The prognostic importance of fibronectin and sialic acid levels in human pituitary adenomas

In this study, fibronectin and sialic acid levels were determined in human pituitary adenomas. The mean fibronectin and sialic acid levels for human pituitary adenomas were found to be 31.64 ± 15.82 μg/mg protein and 21.90 ± 9.82 μg/mg protein, respectively, versus 6.30 ± 2.96 μg/mg protein and 9.88 ± 2.81 μg/mg protein for the normal brain tissues. Fibronectin and sialic acid levels were significantly higher (P < 0.001) in human pituitary adenomas than the normal brain tissues. In human infiltrative and non-infiltrative pituitary adenomas, the mean fibronectin and sialic acid levels were found to be 40.87 ± 15.90 μg/mg protein, 27.59 ± 11.10 μg/mg protein and 22.40 ± 9.51 μg/mg protein, 16.21 ± 3.20 μg/mg protein, respectively. Fibronectin and sialic acid levels were slightly elevated (P < 0.05) in human infiltrative pituitary adenomas compared with non-infiltrative adenomas.     

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma

Purpose: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.

Methods and Materials: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily × 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m² days 1–3, cisplatin 30 mg/m² days 1–3 and 29–31, and etoposide 50 mg orally days 1–14 and 29–42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m² every 8 weeks × 4 cycles was given after radiation therapy.

Results: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3–4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m² days 1–3, cisplatin 20 mg/m² days 1–3 and 29–31, and oral etoposide 50 mg days 1–21 and 29–49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m² every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 μg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean ± SD 2 hr and 6 hr plasma concentrations were 0.92 ± 0.43 μg/ml and 0.36 ± 0.12 μg/ml, respectively. Estimated duration of exposure to >0.1 μg/ml etoposide was 10–17 hr.

Conclusions: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.     

In Vivo Accumulation of Etoposide in Peripheral Leukemic Cells in Patients Treated for Acute Myeloblastic Leukemia; Relation to Plasma Concentrations and Protein Binding

Since etoposide interacts with the nuclear enzyme topoisomerase II, the drug concentrations in the malignant cells during chemotherapy may have clinical correlates. Plasma protein binding of etoposide is extensive (94%) and alterations of the non-proteinbound fraction affect pharmacokinetic behavior of the drug. The pharmacokinetics of etoposide was therefore studied in plasma, total and non-proteinbound concentrations, and in leukemic cells isolated from peripheral blood samples from 22 patients after the first dose of the induction treatment for acute myelocytic leukemia. Fourteen patients received 100 mg/m² and eight patients 200 mg/ m² as a 1 h infusion. The mean area under the concentration versus time curve AUC_(0-x) in plasma was at the lower dose level 78.4 ± 29.1 (mean ± S.D.) μg/ml x h and 201.0 ± 56.5 μg/ml x h at the higher dose level. The fraction of non-proteinbound etoposide in plasma was 5.2 ± 3.4 and 5.4 ± 2.1% in the two treatment groups. AUC_(0-16h) in leukemic cells was 8.4 ± 8.7 and 22.4 ± 12.1 μ/ml x h at the two dose levels, respectively. The cellular etoposide concentration was 12.1 ± 7.9 and 14.7 ± 5.1% of the plasma concentration at the end of the infusion. The interpatient variability in cellular drug levels was considerable and exceeded the variability in plasma concentrations. Cellular accumulation of etoposide could be important for treatment outcome.     

Carcinoma of the intact uterine cervix treated with radiotherapy alone: A french cooperative study: Update and multivariate analysis of prognostics factors

: To determine independent prognostic factors in a group of 1875 patients with invasive carcinoma of the intact uterine cervix treated with radiotherapy alone in a French cooperative study from 1970 to 1993.

