White blood cells, C-reactive protein and erythrocyte sedimentation rate in pneumococcal pneumonia in children

PURPOSE: To profile cancer patients aged 80 and older undergoing radiotherapy and to study the tumor response and side effects of therapy. METHODS AND MATERIALS: We retrospectively analyzed the records of patients aged 80 and older who received radiation therapy at James A. Haley Veterans Hospital and H. Lee Moffitt Cancer Center between 1988 and 1995. A total of 203 patients aged 80-94 received radiotherapy during this period. Treatment sites included head and neck [50], breast [16], chest [37], pelvis [53], and miscellaneous [39]. Age, treatment site, field size, total dose, response to treatment, treatment interruptions, incidence and severity of weight loss, myelosuppression, diarrhea, mucositis, dermatitis, and follow-up status are assessed using our departmental records and hospital tumor registry. RESULTS: Of 191 patients evaluated, 179 (94%) completed the treatment without serious complications. A total of 195 sites were irradiated. Twelve patients (6%) required interruption of the treatment. Therapeutic responses were seen in 86 out of 112 patients (77%) treated with curative intent (with 67% complete response) and in 67 out of 83 patients (81%) treated with palliative intent. The causes of treatment interruptions included weight loss from diarrhea, dysphagia, and progressive disease. Treatment interruptions were more likely in patients treated with large treatment fields. In patients treated for upper aero-digestive tract cancer, Grade 3 and 4 mucositis was noted in 20 and 2% of patients, respectively. Grade 1 and 2 enteritis was noted in 43% of patients treated for pelvic malignancies. Grade 3 dermatitis was noted only in 2% of patients. CONCLUSION: Radiotherapy is highly effective and well tolerated by the oldest old. Age is not a contraindication to aggressive radiotherapy.     

Complications of absorbable pelvic mesh slings following surgery for rectal carcinoma

PURPOSE: To evaluate the intraoperative, postoperative, and long-term complications of an absorbable pelvic mesh sling after surgery for rectal carcinoma. METHODS: A retrospective review of medical records from April 8, 1991, through April 8, 1996. RESULTS: Twenty patients with a mean age of 57 (range, 37-79) years underwent pelvic mesh sling placement. The tumor stages were as follows: Stage I, 5; Stage II, 2; Stage III, 11; and Stage IV, 1. A recurrent perianal basal cell carcinoma was not included in the staging group. Surgery consisted of 18 abdominoperineal resections, 1 total proctocolectomy, and one Hartmann's procedure. Mean follow-up was 18 (range, 2-49) months. There were no intraoperative complications related to mesh placement. Twenty-nine complications occurred in 14 patients during the immediate postoperative period. Five were possibly mesh-related and included a pelvic abscess, perineal seroma, toxic perineal wound, pulmonary embolus, and lower extremity deep venous thrombosis, respectively. A mild postoperative ileus developed in 17 patients (85 percent), and a diet was initiated at a mean of seven (range, 4-24) days. Fourteen patients received postoperative radiotherapy with a mean dose of 5,339 (range, 2,500-7,020) cGy delivered in 180-cGy fractions. There were 14 immediate complications caused by radiotherapy in 11 patients, but only two patients required delays in treatment. Two patients had diarrhea alone, six developed perineal dermatitis alone, and three patients had both diarrhea and perineal dermatitis. All patients with diarrhea had received chemoradiation. One patient developed a partial small-bowel obstruction following radiation. CONCLUSIONS: Absorbable pelvic mesh sling placement can be performed with minimum morbidity and is recommended following surgery for rectal cancer when radiation is anticipated as part of multimodality therapy.     

In vitro evaluation of the cytotoxic, hemolytic and clastogenic activities of Rhizostoma pulmo toxin(s)

A 36-year-old woman with early recurrence of uterine cervical cancer had received radiotherapy and a CDDP-containing chemotherapy regimen. She was treated with oral etoposide by administration of 50 mg/day for 21 consecutive days at 14-day intervals. After two courses, complete remission was demonstrated by disappearance of the cervical tumor mass and pelvic lymph node enlargement on MRI. Leukopenia (grade 3) occurred after five courses, as well as alopecia (grade 2) and gastrointestinal discomfort (grade 1) after two courses. The patient has shown no sign of recurrence for 1.5 years. This method might be quite effective for patients with recurrent cervical cancer as well as allowing outpatient treatment and improving the quality of life.     

Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome

OBJECTIVES: Massive intestinal resection results in short bowel syndrome and necessitates prolonged parenteral feeding. The purpose of this work was to assess the impact of late complications of short bowel syndrome, including intestinal bacterial overgrowth and enterocolitis, on the duration of parenteral nutrition (PN) in comparison with factors evident in the neonatal period. METHODS: Retrospective chart review. RESULTS: Of 49 children, 42 were weaned from parenteral nutrition after a treatment course of 17 +/- 14 months. In these 42, postresection small intestinal length equaled 81 +/- 65 cm; 45% had an ileocecal valve. Small intestinal length in the seven children who were PN dependent was 31 +/- 30 cm (p < 0.05); none had an ileocecal valve (p < 0.05). Bacterial overgrowth occurred in all seven PN-dependent children and in 23 of 42 children eventually weaned from PN (p < 0.05). When bacterial overgrowth was identified before weaning (n = 12), the duration pf PN was 28 +/- 17 months, but when bacterial overgrowth was first identified only after weaning (n = 11), the duration of PN was 16 +/- 13 months (p < 0.05). Small intestinal inflammation correlated with bacterial overgrowth (r = 0.69). Those children with severe enteritis identified before weaning remained on the PN regimen for 36 +/- 15 months, in comparison with 21 +/- 14 months in those with mild enteritis and 13 +/- 11 months in those without inflammation (p < 0.02). CONCLUSIONS: Although the length of small intestine remaining after resection is the best immediate predictor of final success in terminating PN in children with short bowel syndrome, PN is prolonged by bacterial overgrowth and associated enteritis in those who will ultimately be weaned.     

Malabsorption following radiation therapy

Gastrointestinal injury is known to occur following radiation therapy of tumors in the abdominopelvic compartment. Chronic radiation changes may be associated with diarrhea and malabsorption. A patient with transitional cell carcinoma of the bladder developed diarrhea following radiotherapy and was treated symptomatically for nine years with the assumption that the diarrhea was secondary to radiation enteritis. Further evaluation including endoscopic cholangiopancreatography, revealed pancreatic insufficiency with steatorrhea as the probable cause of the patient's diarrhea. Although temporally related to radiation therapy, the etiology of his pancreatic insufficiency remains speculative. All patients developing diarrhea and/or malabsorption following radiotherapy should be evaluated thoroughly for treatable causes.     

Phase II study of mitoguazone, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with diffuse histologic subtypes of non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Study (PE481)

Mitoguazone, an investigational agent with significant activity in advanced lymphoma, was added to a modified CHOP regimen (COPA) in an effort to improve the activity of standard therapy in 66 previously untreated patients with stages II-IV lymphoma and diffuse histology of intermediate or high grade other than lymphoblastic in this phase II pilot study. The regimen was well tolerated and the complete response rate in diffuse large cell lymphoma was 55%. Sixty-five percent of all complete responders were in complete response for at least one year. Despite these excellent results. it is unlikely that the addition of mitoguazone improved results compared with those obtained with standard therapy alone, since similar results have been frequently reported with the latter.     

Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma: an Eastern Cooperative Oncology Group trial

PURPOSE: This multicenter cooperative group phase I/II trial evaluated the toxicity and efficacy of escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: From November 1990 through October 1991, 35 patients with advanced urothelial cancer previously untreated with chemotherapy were treated with escalated dosages of M-VAC (M-VACII). In patients with prior pelvic radiotherapy, standard M-VAC (M-VACI) was administered plus rhG-CSF. For other patients, M-VACII dosages were methotrexate 40 mg/m2 (days 1, 15, and 22), vinblastine 4 mg/m2 (days 2, 15, and 22), doxorubicin 40 mg/m2 (day 2), and cisplatin 100 mg/m2 (day 2). In addition, rhG-CSF was administered at a dosage of 300 micrograms subcutaneously on days 4 to 11. Cycles were repeated every 4 weeks. For patients who tolerated the first course of therapy, subsequent escalation by 25% of all drugs was performed. RESULTS: Six complete responses and 15 partial responses were observed (60%; 95% confidence interval, 42% to 76%). The median duration of response was 4.6 months, and the median survival time was 9.4 months (range, 0.5 to 23.5+). Twenty-eight of 35 patients experienced grade 3 or 4 leukopenia, including 14 patients who developed fever associated with neutropenia. Eight (23%) early deaths were observed. CONCLUSION: This regimen (M-VACII) with escalated dosages of M-VAC was associated with significant toxicity and had no apparent benefit over M-VACI therapy with regard to complete response rate or survival. Further evaluation of the dose-intensity of the components of this regimen in this disease is likely to be of limited benefit to patients.     

