MRI-derived radiomics to guide post-operative management of glioblastoma: Implication for personalized radiation treatment volume delineation.

Background: The glioblastoma's bad prognosis is primarily due to intra-tumor heterogeneity, demonstrated from several studies that collected molecular biology, cytogenetic data and more recently radiomic features for a better prognostic stratification. The GLIFA project (GLIoblastoma Feature Analysis) is a multicentric project planned to investigate the role of radiomic analysis in GB management, to verify if radiomic features in the tissue around the resection cavity may guide the radiation target volume delineation. Materials and methods: We retrospectively analyze from three centers radiomic features extracted from 90 patients with total or near total resection, who completed the standard adjuvant treatment and for whom we had post-operative images available for features extraction. The Manual segmentation was performed on post gadolinium T1w MRI sequence by 2 radiation oncologists and reviewed by a neuroradiologist, both with at least 10 years of experience. The Regions of interest (ROI) considered for the analysis were: the surgical cavity ± post-surgical residual mass (CTV_cavity); the CTV a margin of 1.5 cm added to CTV_cavity and the volume resulting from subtracting the CTV_cavity from the CTV was defined as CTV_Ring. Radiomic analysis and modeling were conducted in RStudio. Z-score normalization was applied to each radiomic feature. A radiomic model was generated using features extracted from the Ring to perform a binary classification and predict the PFS at 6 months. A 3-fold cross-validation repeated five times was implemented for internal validation of the model. Results: Two-hundred and seventy ROIs were contoured. The proposed radiomic model was given by the best fitting logistic regression model, and included the following 3 features: F_cm_merged.contrast, F_cm_merged.info.corr.2, F_rlm_merged.rlnu. A good agreement between model predicted probabilities and observed outcome probabilities was obtained (p-value of 0.49 by Hosmer and Lemeshow statistical test). The ROC curve of the model reported an AUC of 0.78 (95% CI: 0.68-0.88). Conclusion: This is the first hypothesis-generating study which applies a radiomic analysis focusing on healthy tissue ring around the surgical cavity on post-operative MRI. This study provides a preliminary model for a decision support tool for a customization of the radiation target volume in GB patients in order to achieve a margin reduction strategy.

Association of 99mTc-MIBI brain SPECT and proton magnetic resonance spectroscopy (1H-MRS) to assess glioma recurrence after radiotherapy.

AIM: The aim of this study was to compare 99mTc-MIBI brain SPECT and proton magnetic resonance spectroscopy (1H-MRS) findings and to evaluate their association. METHODS: Both exams were performed on 30 glioma patients, previously operated and treated with radiotherapy, having MRI doubtful between recurrence and radiotherapy effects. SPECT images were acquired 15 minutes after radiopharmaceutical administration with a dual-head gamma camera. T1/B1 uptake ratio was calculated between a tumor ROI (T1) and a normal mirror symmetric ROI (B1) and T2/B2 ratio was obtained between a ROI in the hottest neoplastic part (T2) and a normal mirror symmetric ROI (B2). 1H-MRS was performed using a 1.5 T system equipped with a spectroscopy package. SPECT and 1H-MRS data were compared with histology after new surgery or with follow-up. RESULTS: SPECT and 1H-MRS showed recurrence in 18 patients (confirmed by biopsy, coinciding only in 17 cases) and were negative in 10 (1 false negative). SPECT and 1H-MRS disagreed in 2 cases of recurrence (1 diagnosed by brain SPECT, 1 by 1H-MRS). T1/B1 ratio mean value (4.26+/-2.5) was significantly lower than T2/B2 (4.93+/-2.81; P<0.001). SPECT and 1H-MRS sensitivity in detecting recurrence was 90%, specificity 100%, accuracy 93%, negative predictive value (NPV) 83% and positive predictive value (PPV) 100%; the associated exams sensitivity was 95%, specificity 100%, accuracy 96.6%, NPV 90.9%, PPV 100%. CONCLUSIONS: Brain SPECT and 1H-MRS have equivalent values of diagnostic parameters in differentiating tumor recurrence and radiation effects, and their association might provide additional information.

