Pamidronate infusions as single-agent therapy for bone metastases: a phase II trial in patients with breast cancer

Pamidronate is a potent biphosphonate which modulates tumour-induced osteolysis (TIO) by inhibiting osteoclast-mediated bone resorption. In a phase II trial, 69 breast cancer patients with symptomatic progressive bone metastases were given infusions of pamidronate 60 mg over 1 or 4 h every 2 weeks for a maximum of 13 infusions or until progressive disease (PD) at any site. No other systemic anticancer therapy was allowed. Pain was measured using a visual analogue scale, mobility using a detailed eight-point questionnaire and analgesic intake using a six-point scale. Improvements in pain, mobility and analgesic scores occurred in 61, 50 and 30% of patients, respectively, with 33, 21 and 16% achieving a 40% improvement for > or = 8 weeks. At trial discontinuation, baseline levels of pain and mobility had improved by 27% (P = 0.001) and 20% (P = 0.004), respectively, despite a one category reduction in analgesic intake in 27% of patients. Using this relatively high dose of pamidronate, symptomatic response was independent of the number of bone metastases and also of infusion rate. The infusions were well tolerated with no major toxicities reported. Pamidronate infusions provide useful palliation for breast cancer patients with symptomatic bone metastases.     

Prognostic significance of bone metastases in patients with metastatic prostate cancer

BACKGROUND: The distribution of bone metastases on a bone scan has not been duly considered when assessing the prognosis of metastatic prostate cancer. METHODS: The medical records of 76 patients with newly diagnosed, untreated metastatic prostate cancer were reviewed. According to the distribution of bone metastases on the initial bone scan, we divided the patients into three groups: Group I (having bone metastases exclusively within the pelvis and the lumbar spine), Group II (having bone metastases exclusively outside these bones), and Group III (having bone metastases in both areas). RESULTS: Among the responders to androgen deprivation, those in Group I survived significantly longer than did those in Groups II or III. Because the extent of the disease and the distribution of histologic differentiation in Groups I and II were similar, the results indicate that the presence of bone metastases outside the pelvis and the lumbar spine is predictive of short survival time. This prediction was not possible when the extent of disease (EOD) grading system was used. CONCLUSION: The distribution of bone metastases on the initial bone scan should be considered as a variable for the prognostic stratification of patients with metastatic prostate cancer.     

Common goal determination in occupational health--experiences in North-Rhine Westphalia with a system of health conferences

There is a pressing need for new agents for the treatment of hormone-resistant prostate cancer (HRPC). Pyrazoloacridine (PZA) has antitumor activity in several in vitro and in vivo tumor systems, and was selected for testing in clinical trials by the National Cancer Institute (NCI). We conducted a phase II trial of PZA for the treatment of HRPC. Seventeen male patients with HRPC were treated with PZA at 750 mg/m2 i.v. given over a period of 3 hr every 3 weeks. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. The 17 patients were treated and fully evaluable. One patient experienced a significant decrease in PSA, from over 10,000 ng/ml to 423 ng/ml, along with an improvement in bone scan findings. However, no other patient obtained an objective or PSA response (overall PSA response rate = 5.9%). Median survival duration was 15.3 months. Toxicity was moderate. If PSA is used as a marker of response, single-agent PZA appears to lack efficacy in the treatment of HRPC. However, the one unambiguous response, and the favorable toxicity profile observed, may warrant further evaluation of this agent.     

Management of hormone refractory prostate cancer: current standards and future prospects

PURPOSE: Recent advances in the biology and treatment of hormone refractory prostate cancer are reviewed. MATERIALS AND METHODS: A MEDLINE literature search of secondary hormonal therapy and chemotherapy for hormone refractory prostate cancer was performed. Recent advances in the biology of hormone refractory prostate cancer, changes in the measurement of response to therapy, and testing of new drugs and combinations of drugs were reviewed. RESULTS: Historically the treatment of hormone refractory prostate cancer has been disappointing. Useful parameters to monitor clinical response have been lacking but perhaps more importantly a scarcity of apparently active drugs has contributed to these results. Recently several developments have improved the outlook for treatment of hormone refractory prostate cancer. Recognition of antiandrogen withdrawal responses has had important ramifications for clinical trial interpretation and patient care. Secondary hormonal therapies, such as alternative antiandrogens and anti-adrenal agents, are well tolerated and can provide significant clinical benefits. Combining prostate specific antigen values with quality of life and measurable disease responses has made clinical trial end points more objective and more clinically relevant for the patient. Furthermore, a better understanding of the biology of hormone refractory prostate cancer, refinements in measuring response to treatment and availability of agents with proved palliative capabilities and/or generating greater than 50% response have all lead to improvements in treatment management. In 2 randomized studies mitoxantrone in combination with steroids has demonstrated significant palliative benefit compared with steroids alone. In phase II studies more than half of patients respond to estramustine combinations with vinblastine, etoposide or paclitaxel. Other novel combinations and new drugs currently are being tested. CONCLUSIONS: Recent advances suggest that available therapies for hormone refractory prostate cancer can have a meaningful impact on the disease. Improving treatment of hormone refractory prostate cancer remains an area of active investigation.     

