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Biomedical subjects

John Crowley

Publications and source records attributed to John Crowley.

31 records · Page 2Linked to original sources
PubMed2004

Randomized phase II trial of sequential chemotherapy in advanced non-small cell lung cancer (SWOG 9806): carboplatin/gemcitabine followed by paclitaxel or cisplatin/vinorelbine followed by docetaxel.

PURPOSE: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new drugs or new strategies to better use currently available agents. Sequential administration offers an opportunity to increase drug diversity while maintaining dose intensity. On the basis of the data indicating the activity of taxanes as second-line therapy and the lack of efficacy for more than three cycles of platinum-based therapy, this randomized Phase II study tested the concept of planned sequential chemotherapy in advanced NSCLC. EXPERIMENTAL DESIGN: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0-1 and normal organ function were eligible. THERAPY: arm 1, carboplatin (area under the curve = 5.5 mg/ml x min day 1) and gemcitabine (1000 mg/m(2) days 1 and 8 every 21 days x 3) followed by paclitaxel (225 mg/m(2) every 21 days x 3) or arm 2, cisplatin (100 mg/m(2) day 1), vinorelbine (25 mg/m(2) days 1 and 8 every 21 d x 3) followed by docetaxel (75-100 mg/m(2) every 21 days x 3). RESULTS: Two-hundred four patients were accrued, of whom, 178 were eligible and evaluable. Eighty percent of patients were stage IV on arm 1 and 85% on arm 2. Response rates were 21 and 28% on arms 1 and 2, respectively. Median, 1-year and 2-year survivals were 9 months, 34 and 13%, and 9 months, 36 and 8%, on arms 1 and 2, respectively. CONCLUSIONS: Sequential therapy, as used in this study, resulted in comparable efficacy to previous Southwest Oncology Group trials of two drug combinations in this population; however, it failed to meet criteria for further study.

Adenocarcinoma↗
PubMed2004

Bronchioloalveolar carcinoma: a model for investigating the biology of epidermal growth factor receptor inhibition.

Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Magnitude of response with myeloma frontline therapy does not predict outcome: importance of time to progression in southwest oncology group chemotherapy trials.

PURPOSE: Four Southwest Oncology Group (SWOG) standard-dose chemotherapy protocols for multiple myeloma (MM) initiated between 1982 and 1992 were evaluated. The purpose was to clarify the predictive value of specific levels of myeloma-associated monoclonal protein reduction and time to first progression using mature data sets. PATIENTS AND METHODS: Study data on 1,555 eligible previously untreated patients with MM enrolled onto SWOG phase III trials 8229, 8624, 9028, and 9210 were used in these analyses. Six-month and 12-month landmark analyses were performed to evaluate the outcome for patients in each response category. RESULTS: The overall and event-free survivals for the four protocols combined were 33 months and 18 months, respectively. Using 6- and 12-month landmarks, the median survivals of 30 to 35 months were not different for responders (> or = 50% and > or = 75% regression) versus nonresponders in patients without disease progression before the landmarks. Conversely, at the 6- and 12-month landmarks, the median survivals for patients who had experienced disease progression were 13 and 15 months, respectively, versus a 34-month median for patients who did not experience progression. Using the Cox survival model, with response and progression considered as time-dependent covariates, survival duration was influenced more by the occurrence of progression than by the occurrence of response. CONCLUSION: The magnitude of response, as a single variable, does not predict survival duration. Patients with response and stable disease have equivalent outcome. Only patients with progressive disease have a poorer outcome. The best indicator of survival is time to first progression.

Adult↗
PubMed2004

Phase II trial of cisplatin/etoposide and concurrent radiotherapy followed by paclitaxel/carboplatin consolidation for limited small-cell lung cancer: Southwest Oncology Group 9713.

PURPOSE: Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC. PATIENTS AND METHODS: Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m(2) on days 1, 8, 29, and 36, and etoposide 50 mg/m(2) on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m(2), both drugs administered on day 1 of a 21 day cycle for three cycles. RESULTS: The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%. CONCLUSION: Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.