Adjuvant radiochemotherapy in high-risk rectal cancer results of a prospective non-randomized study.

AIMS AND BACKGROUND: In 1990 the National Institutes of Health Consensus Conference recommended adjuvant combined therapy for patients with radically resected rectal cancer at high risk for relapse (ie, stage II-III). The purpose of our prospective non-randomized study was to verify the feasibility and effectiveness of postoperative radiochemotherapy in terms of improvement in disease-free and overall survival in this patient subgroup. STUDY DESIGN: From January 1990 to October 1998, 191 consecutive patients with radically resected stage II-III rectal cancer were treated. A total of 159 patients with a 24-month follow-up were assessable for toxicity and survival. Anterior resection was performed in 129 (81%) and abdomino-perineal resection in 30 (19%) patients. Fifty-four (34%) stage II and 105 (66%) stage III patients entered the study. Within 45-60 days of surgery, all patients received 5-fluorouracil chemotherapy at the dose of 500 mg/m2 as an i.v. bolus on days 1-5, every 4 weeks, for 6 cycles. Chemotherapy cycles III and IV were administered at the same daily dose on radiotherapy days 1-3 and 29-31. Radiotherapy consisted of 45 Gy/25 fractions plus a boost dose of 5.4 Gy. RESULTS: After a median follow-up of 57 months (range, 25-123), overall recurrent disease was reported in 58 (36%) patients: local, systemic, and both local and systemic relapses in 12 (8%), 37 (23%) and 9 (6%) cases, respectively. According to local extension, recurrence rates were 15% and 48% in stage II and III, respectively. Five-year overall and disease-free survival were 71% and 66%, respectively. Overall survival was 87% in stage II and 62% in stage III patients, and disease-free survival was 84% and 56% in stage II and III disease, respectively. According to univariate and multivariate analyses, significant prognostic factors for better tumor control were: stage (II vs III, P <0.001), the number of involved nodes (< or = 3 vs > 3, P <0.0001), and no extracapsular node invasion (P <0.0001). The recommended dose of the combined radiochemotherapy regimen was generally well tolerated. The incidence of any > or = grade 3 acute toxicity (according to the WHO scale) was 13% diarrhea, 11% proctitis, 5% perineal dermatitis and 4% myelosuppression. Four (3%) patients had radiotherapy-related severe late toxicity which required surgery. CONCLUSIONS: The study provided recurrence rates and survival similar to other adjuvant radiochemotherapy regimens published in the literature. However, in view of the low 5-year survival rate recorded in stage III patients, a different approach should be investigated.

Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis.

BACKGROUND AND PURPOSE: Hypofractionated radiotherapy is often administered in metastatic spinal cord compression (MSCC), but no studies have been published on the incidence of radiation-induced myelopathy (RIM) in long-term surviving patients. Our report addresses this topic. PATIENTS AND METHODS: Of 465 consecutive MSCC patients submitted to radiotherapy between 1988 and 1997, 13 live patients (seven females, six males, median age 69 years, median follow-up 69 months) surviving for 2 years or more were retrospectively reviewed to evaluate RIM. All patients underwent radiotherapy. Eight patients underwent a short-course regimen of 8 Gy, with 7 days rest, and then another 8 Gy. Five patients underwent a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5. Only one patient also underwent laminectomy. Full neurological examination and magnetic resonance imaging (MRI) were performed. RESULTS: Of 12 patients submitted to radiotherapy alone, 11 were ambulant (eight without support and three with support) with good bladder function. In nine of these 11 patients, MRI was negative; in one case MRI evidenced an in-field relapse 30 months after the end of radiotherapy, and in the other, two new MSCC foci outside the irradiated spine. In the remaining patient RIM was suspected at 18 months after radiotherapy when the patient became paraplegic and cystoplegic, and magnetic resonance images evidenced an ischemic injury in the irradiated area. The only patient treated with surgery plus postoperative radiotherapy worsened and remained paraparetic. Magnetic resonance images showed cord atrophy at the surgical level, explained as an ischemic necrosis due to surgery injury. CONCLUSIONS: On the grounds of our data regarding RIM in long-term surviving MSCC patients, we believe that a hypofractionated radiotherapy regimen can be used for the majority of patients. For a minority of patients, more protracted radiation regimens could be considered.