A practical approach to breast ductal carcinoma in situ and tumors with an extensive intraductal component

Seventy-two patients were admitted in a multicentre trial with the purpose of assessing the clinical efficacy and safety of the hormonal control and tolerance of leuprolide acetate in a once-a-month depot injection formulation for the treatment of disseminated prostate cancer. During a 1-year follow-up, there were ten withdrawals for different reasons. At baseline and at 6 months of treatment the following parameters were evaluated: clinical examination, routine blood analysis, PAP, PSA, LH and testosterone, as well as bone scan. LH and testosterone determinations were repeated at 2, 4, 8, 12, 16, 20 and 24 weeks. Testosterone reached castration levels within the second week and was maintained until the end of the study. In agreement with the NPCP criteria, 65 patients were assessed as: complete response 3%, partial response 40%, disease stabilization 36%, and progression 21%. In summary, a once-a-month injection of leuprolide acetate offers a safe and effective alternative to surgical castration.     

Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables

BACKGROUND: A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. METHODS: Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 micrograms/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response. RESULTS: Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. CONCLUSION: Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeutic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin.     

Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin

OBJECTIVES: Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. METHODS: A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. RESULTS: Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. CONCLUSIONS: Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.     

Effect of cell differentiation in prostatic cancer on basal PSA

The effect of cell differentiation on PSA production in patients with prostate cancer has been evaluated. With this intention 70 patients were included and were analyzed for age, T stage, cell differentiation, bone scan involvement and PSA level prior to therapy. In well-differentiated tumours mcan PSA was 31.3 ng/mL, 56.6 in those with moderate differentiation and 31.6 in poorly differentiated ones (p > 0.05). Multivariate analysis shows no significant differences between both variables, but and inverse relationship between cell differentiation and PSA production (r = -0.27, p > 0.05) can be seen. The most influential variable on PSA levels was de extent of bone scan involvement. Cell differentiation as confusion variable to interpret PSA values in poorly differentiated tumours deserves further study to know the exact role of this protein as a treatment response criterion in prostate cancer.     

A new parameter for measuring metastatic bone involvement by prostate cancer: the Bone Scan Index

In this report, we describe a method for quantitative bone scan interpretation (the Bone Scan Index or BSI) in advanced prostate cancer. The BSI estimates the fraction of the skeleton that is involved by tumor, as well as the regional distribution of the metastases in the bones. The purpose of this report is to describe the development and validation of this method in terms of reproducibility and the application of BSI for determining extent of disease and monitoring disease progression. We analyzed 263 bone scans from 90 patients being studied under four protocols at Memorial Sloan-Kettering Cancer Center for progressive, androgen-independent prostate cancer (AIPC), who had bone scans as a part of their work-up. We determined: (a) the intraobserver and interobserver variability of the BSI; (b) the comparison between a change in BSI and prostate-specific antigen (PSA); (c) the regional distribution of bony metastases in early stage D prostate cancer (<3% skeletal involvement); and (d) the rate of growth of bony metastases from prostate cancer. A cube root transformation of the percentage of involvement of the entire skeleton was used to stabilize the variance over the entire span of values (0-60% tumor involvement). The range of interobserver variability between readers was 0.2-0.5 times the cube root of the BSI (69 scans, 18 patients). Intraobserver variability was minimal when the same reader read the same scans after a 2-year interval, showing a correlation coefficient of 0.97 (reader 1) and 0.99 (reader 2), P < 0.001. There was a parallel rise in the BSI and the PSA in 24 patients (105 scans) treated for AIPC with hydrocortisone followed by suramin at PSA relapse (Pearson's moment correlation, 0.71). In a group of 27 patients with limited bone involvement by AIPC (i.e., <3% BSI), the distribution of early metastases was not random within the skeleton but was distributed in the central skeleton in a manner that matched the distribution of the normal adult bone marrow. Also, in a group of 21 patients (62 scans), the change in BSI as a function of time after diagnosis was explored graphically. The progression of bone scan changes in AIPC, from early involvement (<3%) to late involvement, was fitted to a Gompertzian equation. It showed a rapid exponential growth phase, with an estimated tumor doubling time of 43 days when the BSI was 3.3%. The change in BSI rapidly approached a more gradual slope as the percentage of skeletal involvement increased. The BSI provides a reproducible new parameter for quantitative assessment of bone involvement by AIPC. These results suggest that the BSI will be useful for stratifying patients entering treatment protocols for extent of tumor involvement of bone. Although further study is necessary, serial bone scan BSI appears capable of quantifying both the progression of bony involvement by tumor as well as the response to treatment.     

