Nonlinearity-generated resilience in large complex systems.

We consider a generic nonlinear extension of May's 1972 model by including all higher-order terms in the expansion around the chosen fixed point (placed at the origin) with random Gaussian coefficients. The ensuing analysis reveals that as long as the origin remains stable, it is surrounded by a "resilience gap": there are no other fixed points within a radius r_{*}>0 and the system is therefore expected to be resilient to a typical initial displacement small in comparison to r_{*}. The radius r_{*} is shown to vanish at the same threshold where the origin loses local stability, revealing a mechanism by which systems close to the tipping point become less resilient. We also find that beyond the resilience radius the number of fixed points in a ball surrounding the original point of equilibrium grows exponentially with N, making systems dynamics highly sensitive to far enough displacements from the origin.

Toward sensitive immuno-based detection of tau protein by surface plasmon resonance coupled to carbon nanostructures as signal amplifiers.

Interest on Tau protein is fast increasing in Alzheimer's disease (AD) diagnosis. There is the urgent need of highly sensitive and specific diagnostic platforms for its quantification, also in combination with the other AD hallmarks. Up to now, SPR has been poorly exploited for tau detection by immunosensing, due to sensitivity limits at nanomolar level, whereas the clinical requirement is in the picomolar range. Molecular architectures built in a layer-by-layer fashion, biomolecules and nanostructures (metallic or not) may amplify the SPR signal and improve the limit of detection to the desired sensitivity. Mostly gold nanostructures are widely employed to this aim, but great interest is also emerging in Multi Walled Carbon Nanotubes (MWCNTs). Here MWCNTs are modified and then decorated with the secondary antibody for tau protein. Eventually we took advantage from MWCNTs-antibody conjugate to obtain a sandwich-based bioassay with the capability to increase the SPR signal of about 102 folds compared to direct detection and conventional unconjugated sandwich. With respect to these results, we hope to give a strong impulse for further investigation on studying possible roles of carbon nanotubes in optical-based biosensing.

Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

Dual-source CT coronary angiography: prospective versus retrospective acquisition technique.

PURPOSE: The aim of our work was to compare image quality and radiation dose in a group of patients who underwent cardiac dual-source computed tomography (DSCT) with prospective electrocardiographic (ECG) gating with those of a control group studied with retrospective gating. MATERIALS AND METHODS: Sixty patients were randomly assigned to two groups of 30 individuals each. Patients with heart rates >70 bpm and body mass index (BMI) >30 kg/m(2) were excluded. Group A was examined with prospective ECG gating and group B with retrospective gating. The dose-length product (DLP) was recorded to calculate the radiation dose, whereas the effective dose was normalised to a standard 12-cm scan of the heart. RESULTS: Applying the best reconstruction interval, 98.6% of segments in the prospective group and 99.3% in the retrospective group were diagnostic. No significant difference (p>0.05) in image quality was observed between groups. Mean normalised radiation dose was 4.91 ± 0.4 mSv in the prospective-gating group and 14.62 mSv ± 4.36 in the retrospective-gating group (p<0.01). CONCLUSIONS: Coronary CT with prospective ECG gating, a standard feature on new scanners, allows for a significant reduction in radiation dose without causing any significant decrease in image quality or in the number of segments assessed. The prospective technique is thus recommended for patients with heart rates £70 bpm and BMI £30 kg/m(2).

"Short Course" of Nonpegylated Liposomal Doxorubicin Plus Paclitaxel and Trastuzumb as Primary Systemic Therapy for Operable and Locally-Advanced Breast Cancer: A Phase II Study (PacLiDox 07).