Hypofractionated radiotherapy with concurrent 5-fluorouracil radiosensitisation for recurrent or locally advanced colorectal cancer. A phase II study

In a pilot study we treated 19 patients suffering from recurrent or locally advanced inoperable colorectal cancer, with concurrent hypofractionated radiotherapy (4-5 Gy/fraction, 2 fractions per week) and 5-fluorouracil bolus, 1 hour before RT at doses of 300 mg/m2. For 16 patients treated with radical intent the Normalised Total Dose for alpha/beta = 10 Gy ranged between 56-74 Gy (median 62 Gy). The schedule used was very well tolerated. Moderate grade II haematological toxicity was observed in 11% of cases and diarrhoea grade II/III resulting in 2-4 weeks treatment delay was observed in 26% of cases. One case with bowel perforation and one with painful subcutaneous fibrosis was observed during 12-27 months of follow-up. Out of 16 patients treated with radical intent 4 (25%) showed complete response and the overall response rate was 56% (9/16). The one-year symptom-free survival was obtained in 11/16 (69%) radically treated patients. It is concluded that hypofractionated radiochemotherapy with 5-fluorouracil for recurrent or locally advanced colorectal cancer is an effective regimen and has acceptable acute and late toxicity. Further investigation is required.     

Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer

We conducted a prospective Phase II study to determine the response rate, toxicity, and 2-year survival rate of concurrent weekly paclitaxel and radiation therapy (RT) for locally advanced unresectable non-small cell lung cancer. The weekly paclitaxel regimen was designed to optimize the radiosensitizing properties of paclitaxel. Thirty-three patients with unresectable stage IIIA and IIIB non-small cell lung cancer from six institutions were entered into the study between March 1994 and February 1995. Weekly i.v. paclitaxel (60 mg/m2; 3-h infusion) plus concurrent chest RT (60 Gy over 6 weeks) was delivered for 6 weeks. Twenty-nine patients were evaluable for response. Three patients achieved a complete response (10%), and 22 patients (76%) achieved a partial response, for an overall response rate of 86% (95% confidence interval, 68-96%). One patient progressed during the therapy, and three patients had stable disease. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (37%). One patient died of pneumonia after completion of therapy. Additional grade > or =3 toxicities included pneumonitis (12%) and neutropenia (6%). One patient had a grade 3 hypersensitivity reaction. The median overall survival duration for all 33 patients who entered the study was 20 months, and 1-, 2-, and 3-year overall survival rates were 60.6%, 33.3%, and 18.2%, respectively. The median progression-free survival duration for all 33 patients was 10.7 months, and 1-, 2-, and 3-year progression-free survival rates were 39.4%, 12.1%, and 6.1%, respectively. Weekly paclitaxel plus concurrent RT is a well-tolerated outpatient regimen. The survival outcome from this regimen is encouraging and seems to be at least equivalent to that of other chemotherapy/radiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/RT in Phase II trials in the neoadjuvant setting and in combination with other cytotoxic agents.     

Patterns of recurrence following pelvic exenteration and external radiotherapy for locally advanced primary rectal adenocarcinoma

BACKGROUND: Local recurrence remains the main site of failure after pelvic exenteration for locally advanced primary rectal adenocarcinoma. This is a report on the patterns of recurrence in a group of such patients treated with pelvic exenteration and radiotherapy. METHODS: Between 1980 and 1992, we treated 49 patients. Thirty-one received preoperative radiotherapy (pre-RT), 4,500 cGy. Six weeks later, we performed posterior pelvic exenteration (PPE) in 21 patients, and total pelvic exenteration (TPE) in 10. Nine patients received postoperative radiotherapy (post-RT), 5,000 cGy after a PPE. Nine patients had surgery only, PPE (n = 7) and TPE (n = 2). RESULTS: Surgical mortality occurred in 16% of those patients who received pre-RT. The median follow-up was 52 months. Recurrences occurred in 23% of those patients who received pre-RT (local, one; local/distant, one; distant, four); in 88% of those patients treated with surgery only (local/distant, four; distant, four); and in 11% of those treated with post-RT (distant, one). The 5-year survival for patients who received radiotherapy was 66 versus 44% for those treated with surgery only. CONCLUSION: Local control of locally advanced primary rectal adenocarcinoma requiring a pelvic exenteration is improved by the addition of radiotherapy. When recurrences do occur they are predominantly at extrapelvic sites.     