Mu-Ghayeb: a culture-specific response to bereavement in Oman

BACKGROUND: Preoperative endocrine therapy has been suggested to improve surgical radicality and/or patient prognosis in prostate cancer. METHODS: Patients with clinical stage A2, B, and C prostate cancer were randomized to either group I (n = 113) or group II (n = 111). Group I patients were to receive preoperative endocrine therapy consisting of leuprolide and chlormadinone for 3 months, followed by radical prostatectomy with lymph node dissection. Group II patients were to undergo the surgery before endocrine therapy. RESULTS: Group I patients showed a remarkable decrease in prostate-specific antigen (PSA) (mean +/- SE: 41.8 +/- 8.6 ng/mL to 2.7 +/- 0.7 ng/mL) and prostate volume (29.8 +/- 1.7 mL to 21.2 +/- 1.6 mL) during the preoperative therapy. Histopathologic analysis showed a significant difference in the rates of down-staging (19.1% in group I versus 3.3% in group II), positive surgical margins (63.8% versus 81.3%) and positive lymph node metastasis (20.7% versus 36.5%). No significant difference was detected in operating features. Subgroup analyses indicated that beneficial effects were correlated positively with degree of histologic differentiation and negatively with the basal PSA level. CONCLUSIONS: Preoperative endocrine therapy reduced local extension of prostate cancer, and the effects depended on histologic differentiation and PSA level. Long-term follow-up data are needed to determine the effects on the patient prognosis.     

Cladribine (2-CDA) given as subcutaneous bolus injections is active in pretreated Waldenstr?m's macroglobulinaemia. Swiss Group for Clinical Cancer Research (SAKK)

Clinical trials with intravenous cladribine infusions in pretreated patients with Waldenstr?m's macroglobulinaemia have shown a response rate of 40%. Our pharmacokinetic studies revealed that the bioavailability of subcutaneous cladribine is complete but that the concentration-time profile is very different from intravenous administration. We designed this phase II multi-institutional trial to study the activity and toxicity of cladribine given as s.c. bolus injections in patients with symptomatic Waldenstr?m's macroglobulinaemia. Between May 1993 and October 1995, 25 patients were accrued: male/female 18/7, median age 65 years (range 44-85). All except one patient had been pretreated with more than one regimen (median 2, range 0-10). 18 patients had progressed under previous therapy and six were in relapse. All patients received cladribine for a total dose of 0.5 mg/kg per cycle as s.c. bolus injections divided over 5 d at > or = 4 week intervals, for a maximum of six cycles. All 25 patients were evaluable for toxicity and response. A total of 67 cycles were administered (median 3 cycles, range 1-6). Overall response rate including disease stabilization which had been progressive under previous therapy was 68%. 10 patients (40%, 95% CI 21-61%) achieved a partial remission. Seven responders had been progressive under previous therapy. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4.4 (range 0.5-33) and 8 months (5-29), respectively. Four patients (16%) suffered from infections W.H.O. grade > or = 2 (pneumonia grade 2, Staphylococcus septicaemia grade 3, viral encephalitis and pneumonia, both grade 4 with complete resolution). No other severe adverse events were observed. Cladribine given as s.c. 5 d bolus injections was found to be active in pretreated Waldenstr?m's macroglobulinaemia and resulted in durable remissions.     

