Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial.

Fluconazole is recommended in the prophylaxis of oropharyngeal candidiasis (OPC) in patients undergoing radiotherapy for head-neck tumours; however, the actual effectiveness of fluconazole in this setting remains unclear. Adult patients with cervico-cephalic carcinoma submitted to radical or adjuvant radiotherapy were randomized to 100 mg fluconazole (n = 138) or matched placebo (n = 132) oral suspension once daily from the sixth session of radiotherapy up to the end of treatment. The final analysis of the investigation showed a higher rate of the OPC outbreak-free survival in the fluconazole compared with placebo (P = 0.008 in the log-rank test). The mean time (95% CI) to OPC outbreak was 56 (53-59) days in the fluconazole group and 47 (43-51) days with placebo. The mean duration of radiotherapy was 43.5 and 39.9 days, respectively in the two groups (P = 0.027). Adverse effects were reported in 70.3% of patients in the fluconazole group and in 67.4% with placebo. The results showed prophylaxis with fluconazole given in irradiated patients with head-neck tumours significantly reduces the rate and the time to development of OPC compared with placebo.

Total body irradiation in acute myeloid leukemia and chronic myelogenous leukemia: influence of dose and dose-rate on leukemia relapse.

From June 1981 to March 1987, 106 patients--59 with acute myeloid leukemia (AML) and 47 with chronic myelogenous leukemia (CML)--were treated with Cyclophosphamide 60 mg/kg X 2 d and total body irradiation (TBI-990 cGy/3fr/3d described dose) before allogeneic bone marrow transplantation. Seventy-nine patients are evaluable for risk of relapse: 32 with chronic myelogenous leukemia (23 in first chronic phase, 9 in accelerated phase) and 47 with acute myeloid leukemia (38 in first complete remission, 9 in subsequent phases). Actual TBI doses delivered to these patients varied between 839 and 1250 cGy (mean 956 +/- 101)/3 fr/3d, with dose rates between 2.7 and 7.25 cGy/min (mean 4.2 +/- 1.8). Patients receiving high (greater than 990 cGy) and low (less than or equal to 990) dose and/or dose rate (greater than 4 cGy/min and less than or equal to 4, respectively) have been evaluated overall and stratified by type of leukemia and phase of disease. When the patients are considered altogether, high total dose is significantly correlated with decreased risk of relapse (p = 0.0005) as well as high dose rate (p = 0.03). When considering specific subgroups, the influence of total dose on relapse rate is evident both for "early" and "advanced" leukemias, while an impact of dose rate appears only for chronic myelogenous leukemia in 1st chronic phase. Pertinent radiobiological and clinical literature is reviewed, and a possible role of dose fractionation and dose rate in leukemic control rate is evidenced; in this TBI setting, total dose not less than 990 cGy/3fr/3d and dose rate not less than 4 cGy/min have to be guaranteed.

Alternating chemo-radiotherapy in bladder cancer: a conservative approach.

PURPOSE: The aim of this Phase II study was to determine a bladder-sparing treatment in patients with invasive bladder cancer, allowing a better quality of life. Objectives were to test toxicity and disease-free and overall survival of patients given an alternated chemo-radiotherapy definitive treatment. METHODS AND MATERIALS: Seventy-six patients with bladder cancer Stage T1G3 through T4 N0 M0 were entered in the same chemotherapy regimen (Cisplatin 20 mg/mq and 5-Fluorouracil 200 mg/mq daily for 5 days) alternated with different radiotherapy scheduling, the first 18 patients received two cycles of 20 Gy/10 fractions/12 days each; the second group of 58 patients received two cycles of 25 Gy/10 fractions/12 days each (the last 21 patients received Methotrexate 40 mg/mq instead of 5-Fluorouracil). RESULTS: A clinical complete response was observed in 57 patients (81%), partial response in 7 patients (10%), and a nonresponse in 6 patients (9%). At a median follow-up of 45 months, 33 patients (47%) were alive and free of tumor. The 6-year overall survival and progression-free survival was 42% and 40%, respectively. Systemic side effects were mild, while a moderate or severe local toxicity was observed in 14 patients and 13 patients (about 20%), respectively. CONCLUSION: Our conservative combination treatment allowed bladder-sparing in a high rate of patients and resulted in a survival comparable to that reported after radical cystectomy.

Chemo-radiotherapy and autologous bone marrow transplantation in poor prognosis neuroblastoma.