Adult↗
PubMed2003

In-situ near infrared spectroscopy to monitor key analytes in mammalian cell cultivation.

The use of in-situ near infrared spectroscopy (NIRS) as a tool for monitoring four key analytes in a CHO-K1 animal cell culture was investigated. Previous work using on-line NIRS to monitor bioprocesses has involved its application ex-situ where the analyzer is physically outside the fermentor, or to microbial bioprocesses. This novel application of NIRS to monitor analytes within an animal cell culture using a steam sterilizable in-situ fiber optic probe is very important for furthering the use of NIRS within the bioprocessing industry. The method of calibration used to develop the models involved the use of large data sets so that all likely variation in stoichiometry was incorporated within the models. Successful models for glucose, lactate, glutamine, and ammonia were built with Standard Error of Predictions (SEP's) of 0.072 (g/L), 0.0144 (g/L), 0.308 (mM), and 0.036 (mM), respectively of the total concentration range.

Ammonia↗
PubMed2003

Treatment of multiple myeloma.

Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

Amyloidosis↗
PubMed2003

Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504.

PURPOSE: To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer (NSCLC). Results were compared with those of the predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. PATIENTS AND METHODS: Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33, and concurrent thoracic radiotherapy (total dose of 61 Gy). Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2. RESULTS: Stage subsets (tumor-node-metastasis system) in 83 eligible patients were as follows: T4N0/1, 31 patients (37%); T4N2, 22 patients (27%), and T1-3N3, 30 patients (36%). Concurrent chemoradiotherapy was generally well tolerated, but two patients died from probable radiation-associated pneumonitis. Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively. CONCLUSION: Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019. Nevertheless, this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach. Phase III trials evaluating the S9504 regimen have been initiated to validate these results.

Adult↗
PubMed2003

Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression.

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

MDS-type abnormalities within myeloma signature karyotype (MM-MDS): only 13% 1-year survival despite tandem transplants.

Cytogenetic abnormalities (CA), especially of chromosome 13, have been used to identify a subgroup of previously untreated multiple myeloma (MM) patients with very poor prognosis despite high-dose therapy (HDT). We examined the prognostic implications of CA in 1000 MM patients receiving melphalan-based tandem autotransplants (median follow-up, 5 years). Negative consequences for both overall survival (OS) and event-free survival (EFS) in the presence of any CA were confirmed, especially when detected within 3 months of HDT. In the context of standard prognostic factors (SPF), 'MM-MDS' (MM karyotype that contains, in addition, CA typical of MDS) imparted a poor OS and EFS, after adjusting for any CA and all individual CA. One-year mortality was also high, especially for the MM-MDS subgroup with trisomy 8 within a MM signature karyotype (87%vs 34% in its absence, P < 0.001). No patient remained event free 5 years post transplant in the presence of these baseline high-risk CA. However, certain trisomies (e.g. chromosomes 7 and 9) and del 20 had favourable clinical consequences. The higher risk that is associated with CA compared with SPF justifies routine cytogenetic studies in all patients with MM at diagnosis and whenever additional treatment decisions are considered, such as in planning HDT either for initial response consolidation, at the time of primary unresponsiveness to induction therapy, or at relapse.

Antineoplastic Agents, Alkylating↗
PubMed2003

Antenatal screening for human platelet antigen-1a: results of a prospective study at a large maternity hospital in Ireland.

