropriate prescribing. This study aimed to evaluate pulse oximetry in a general practice setting and to screen for severe undetected hypoxaemia fulfilling the LTOT prescription criteria in patients with COPD. All COPD patients attending surgery in two practices were screened with oximeters for hypoxaemia. Those with an oxygen saturation of < or = 92% were referred to hospital for formal arterial blood gas analysis and an oxygen concentrator assessment. GPs were asked to evaluate their experience in the ease of use and application of oximetry. The number of patients receiving oxygen by concentrator before the study was compared with the national rate and the number after the study with the estimated need suggested by epidemiological studies. Over a 12-month period a total of 114 patients were screened in the two practices with a combined list size of 15,742. Thirteen patients had saturations of < or = 92%. Two refused and 11 underwent formal arterial gas analysis. Three had PaO2 < 7.3 kPa and new prescriptions for oxygen concentrators were made in these previously unsuspected severely hypoxaemic subjects as a result. One other hypoxaemic subject was referred and found to have another treatable medical condition. The initial prevalence of concentrator prescription (0.013% CI 0.003, 0.047) was similar to the national rate (0.024%) and the prevalence observed after screening (0.031%, CI 0.013, 0.073) fell within the lower suggested prescription need of previous epidemiological data (0.02-0.10%). All practitioners found the oximeters simple to use and helpful in assisting with assessment of the severity of their patient's condition. Oximetry provides a readily usable non-invasive method of screening and when applied to all COPD patients seen in general practice can reveal those fulfilling the criteria for long term oxygen who would otherwise not be identified as needing this treatment.
The special nature and course of lymphocyte rich variants of Hodgkin's disease (HD) has been the subject of pathological and clinical studies since the 1930s. Patients with lymphocyte predominant (LP) HD, predominantly male and 25-45 years old, usually present with early clinical stage, cervical or inguinal involvement and few if any adverse prognostic factors. The disease progresses slowly, with fairly frequent relapses which are rarely fatal. Nonetheless, cases with advanced stage and deaths from Hodgkin's disease have been observed in LPHD. Recently, immunological studies have lead to a clear distinction between LPHD and classical HD including a lymphocyte rich classical version (LRCHD). Secondary low-grade NHLs occur more frequently after LPHD than after classical HD. They seem to be disease-related rather than treatment-induced. LPHD patients in earlier studies have tended to have a better prognosis than classical HD patients. When cohorts of the same clinical stage are compared, under modern protocol treatment this advantage seems to be minimal or absent. LPHD patients tend to relapse frequently but they survive these relapses better than classical HD patients. The resemblance to non-neoplastic disorders, capability for ongoing mutation, favorable clinical presentation and good survival rates after relapse all suggest that the optimal primary treatment strategy might be less intensive for LPHD than for classical HD. Late toxicities, which contribute considerably to the death rate, could thus be reduced. The long survival of several early stage LPHD patients without any treatment beyond lymph node excision could favour a 'watch-and-wait' strategy, albeit only after rigorous staging. New experimental therapy techniques such as immunotherapy might also be suitable. These possibilities must first be tested in a large-scale prospective study.
The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.
Bioinformatics has developed as a key discipline to support science. Integrated access to the various new and established information resources is a key requirement for their future utility. A strategy for this integration has been developed and is being demonstrated to a core group of European users.
PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.
BACKGROUND: A survival disadvantage for black women with breast cancer, which persists after controlling for stage of the disease, has been reported. This study investigates the effects of race and socioeconomic status (SES) on breast cancer survival after controlling for age, stage, histology, and type of treatment. METHODS: Kaplan-Meier and Cox proportional hazards models were used to analyze the interaction between race and SES in predicting survival in a sample of 163 black, 205 Hispanic and 964 white women with breast cancer treated at M.D. Anderson Cancer Center a (1987-1991). RESULTS: The results of univariate and multivariate analyses indicate that race was not a significant predictor of survival after adjusting for SES and other confounding factors such as demographic and disease characteristics. SES remained a significant predictor of survival after all adjustments were made. There was no evidence of differences in type of treatment by race or SES if adjustments were made for stage. CONCLUSIONS: These results suggest that institutional factors, such as access to treatment, do not explain survival differences by race or SES. Other factors associated with low SES, such as life-style and behavior, may affect survival.
PURPOSE: We studied the correlation between prostate specific antigen (PSA) doubling time or, equivalently, log slope PSA and clinical recurrence in patients with detectable PSA after radical retropubic prostatectomy who were followed expectantly. MATERIALS AND METHODS: In patients with PSA recurrence after radical retropubic prostatectomy log slope PSA was determined from the difference in the 2 log PSA values divided by the time between readings in months. For a given slope the corresponding PSA doubling time was calculated as log x 2 divided by the slope of the log PSA line. When the initial PSA value was considerably greater than 0.4 ng./ml., the log slope PSA plot was extrapolated to determine the time point at which PSA would have become detectable (0.4 ng./ml.). The relationship between these values, and the time and pattern of clinical recurrence were studied. RESULTS: In this series of 77 patients 80% with PSA doubling time of 6 months or greater remained clinically disease-free compared to 64% with PSA doubling time less than 6 months. PSA doubling time had better correlation with time to clinical recurrence after PSA became detectable (p <0.001 Cox proportional hazards model) than Gleason sum, pathological stage or margin status. Biochemical recurrence within 3 months was associated with early clinical recurrence (p <0.002). In addition, short PSA doubling time, that is a high log slope, regardless of the time at which PSA became positive was strongly associated with clinical recurrence (p <0.001). Distant recurrence was invariably associated with short PSA doubling time. Conversely, local recurrence reliably correlated with long PSA doubling time, that is a low log slope. CONCLUSIONS: After PSA became detectable PSA doubling time or, equivalently, log slope PSA, was a better indicator of the risk and time to clinical recurrence after radical retropubic prostatectomy than preoperative PSA, specimen Gleason sum or pathological stage. Hormone treatment may be targeted to patients at high risk for early metastatic clinical recurrence, appropriately timed radiation can be offered for proved local recurrence in those with long PSA doubling time and expectant treatment may be proposed for those with long PSA doubling time who remain clinically disease-free. Frequent and expensive imaging does not appear to be cost-effective in this latter group.