Effect of UFT on treatment of urological cancer--effect of UFT on treatment of invasive bladder cancer and advanced prostate cancer. Ibaraki Urological Cancer Chemotherapy Study Group

A prospective randomized joint study was conducted to evaluate the usefulness of UFT 1) as a postoperative adjuvant therapy in patients with invasive bladder cancer who had undergone curative combination therapy with operation and/or chemotherapy and/or radiation therapy, 2) as an endocrine chemotherapy in patients with newly diagnosed stage C/D prostate cancer, for a period of 3 years from January, 1992. For bladder cancer, of 36 patients with invasive bladder cancer, clinically cured by combination therapy, 20 patients were treated with UFT as an adjuvant chemotherapy over 12 months, and they were compared to 16 patients with no adjuvant therapy. After excluding 10 inappropriate patients, 12 patients in the UFT treatment group and 14 patients with no adjuvant treatment group were observed. For prostate cancer, of 29 patients with clinically stage C/D prostate cancer, 13 were treated with endocrine therapy in combination with UFT, and 16 patients were treated with endocrine therapy alone. After excluding 7 inappropriate patients, 10 patients with endocrine chemotherapy and 12 patients with hormonal therapy were observed. The non-recurrence rate, survival rate and side effects of UFT were evaluated. In the study of bladder cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. In the study of prostate cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. These findings suggest UFT is less useful as an adjuvant therapy for the invasive bladder cancer and as an endocrine chemotherapy for newly diagnosed advanced prostate cancer.     

Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology

Whether the current generation of cytokine gene-transduced tumor vaccines will show clinical efficacy is under study. Fortunately, the large safety profile so far observed with gene-transduced tumor vaccines can allow outpatient testing in large populations of patients in the adjuvant therapy situation. This will allow large studies statistically powered to see potentially important adjuvant therapy effects in the range that are observed for tamoxifen in breast cancer. For example, the outpatient, adjuvant therapy safety context has been established in the use of GM-CSF gene-transduced autologous prostate cancer vaccines following radical prostatectomy. Similar adjuvant therapy clinical trial efforts are anticipated with allogeneic breast, colon, pancreatic, and ovarian cancer in addition to prostate, renal cell carcinoma, and melanoma. The reverse translation of early clinical data back to basic laboratory research also suggests the field of cytokine gene-transduced tumor vaccine research will remain vibrant. Efforts are currently being directed on optimizing DC activation with polycistronic constructs of cytokine genes, and overexpressing the most relevant tumor-associated peptides. As in the case of antineoplastic drug development, not all lead compounds will become approved drugs in medical oncology. Rigorous yet innovative clinical trial designs will be key to the accelerated identification of cytokine gene-transduced vaccines that improve survival in cancer patients.     

Aprotinin inhibits plasmin-induced platelet activation during cardiopulmonary bypass

PURPOSE: We correlated the expression of bcl-2 with accumulation of p53 protein in bone marrow metastases from patients with androgen independent prostate cancer and a history of hormonal ablation therapy. These results were correlated with clinical parameters, including the extent of bone marrow metastases and patient survival. MATERIALS AND METHODS: All 43 patients studied had evidence of prostate cancer progression following androgen deprivation therapy and histologically confirmed bone marrow metastases. Decalcified tissue sections were used for immunohistochemical evaluation of bcl-2 protein and p53 protein accumulation. RESULTS: We previously established that p53 protein accumulation as detected by immunohistochemistry is a reliable indicator of p53 gene mutation in prostate cancer. Immunoreactivity was demonstrated for p53 protein in 22 of 43 cases and for bcl-2 protein in 14. A total of 28 cases (65%) exhibited immunohistochemical evidence of p53 and/or bcl-2 expression, and 15 (35%) were negative for p53 and bcl-2. The expression of bcl-2 and accumulation of p53 were independent events (p < 0.01). The expression of bcl-2 or accumulation of p53 protein in prostate cancer metastases did not significantly influence patient survival or the extent of metastatic disease. CONCLUSIONS: The presence or absence of p53 protein accumulation and/or bcl-2 expression did not correlate with tumor burden or patient survival in stage D androgen independent prostate cancer bone marrow metastases. The expression of bcl-2 protein occurs independently of and is inversely correlated with p53 mutations in advanced prostate cancer.     