BACKGROUND: Schedules with anthracyclines and taxanes are one of the best options for primary chemotherapy. The addition of trastuzumab showed an impressive percentage of pathological complete responses in Buzdar trial (66.7%). Recently, nonpegylated liposome-encapsulated doxorubicin (NLD) has been widely used in advanced breast cancer with high response rates (98.1 % in Cortes study). The aims of our study were to assess pathological responses and toxicity of NLD plus paclitaxel (and trastuzumab in patients with HER2 overexpression). METHODS: Thirty patients entered the study: 9 locally advanced and 21 operable. Median age was 58.5 years (range: 31-73). 23 patients without HER2 overexpression (or FISH not amplified) were treated with NLD 50 mg/m2 every three weeks for 3 courses and weekly paclitaxel 80 mg/m2 for 8 courses. 7 patients with HER2 overexpression or FISH amplified were treated with the same schedules plus trastuzumab (Herceptin) 4 mg/kg for the first administration and 2 mg/kg for the following 7 weekly administrations. RESULTS: Pathological complete response (pCR) was documented in 1 patient (treated with trastuzumab); no residual tumor (infiltrating or "in situ") on breast was documented in other 2 patients. Objective clinical responses were documented in 22 patients (73.3%): 8 complete, 10 partial and 4 "minimal" responses. 7 patients have shown stable and 1 progressive disease. Clinical response in patients with HER2 overexpression treated with trastuzumab was 100% (4 complete and 3 partial responses). Conservative surgery was performed in 8 (38%) and mastectomy in 13 (62%) out of 21 operable patients; however, 7 out of 14 responding patients with operable disease underwent quadrantectomy (50%). Main toxicity was neutropenia: febrile in 2 patients (7%) and gr. 3-4 in 13 (43%). Other grade 3 toxicities were as follows: vomiting in 1 patient, asthenia in 1 patient, joint symptom in 1 patient. 3 patients were withdrawn from the study. No episodes of left ventricular ejection fraction (LVEF) < 50% were recorded (with a median reduction of 8%). CONCLUSIONS: A "short course" of paclitaxel and NLD is active in terms of clinical response and conservative surgery for patients with potentially operable and locally advanced breast cancer; toxicity was manageable. High activity of the combination with trastuzumab has been confirmed. However, with this "short course" schedule, the result in term of clinical responses didn't turn into complete pathological responses.

Activity and safety of erlotinib as second- and third-line treatment in elderly patients with advanced non-small cell lung cancer: a phase II trial.

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Efficacy of this drug was documented in the BR.21 trial showing that adenocarcinoma, female gender, Asian ethnicity and never-smoker status are predictive of clinical response to erlotinib. Retrospective studies documented the same benefits for elderly patients as young patients in terms of response, progression-free survival, and overall survival. The primary aim of our trial was to confirm these findings in a prospective way; the secondary aim was to identify if the aforementioned clinical characteristics may be predictive of response even in elderly patients. The trial included 31 patients with pretreated stage IIIB (2) and IV (29) non-small cell lung cancer (NSCLC). Median age was 75 years (range: 65-85). Twenty-seven patients were current/former-smokers and four never-smokers. Twenty-three patients are evaluable for response. Objective response rates were reported in five patients (16%). Five patients had stable disease (16%) and 13 progressive disease (43%). Seven patients had a "clinical benefit" from erlotinib (22.5%; 95% C.I.: 7.9-37.2%). Grade 3 skin rash was recorded in three patients (10%). Median survival was 9 months (range 1-30). Median time to progression was 3 months (range: 1-24 months). Our study confirmed erlotinib activity and safety as second- and third-line treatment in elderly patients with advanced NSCLC, especially in terms of median survival. Even though this trial does not allow us to draw a definitive conclusion about the role of a particular clinical characteristic predictive of response, the "clinical benefit" was documented especially in females, in patients with adenocarcinoma histology and skin rash, confirming previous retrospective data.

Preliminary experience with abdominal dual-energy CT (DECT): true versus virtual nonenhanced images of the liver.

PURPOSE: The aim of this work was to compare the quality and noise of true non-enhanced (TNE) and virtual non-enhanced (VNE) images in patients undergoing dual-energy computed tomography (DECT) of the liver. MATERIALS AND METHODS: Twenty consecutive patients (mean age 54.7±19.9 years) prospectively underwent abdominal DECT to assess the liver using a triphasic protocol consisting of precontrast, arterial-phase and portal-phase acquisitions. Exclusion criteria were allergy to iodinated contrast material, impaired renal function and a body mass index (BMI) >35 kg/m(2). The DE portal-phase acquisition was performed with automatic dose modulation (CARE Dose 4D). Nonionic iodinated contrast material (Iomeron 400) was administered at 0.625 gI/kg with a flow rate of 3.5 ml/s. Axial VNE images were reconstructed based on the portal data set using a collimation and an increment of 5 mm and were compared with TNE images reconstructed with the same parameters. The average image quality and noise were analysed by two radiologists in separate reading sessions. RESULTS: No statistically significant difference (p>0.05) in image quality was observed between VNE (4.00±0.85) and TNE images (4.35±0.58). A sufficient diagnostic quality was found in 95.0% (19/20) of VNE images and in 100% of TNE images. No statistically significant difference (p<0.05) was observed in the average image noise of VNE (9.5±0.7) and TNE (12.3±1.1) images. CONCLUSIONS: Abdominal DECT allows acquisition of liver VNE images with similar image quality and lower noise than TNE. Nevertheless, a few technical limitations related to the small field of view of the second detector in patients with a high BMI and heterogeneous iodine subtraction restrict the application of this technique to selected patients only.