: Patients were staged according to the UICC-FIGO and MDAH substaging. The distribution per FIGO stage was Ia-Ib: 25.5%; IIa: 29%; IIIa: 5%; IIIb: 25%, and IV: 3.5%. Ninety-two percent had squamous cell carcinoma. The maximum diameter of the clinically detectable cervical disease was less than 3 cm in 24.5% of Stages I–II and in 10% of Stages III–IV, more than 5 cm in 13.5% of Stages I–II, and in 16% of Stages III–IV. Nodal involvement was shown on lymphangiogram in 16% of Stages I–II and in 32.5% of Stages III–IV.

: 1) Univariate analysis of Stages I and II: stage, cervical disease diameter, and nodal involvement are significant prognostic factors. Five-year specific survival rate (5ySS) in 83.5% in Stage Ib, 81% in IIa and 71% in IIb. Five-year disease-free survival rate (5yDFS) is 86% in tumors less of 3 cm, 76% in tumors of 3 to 5 cm, and 61.5% in tumor larger than 5 cm. Lymphangiogram strongly influences the 5-year pelvic disease-free survival rate (5yPDFS): respectively, 90% in nonpositive lymphangiogram vs. 65% when positive. A significant drop in specific and disease-free survival is observed (10 and 14%, respectively (p = 0.04) when comparing adenocarcinoma and squamous cell carcinoma. Age is a significant prognostic factor for specific because patients aged less than 30 years old have 91% vs. about 75% for patients over 30 years (p = 0.03). 2) Univariate analysis of Stages III–IV: Stage and positive lymphagiogram are predictive factors for relapse and death. Te MDAH substaging is more reliable to predict the probability of pelvic disease-free survival in Stage III. At 5 years, the FIGO Stages IIIa and IIIb have a rather similar PDFS (65% vs. 59%). Conversely, the difference of survival rates between MDAH Stage IIIA and Stage IIIB is more demonstrative (69% vs. 47.5%). 3) Multivariate analysis (Cox P. H. R. model). Nodal involvement and stage remain significant for all three models in all stages (p < 0.0001). Age above 70 years influences specific survival for Stage I–II (p = 0.01). Tumors larger than 5 cm and adenocarcinoma also appear to be independent prognostic factors for specific and disease-free survival in Stage I–II (p = 0.05 and p = 0.005, respectively).

: The relevance of tumor size (less or greater than 4 cm) is now recognized in the 1995 revised FIGO staging in Stage Ib but unfortunately not in other stages. Tumor size per stage and nodal status should be systematically recorded to allow a better prediction of failure rates and to compare literature reports.     

Role of β-carotene on the changes in activity patterns and levels of biotransforming enzymes in transplantable murine lymphoma

The differential levels of induction of hepatic microsomal cytochrome P-450 (cyt. P-450), UDP-glucuronyl transferase (UDPGT) and cytosolic glutathione-S-transferase (GST) activities were evaluated over various periods of time, following tumor transplantation in male Swiss albino mice in the presence and absence of β-carotene supplementation in their basal diet (100 mg/kg). An increase in the total hepatic microsomal cytochrome P-450 and UDP-glucuronyl transferase and cytosolic GSH-transferase activities (1.5 to 2 fold) occurred during the later stage of tumor progression (22 ± 2 days onwards). However, β-carotene supplementation throughout the study increased or decreased the random activity trends of the above markers significantly (P < 0.05−< 0.01). Finally, β-carotene supplementation could enhance the survival of the host bearing lymphoma by almost 2-fold (50–60 days) over and above the lymphoma controls (30–35 days).     