Short-course palliative radiotherapy in non-small-cell lung cancer: results of a prospective study.

From February 1993 to October 1997, 91 consecutive patients with inoperable (stage IIIB-IV) histologically confirmed non-small-cell lung cancer underwent palliative hypofractionated radiotherapy. Recently, the Medical Research Council studies on hypofractionated short-course radiotherapy (8.5 Gy x 2) have reported high control of symptoms caused by thoracic disease without toxicity. Based on these experiences and our previous positive trial on short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression, a prospective study of short-course palliative radiotherapy in non-small-cell lung cancer was carried out. The regimen was 16 Gy given in two 8-Gy fractions, 1 week apart. Eighty-one patients were evaluable for response to treatment. Forty-eight (59%) patients were 65 years or older. Forty (49%) patients were naive to radiotherapy, whereas 41 (51%) had previous cisplatin-based chemotherapy. All but four stage IV patients (95%) had poor Eastern Cooperative Oncology Group performance status (i.e., 2-3). Clinical palliation was achieved in 62 (77%) patients. Performance status improved in 59 (73%) patients. The median palliation time ranged from 28% to 57% of patient survival. The median survival from the beginning of treatment was 148 days (range, 5-681 days). No difference in overall survival according to stage and previous chemotherapy was observed. Only performance status conditioned survival (performance status 1-2 vs. performance status 3; p = 0.0289). Short-course radiotherapy gave good results in terms of clinical palliation for thoracic symptoms, even in patients with poor performance status and pretreated with chemotherapy. The median palliation time was approximately 50% of patient survival time. Treatment was generally well tolerated-only 4 (5%) patients experienced World Health Organization grade III dysphagia. No late toxicity was recorded. The two-fraction regimen had social and economic advantages compared with the conventional ones.

Comparison of two different radiotherapy schedules for spinal cord compression in prostate cancer.

AIMS AND BACKGROUND: To assess the clinical outcome and toxicity of two different radiotherapy (RT) schedules for the management of metastatic spinal cord compression from prostate cancer, we performed a prospective analysis of 44 patients with the complication. METHODS: Two different RT schedules were adopted, a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5, and a short-course regimen of 8 Gy, 7 days rest, and then 8 Gy. The split-course RT was adopted for all prostate cancer patients referred to our center between 1986 and 1992. Starting in 1993, the short-course RT was added for patients with a poor prognosis (i.e., paresis or paraplegia, low performance status, and/or short life expectation), whereas others still underwent the split-course regimen. So, 27 (61%) patients were treated with the split-course and the other 17 (39%) with the short-course regimen. Medium follow-up was 48 months (range, 6 to 123). RESULTS: Back pain total response rate was 82%. Effectiveness of RT on motor and bladder capacity was conditioned by pretreatment status of patients. All 20 (100%) walking cases maintained the function, whereas 11 of 24 (46%) with motor impairment regained the ability. The difference in response rate was statistically significant (P < 0.001). All 36 (100%) patients, able to void at presentation preserved the capacity, whereas 3 of 8 (38%) with sphincter dysfunction no longer needed an indwelling catheter. Posttreatment neurologic status was the only factor found to affect survival. Median survival, 9 months for the whole group, was 10 and 2 months for posttreatment walking and nonwalking patients, respectively (10 vs 2 months, P < 0.001). Neither presence of other metastases nor RT regimen used (split vs short-course) conditioned response rate, duration of response or survival. Acute or late, severe toxicity was never recorded. No patient complained of spinal cord morbidity. CONCLUSIONS: Both split-course and short-course RT schedules were effective and without complications. Early diagnosis was the most important prognostic factor, but there was also recovery of function in about half of the patients unable to walk, and about one-third of patients with bladder dysfunction before treatment. Since length of the course of therapy is a factor with an important impact on the patient's quality of life, the short-course RT regimen adopted in the trial merits further investigation.