Protease inhibitors for the treatment of human immunodeficiency virus infection

The pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration of protease inhibitors are reviewed. Protease inhibitors are a novel class of drugs used for the treatment of human immunodeficiency virus (HIV) infection. Saquinavir, ritonavir, indinavir, and nelfinavir have been approved in the United States; several other agents are under development. Protease inhibitors selectively block HIV protease, an enzyme involved in the later stages of HIV replication. Various pharmacokinetic differences exist among these agents, including differences in bioavailability, protein binding, and drug interactions. The drugs undergo extensive hepatic metabolism; dosage adjustments should be considered for patients with hepatic dysfunction. Clinical trials have shown protease inhibitors to be effective in reducing HIV RNA levels and increasing CD4+ lymphocyte counts. When protease inhibitors are used in combination with other antiretroviral agents, an additional beneficial effect on these markers occurs. Adverse effects of saquinavir and nelfinavir include mild gastrointestinal disturbances such as diarrhea. Ritonavir is less well tolerated because of gastrointestinal disturbances and circumoral and peripheral paresthesia. Indinavir has been associated with nephrolithiasis and asymptomatic hyperbilirubinemia. The development of resistance to protease inhibitors may be related to suboptimal dosages, noncompliance, or partial compliance. Protease inhibitors are potent and highly selective agents that block a critical step in HIV replication. They are effective and relatively well tolerated, but they are expensive, have extensive drug interaction profiles, and require careful compliance with the prescribed regimen.     

Phase II study of rapid-scheduled etoposide in paediatric soft tissue sarcomas

Twenty three patients with paediatric soft tissue sarcomas who had relapsed or refractory disease were treated with a rapid schedule of intravenous etoposide (100 mg/m2 daily on three consecutive days, weekly over 3 weeks). The regimen was well tolerated with predictable myelotoxicity. In 19 patients with rhabdomyosarcoma, there was a response rate of 42%. This appears to be better than previously reported with conventional three weekly schedules. These data indicate that for rhabdomyosarcoma, as for some other tumours, a divided dose regimen may be the optimal schedule and is worthy of further evaluation.     

Ad hoc survey of hepatitis B vaccination campaign in newborns of HBsAg positive mothers and in 12-year-old subjects in southern Italy

Subtotal colectomy with ileorectostomy has been proposed for the management of colon inertia-type constipation. However, many patients experience frequent bowel movements, watery diarrhea, or both after such a treatment. The purpose of this study is to determine the proper colectomy with which to treat colon dysmotility constipation without the negative side effects of frequent bowel movements, watery diarrhea, or both. Forty idiopathic constipation patients were studied. All of the patients showed a prolonged right or left colon transit time and normal transit time of the sigmoid and rectum. They received different types of colectomies (left, right, and subtotal) according to the distribution or accumulation of markers in the colon. Within 3 months of surgery, all of the patients experienced a dramatic improvement of their symptoms without frequent bowel movements or watery diarrhea. No significant complications developed after surgery. All the patients were followed up for at least 2 years. Most of them (37 cases) still had satisfactory bowel movements and no other constipation symptoms. However, 3 of the 40 cases developed symptoms of constipation 1 1/2 to 2 years after surgery. They all received subtotal colectomy with ileorectal anastomosis subsequently. They reobtained satisfactory bowel movements and experienced a subsidence of other constipation symptoms 3 months later. These results suggest that directed segmental colectomy can improve colonic inertia constipation without the consequence of frequent bowel movements and diarrhea.     