Tamoxifen antagonizes proliferation and invasion of estrogen receptor-negative metastatic follicular thyroid cancer cells via protein kinase C

Tamoxifen inhibits invasion and growth of estrogen-receptor negative follicular thyroid cancer (FTC) cells in vitro and in vivo. To study the mechanisms involved, we documented the effects of tamoxifen and staurosporine on three metastatic FTC-cell lines. TPA(10 ng/ml) enhanced invasion and growth of FTC by 15% (Pb < 0.02). Tamoxifen (1.5 μmol/l) inhibited invasion of FTC133 by 36% (FTC236 30%; FTC238 32%; P < 0.01). TPA reversed the tamoxifen-mediated inhibition of invasion by 35% in FTC133 and 30% in FTC238 (P < 0.02). Staurosporine (10 ng/ml) inhibited invasion and growth of all FTC. At 0.1–1 ng/ml it enhanced the inhibitory effects of tamoxifen, but did not further inhibit invasion or growth at higher concentrations. We conclude that the antiproliferative and antiinvasive effects of tamoxifen on follicular thyroid cancer cells are at least partly mediated by an inhibition of protein kinase C.     

Circulating immune complexes in chronic myeloid leukemia patients at various stages of the disease

Circulating immune complexes (CICs) in sera from patients suffering from chronic myeloid leukemia (CML) at initial diagnosis, in ‘remission’, at relapse and in blastic crisis have been quantitated using fluid [¹²⁵I]Clq binding assay in terms of per cent binding activity and μg/ml aggregated human globulin (AHG) equivalents. The Clq binding activity (Clq-BA) has been compared within the groups of CML patients in different phases of the disease as well as with sera obtained from normal healthy donors. The results showed that the mean Clq-BA was significantly increased in CML patients at initial diagnosis (25.74 ± 3.48, p < 0.001), in relapse (53.36 ± 6.9, p < 0.001) and in blastic crisis (60.5 ± 8.7, p < 0.001) when compared to control sera. Sera of ‘remission’ patients showed significant decrease in Clq-BA when compared to sera collected in active phases of the disease, however, the values were still significantly higher (12.87 ± 1.58, p < 0.02) than those of normal healthy donors. When the levels of CICs as assessed by Clq-BA were compared with the WBC/blast counts of CML patients in chronic as well as blastic phase, it was noted that the variations in numbers of circulating leukemic cells do not correlate with the CIC levels. The significance of assessment of CIC levels in monitoring the disease in CML patients is discussed.     

Postremission therapy with two different dose regimens of cytarabine in adults with acute myelogenous leukemia

Sixty-seven out of 105 (64%) adults with de novo acute myelogenous leukemia (AML), achieving complete remission after induction chemotherapy, entered two successive postremission treatment protocols. Between 1987 and 1989, 35 patients received an intermediate dose of cytarabine (IDAC) along with other drugs. Between 1990 and 1993, 32 patients received high dose cytarabine (HIDAC) with similar other drugs. Patients treated with IDAC had a median survival of 13.8 months (95% Cl 11.2–23.1 months) and a 2 year survival of 34.3 ± 8.0%. Patients receiving HIDAC had a median survival of 35.5 months (95% Cl, lower limit 29.8 months) and a 2 year survival of 71.6 ± 9.4% (P < 0.002). The 2 year actuarial leukemia-free survival (LFS) was 17.8 ± 6.6% in the IDAC group and 67.3 ± 10.0% months in the HIDAC group (P = 0.004). The HIDAC group had a significant 2 year survival advantage over the IDAC group only in patients younger than 45 years. The 2 year survival in the first group was 83.3 ± 10.8% versus 23.5 ± 10.3% in the IDAC group (P = 0.0001). In patients older than 45 years, no significant differences in 2 year survival was noticed (52.9 ± 15.78 versus 44.4 ± 11.7, P = 0.8). Censoring the 21 patients who underwent bone marrow transplantation (BMT) at BMT did not change significantly the survival analysis of the patients in each group. This study is consistent with previous reports favoring HIDAC intensification in the postremission treatment of young patients with AML.     

Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571)

Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were determined in four subsequent patients by liquid chromatography and mass spectrophotometric assay. Levels of IM were found to be approximately two logs lower in CSF than in plasma (0.044 μg/ml (0.088 ± 0.029 μM) vs 3.27 μg/ml (6.54 ± 0.93 μM)). CSF levels were substantially below the concentration required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.     