[Adjuvant radio-chemotherapy in cancer of the rectum treated with radical surgery and with high risk of recurrence. Preliminary results of a prospective study]. / Radio-chemioterapia adiuvante nel cancro del retto radicalmente operato e con alto rischio di ricaduta. Risultati preliminari di uno studio prospettico.

UNLABELLED: INTRODUCTION MATERIAL AND METHODS: From January, 1990, to December, 1995, 138 consecutive patients with radically resected stage II and III rectal and rectosigmoid cancers were treated with adjuvant radiochemotherapy. Eighty-one patients with 24 months' follow-up were assessable. Low anterior resection (LAR) was performed in 64 (79%) patients and abdominoperineal resection (APR) in 17 (21%). Twentynine (36%) stage II and 52 (64%) stage III patients entered the study. Within 45-60 days from surgery all patients received 5-Fluorouracil chemotherapy at the dose of 500 mg/m2/iv/d 1-5, every 4 weeks, for six cycles. Chemotherapy cycles 3 and 4 were administered at the same daily dose on radiotherapy days 1-3 and 29-31. Radiotherapy total dose consisted of 45 Gy/1.8 Gy/day administered in 5 weeks with 18 MV photon beam to the pelvis with the four field "box" technique. Perineal scar was encompassed only after APR. A boost dose of 5.4 Gy to the tumor bed was given in 3 fractions of 1.8 Gy. Median follow-up was 37 months (range: 24-74 months). RESULTS AND DISCUSSION: Overall recurrent disease was reported in 28 of 81 patients (34%): local, systemic and both local and systemic relapses in 9 (11%), 14 (17%) and 5 (6%) cases, respectively. According to local extension, recurrence rates were 10% and 48% in stages II and III, respectively. Five-year overall and disease-free actuarial survivals were 64% and 61%, respectively. Median time to relapse was 15 months (range: 7-43 months). Significant prognostic factors for better tumor control were: stage (II vs III), disease site (proximal vs distal rectum), the surgical procedure (LAR vs APR), the number of involved nodes (< or = 4 vs > 4) and no extracapsular node invasion. The recommended dose of combined radiochemotherapy regimen used in this trial was generally well tolerated. The incidence of any grade > or = 3 acute toxicity (according to WHO grading) was 20% diarrhea, 6% tenesmus and 4% myelosuppression. Five (6%) patients had cronic diarrhea and other 3 (4%) radiotherapy-related severe late toxicity which required surgery. CONCLUSIONS: This study seems to provide similar survival and recurrence notes to other radio-chemotherapy regimens published in the literature. However, a more aggressive approach is warranted in stage III patients considering the low 5-year survival recorded.

Hyperinsulinaemia, regional adipose tissue distribution and left ventricular mass in normotensive, elderly, obese subjects.