Approximating dipoles from human EEG activity: the effect of dipole source configuration on dipolarity using single dipole models

Long-term daily administration of oral bisphosphonates has been effective in the treatment of postmenopausal osteoporosis, but the duration, mode and cost of the therapy may sometimes affect patient compliance. In Italy, the bisphosphonate clodronate is also available via the intramuscular (i.m.) route of administration, and the present study was performed to test its efficacy in postmenopausal osteoporosis. Ninety osteoporotic postmenopausal women were enrolled in a randomized, controlled 3 year study. The diet of all patients was adjusted to provide 1200-1300 mg of calcium daily, eventually by administration of supplements. Patients were randomly assigned to no therapy (30 patients) or to receive clodronate 100 mg i.m. either every 2 weeks (30 patients) or 1 week (30 patients). The i.m. injection caused substantial pain at the site of injection, which led to treatment withdrawal in almost 50% of the patients receiving weekly dosing. In control patients, a progressive, slow decline in spine and femoral bone mineral density (BMD), which became statistically significant at the end of the second year of observation, was observed. In the patients given weekly i.m. clodronate, spinal BMD rose by 3.8% (+/-7.3 SD) within 6 months. A slight, nonsignificant increase was observed thereafter, such that, at the completion of 3 years of observation, the mean gain was 4.5% (+/-6.3). In the patients treated with injections of 100 mg of clodronate every two weeks the increase in BMD was somewhat lower and slower, becoming significant only at month 24 (2.9+/-4.6%). In none of the two active groups was the femoral neck BMD changed significantly during the 3 years of the study. A significant increase in trochanter and Ward's triangle BMD was observed at month 12 only in the patients on the highest dose of clodronate. In both groups treated, the hip BMD changes were significantly different from those observed in control patients. The biochemical markers of bone turnover were suppressed in both clodronate groups. These results indicate that intermittent i.m. clodronate administration can provide clinically relevant benefits to skeletal bone density in osteoporotic postmenopausal women, but the in situ pain may limit its extensive use.     

A pilot study on concurrent platinum chemotherapy and intracavitary brachytherapy for locally advanced cancer of the uterine cervix

This study aims to evaluate the feasibility, toxicity and efficacy of concurrent chemotherapy with platinum compounds and brachytherapy, for locally advanced carcinoma of the cervix (Stages IIA/B, IIIA). The hypothesis was that synchronous chemo-brachytherapy may be sufficient to cause down-staging of the tumour, to render it operable, and hopefully improve the prognosis. 36 women with locally advanced cervical cancer were treated with concomitant brachytherapy and chemotherapy before surgery and/or definitive external radiotherapy. All patients received two caesium-137 Selectron MDR applications, 1 week apart. The dose calculated to point A for each implant was 20-25 Gy. Chemotherapy consisting of continuous cisplatin infusion (50 mg m2) and of carboplatin (300 mg m-2) was given simultaneously with intracavitary irradiation during the first and second application, respectively. The combined therapy was followed when feasible by radical hysterectomy, pelvic lymphadenectomy and pelvic radiotherapy. Patients deemed ineligible for surgery because of poor response were given full dose external radiotherapy. 31/36 patients were treated by Wertheim hysterectomy of whom 10 had negative lymph nodes and resection margins. Definitive external radiotherapy was given in the remaining five patients. Overall, 83% were disease free at 2.8 years mean follow-up. The most frequent acute side-effects of chemobrachytherapy were nausea and vomiting. No renal toxicity was observed. Thrombocytopenia was seen in five patients and was responsible for delayed surgery in four patients. Concerning late effects, two patients developed grade 2 intestinal sequelae, two mild frequency and two vaginal stenosis. One rectovaginal and one vesicovaginal fistula developed in two patients; and a third patient had a fistula associated with tumour recurrence. Concurrent brachytherapy and chemotherapy with platinum compounds is well tolerated and effective in reducing tumour bulk before definitive local treatment (surgery or external radiotherapy), in patients with locally advanced carcinoma of the uterine cervix.     

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.     

Hepatitis G virus RNA and hepatitis G virus-E2 antibodies in Dutch hemophilia patients in relation to transfusion history