Effect of thymosin and phorbol ester on purine metabolic enzymes and cell surface phenotype in a malignant T-cell line (MOLT-3)

Previous studies have shown that thymosin (fraction 5) is able to induce surface differentiation markers on normal murine bone marrow T-cell precursors. Phorbol ester (TPA) promotes differentiation of human leukaemic lymphoblasts as assessed by changes in phenotypic surface markers and terminal deoxynucleotidyl transferase (TdT) activity. Changes in levels of purine degradative enzymes occur during T-cell maturation with a fall in adenosine deaminase (ADA) and a rise in purine nucleoside phosphorylase (PNP) and 5′ nucleotidase (5 'NT) activities. We have now investigated the effect of both thymosin (fraction 5) and TPA on a human leukaemic T-cell line (MOLT-3) in expression of the surface antigenic markers NAI/34 (a marker of immature thymocytes) and OKT11 (which corresponds to the sheep erythrocyte receptor) and of TdT, ADA, PNP and 5 'NT.

Thymosin (after 96 h incubation) significantly reduced the number of cells positive for NAI/34 from 76.0 ± 5.0% (mean ± S.D.) to 51.3 ± 9.3% (p < 0.01) but caused no significant change in the percentage of TdT or OKT11 positive cells. ADA levels were significantly reduced (p < 0.02) and 5 'NT levels were significantly elevated (mean increase 303 ± 142% of control, (p < 0.001) but the increase in PNP level (108 ± 16.8% of control) was not significant (p > 0.05). On the other hand, TPA (after 96 h incubation) significantly reduced cells positive for NAI/34 from 76.0 ± 5.0 to 30.0 ± 9.8% and for TdT from 81.7 ± 6.5 to 17.3 ± 4.4% and increased OKT11 positive cells from 67.3 ± 5.5 to 89.0 ± 2.8% (p < 0.001). TPA caused no significant change in 5 'NT or ADA levels (p > 0.05), but an increase in PNP level to 158 ± 12.9% of control (p < 0.02). The present study demonstrates for the first time that the normal thymic hormone, thymosin is capable of inducing differentiation changes in thymic derived human leukaemic cells. In addition, it shows that different inducing agents may cause different patterns of differentiation changes in leukaemic cells.     

Effect of tamoxifen on intraperitoneal N-nitroso-N-methylurea induced tumors

The effect of tamoxifen (TAM) was evaluated on a mammary tumor model induced in Sprague-Dawley rats by intraperitoneal administration of three N-nitroso-N-methylurea (NMU) doses. Animals received TAM (1 mg/kg per day) from 10 days before the first NMU dose up to 140 days later. Thereafter, treatment was discontinued and the observation period was extended 60 days longer. Mean overall latency period, tumor number per rat and tumor incidence were recorded. Significant differences between treated and control batches were observed in tumor number per rat (1.8 ± 1.1 versus 5.2 ± 1.6; P < 0.05) and in tumor incidence (50% versus 100%; P < 0.05), respectively. No significant difference in latency period between both batches was recorded. All lesions induced in the control batch were malignant, whereas only 45% of those induced in TAM-treated animals were malignant and the remaining 55% were preneoplastic. At 60 days after treatment discontinuance, tumor incidence increased to 90% and also tumor number per rat increased to 4.6 ± 1.5. TAM effect was also evaluated in rats with NMU-induced tumors by treatment with 1 mg/kg per day during 60 days starting when tumors reached a 1.5-cm diameter. Regression to less than 80% of initial size in 49% of the tumors was observed, while in ovariectomized rats, 33% of tumors regressed. Estrogen receptor content, ER (fmol/mg protein) and Kd (nM) in control tumors were: 56 ± 10 and 0.5 ± 0.1. In tumors of TAM-treated animals, ER was less than 5 fmol/mg protein. Findings demonstrate that TAM significantly decreased the appearance of tumors induced in rats by i.p. injection of NMU and when TAM treatment was initiated after tumor induction, some tumors failed to respond to hormonal manipulation. Differential tumor growth response after TAM or oophorectomy in each tumor indicates that in the same rat it is possible to distinguish hormone-dependent and hormone-autonomous tumor populations. Hormonal regulation of tumor growth can be under intrinsic control, regardless of the hormonal status of the whole organism.     

Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer

The modifying effects of dietary feeding of extract of leaves of ginkgo (Ginkgo biloba) (EGb) and bilobalide isolated from EGb on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of EGb and bilobalide on proliferating cell nuclear antigen (PCNA) index in ‘normal-appearing’ crypts and activities of detoxifying enzymes of cytochrome P450 (CYP), glutathione S-transferase (GST) and quinine reductase (QR) activity in the liver. To induce ACF, rats were given two weekly subcutaneous injections of AOM (20 mg/kg body wt). They also received the experimental diets containing EGb (50 or 500 ppm) and bilobalide (15 or 150 ppm) for 4 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (106±10) at the end of the study (week 4). Dietary administration of EGb and bilobalide caused significant reduction in the frequency of ACF: 50 ppm EGb, 73±17 (31% reduction, P<0.001); 500 ppm EGb, 56±13 (47% reduction, P<0.001); 15 ppm bilobalide, 79±17 (25% reduction, P<0.01); and 150 ppm bilobalide, 71±30 (33% reduction, P<0.01). Immunohistochemically, EGb or bilobalide administration significantly lowered PCNA index in normal-appearing crypts. Feeding with EGb or bilobalide increased activities of CYP as well as GST and QR in the liver. These findings might suggest possible chemopreventive ability of EGb or bilobalide, through alterations in cryptal cell proliferation activity and drug metabolizing enzymes' activities, in colon tumorigenesis.     

Different cutoff values of Cyfra 21-1 for cavitary and noncavitary lung cancers

Study objectives: Cell lysis and tumor necrosis release cytokeratin, a tumor marker of lung cancer, into the serum. The serum cytokeratin level can also be elevated in benign cavitary lung diseases. The purpose of this study was to evaluate whether Cyfra 21-1 can differentiate malignant lung diseases from benign diseases with cavitary lesions. Design: This study is a retrospective review of the case records of patients with lung lesions seen during a 4-year period from January 1993 to May 1996. Setting and patients: Serum Cyfra 21-1 levels were measured in 306 patients with lung cancer (n=143) or benign lung disease (n=163). The patients were grouped according to radiologic evidence of cavitary lung lesions. Lung cancer included both non-small cell (n=123) and small cell (n=20) lung cancers, and the benign diseases include tuberculosis (n=87), abscess (n=26), pneumonia (n=4), and others (n=46). Measurements and results: Although Cyfra 21-1 clearly differentiated cavitary lung cancer (15.0, 9.1–29.8 ng/ml, median and interquartile range, n=39) from benign cavitary disease (P<0.001), and noncavitary lung cancer from benign noncavitary disease (1.7, 0.9–2.6 ng/ml, n=108, P<0.001), it could not differentiate noncavitary lung cancer (5.0, 2.1–12.4 ng/ml, n=104) from benign cavitary diseases (3.3, 1.4–8.3 ng/ml, n=55, P=0.45). Conclusions: Serum Cyfra 21-1 is a useful tumor marker for differentiating benign from malignant lung diseases. However, different cutoff values are needed, depending on the presence of cavitary lesions. We recommend cutoff values of 30 ng/ml for cavitary lung diseases and 6 ng/ml for noncavitary lung diseases. If there are no radiologic data, a cutoff value of 15 ng/ml is recommended.     

Significant pelvic recurrence in high-risk pathologic stage I--IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy

To evaluate the risk of pelvic recurrence (PVR) in high-risk pathologic Stage I–IV endometrial carcinoma patients after adjuvant chemotherapy alone.

