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P N Lara

Publications and source records attributed to P N Lara.

18 recordsLinked to original sources
PubMed2006

Clinical implications of neuroendocrine differentiation in prostate cancer.

The cellular signaling pathways of the prostate play a central role in the induction, maintenance, and progression of prostate cancer (CaP). Neuroendocrine (NE) cells demonstrate attributes that suggest they are an integral part of these signaling cascades. We summarize what is known regarding NE cells in CaP focusing on NE cellular transdifferentiation. This significant event in CaP progression appears to be accelerated by androgen deprivation (AD) treatment. We examine biochemical pathways that may impact NE differentiation in a chronological manner focusing on AD therapy (ADT) as a central event in inducing androgen-independent CaP. Our analysis is limited to the common adenocarcinoma pattern of CaP and excludes small-cell and carcinoid prostatic variants. In conclusion, we speculate on the future of treatment and research in this area.

Adenocarcinoma↗
PubMed2001

Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment.

PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician's decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9). CONCLUSION: Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.

Adolescent↗
PubMed2001

Activity of high-dose toremifene plus cisplatin in platinum-treated non-small-cell lung cancer: a phase II California Cancer Consortium Trial.

PURPOSE: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status. MATERIALS AND METHODS: A phase II trial of high-dose toremifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled. RESULTS: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6-37). Median overall survival was 8.1 months (95% CI 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-epsilon overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type. CONCLUSION: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.

Adult↗
PubMed2001

Gemcitabine in combination with new platinum compounds: an update.

Combinations of gemcitabine (Gemzar) with cisplatin (Platinol) are among the most active new chemotherapy regimens developed for advanced non-small-cell lung cancer. Carboplatin (Paraplatin) is a platinum analog devoid of many of the nonhematologic toxicities associated with cisplatin. Although few direct comparisons have been made, when administered by area under the concentration-time curve (AUC) dosing, carboplatin is probably equivalent to cisplatin in advanced non-small-cell lung cancer and provides an improved therapeutic index. Based on its favorable toxicity profile, carboplatin has supplanted cisplatin for use in combination with paclitaxel in several different tumor types. Initial trials combining gemcitabine and carboplatin using standard days 1, 8, and 15 dosing of gemcitabine suggested that thrombocytopenia was problematic. More recently, 21-day schedules in which gemcitabine is administered only on days 1 and 8 have demonstrated both efficacy and improved toxicity profiles. Here we review recent studies investigating gemcitabine plus carboplatin and preliminary data regarding combinations of gemcitabine with the new platinum analog oxaliplatin.

Antimetabolites, Antineoplastic↗
PubMed2001

Neoadjuvant therapy for non-small cell lung cancer.

Clinical trials evaluating neoadjuvant or preoperative therapy for locally advanced non-small cell lung cancer (NSCLC) have demonstrated the feasibility, tolerability and activity of this approach. Three randomized trials have reported improved survival in patients with stage III NSCLC treated with preoperative chemotherapy followed by surgical resection compared to surgery alone. Combinations of neoadjuvant chemotherapy plus thoracic radiotherapy have also been investigated, generally resulting in higher rates of pathologic response, but higher toxicity rates as well. The best approach to neoadjuvant therapy remains to be determined and may well be substage dependent. In bulky stage III NSCLC, the role of surgery itself remains unclear and is the subject of an ongoing intergroup trial in the US. Regardless, neoadjuvant therapy has emerged as an important paradigm for clinical research since it serves as an in vivo test of chemosensitivity in patients, and represents a 'window of opportunity' for testing new chemotherapeutic agents and novel strategies. Among the new chemotherapeutic agents being investigated in this setting is docetaxel, one of the most active agents in first- and second-line chemotherapy of NSCLC, and a potent radiosensitizer. Preliminary studies have confirmed the feasibility of integrating docetaxel into neoadjuvant treatment strategies and encouraging results have been reported.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Radioimmunotherapy with (111)In/(90)Y-2IT-BAD-m170 for metastatic prostate cancer.