Obesity is a metabolic condition, related to abnormalities of the glyco-insulinaemic metabolism, and plays a substantial role in the development of cardiovascular disease. The aim of this study was to establish a correlation among left ventricular mass, evaluated echocardiographically according to Penn Convention criteria, blood pressure, evaluated by ambulatory blood pressure monitoring, anthropometric indices for evaluation of body mass index and waist to hip ratio circumference, regional adipose tissue distribution, evaluated by ultrasound measurements of visceral adipose tissue, and insulin resistance, evaluated by hyperinsulinaemia by oral glucose tolerance test. We selected two groups of elderly male subjects well matched for age (68.5 +/- 6.4 years): 29 obese and 20 lean, with a body mass index, respectively, of 34.6 +/- 2.9 and 23.4 +/- 2.3. Statistical analysis was carried out by Student's t-test and linear regression analysis. In spite of the fact that statistical analysis showed a higher, though not statistically significant, systolic and diastolic mean blood pressure in the lean subjects, we found an increased left ventricular mass in obese subjects (P < 0.0001). The area under the insulin curve was higher in obese than in lean subjects (P < 0.0001) while the area under the glucose curve was not significantly different in the two groups. Furthermore, linear regression analysis showed that in obese subjects left ventricular mass was strictly correlated with visceral adipose tissue (r = 0.607; P < 0.0001) and hyperinsulinaemia (r = 0.615; P < 0.0001). In conclusion, our data suggest that centripetal adipose tissue distribution and hyperinsulinaemia, independent of blood pressure values, are closely correlated with left ventricular mass.

Short-course radiotherapy (8 Gy x 2) in metastatic spinal cord compression: an effective and feasible treatment.

PURPOSE: To evaluate the clinical outcome and toxicity of a short-course regimen of radiotherapy (RT) in selected metastatic spinal cord compression (MSCC) patients. METHODS AND MATERIALS: Between 1993 and 1995, 53 consecutive patients with MSCC from low radio-responsive primary tumors (non small cell lung, kidney, head and neck and gastrointestinal carcinomas, melanoma and sarcomas), or more radio-responsive ones (breast and prostate carcinomas, myeloma and lymphomas) with paresis, plegia, low performance status (PS ECOG > or = 2), and/or short life expectation, underwent short-course RT; a single fraction of 8 Gy repeated after 1 week in responders or stable patients, for a total dose of 16 Gy. Of 49 (92%) evaluable cases, 4 (8%) underwent surgery plus RT and the other 45 RT alone. Medium doses of parenteral dexamethasone (8 mg x 2/d) were given in all cases and precautional anti-emetics to those treated with fields covering the upper abdomen (20 of 49 cases). Median follow up was 25 months (range, 6-34). Response was assessed according to back pain, and motor and bladder capacity before and after RT. RESULTS: Pain relief was achieved in 67% of patients and motor function response rate reached 63%. Early diagnosis and therapy were very important in predicting response to RT; all but two (91%) pretreatment walking patients and all but one (98%) with good bladder function preserved these capacities. On the contrary, when diagnosis was late, only 38% of nonambulatory patients and 44% of those with bladder retention improved. Median survival was 5 months, with a 30% probability of survival for 1 year. Length of survival was significantly longer for patients able to walk before and/or after RT. Good agreement between survival and duration of response was found with no evidence of relapse in the irradiated spine. Sickness appeared only in a few cases. Slight esophagitis was more frequent: dysphagia for solid foods in one-third of patients irradiated on the thoracic spine. Late toxicity was never recorded. CONCLUSION: The short-course RT adopted gave a clinical outcome comparable with that resulting from more protracted regimens with only slight side effects. The use of a few large treatment fractions could be explored considering the associated advantages for patients and radiotherapy centers often overloaded by long patient waiting lists.

Allogeneic matched T-cell-depleted bone marrow transplantation for acute leukemia patients.