Allogeneic peripheral blood progenitor cells for treatment of relapse after bone marrow transplantation

Donor leukocyte infusions (DLI) are an effective therapy for patients who relapse with leukemia after bone marrow transplantation (BMT). Severe graft-versus-host disease and prolonged periods of pancytopenia compromise the success of this treatment in a substantial number of patients. We used filgrastim-mobilized peripheral blood progenitor cells (PBPCs), in some cases preceded by cytoreductive therapy, to circumvent some of the problems associated with DLI. Eleven patients (median age 41 years) received a total of 20 donor cell infusions. Their diagnosis was CML in hematological (two patients) or cytogenetic relapse (two patients), six patients suffered from acute myeloid leukemia (AM; n = 5) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+). One patient had multiple myeloma (MM). All six patients with acute leukemias received cytoreductive therapy prior to PBPC infusions; three patients with CML were pretreated with IFN alpha. Four of four patients with CML responded to PBPC infusions and currently are in complete clinical and molecular remission for time periods between 1 and 12 months. Six of six patients with acute leukemias achieved a complete remission. All of them relapsed after a median remission duration of 24 weeks (range 11-49 weeks). Three patients relapsed at extramedullary sites (CNS, testes, skin). Four of six acute leukemia patients received further cytoreductive therapy. All patients responded again and are in complete remission for time periods between 14 and 615 days. Two patients with acute leukemias have died due to dissemination of the disease. The patient with MM did not respond and is alive with disease. Severe (grade III) acute GVHD developed in two of 11 patients, three patients developed grade II disease, six patients did not show any signs of GVHD. Extensive chronic GVHD has developed in two cases to date. Patients with chemotherapy prior to PBPC infusion developed neutropenia and thrombocytopenia with a maximum duration of 20 and 14 days, respectively; prolonged periods of neutropenia did not occur. Two patients developed long-lasting thrombocytopenia in spite of PBPC infusion, in one case followed by leukemic relapse. Repeated courses of chemotherapy and PBPC infusion were generally tolerated well; no early deaths due to treatment-related toxicity or GVHD were observed. We conclude that the use of allogeneic PBPC instead of DLI in patients with relapse after BMT is technically feasible and safe. The efficacy of PBPC infusions seems comparable to DLI in patients with CML. Patients with acute leukemias also achieved complete albeit transient remissions. Aggressive chemotherapy followed by PBPC infusions resulted in only limited duration of cytopenia. The usage of PBPC infusion instead of non G-CSF-mobilized donor cells for treatment of relapse after BMT may reduce pancytopenia-related complications and merits further investigation.     

Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma

PURPOSE: The camptothecin derivative irinotecan has demonstrated clinical activity in metastatic colorectal carcinoma in both chemotherapy-naive and fluorouracil-refractory patients. 9-Aminocamptothecin (9-AC; NSC 603071), another camptothecin derivative, was selected for clinical development based on preclinical activity, including cures in human tumor xenografts resistant to standard anticancer agents. We report a phase II trial of 9-AC in patients with previously untreated metastatic colorectal carcinoma. PATIENTS AND METHODS: Colorectal cancer patients with measurable disease, a performance status of 0 to 2 (Zubrod), and no prior chemotherapy for metastatic disease received 9-AC. A cycle of therapy was 35 microg/m2/h for 72 consecutive hours (840 microg/m2/d for 3 days) and rest on days 4 to 14; a course of therapy was defined as two cycles (28 days). Patients were assessed for response after two courses. RESULTS: Seventeen patients with metastatic colorectal cancer were entered onto this trial. No complete or partial responses were noted. Treatment was well tolerated; toxic effects consisted mainly of neutropenia, nausea, vomiting, stomatitis, fatigue, and anemia. Grade 3 to 4 toxicity was limited to neutropenia (grade 3 in four patients and grade 4 in six), anemia (grade 3 in two patients), and vomiting (grade 3 in two patients). No grade 3 or 4 diarrhea occurred. Only two patients had their 9-AC dose reduced to 30 microg/m2/h. The median nadir absolute granulocyte count (AGC) was 1,500/microL. The median number of courses given was two and the median time to disease progression was 8 weeks. CONCLUSION: At the dose and schedule used in this trial, 9-AC lacked antitumor activity in metastatic colorectal cancer. 9-AC infusion schedules of longer duration are currently being investigated in this disease.     

Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol)

PURPOSE: Substantial experimental and epidemiological data indicate that 1,25-dihydroxyvitamin D3 (calcitriol) has potent antiproliferative effects on human prostate cancer cells. We performed an open label, nonrandomized pilot trial to determine whether calcitriol therapy is safe and efficacious for early recurrent prostate cancer. Our hypothesis was that calcitriol therapy slows the rate of rise of prostate specific antigen (PSA) compared with the pretreatment rate. MATERIALS AND METHODS: After primary treatment with radiation or surgery recurrence was indicated by rising serum PSA levels documented on at least 3 occasions. Seven subjects completed 6 to 15 months of calcitriol therapy, starting with 0.5 microg. calcitriol daily and slowly increasing to a maximum dose of 2.5 microg. daily depending on individual calciuric and calcemic responses. Each subject served as his own control, comparing the rate of PSA rise before and after calcitriol treatment. RESULTS: As determined by multiple regression analysis, the rate of PSA rise during versus before calcitriol therapy significantly decreased in 6 of 7 patients, while in the remaining man a deceleration in the rate of PSA rise did not reach statistical significance. Overall the decreased rate of PSA rise was statistically significant (p = 0.02 Wilcoxon signed rank test). Dose dependent hypercalciuria limited the maximal calcitriol therapy given (range 1.5 to 2.5 microg. daily). CONCLUSIONS: This pilot study provides preliminary evidence that calcitriol effectively slows the rate of PSA rise in select cases, although dose dependent calciuric side effects limit its clinical usefulness. The development of calcitriol analogues with decreased calcemic side effects is promising, since such analogues may be even more effective for treating prostate cancer.     

Task-specific physical therapy for optimization of gait recovery in acute stroke patients

A randomized controlled pilot trial was conducted to estimate the effects of early, intensive, gait-focused physical therapy on ambulatory ability in acute, stroke patients. Twenty-seven patients with middle cerebral artery infarct of thromboembolic origin confirmed by computed axial tomography scan were stratified and randomly assigned to the experimental group, to a control group that received early, intensive and conventional therapy, or to a group receiving routine conventional therapy that started later and was not intense. Assessments at entry, six weeks, and three and six months by independent evaluators permitted comparisons with reference to clinical measures of motor performance, balance, and functional capacity, and laboratory measures of gait movements. Group results at six weeks demonstrated that gait velocity was similar in the two conventional groups thereby eliminating the timing of the interventions as an important factor. At that point, gait velocity was faster in the experimental group. The difference translated into a moderate effect size of 0.58. The time dedicated to gait training but not to total therapy time was correlated (rs = 0.63) to gait velocity. This effect disappeared at three and six months after stroke. These pilot results justify planning a large trial to test the effectiveness of a therapeutic protocol that focuses on early and intense gait therapy in an effort to facilitate early ambulation following stroke.     

Thermally-induced changes in the metabolism of the eye of the crayfish Paranephrops planifrons: respiration and substrate utilization at three distinct temperatures

Gleason's score (GS) has been reported to be the most valuable prognostic factor in cases of prostate cancer. GS is solely dependent on the histological architecture of the prostate cancer, but, it seems doubtful that histological patterns are sufficient for evaluating the degree of malignancy of prostate cancer. We previously reported that the estimation of volume-weighted mean nuclear volume (MNV) might be a more useful prognosticator for prostate cancer than subjective histological grading. However, the previous study was conducted on patients treated in a single hospital, and the number of subjects was too small to draw a definitive conclusion. In this study, we analyzed a larger number of subjects at another institution using a blinded study design. A retrospective prognostic study of 195 patients with prostate cancer diagnosed between January 1966 and December 1988 at Kyoto University Hospital, and treated by conservative therapy, was conducted. Unbiased estimates of MNV were compared with the clinical stage and histological grading according to GS with regard to the prognostic value. Univariate analysis revealed that estimates of MNV, clinical stage, and GS all correlated significantly with disease-specific survival in cases of prostate cancer. Multivariate analysis of all cases also revealed that all of these factors were significant independent prognosticators of disease-specific survival. However, focusing on clinically localized cases (stages A, B, and C), multivariate analysis revealed that the estimation of MNV was the only powerful prognosticator of prostate cancer. This study indicates that the estimation of MNV is prognostically equal or superior to GS in cases of prostate cancer. We emphasized that the estimates of MNV is a more objective method for histological grading to predict the malignant potential of prostate cancer.