In Genoa, 39 patients affected by disseminated neuroblastoma, one to twelve years old, were treated with intensive chemotherapy (Vincristine 4 mg/sqm c.i. over 5 days, Melphalan 140 mg/sqm), total body irradiation (TBI) (3.3 Gy for 3 days), and unpurged autologous bone marrow transplantation (ABMT) since October 1984 until November 1987. Thirty-two patients were in complete response (first group) and 7 had residual disease (second group) after an intensive chemotherapeutic induction regimen. Actuarial overall survival at 38 months is 52% and disease free survival at 30 months is 28% for the first group. Actuarial overall survival at 25 months is instead 14% for the second group related treatment toxicity has not been too high (3 deaths).

Prophylactic brain irradiation: still an open question (review).

Prophylactic cranial irradiation (PCI) is still an open question despite the fact that ten randomized trials have been published in the past, addressing its impact on overall survival, disease-free survival and incidence of brain recurrences. The majority of these trials allow us to conclude that PCI is only useful in reducing the rate of brain recurrences, without any impact on survival. Nevertheless, there are some isolated monoinstitutional papers indicating a positive impact on survival. As all the published trials vary in the schedule and timing of cranial irradiation, patient selection and systemic treatment, all these factors can explain the impossibility of demonstrating survival effects in individual studies and the difficulty of collecting homogeneous data from their overview. However, even the limited benefit of a reduction in the rate of CNS relapses, shown by most of these studies, appears important due to the poor symptom relief and quality of life of the patients treated for clinically evident brain metastases. The occurrence of late CNS toxicity in prophylactically irradiated patients may hamper a clinical advantage in these individuals.

Alternating chemotherapy with cyclophosphamide, doxorubicin, vincristine and cisplatin, etoposide followed by prophylactic cranial and thoracic irradiation for small cell lung cancer (SCLC): long-term results.

Both CAV (Cyclophosphamide, Doxorubicin, Vincristine) and PE (Cisplatin, Etoposide) are effective and non cross-resistant regimens in the treatment of SCLC. We designed a chemotherapeutic scheme including CAV and PE given in an alternating fashion with the following schedule: Cyclophosphamide 1000 mg/sm, Doxorubicin 50 mg/sm, Vincristine 2 mg/sm I.V. on day 1, alternated every 21 days with Cisplatin 20 mg/sm and Etoposide 80 mg/sm I.V. days 1-5 for 6 cycles. Following chemotherapy (CT) chest radiotherapy in patients (pts) with limited disease (LD) in complete response (CR) or partial response (PR) and prophylactic cranial irradiation (PCI) in CRs were given, 32 pts entered the study and 27 were evaluable: 9/27 (33.3%) had CR (8/15 with LD had CR) and 15/27 (55.5%) PR. The overall median survival was 53.71 weeks: 79.85 weeks for LD pts and 32.86 for ED.4 pts with LD were alive after 2 years and 2 of them are still alive without disease at 44 and 46 months. Toxicity was acceptable in all patients. Alternating chemotherapy with CAV and PE followed by chest and brain RT in responding LD pts is an effective induction treatment for SCLC although long-term survival still remains disappointing.

Neoadjuvant or definitive alternating chemotherapy and radiotherapy for infiltrating bladder cancer.

Thirty-two patients with infiltrating bladder cancer were treated with transurethral resection followed by one course of alternating chemoradiotherapy before radical cystectomy (group A, 20 patients) or two courses as definitive procedure (group B, 12 patients). One course consisted of: cisplatin 20 mg/m2 i.v. and 5-fluorouracil 200 mg/m2 i.v. for 5 consecutive days, the first and the fourth weeks; radiotherapy 20 Gy in 10 fractions in the second and third weeks. At the seventh week the same integrated therapy was restarted in group B. All 32 patients were evaluable for toxicity after the first course: no grade IV toxicity was observed. Significant increase in hematological toxicity was observed in 12 patients who received the second course of chemoradiotherapy: two patients had grade IV toxicity, and five patients had grade III. Fifteen patients of group A underwent radical cystectomy: 40% had a pathological (p) complete response (CR) and 13.3% a partial response Five patients in group A did not receive either the second course of therapy or cystectomy because of age (three patients), vascular obliteration (one patient) and enteritis (one patient). Actuarial disease-free survival in group A is 78% at 21 months. All patients of group B obtained clinical (c) CR and all but one have no evidence of disease at a median follow-up of 10 months (range 6-13). The high pCR and cCR obtained in patients of group A and group B, respectively, appears promising. A longer follow-up and a larger number of patients is required to determine the role of this integrated treatment.

Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in FIGO stage IIB-III cervical carcinoma. GONO (North-West Oncologic Cooperative Group).

Between January 1989 and December 1991, 64 patients with advanced cervical carcinoma FIGO stage IIb-III were randomized to receive radiotherapy (RT) alone or the sequential combination of chemotherapy (CT) and RT. RT consisted of external RT (40 Gy fractionated over 4 weeks)+brachy-therapy (40 Gy to point A)+an additional boost to the parameters (15-20 Gy) in arm RT; CT consisted of cisplatin 60 mg/m2 i.v. day 1 q 15 days administered for 2 cycles before the start of RT and for 4 cycles after the end of radiation treatment in CT+RT arm. Among the 58 evaluable patients objective response rate was as follows: in RT arm, CR in 40.7% of patients, PR in 40.7%, and SD in 18.6%; in CT+RT arm, CR in 42% of patients, PR in 35.5%, and SD in 22.5%. The median duration of response was 12 months (range: 3-38 + months). At a median follow-up of 36 months survival (S) and progression-free survival (PFS) were 83% and 72.4% in RT arm, 72% and 59.3% in CT+RT arm, respectively. No significant difference was observed between the 2 treatment arms, neither in terms of objective response nor in terms of S and PFS. Both treatments were generally well tolerated. In our experience the addition of chemotherapy to standard radiotherapy does not enhance morbidity and does not interfere with the correct delivery of the planned treatment. However, results of this combined modality regimen remain unsatisfactory, since no improvement in pelvic control and survival of patients with advanced cervical carcinoma was observed.

High-risk early-stage ovarian cancer. Randomized clinical trial comparing cisplatin plus cyclophosphamide versus whole abdominal radiotherapy.

From 1985 to 1989 70 patients with high-risk FIGO Stage I-II ovarian carcinoma entered a randomized trial comparing chemotherapy (CT: cisplatin 50 mg/m2 + cyclophosphamide 600 mg/m2 day 1 every 28 days for 6 courses) versus whole abdominal radiotherapy (WAR) given according to the open-field technique (43.2 Gy/24 fractions to the pelvis and 30.2 Gy to the upper abdomen). Protocol violations occurred in 8 patients randomized to WAR who received CT because of their own and/or physician's decision. Since protocol compliance was poor and accrual low the study was prematurely closed. Treatment-related toxicity for patients receiving CT was mild and tolerable, consisting chiefly of controllable grade 3 emesis (71%). Grade 3-4 diarrhea was experienced by 28% of patients treated with WAR; severe enteritis requiring hospitalization was observed in 2 patients. Late bowel obstruction requiring surgery was observed in 1 patient. At a median follow-up of 60 months, 21 patients died and 23 relapsed. Five-year survival was 71% and 53% (p = .16), while relapse-free survival was 74% and 50% (p = .07) for CT and WAR, respectively. Although no firm conclusion can be drawn from the present study, a short-term CT, including cisplatin, appears a safe treatment in comparison to WAR.

Abdominopelvic radiotherapy following surgery and chemotherapy in advanced ovarian cancer.

Thirty advanced ovarian cancer patients have been treated with sequential multimodality treatment including primary surgery, cisplatin or carboplatin-based polichemotherapy, second-look laparotomy followed by abdominopelvic irradiation (moving strip or open-field technique). Toxicity related to the combined treatment was acceptable: only three patients failed to complete and two patients delayed the prescribed course of radiotherapy because of acute myelosuppression or gastroenteric disturbances. One patient without evidence of disease required laparotomy for bowel obstruction one month after completion of radiotherapy. No other chronic toxicity of clinical significance has been observed. Actuarial three-year survival significantly correlated with residual disease at the start of radiotherapy: no residuum, 100%, microscopic disease, 52%; less than 2 cm macroscopic disease, 27.4% (P less than 0.05), whereas recurrences were less frequent only in the group of pathological complete responders (3/9) compared to patients with limited disease (6/11 with micro and 7/10 with macroscopic residuum). In conclusion radiotherapy following surgery and chemotherapy is not associated to serious morbidity but its value in improving progression-free survival rates has to be tested in randomized trials.

Tachycardia: an autosomal, monogenic, biallelic, recessive trait.

A brief commentary of the genetics of blood pressure is presented. The importance of the mechanisms of blood pressure regulation, among which heart rate is relevant, is emphasized. The analysis of a small population to test the quantitative model of the trait heart rate, considered as a metric character, is presented. The analysis of heart rate fitting to a qualitative model of inheritance is carried out. The results displayed might support the hypothesis that tachycardia could be an autosomal, monogenic, biallelic recessive trait.