PURPOSE: Over 31,000 Americans die of androgen-independent metastatic prostate cancer each year. New strategies that do not involve hormonal manipulation but instead recognize the biochemical and molecular characteristics of prostate cancer are needed. Radioimmunotherapy (RIT) uses a tumor-specific monoclonal antibody to deliver systemic, targeted radiation to cancer. The objectives of this Phase I study of (111)In-2IT-BAD-m170 (for imaging) and (90)Y-2IT-BAD-m170 (for therapy) were to determine the toxicity and maximum tolerated dose (MTD), the specificity for targeting metastatic prostate cancer, and the efficacy for palliation of pain. EXPERIMENTAL DESIGN: M170 is a mouse monoclonal antibody that targets adenocarcinomas. Patients with adequate renal and liver function, rising prostate-specific antigen, and androgen-independent metastatic prostate cancer were eligible. After estimation of dosimetry and pharmacokinetics with (111)In-2IT-BAD-m170, a single dose of (90)Y-2IT-BAD-m170 (0.185, 0.370, 0.555, or 0.740 GBq/m(2)) was administered to cohorts of three patients. Pain was assessed objectively by questionnaires before and for 8 weeks after RIT; weekly prostate-specific antigen levels were obtained for 2 months after RIT. RESULTS: The MTD of (90)Y-2IT-BAD-m170 was 0.740 GBq/m(2) for patients that had up to 10% of the axial skeleton involved with prostate cancer. Toxicity was almost exclusively confined to reversible myelosuppression. Metastatic prostate cancer was targeted by (111)In-2IT-BAD-m170 in all 17 patients. The mean radiation dose delivered to 39 bone and 18 nodal metastases by (90)Y-2IT-BAD-m170 was 10.5 Gy/GBq (range 2.8-25.1). Thirteen of 17 patients reported pain before (90)Y-2IT-BAD-m170; 7 of these 13 had a partial or complete resolution of pain that lasted an average of 4.3 weeks. CONCLUSIONS: This study determined the MTD of (111)In/(90)Y-2IT-BAD-m170 in patients with metastatic prostate cancer. The drugs were well tolerated, targeted metastases, and temporarily palliated pain.

Adenocarcinoma↗
PubMed2001

Integration of new chemotherapeutic agents into chemoradiotherapy for stage III non--small cell lung cancer: focus on docetaxel.

Randomized clinical trials have shown that combinations of chemotherapy plus thoracic radiation improve survival compared with radiotherapy alone in stage III non--small cell lung cancer (NSCLC). Furthermore, two recent studies have concluded that concurrent chemoradiotherapy produces superior results to sequential administration. Dependent on the dose and schedule used, chemotherapy may contribute by eradicating distant micrometastases by improving local control as a radiosensitizer, or through both mechanisms. In general, sequential approaches in which full-dose platinum-based chemotherapy precedes thoracic radiation or surgery have improved outcome by impacting distant metastases. In contrast, concurrent chemoradiotherapy using low-dose cisplatin is reported to improve survival by reducing local recurrence without an impact on distant failure rates. In view of these observations, chemoradiotherapy strategies integrating both radiosensitizing agents and dose levels of chemotherapy effective against micrometastases may prove to be most efficacious. Because distant metastases remain the major site of failure, it also is likely that more effective chemotherapy will be required to further improve the current level of response and survival. Fortunately, several newly available chemotherapeutic agents are both highly active against NSCLC and are potent radiosensitizers. In this report we review recent data regarding integration of new chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC, focusing on trials investigating docetaxel. Encouraging results, including those of the Southwest Oncology Group trial 9504, suggest that docetaxel will play a major role in the future of combined-modality therapy for locally advanced NSCLC. Semin Oncol 28 (suppl 9):26-32.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Malignant thymoma: current status and future directions.

Malignant thymomas are rare indolent tumours of the anterior superior mediastinum. Despite a benign histologic appearance, some thymomas invade nearby structures or metastasize. Patients are commonly asymptomatic, but some may present with unusual paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, or hypogammaglobulinemia. Since tumour biopsy may potentially disrupt the thymic capsule, it is often not performed. Patients are therefore diagnosed and staged at the time of definitive surgery. Thymomas can generally be categorized into two stages: non-invasive and invasive. Prognosis closely parallels the disease stage. Surgery is the principal treatment and is curative in early stage disease. Radiation therapy, either alone or in combination with chemotherapy, is an option for both incompletely or completely resected disease. Chemotherapy is offered to patients with locally advanced, recurrent, or metastatic thymoma, with excellent responses and prolonged survival. Multicentre co-operative group clinical trials are required to assess novel thymoma therapies to maximize patient resources in this uncommon tumour.

Combined Modality Therapy↗
PubMed2000

Gemcitabine/carboplatin combination regimens: importance of dose schedule.