Between 1992 and 1998, 43 high-risk endometrial cancer patients received adjuvant chemotherapy. All patients underwent primary surgery consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy. No patients received preoperative radiation therapy (RT). Regional lymph nodes and peritoneal cytology were sampled in 62.8% and 83.7% of cases, respectively. Most patients had Stage III–IV disease (83.7%) or unfavorable histology tumors (74.4%). None had evidence of extra-abdominal disease. All patients received 4–6 cycles of chemotherapy as the sole adjuvant therapy, consisting primarily of cisplatin and doxorubicin. Recurrent disease sites were divided into pelvic (vaginal, nonvaginal) and extrapelvic (para-aortic, upper abdomen, liver, and extra-abdominal). Median follow-up was 27 months (range, 2–96 months).

Twenty-nine women (67.4%) relapsed. Seventeen (39.5%) recurred in the pelvis and 23 (55.5%) in extrapelvic sites. The 3-year actuarial PVR rate was 46.5%. The most significant factors correlated with PVR were cervical involvement (CI) (p = 0.01) and adnexal (p = 0.05) involvement. Of the 17 women who developed a PVR, 8 relapsed in the vagina, 3 in the nonvaginal pelvis, and 6 in both. The 3-year vaginal and nonvaginal PVR rates were 37.8% and 26%, respectively. The most significant factor correlated with vaginal PVR was CI (p = 0.0007). Deep myometrial invasion (p = 0.02) and lymph nodal involvement (p = 0.03) were both correlated with nonvaginal PVR. Nine of the 29 relapsed patients (31%) developed PVR as their only (6) or first site (3) of recurrence. Factors associated with a higher rate of PVR (as the first or only site) were CI and Stage I–II disease.

PVR is common in high-risk pathologic Stage I–IV endometrial cancer patients after adjuvant chemotherapy alone. These results support the continued use of locoregional RT in patients undergoing adjuvant chemotherapy. Further studies are needed to test the addition of chemotherapy to locoregional RT.     

Effect of balloon occluded arterial infusion of anticancer drugs on the prognosis of cervical cancer treated with radiation therapy

: The effect of local injection of anticancer drugs by ballon catheter, i.e., balloon occuluded arterial infusion (BOAI), on the prognosis of cervical cancer treated with radiotherapy were retrospectively estimated.

: Sixty-five patients with cervical cancer (Stage I–IV) treated by irradiation were included in the study. Among the 65 cases, 2 were in Stage I, 13 in Stage II, 40 in Stage III, and 10 in Stage IV. Patients who received surgical resection were excluded. Thirty-nine patients received BOAI and 44 received brachytherapy. Twenty-six patients were not indicated for BOAI because of insufficient renal function, hepatic complications, hemotological complications, and refusal from the patients. Cisplatin (0.9–1.7 mg/kg), Adriamycin (0.7–0.9 mg/kg), and Pepleomycin (0.4–0.6 mg/kg) were administered simultaneously into the bilateral internal iliac arteries by BOAI. External irradiation was given by 10 MV x-ray. Total dose administered to the regional lymph nodes by the external irradiation was 48.3 ± 8.7 Gy. Radium was used at brachytherapy. The dose delivered by the brachytherapy at point A was 45.3 ± 14.9 Gy. Patients without brachytherapy received 26.1 ± 19.1 Gy of boost irradiation by the external photon beam. The survival probabilities of the patients were calculated by Kaplan-Meier method.

: The 5-year survival rates of the Stage III patients with and without BOAI were 53 ± 13% and 24 ± 18%, respectively (p = 0.036). By multivariate analyses using Cox's proportional hazard model, stage and BOAI were selected as significant predictors of the prognosis. Transient bone marrow suppression was observed in about half of the patients with BOAI. No significant increase of the incidence of the late radiation damage by BOAI in rectum or in urinary bladder was observed.

: Balloon occuluded arterial infusion of anticancer drugs may improve the prognosis of the patients with cervical cancer without increasing the incidence of the late radiation damage. A larger scale prospective randomized study is desired.     