OBJECTIVE: Fetomaternal mismatch for human platelet antigen (HPA)-1a accounts for approximately 85% of cases of neonatal alloimmune thrombocytopenia. The purpose of the study was to determine the prevalence of the HPA-1a negative platelet phenotype in a cohort of pregnant women in Ireland, the rate of alloimmunisation to HPA-1a in HPA-1 mismatched pregnancies and the associated incidence of neonatal alloimmune thrombocytopenia. DESIGN: A prospective case-control study. SETTING: The antenatal clinics of a large maternity teaching hospital. POPULATION OF SAMPLE: Pregnant women, regardless of parity, presenting at the antenatal clinics. METHODS: An enzyme-linked immunosorbent assay (ELISA) designed for simultaneous HPA-1a typing and antibody detection was used. Further analysis for HPA-1a alloantibodies was performed using commercial ELISA's (GTI PakPlus and Pak1) and the monoclonal antibody immobilisation of platelet antigens assay. Confirmation of serological typing was by the polymerase chain reaction technique using sequence-specific primers (PCR-SSP). MAIN OUTCOME MEASURES: The presence of the HPA-1a negative phenotype and its association with the development of maternal anti-HPA-1a and infant thrombocytopenia. RESULTS: Eighty-four of 4090 consecutive women enrolled in the study tested positive for HPA-1a in the screening ELISA. Confirmatory genotyping was performed on 67 women (representing 80% of the cohort), and 54 women (representing 3272 non-selected pregnancies), were homozygous for the HPA-1b allele (1.7%). Three of 34 (9%) women who delivered HPA-1a positive babies had detectable anti-HPA-1a and all three babies had neonatal alloimmune thrombocytopenia, for an overall incidence of 1:1100 non-selected pregnancies. CONCLUSIONS: The observed prevalence of 1.7% for the HPA-1a negative platelet phenotype is as expected from studies in other countries. While we have demonstrated the practicability of antenatal HPA-1a screening, further research is warranted to investigate maternal parameters predictive of severe fetal thrombocytopenia in HPA-1a alloimmunised pregnancies.

Antigens, Human Platelet↗
PubMed2002

Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.

Bone marrow plasma cells (PCs) from 74 patients with newly diagnosed multiple myeloma (MM), 5 with monoclonal gammopathy of undetermined significance (MGUS), and 31 healthy volunteers (normal PCs) were purified by CD138(+) selection. Gene expression of purified PCs and 7 MM cell lines were profiled using high-density oligonucleotide microarrays interrogating about 6800 genes. On hierarchical clustering analysis, normal and MM PCs were differentiated and 4 distinct subgroups of MM (MM1, MM2, MM3, and MM4) were identified. The expression pattern of MM1 was similar to normal PCs and MGUS, whereas MM4 was similar to MM cell lines. Clinical parameters linked to poor prognosis, abnormal karyotype (P =.002) and high serum beta(2)-microglobulin levels (P =.0005), were most prevalent in MM4. Also, genes involved in DNA metabolism and cell cycle control were overexpressed in a comparison of MM1 and MM4. In addition, using chi(2) and Wilcoxon rank sum tests, 120 novel candidate disease genes were identified that discriminate normal and malignant PCs (P <.0001); many are involved in adhesion, apoptosis, cell cycle, drug resistance, growth arrest, oncogenesis, signaling, and transcription. A total of 156 genes, including FGFR3 and CCND1, exhibited highly elevated ("spiked") expression in at least 4 of the 74 MM cases (range, 4-25 spikes). Elevated expression of these 2 genes was caused by the translocation t(4;14)(p16;q32) or t(11;14)(q13;q32). Thus, novel candidate MM disease genes have been identified using gene expression profiling and this profiling has led to the development of a gene-based classification system for MM.

Bone Marrow Cells↗
PubMed2002

Partitioning and peeling for constructing prognostic groups.

We investigate methods for identifying groups of patients with different prognosis. Our focus is on procedures that yield interpretable descriptions for groups of patients and corresponding regions of the predictor space. These strategies include tree-based methods and techniques which construct a single prognostic group through 'peeling' or refining of a larger group patients. The peeling methods are relatively new and are developed in detail. Simulations and examples for describing groups of patients with poor outcomes using data from a clinical trial for patients with multiple myeloma are presented.

Algorithms↗