Lerner's homeostasis and blood pressure.

Lerner's concept of developmental homeostasis, formerly elaborated with regard to the study of morphological traits, is proposed as a way of analysing the heritability of blood pressure. The important and controversial contribution of the autonomic nervous system to blood pressure regulation is also discussed with the aid of the hyperkinetic state, an entity described by Julius and Schork, and considered as an etiological factor in the occurrence of borderline hypertension. Experimental support through an analysis of a study performed on 87 pedigrees of normal healthy individuals is provided. The analysis calculates the heritabilities of systolic and diastolic blood pressure as well as heart rate. A classification in four categories, taking into account the hyperkinetic state, using the combined values of heart rate and mean arterial blood pressure is proposed, and its value regarding the categorization of normal individuals is emphasized and discussed simultaneously with the heritabilities calculated, in an attempt to explain the contribution of Lerner's theory to the inheritance of blood pressure.

Combined treatment with lasertherapy (Nd:YAG) and endocavitary radiation in the palliation of rectal cancer.

BACKGROUND/AIMS: The ideal treatment for patients with advanced rectal cancer and who cannot undergo a radical therapy is still undefined. The association between lasertherapy (LT) and internal radiotherapy (IRT) could affect both technical results and quality of life. This study was aimed at evaluating the association of LT and IRT in the palliative treatment of rectal cancer. MATERIAL AND METHODS: Between January and April 1994, 9 patients (2 males, 7 females) with rectal cancer underwent a combined treatment modality in order to control their symptoms. All patients were unfit for surgery and EUS showed an invasion of the whole muscular layer. After laser recanalization, brachytherapy was applied at a one week interval from last laser session. Two fractions of 10 Gy were administered at one week intervals. RESULTS: The mean number of laser sessions to obtain a complete recanalization was 3 (range:2-5) and no complications occurred. After IRT, we obtained a good result in 7/9 patients (79%) and 2 patients required further LT. The mean follow-up was 146 days (range:74-240): during this period no laser treatment was performed. Four patients complained of acute perineal pain and tenesmus after brachytherapy: in one patient, a colostomy was performed. CONCLUSION: We deem that the administration of two fractions of 10 Gy is not advisable, particularly for the treatment of non-circumferential lesions, due to the severe side effects we observed.

Treatment of FIGO stage Ib cervical carcinoma with nodal involvement.

One hundred and eighty one patients with stage Ib cervical cancer underwent hysterectomy with pelvic lymphadenectomy. The overall incidence of lymph node metastases was 20%. Twenty seven (71%) patients with nodal involvement were treated by external radiotherapy (TCT) and 11 (29%) by both chemotherapy and radiotherapy (Lin. Acc.). The overall survival at 5 years was 80%; it was 43% for patients with positive nodes and 89% for patients without metastatic nodal disease. The 3 year survival of patients with positive nodes who underwent radiation therapy by TCT was 58%, while it was 72% for those treated by chemotherapy plus radiotherapy. We observed a recurrence in 23% of the cases, 52% in patients with positive nodes and 15% in those with negative nodes. The association chemo-radiotherapy in patients with metastatic lymph nodes seems to improve the survival and reduce the recurrence rate.

[The correlation of arterial pressure with weight and body mass index]. / Correlación de presión arterial con peso e índice de masa corporal.

OBJECTIVES: To analyze the influence of weight and different body mass indexes on blood pressure (BP) values. The study was carried out in 823 volunteers (345 males, 478 females), aged 25/80 years. A standardized protocol, based on the recommendations provided by the V Joint National Committee was set up. The means of three consecutive readings taken at 2-min. intervals on three occasions were used. Weight and height were determined and the indexes were calculated. Correlations between weight and the selected indexes, with SBP and DBP, respectively, by sex and age interval were performed. The most representative indexes were body mass index (BMI) followed by lean BMI and weight. Analysis of BP values are BMI, for a period starting at 25 years and ending at 74 year, for both SPB and DBP, in comparison with the Humboldt Study data was performed, showing a strikingly similar pattern of behavior with our data. Additionally, weight and BMI are more closely associated with DBP in males than in females. Conversely, this association is closer in women with SBP. The importance of the ethnic factor is emphasized in order to establish body mass index cut-off values regarding the population under study, because the values proposed by the American Heart Association are probably rather high for our population.