Phase I trial of PT-100 (PT-100), a cytokine-inducing small molecule, following chemotherapy for solid tumor malignancy

PT-100 upregulates cytokine expression competitively inhibiting the dipeptidyl peptidase activity of fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV). This dose-escalation study was conducted to evaluate the safety of PT-100 in patients receiving myelosuppressive chemotherapy and to assess its effects on neutrophil recovery.

PT-100 was administered orally for 7 days as a 200 μg, 400 μg, 800 μg, or 1,200 μg total daily dose (divided twice daily) to 6, 6, 17, and 5 patients, respectively. Patients received 2 cycles of chemotherapy: The first cycle served as each individual patient's control. Patients had to develop Grade 3+ neutropenia in Cycle 1 in order to receive PT-100 in Cycle 2. Most patients received PT-100 on Days 2-8 of chemotherapy in Cycle 2, except at 800 μg where an additional cohort (n = 8) was treated on a Days 5-11 schedule. Five of 7 patients receiving 800 μg on Days 2-8 experienced a ≥1-day improvement in Grade 3+ neutropenia in Cycle 2 versus Cycle 1. Overall, PT-100 was well tolerated. A reduction in chemotherapy-related nausea, vomiting, fatigue, alopecia, and diarrhea was noted in patients receiving PT-100. Edema/peripheral swelling, hypotension, hypovolemia, and dizziness were the most common nonhematologic adverse events considered related to PT-100. Two Grade 3 adverse events were considered related to PT-100: syncope (1,200 μg) and orthostatic hypotension (800 μg). A maximum tolerated dose was not reached. Given the accelerated neutrophil recovery, preclinical evidence of antitumor activity, and tolerable toxicities of PT-100, additional studies to optimize the PT-100 dosing schedule in patients receiving myelosuppressive chemotherapy are needed.     

Phase II study of irinotecan and carboplatin in patients with the refractory or relapsed small cell lung cancer

We examined the safety and efficacy of the combination of irinotecan plus carboplatin in patients with refractory or relapsed small cell lung cancer (SCLC). Patients with previously treated SCLC were eligible. Patients were treated every 3 weeks with carboplatin (with a target area under the concentration versus time curve of 5 mg min/ml using the Calvert formula on day 1) plus irinotecan (50 mg/m² on days 1 and 8). From May 2000 to January 2002, 24 patients were eligible. None of the 22 patients achieved a complete response, but 15 achieved a partial response with an overall response rate of 68.2% (95% confidence interval, 45.1–86.1%). In 13 patients with sensitive disease, the response rate was 92.3% (95% confidence interval, 64.0–99.8%). The median survival time (MST) was 194 days (range 27–605 days). The MST did not differ significantly between patients with sensitive disease (245 days) and those with refractory disease (194 days, P=0.88). One patient died of treatment-related sepsis. Grade 3–4 hematologic toxicities included leukopenia in 58% of patients, neutropenia in 63%, thrombocytopenia in 58%, and anemia in 67%. Grade 3 diarrhea developed in 21% of patients and grade 3–4 infection in 13%. No patients had grade 4 diarrhea or grade 3–4 nausea and vomiting. This regimen is effective and well tolerated in patients with relapsed or refractory SCLC. However, the search for even more active regimens should be continued.     

Late radiation effects to the rectum and bladder in gynecologic cancer patients: the comparison of LENT/SOMA and RTOG/EORTC late-effects scoring systems

To test the correlation of LENT/SOMA and RTOG/EORTC late-effect scales for rectum and bladder, 116 cases with gynecologic malignancies that were treated with radiotherapy were assessed with both scales.

All cases had been treated at least 6 months before the date of assessment with external beam radiotherapy (50–54 Gy to midline) and 1–2 fractions of HDR brachytherapy (2 × 8.5 Gy to point-A for 32 inoperable cases; 1 × 9.25 Gy to 5–9 mm from the ovoid surface for 84 postoperative cases). The patients were questioned with both scales, and the correlation between the two scales was analyzed by Spearman’s rho (rank correlation) test.