PURPOSE: We evaluated the efficacy and toxicity of a conditioning regimen designed to overcome the increased risk of rejection and relapse associated with T-cell-depleted bone marrow transplants. PATIENTS AND METHODS: Fifty-four patients with acute leukemia received an allogeneic T-depleted bone marrow transplant from an HLA-matched (n=52) or one locus mismatched (n=2) sibling donor between June 1989 and November 1993. Nineteen acute myeloid leukemia patients and 17 acute lymphoid leukemia patients were in complete remission, and 11 acute myeloid leukemia patients and 7 acute lymphoid leukemia patients were in relapse. Patients were preconditioned with hyperfractionated total body irradiation of 1.2 Gy three times a day on days -9 to -6 (total 14.4 Gy), 10 mg/kg thiotepa on day -5, 4 mg/kg rabbit antithymocyte globulin on days -4 to -1, and 50 mg/kg cyclophosphamide on days -3 and -2. RESULTS: All patients were fully engrafted at a median of 15 days after transplant. No patient rejected the transplant or developed acute or chronic graft-versus-host disease. Of 19 patients with acute myeloid leukemia in complete remission, 14 survive. Four of the 11 patients with acute myeloid leukemia in relapse survive. Twelve acute myeloid leukemia patients died (three of relapse, eight of toxicity, one of other causes). Eleven of 24 patients with acute lymphoid leukemia (one treated in relapse) are alive in complete remission; the other 13 died (nine of relapse, four of toxicity). Interstitial pneumonia, the main cause of toxic death, occurred in 9.26% of total patients. The median follow-up time at this writing is 30 months. CONCLUSIONS: The absence of rejection and graft-versus-host disease and the relatively low relapse and toxicity rates are evidence for the efficacy of our conditioning regimen.

Radiotherapy without steroids in selected metastatic spinal cord compression patients. A phase II trial.

A phase II trial was planned to investigate the feasibility of radiotherapy (RT) without steroids in 20 consecutive patients with metastatic spinal cord compression (MSCC), no neurologic deficits, or only radiculopathy, and no massive invasion of the spine at magnetic resonance imaging (MRI) or computed tomography (CT). Aiming at an early diagnosis, MRI or CT was prescribed for all cancer patients with back pain and osteolysis, even when there were no signs of neurologic spinal compression. All patients were given 30 Gy in 10 fractions over 2 weeks with no steroids. Back pain and motor capacity were the parameters adopted to verify response to RT. Sixteen of 20 patients (80%) were able to walk without support, and 14 (70%) had no radiculopathy. Seventeen of 20 cases (85%) achieved relief from back pain. Regarding motor function, all patients (100%) responded to RT because the 16 patients able to walk without support at diagnosis did not deteriorate and the other 4, who needed support, became ambulatory without motor impairment. Median survival time was 14 months. Eight of 20 (40%) treated patients are still alive (14 to 36 months after end of RT), fully ambulatory, and free from relapse in the treated spine. Acute side effects were documented in only 2 patients (10%) and were managed without steroids. The results of this study suggest that RT without steroids is a feasible regimen for MSCC patients with good motor function. Elimination of steroids from the standard treatment for MSCC avoids cortisone side effects above all in those patients with diabetes, hypertension, peptic ulcer, and other steroid-sensitive medical problems.

[Testicular seminoma in stages I and II non-bulky. 16 years' experience]. / Il seminoma del testicolo negli stadi I e II non-bulky. Sedici anni di esperienza.

From June 1977 through June 1993, ninety-five patients with testicular seminoma were treated in our center. This paper reports on 67 assessable patients--52 with stage I and 15 with non-bulky stage II disease. Median follow-up is 8 years (range: 4-16 years). Postorchiectomy radiotherapy consisted in 30 Gy (1.5 Gy/day) precautionary treatment to ipsilateral hemipelvis and paraaortic nodes (stage I) or 40-45 Gy to the same area plus 25.5-30 Gy prophylactic irradiation to mediastinum and supraclavicular fossae (stage II). Ten-year actuarial survival is 100%-96.8% +/- 2.2 considering deaths from other diseases. Ten-year disease-free survival is 95.3% +/- 2.6. The 3 relapsed patients were rescued with chemotherapy or radiotherapy (1 and 2 cases, respectively). Acute side-effects were nausea (30% of cases) and vomiting (18%) which disappeared after oral antiemetics. Late toxicity-asymptomatic osteolysis of the ipsilateral pubic region--was observed in 1 patient only (1.5%) who received cobalt therapy to inguinal canal and hemiscrotum (40.5 Gy in 27 fractions). The current diagnostic and therapeutic approaches to testicular seminoma are discussed. In stage I the conventional treatment is low-dose (20-25 Gy) subdiaphragmatic radiotherapy and a policy of surveillance is justified only for clinical trials. In non-bulky stage II disease lumboaortic and hemipelvic irradiation (36-40 Gy) is the treatment of choice whereas precautionary irradiation should not be given to the mediastinum. If abdominal CT scans show nodal metastases, chest CT is necessary for staging instead of chest X-ray films. When abdominal CT findings are negative or questionable, bi-pedal lymphography must be performed. Residual testis US should be the routine examination for the early diagnosis of metachronous contralateral seminoma. The semen should be tested for further storage and sexual functions should be accurately analyzed to distinguish between organic and psychologic causes. Although limited, our experience demonstrates the good prognosis of this condition and the optimal tolerance in testicular seminoma patients even with a radiotherapy regimen which is now considered suboptimal, though it was the standard about 10 years ago.