PURPOSE: Docetaxel is a highly active antineoplastic agent; however, grade IV leukopenia occurs in the large majority of patients treated with a dose of 100 mg/m2 every 3 weeks. Recent experience with weekly paclitaxel has demonstrated a bone marrow-sparing effect when a weekly administration schedule is used. We investigated a weekly schedule of docetaxel in an attempt to alter the toxicity profile and improve the therapeutic index. PATIENTS AND METHODS: Thirty-eight patients with advanced, refractory malignancy entered this phase I trial between October 1996 and June 1997. Docetaxel was administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Sequential cohorts of patients were treated at the following dose levels: 20, 25, 30, 36, 43, and 52 mg/m2. Patients were reevaluated after one course (8 weeks); patients with objective response or stable disease continued treatment for a maximum of four courses or until disease progression. RESULTS: Thirty-five patients completed at least one course of therapy. Myelosuppression was not a dose-limiting toxicity (DLT) at any of the doses tested. Only five episodes of grade III leukopenia occurred (14% of patients, 2% of doses), and no grade IV leukopenia was produced. No grade III or IV thrombocytopenia or anemia was observed. Grade III fatigue and asthenia were observed in all three patients treated at 52 mg/m2/wk and in two of 10 at 43 mg/m2/wk. Other grade III toxicity included acral erythema (n = 1), neuropathy (n = 1), peripheral edema (n = 1), and diarrhea (n = 1). The DLTs of this docetaxel schedule are fatigue and asthenia. Although the maximum-tolerated dose by definition of this study was 43 mg/m2/wk, we selected 36 mg/m2/wk for ongoing phase II studies. CONCLUSION: The toxicity profile of docetaxel is markedly altered when the drug is administered by a weekly schedule. Myelosuppression is mild and uncommon. Fatigue and asthenia are the DLTs; other nonhematologic toxicities, which included peripheral edema and neuropathy, are uncommon, and the arthralgia/myalgia syndrome was not observed. Weekly administration of docetaxel may provide a better tolerated, efficacious use of this drug; further investigation of weekly docetaxel as a single agent and in combination regimens is warranted.     

Single dose pharmacokinetics of manidipine in hepatic impaired patients and healthy controls

The pharmacokinetics and safety of a single oral dose of 20 mg manidipine dihydrochloride have been studied in 8 patients with mild to moderate hepatic impairment (grade A or B in Child's classification, or score < or = 7 in Pugh's modification of Child's classification), and in 12 healthy subjects. They received one 20 mg manidipine dihydrochloride tablet with 100 ml of tap water after a standard breakfast. Manidipine was determined using HPLC with electrochemical detection from plasma samples taken up to 24 or 36 h after dosing. The medication was well tolerated. A trend toward higher Cmax, AUC, and MRT was observed in patients with a more severe hepatic impairment, as a consequence of reduction in the liver metabolic function. Patients with grade A hepatic impairment did not exhibit significantly altered pharmacokinetics with respect to healthy subjects, while grade B impairment patients had significantly higher AUC and MRT. Tmax values pointed to reduced absorption rate in patients compared to healthy subjects; the changes were more evident in grade B than grade A patients, although statistical significance was not reached. The reduction in absorption rate in grade B patients is probably related to their higher mean age, since this effect has been reported for manidipine. The pharmacokinetics of manidipine seem only modified in patients with a certain degree of hepatic impairment (at least Pugh grade 6 and Child grade B); therefore, adaptation of the dosing regimen does not seem to be generally recommendable, but should be modulated according to the liver status of the patient.     

Initial response and subsequent course of Crohn's disease treated with elemental diet or prednisolone

Elemental diet is as effective as corticosteroids in the treatment of previously untreated Crohn's disease. It is unclear whether a poor nutritional state is a prerequisite for efficacy of elemental diet, whether previously treated patients respond as well, or how duration of remission using elemental diet compares with corticosteroid induced remission. Forty two patients with active Crohn's disease were stratified for nutritional state and randomised to receive Vivonex TEN 2.1 l/day for four weeks, or 0.75 mg prednisolone/kg/day for two weeks and subsequent reducing doses. Nine of 22 (41%) patients assigned to nutritional treatment were intolerant of the diet. Thirty patients completed four weeks treatment. Disease activity decreased on elemental diet from mean (SEM) 4.8 (0.9) to 1.7 (0.6), p < 0.05, and on prednisolone from 5.3 (0.5) to 1.9 (0.6), p < 0.05. For each treatment, nourished and malnourished patients responded similarly. Patients with longstanding disease responded as well as newly diagnosed patients. The probability of maintaining remission at six months was 0.67 after prednisolone, 0.28 after elemental diet, and at one year was 0.35 after prednisolone and 0.09 after elemental diet, p < 0.05. When tolerated, elemental diet is as effective in the short term as prednisolone in newly and previously diagnosed Crohn's disease, and its benefit is independent of nutritional state. The subsequent relapse rate after elemental diet induced remission, however, is greater than after treatment with prednisolone.