There were 64 cases with uterine cervix carcinoma and 52 cases with endometrium carcinoma, The overall (external + brachy) doses to ICRU points were 57.8 ± 3.8 Gy for rectum and 59.3 ± 4.9 Gy for bladder. The statistical analysis of LENT/SOMA and RTOG/EORTC scales revealed a very good correlation for rectum (r = 0.81; p < 0.01) and a good correlation for bladder (r = 0.72; p < 0.01).

The LENT/SOMA system is a further step on the reporting of late radiation effects. Some modifications will improve its precision, and multicentric randomized studies are needed to test its validity.     

Decreased plasma levels of cholecystokinin in healthy males after chronic ingestion of a heat-treated soya product

Administration of raw soya containing a trypsin inhibitor stimulated excessive release of cholecystokinin (CCK) which led to pancreatic hypertrophy, hyperplasia and cancer in the rats (Booth et al. (1964) Proc. Soc. Exp. Biol. Med., 116, 1067). More postprandial CCK release in healthy humans was observed after ingestion of a single dose of raw soya than heat-treated soya (Calam et al. (1989) Br. J. Nutr., 58, 175). The effect of chronic ingestion of a heat-treated soya product on postprandial CCK release was investigated in six healthy adult males after ingestion of a 36-oz. portion of soymilk daily for 1 month and at 2–3 months after termination of soymilk ingestion. Subjects fasted for 15 h, ingested Lipomul (1.5 g/kg) and provided blood at timed intervals for CCK analysis. The results show that 1-month ingestion of soymilk decreased the magnitude of Lipomul-induced postprandial CCK release in plasma of all six subjects by 5–60% (P < 0.05) compared to those obtained at 2–3 months after the withdrawal from soymilk ingestion. Plasma pancreatic polypeptide (PP) levels were similarly decreased in five of the six subjects by 19–67% (P = 0.03) in line with the regulation of PP by CCK. Thus, prolonged exposure of humans to a heat-treated soya inhibited slightly meal-induced CCK release in contrast to that found in rats after raw soya diets.     

Bioavailability and Pharmacokinetic Features of Etoposide in Childhood Acute Lymphoblastic Leukemia Patients

The bioavailability and pharmacokinetic characteristics of etoposide were studied in 12 relapsed B-lineage acute lymphoblastic leukemia (ALL) patients after both intravenous (i.v.) infusion and oral administration. Following a 1 hour i.v. infusion of SO mg/m² etoposide, the elimination half-life ranged from 49.8 min to 509.4 min (mean ± SD = 218.6 ± 134.7 min), the MRT ranged from 71.8 to 734.9 min (mean ± SD = 315.4 ± 194.3 min) and the systemic clearance of etoposide ranged from 15.7 to 38.0 ml/min/m² (mean ± SD = 24.1 ± 7.0 ml/min/m²). The AUC ranged from 2234.9 to 5427.0 μM±min) (mean ± SD = 3827.8 ± 1069.5 μM±min) and V_c ranged from 2026.9 to 13505.2 rnl/m² (mean ± SD = 6825.4 ± 3278.5 ml/m²). The maximum plasma etoposide levels ranged from 6.0 to 28.4 μM (mean ± SD = 13.6 ± 6.3 μM). The bioavailability of oral etoposide was determined by comparing the AUC following i.v. infusion to the AUC following oral administration in the same patient. The overall bioavailability (mean ± SD) was 60.6 ± 22.4% (ranged from 17.6% to 91.2%). The elimination half-life following oral administration (mean ± SD) was 209.8 ± 196.3 min (ranged from 51.0 to 794.2 min). The time required to reach the maximum plasma etoposide concentration was 145.4 ± 118.7 min (ranged from 23.7 to 396.9 min). To our knowledge, this is the first report concerning the bioavailability of etoposide in pediatric leukemia patients. All of the other pharmacokinetic properties of etoposide in pediatric B-lineage ALL leukemia patients reported here were similar to those described previously.