Ondansetron.

Ondansetron is the first selective antagonist of the 5-hydroxytryptamine receptors (type 3) marketed for the prevention of emesis induced by antineoplastic agents. Ondansetron has been shown to be more active and less toxic than high-dose metoclopramide in patients submitted to cisplatin chemotherapy. Furthermore, when dexamethasone was added to ondansetron, its antiemetic efficacy increased significantly. In the prevention of emesis induced by a high single dose of cisplatin or by repeated low doses, ondansetron combined with dexamethasone has been shown to be the more efficacious and less toxic antiemetic treatment. However, in the prevention of delayed emesis from cisplatin, its role is still to be defined. In patients submitted to moderately emetogenic chemotherapeutic agents, ondansetron has shown an efficacy superior or equal to standard doses of metoclopramide, but is less toxic. Moreover, when compared with dexamethasone, its antiemetic efficacy and tolerability is similar; in this group of patients ondansetron should be used only when steroids fail. Ondansetron toxicity is generally mild; in particular, it does not induce extrapyramidal reactions. The most frequent side-effects are headache and constipation.

Antiemetic activity of two different high doses and schedules of metoclopramide in dacarbazine-treated cancer patients.

The antiemetic activity of two different high doses and schedules of metoclopramide in dacarbazine-treated cancer patients was compared in a double-blind crossover study. Regimen A consisted of metoclopramide [2 mg/kg x 4 intravenously (i.v.)] plus methylprednisolone (250 mg x 2 i.v.) plus diphenhydramine (50 mg x 2 i.v.). Regimen B consisted of metoclopramide (3 mg/kg x 2 i.v.) plus dexamethasone (20 mg i.v.) and diphenhydramine (50 mg i.v.). Both treatments were administered for the first 2 days of 5-day dacarbazine chemotherapy. Thirty-two patients (13 men and 19 women) affected by melanoma and sarcoma were entered in the study. Complete protection against nausea and vomiting for the first 2 days of chemotherapy in both antiemetic regimens was not significantly different. Patient preference and tolerance of the two antiemetic treatments were similar. Regimen B, employing a lower dosage of metoclopramide and steroids and using a more simple schedule of administration should be the preferred treatment.

Intra and interobserver variability in cancer patients' performance status assessed according to Karnofsky and ECOG scales.

The Karnofsky (K) and ECOG (E) performance status (PS) scales are widely used to evaluate the functional status of cancer patients to determine their eligibility for clinical trials and their prognosis, but knowledge of inter and intraobserver variability of these scales is scarse. We therefore planned a prospective study on 209 consecutive cancer patients to evaluate this critical point. Two independent observers evaluated the KPS and EPS of each patient by interviewing them on the same day. After their interviews the patients were asked to fill in, again on the same day, a self-evaluation scale concerning their ability to perform the routine activities of daily life. The 209 patient self-evaluation scales were presented twice, randomly and blinded, to the two observers who had participated in the evaluation of PS as well as to one other observer who had not. The interobserver correlation for both scales was very high (K = 0.921 for KPS and K = 0.914 for EPS) as was the intraobserver correlation (for KPS: K = 0.993, K = 0.960, and K = 0.959 and, respectively, for EPS: K = 0.982, K = 0.970, and K = 0.920). On the basis of these results, it appears that evaluation of PS made by a clinical oncologist using K or E scales can be very reliable and is a guarantee of optimal selection of cancer patients for inclusion in clinical trials.