Platinum compounds, either cisplatin (Platinol) or carboplatin (Paraplatin), in combination with a number of new chemotherapeutic agents, have demonstrated improved response or survival compared to cisplatin alone or older platinum-based regimens. Gemcitabine (Gemzar)-platinum combinations are of particular interest because of their interactive mechanisms of action, demonstrated preclinical synergism, and the single-agent activity of gemcitabine. Indeed, gemcitabine and cisplatin regimens have proven to be among the most efficacious in the palliative treatment of advanced non-small-cell lung cancer. In view of the reduced nonhematologic toxicities associated with the platinum analogue, carboplatin, several combinations of new agents and carboplatin have been developed and incorporated into clinical practice. This article describes recent clinical trials evaluating gemcitabine plus carboplatin, and the impact of the dosing schedule on the feasibility and tolerability of this combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

PURPOSE: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are uncommon disorders that are generally fatal if left untreated. Plasma exchange therapy is associated with high response rates and improved short-term survival, but most previous studies have been limited by small numbers of patients or short duration of follow-up. METHODS: We performed a retrospective cohort analysis in 126 consecutive patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, most of whom were treated principally with plasma exchange at the Sacramento Medical Foundation Blood (Center and the University of California Davis Medical Center between 1978 and 1998. We measured the effect of therapeutic plasma exchange on 30-day mortality, response rate, and overall survival, and determined which factors were associated with 30-day mortality and relapse. RESULTS: The overall 30-day mortality was 10% of the 122 patients who received plasma exchange as their principal treatment (a median of 9 exchanges and a mean cumulative infused volume of 43 +/- 77 L fresh frozen plasma); 56% were complete responders and 21% were partial responders. The relapse rate was 13%. The estimated 2-year survival was about 60%; among patients without serious underlying comorbid conditions, the estimated 2-year survival was about 80%. Each unit increase in clinical severity score (on a 0 to 8 scale) was associated with a 2.2-fold (95% confidence interval [CI]: 1.3 to 3.9) increase in the odds of 30-day mortality. Patients who were febrile at presentation were substantially less likely to suffer a relapse (odds ratio = 0.2; 95% CI: 0.03 to 0.9). CONCLUSION: Plasma exchange therapy produced high response and survival rates in this large cohort of patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. The Clinical Severity Score may be useful in predicting 30-day mortality, whereas fever at onset was associated with a lesser risk of relapse. Prospective studies should stratify patients according to these prognostic factors.

Adult↗
PubMed1999

Treatment options in androgen-independent prostate cancer.

Metastatic prostate cancer is a leading cause of cancer-related death in men. Although most patients will respond to androgen ablation as initial systemic therapy, nearly all patients will develop androgen-independent prostate cancer (AI CaP) and will succumb to the disease. Advances in molecular biology have demonstrated mutations in and persistent expression of the human androgen receptor in metastatic disease. Furthermore, recent evidence indicates that an apoptotic block through p53 mutations or bcl-2 overexpression may have a potential role in the poor responses seen with standard chemotherapy. Presently, the six general treatment options available for AI CaP are best supportive care, radiation therapy, radioisotopes, secondline hormonal therapy, chemotherapy (single agent or combination), and investigational therapies such as monoclonal antibodies, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, and antiangiogenesis agents, among others. None of these modalities have produced durable remissions, although some have demonstrated palliative benefit. The next generation of clinical trials should not consist of futile hormonal manipulations or repetitive chemotherapy. Therapeutic strategies aimed at circumventing molecular blocks to cell death or targeting unique cancer molecules and genes will be more likely to improve quality of life and longevity. Furthermore, the aggressive use of palliative care will ensure effective caring for patients and the healing of families in the absence of cure.

Adenocarcinoma↗
PubMed1998

High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically.

PURPOSE: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. METHODS: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. RESULTS: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. CONCLUSIONS: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Aged↗
PubMed1997

Neovaginal malignant melanoma following surgery and radiation for vulvar squamous cell carcinoma.

The causal link between therapeutic irradiation and malignant melanoma has not been firmly established. The authors report a novel case of a malignant melanoma arising from a therapeutically irradiated neovagina reconstructed from skin flaps following radical vulvectomy with inguinal lymph node dissection 16 years earlier. The diagnosis was established by light microscopy and immunohistochemical staining. Reports of melanoma arising from sites of previous radiation therapy are reviewed. Our observations suggest that therapeutic radiation may be a factor in the development of malignant melanoma, particularly in non-sun-exposed areas, including the genital tract.