PURPOSE: To determine the appropriate irradiation dose after four cycles of modern combination chemotherapy in nonbulky involved field (IF/BF) and noninvolved extended-field (EF/IF) sites in patients with intermediate-stage Hodgkin's disease (HD). MATERIALS AND METHODS: HD patients in stage I to IIIA with a large mediastinal mass, E stage, or massive spleen involvement were treated with two double cycles of alternating cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) plus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by EF irradiation in two successive trials (HD1 and HD5). In the HD1 trial (1983 to 1988), 146 patients who responded to chemotherapy were randomized to receive 20 Gy (70 patients) or 40 Gy (76 patients) of EF irradiation in all fields outside bulky disease sites. A cohort of 111 patients who fulfilled the same inclusion criteria in the subsequent trial HD5 (1988 to 1993) were treated with 30 Gy. Bulky disease always received 40 Gy. RESULTS: Freedom-from-treatment-failure (FFTF) and survival (SV) curves showed no differences between the 20-, 30-, and 40-Gy groups. However, acute toxicities were more frequent in the 40-Gy arm. Analysis of relapse patterns showed that 18 of 26 relapsing patients either failed to respond in initial bulky sites (n = 5) or had an extranodal relapse (n = 9) or both (n = 4). After 5 years, the cumulative risk for relapse in bulky sites is 10%, despite 40 Gy of radiation. CONCLUSION: Our results strongly suggest that there is no relevant radiotherapy dose effect in the range between 20 Gy and 40 Gy in IF/BF and EF/IF after 4 months of modern polychemotherapy in patients with intermediate-stage HD. Relapse patterns indicate that patients destined to relapse need more systemic, rather than local, treatment. Based on our data, we conclude that 20 Gy is sufficient in EF/IF of intermediate-stage HD following four cycles of modern polychemotherapy.
There is wide consensus that lymphocyte predominance Hodgkin's disease (LPHD) represents a distinct clinicopathological entity of B-cell origin. However, inconsistent results of immunophenotyping studies and low confirmation rates among multi-center trials pose the question of whether LPHD really expresses heterogeneous marker profiles or whether it represents a mixture of morphologically similar entities. Among 2,836 cases reviewed by the German Hodgkin Study Group, immunophenotyping was performed on 1) cases classified or confirmed as LPHD by the reference panel (n = 104) or 2) cases not confirmed as LPHD but classified as classical HD (cHD) within the reference study trial (n = 104). In most cases, immunohistochemistry revealed a phenotype either LPHD-like (CD20+, CD15-, CD30-, CD45+) or cHD-like (CD15+, CD30+, CD20-, CD45-). In 27 cases, the immunophenotype was not fully conclusive. Additional markers for Epstein-Barr virus and CD57 and in situ hybridization for mRNA light chains allowed for a more clear-cut distinction between LPHD and cHD. However, in 25 of 104 cases, immunohistochemistry disproved the morphological diagnosis of LPHD of the panel experts, whereas 13 cases originally not confirmed as LPHD showed a LPHD-like immunopattern. Immunohistochemically confirmed LPHD cases showed a significantly better freedom from treatment failure (P = 0.033) than cHD; this was not observed in the original study classification based only on morphology (P > 0.05). Significantly better survival for LPHD cases improved from P = 0.047 (original study classification) to P = 0.0071 when classified by immunohistochemistry. Our results show that LPHD is a more immunohistochemical rather than a purely morphological diagnosis. Immunophenotyping of HD biopsies suspected of being LPHD is mandatory when a modified therapy protocol, that is, one different from those used in cHD, is discussed.
Antibodies against CD15, -30, and -20 are often used to support morphological diagnosis of Hodgkin's Disease (HD). The classical HD, i.e., the non-lymphocyte-predominance types, are CD15+, CD30+, and CD20- in general. However, the results for CD15 are less clear-cut in many studies, showing up to 40% of classical HD that lack positivity for this maker. Little is currently known about the relevance of antigen expression in relation to clinical outcome in HD. Therefore, the three markers were analyzed in 1751 cases from the German Hodgkin Study Group, using micro-wave epitope retrieval to optimize staining sensitivity. Eighty-three percent of the cases showed a classical immunophenotype (CD15+, CD30+, CD20-), twelve percent lacked CD15 positivity (CD15-, CD30+, CD20-), and five percent showed other combinations. For 1286 cases, clinical follow-up was available, which revealed significant differences for freedom from treatment failure (P = 0.0022) and overall survival (P = 0.0001) between cases with classical immunophenotype and CD15 negativity (CD30+, CD20-). Multivariate Cox regression using the three markers, age, sex, histology, stage, B-symptoms (fever, sweats, weight loss > 10% of body weight), hemoglobin, and erythrocyte sedimentation rate as factors showed that lack of CD15 expression in classical HD is an independent negative prognostic factor for relapses (P = 0.022) and survival (P = 0.0035). In conclusion, immunohistochemistry is able to identify classical HD cases with unfavorable clinical outcome.