Double-blind crossover trial of single vs. divided dose of metoclopramide in a combined regimen for treatment of cisplatin-induced emesis.

In a double-blind crossover antiemetic study in cisplatin-treated cancer patients, metoclopramide 4 mg/kg as a single intravenous dose (regimen A) was compared with 3 mg/kg in two doses (regimen B). In both regimens, metoclopramide was combined with dexamethasone and diphenhydramine. 65 consecutive, chemotherapy-naïve inpatients (45 males and 20 females) treated with high doses (at least 50 mg/m2) of cisplatin entered the study and 54 completed both treatments. Complete protection from vomiting and nausea, mean number of emetic episodes, mean maximum intensity of nausea and mean duration of emesis or nausea were similar with the two antiemetic regimens. 23 patients (43%) did not express a treatment preference, while 16 (30%) preferred regimen B and 15 (28%) preferred regimen A. Side-effects were similar with the two metoclopramide schedules. A combined antiemetic regimen of a single high dose of metoclopramide (4 mg/kg) can preserve efficacy and tolerability and thus should be preferred.

Presence of glyoxalase II in mitochondria from spinach leaves: comparison with the enzyme from cytosol.

Glyoxalase II has been purified from cytosol and mitochondria of spinach leaves. Electrophoresis and isoelectric focussing have resolved cytosolic and mitochondrial glyoxalase II in multiple forms: pl 5.3, 5.8 and 6.2 (cytosol) and pl 4.8 (mitochondria). The enzyme of both localizations is a monomer showing a relative molecular mass of about 26 kDa. The values of kinetic constants using several glutathione thiolesters as substrates, are similar for the enzymes from cytosol and mitochondria. These results extend also to plant the presence in mitochondria of peculiar forms of glyoxalase II, likewise recently demonstrated in mammalians.

Glyoxalase II from Zea mays: properties and inhibition study of the enzyme purified by use of a new affinity ligand.

The synthesis of N-(p-nitrocarbobenzoxy)glutathione (N-pNCBG) is reported. N-pNCBG and glutathione (GSH) were coupled to Affi-gel 10 by a thioester linkage and resulted in very effective bound ligands for a fast purification of glyoxalase II from corn. The S-(N-pNCBG)-affinity column showed a glyoxalase II binding capacity of up to 2-fold higher than that of the glutathione-affinity column. A single form of glyoxalase II was evidenced by PAGE in both crude extracts and in the affinity purified enzyme. A 45% recovery of glyoxalase II activity (purification, approx. 433-fold) was obtained for both matrices by a single chromatography. The purified glyoxalase is an acidic protein (pI 4.5) of about 26,000 relative molecular mass. Substrate studies for the corn glyoxalase II show, among possible substrates tested, that S-D-lactyl-glutathione is the preferred substrate. An inhibition study was performed with methyl-, propyl-, hexyl-, p-nitrobenzyl-, p-chlorophenacyl-, carbobenzoxy-, and p-nitrocarbobenzoxy-S-glutathione. Methyl-S-glutathione did not inhibit corn glyoxalase II; the others were found to be linear competitive inhibitors. The derivatives containing a thioether bond are weaker inhibitors than those containing a thioester bond or a carbonyl group. p-Nitrobenzyl-S-glutathione is the weakest inhibitor; the carbobenzoxy-S-derivatives are stronger inhibitors than the p-chlorophenacyl S-derivative.