Aged↗
PubMed1996

Retreatment of recurrent invasive thymoma with platinum, doxorubicin, and cyclophosphamide.

Invasive thymoma recently has been shown to be sensitive to combination chemotherapy and in some cases to be relatively indolent. Two cases of extensive thymoma which responded to primary treatment with a combination of a platinum compound (carboplatin or cisplatin), doxorubicin (Adriamycin), and cyclophosphamide (or PAC) are described. Tumor progression occurred 14 (case 1) and 60 months (case 2) after completion of initial PAC therapy and was treated with the same regimen resulting in a second remission, which lasted 6 months in case 1 and is continuing at 8 months in case 2. Similar reports of secondary responses using the same chemotherapy have been described in breast, lung, and ovarian cancers, as well as in Hodgkin's lymphomas. Our observations suggest that retreatment with the same platinum-based regimen should be considered in patients who have progressive thymomas following a previous chemotherapeutic response and a disease-free interval of greater than 12 months.

Adult↗
PubMedDate not supplied

Phase II trial of edatrexate in relapsed or refractory germ cell tumors: a Southwest Oncology Group study (SWOG 9124).

Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast, lung, and head and neck cancers, as well as in non-Hodgkin's lymphomas. A phase II trial of edatrexate in relapsed or refractory malignant germ cell tumors was conducted by the Southwest Oncology Group (SWOG). Twenty-five patients were enrolled in the trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for four weeks followed by a one-week rest period. The treatment course was repeated every five weeks. Among the 23 patients evaluable for response, there were no objective responses with all patients developing progressive disease. Thirteen patients (56%) developed Grade 3-4 toxicities, predominantly stomatitis and malaise/fatigue/lethargy. One patient developed Grade 4 anemia while another developed grade 4 anemia and thrombocytopenia. No patients discontinued treatment due to toxicity nor were there any toxic deaths. Edatrexate administered in this dose and schedule has no antitumor activity and has substantial toxicity in patients with relapsed or refractory germ cell tumors.

Adolescent↗
PubMedDate not supplied

Detection of low level HER-2/neu gene amplification in prostate cancer by fluorescence in situ hybridization.

PURPOSE: Although expression of the HER-2/neu oncogene has been correlated with tumor progression in prostate cancer, the biologic significance of detecting HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) or evidence for protein overexpression by immunohistochemistry (IHC) remains unclear. In this study, we directly compared HER-2/neu FISH and IHC to determine which may be more predictive of the response to trastuzumab. PATIENTS AND METHODS: Forty patients with prostate cancer were analyzed for gene amplification by FISH performed with HER-2/neu and chromosome 17 (CEP 17) DNA probes (Vysis). Protein expression was examined by immunofluorescence and by IHC using the DAKO HercepTest antibody protocol and a monoclonal antibody to Her-2/neu on archival paraffin sections. The patients included 30 men with primary tumors that were treated with radical prostatectomy. Of these, 15 demonstrated subsequent disease progression within 3 years. Five patients with prostatic intraepithelial neoplasia were tested, as were five with metastatic disease whose samples were obtained before androgen ablation therapy. RESULTS: None of the 30 primary prostate cancer specimens showed overexpression for HER-2/neu by immunofluorescence or by IHC with the DAKO protocol. One sample showed 3+ membrane expression with the monoclonal antibody. In contrast, low copy number gene amplifications (3-8 HER-2/neu signals/nucleus) were detected in 16 of 30 samples (53%) by FISH. Most amplified cells were diploid for CEP 17, demonstrating that amplification was not due to total cell aneuploidy. FISH and IHC determined that prostatic intraepithelial neoplasia samples were normal. Four of five (80%) metastatic samples were amplified for HER-2/neu by FISH. Nearly 70% of metastatic cancer cells among all five specimens demonstrated aneuploidy. A single lymph node metastasis showed 3+ membrane staining by IHC (DAKO). CONCLUSIONS: In contrast to breast cancer, FISH detects HER-2/neu amplification in a substantial proportion of prostate cancers that do not overexpress HER-2/neuby IHC. Although the biologic significance of this finding is uncertain, it has implications for the direction of current and planned clinical trials of trastuzumab in advanced prostate cancer, including determination of patient eligibility.

Adenocarcinoma↗