Adverse effect of 1,25-dihydroxycholecalciferol on erythrocyte precursors in the rat.

Administration of 1,25-dihydroxycholecalciferol (0.5 microgram/d/100 g body weight) to vitamin D repleted rats produced a significant decrease in the number of femoral marrow cells, specially in the erythroid line. Analysis of blood revealed slight anemia with reticulocytopenia. The survival time of 51-Cr-labelled red cells was unaffected by treatment, suggesting that bone marrow became unable to replace cells at a normal rate. The adverse effect on erythropoiesis appeared related to the degree of the concurrent hypercalcemia, which in turn depends upon the calcium content of the diet.

Effect of bicarbonate feeding on immobilization osteoporosis in the rat.

A time course study of immobilization osteoporosis was carried out in an experimental model in which the hind half of the rat was paralyzed by spinal section between the 3rd and 4th lumbar vertebrae. The earliest changes in the femure were a reduction in water content and in bone volume (3 days after operation). A significant reduction in both hydroxyproline and phosphate content was observed 8 days after immobilization. Calcium, magnesium, sodium, citrate, and carbonate were found significantly decreased at 15 days. Bone potassium remained unchanged. The rate of calcium accretion and the size of the exchangeable pools, when expressed per unit of bone mass, were not significantly affected by treatment. Sham-operated rats fed a bicarbonate-enriched diet, showed increased rates of calcium accretion and bone calcium content. The latter was not accompanied by increases in phosphate and carbonate contents. Operated animals fed the same diet showed an increased rate of bone resorption attributed to an assumed higher rate of parathyroid hormone secretion induced by bicarbonate feeding.

Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma.

To evaluate whether androgen deprivation impacts late rectal toxicity in patients with localised prostate carcinoma treated with three-dimensional conformal radiotherapy. One hundred and eighty-two consecutive patients treated with 3DCRT between 1995 and 1999 at our Institution and with at least 12 months follow-up were analysed. three-dimensional conformal radiotherapy consisted in 70-76 Gy delivered with a conformal 3-field arrangement to the prostate+/-seminal vesicles. As part of treatment, 117 patients (64%) received neo-adjuvant and concomitant androgen deprivation while 88 (48.4%) patients were continued on androgen deprivation at the end of three-dimensional conformal radiotherapy as well. Late rectal toxicity was graded according to the RTOG morbidity scoring scale. Median follow up is 25.8 (range: 12-70.2 months). The 2-year actuarial likelihood of grade 2-4 rectal toxicity was 21.8+/-3.2%. A multivariate analysis identified the use of adjuvant androgen deprivation (P=0.0196) along with the dose to the posterior wall of the rectum on the central axis (P=0.0055) and the grade of acute rectal toxicity (P=0.0172) as independent predictors of grade 2-4 late rectal toxicity. The 2-year estimates of grade 2-4 late rectal toxicity for patients receiving or not adjuvant hormonal treatment were 30.3+/-5.2% and 14.1+/-3.8%, respectively. Rectal tolerance is reduced in presence of adjuvant androgen deprivation.

The effects of long term feeding of Solanum glaucophyllum to growing rats on Ca, Mg, P and bone metabolism.

The effects of the long term ingestion of Solanum Glaucophyllum leaves (SG) by the rat was investigated in two series of experiments; the animals were fed a normal (for 8 weeks) or a low Ca diet (for 5 weeks). With both diets, the intestinal absorption of Ca was increased and the endogenous fecal Ca excretion was decreased by SG treatment. Added to a normal Ca diet, SG increased the urinary excretion of Ca, Mg and P and reduced the excretion of hydroxyproline and pyrophosphate. At the histological level, SG induced a higher rate of bone tissue synthesis on trabecular and endosteal surfaces. The bone content of hydroxyproline and citrate increased significantly. The total alkaline phosphatase activity of plasma decreased as a function of SG intake due to a decreased in the activity of the intestinal isoenzyme, which was not compensated by the increase in the bone isoenzyme activity. The Mg absorption was decreased by SG inducing lower Mg balances and lower plasma Mg levels. Added to a low Ca diet, SG increased the severity of the secondary hyperparathyroidism induced by the diet. The urinary excretion of hydroxyproline and the plasma alkaline phosphatase activity (both isoenzymes) were significantly increased. The Na and K content of bone decreased as a function of SG intake. 45Ca kinetic experiments revealed that SG increased the rate of Ca resorption and the rate constant of the fast exchangeable Ca pool, in both diets.