Preoperative coronary risk assessment with dual-source CT in patients undergoing noncoronary cardiac surgery.

PURPOSE: The aim of our work was to assess the role of dual-source computed tomography (DSCT) in the preoperative evaluation of coronary artery disease in patients scheduled for noncoronary cardiac surgery. MATERIALS AND METHODS: One hundred patients were prospectively evaluated. Patients negative for coronary disease at DSCT (n=81) underwent surgery without coronary angiography. Patients positive for significant lesions or with nondiagnostic image quality due to artefacts or severe calcifications underwent coronary angiography (n=19) and were excluded from the study. In patients who underwent surgery with only a DSCT diagnosis, we evaluated the frequency of major adverse cardiac events (MACEs) during the perioperative period and at 3 months follow-up. RESULTS: No MACEs were recorded during the perioperative period; three noncardiac complications (one surgical revision for bleeding, one cardiac tamponade and one respiratory insufficiency) and one death related to severe respiratory insufficiency were observed. None of the 80 patients had MACEs during the 3-month follow-up period. CONCLUSIONS: Coronary evaluation with DSCT is able to rule out the presence of coronary disease in patients scheduled for cardiac surgery, without the need for coronary angiography confirmation. Patients with significant stenosis or nondiagnostic image quality should be referred for coronary angiography.

Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5-29.2%) and 49% (95% CI, 42.2-55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27-3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05-2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites > or =2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.

Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties.

This prospective study focused on risk factors and clinical outcome of pulmonary and cardiac late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We prospectively evaluated 162 children by pulmonary function tests (PFTs) and cardiac shortening fraction (SF) before allo-HSCT and yearly up to the 5th year of follow-up. The 5-year cumulative incidence of lung and cardiac impairment was 35 (hazard rate=0.03) and 26% (hazard rate=0.06), respectively. Patients presenting abnormal PFTs and SF at last follow-up were 19 and 13%, respectively, with a median Lansky performance status of 90% (70-100). Chronic graft-versus-host disease (c-GVHD) was the major risk factor for reduced lung function in univariate (P=0.02) and multivariate analysis (P=0.02). Total body irradiation (TBI) alone and TBI together with pre-transplant anthracycline administration were significant risk factors for reduced cardiac function in univariate analysis, only (P=0.04 and 0.004, respectively). In conclusion, our prospective study demonstrates an asymptomatic post-allo-HSCT deterioration of pulmonary and cardiac function in some long-term survivors, who had been transplanted in childhood, and thus emphasizes the need for lifelong cardiopulmonary monitoring and the development of new strategies both to reduce pre-transplant cardiotoxic regimens and to treat more efficiently c-GVHD.

Lumbar sympathectomy under CT guidance: therapeutic option in critical limb ischaemia.

PURPOSE: Lumbar sympathectomy is a complementary therapeutic option for patients with severe peripheral vascular occlusive disease presenting rest pain or gangrene and not eligible for surgical revascularisation. Traditional surgical sympathectomy was widely used in the past. However, due to its invasive character, it has increasingly been replaced by percutaneous techniques and, in some recent cases, by laparoscopic procedures. Percutaneous lumbar sympathectomy is a safe, cost-effective and widely available treatment option. We report our experience on 19 patients subjected to percutaneous sympathectomy under CT guidance. MATERIALS AND METHODS: Between 1998 and 2000, 19 patients underwent percutaneous sympathectomy under CT guidance. All patients had severe vascular disease of the lower extremities (Fontaine stage IV), with rest pain and gangrene. They were not eligible for surgical revascularisation. Phenol was injected at the level of L2 and L4 using two 22 G needles (15 cm long). Signs of interrupted sympathetic activity usually occur 2'-15' after the procedure with warmth and flushing and dryness of the lower extremities. RESULTS: Percutaneous sympathectomy under CT guidance is a simple, safe and well-tolerated procedure with a low rate of complications. Of the 19 patients, 9 (47.3%) showed clinical improvement, whereas 5 experienced a worsening of ischaemia in the months immediately following the procedure. DISCUSSION: Results suggest that percutaneous lumbar sympathectomy causes a sympathetic blockade in patients with advanced vascular disease of the limbs. CT guidance ensures a high level of precision in drug dosing, thus lowering the risk of complications. Although the results are demoralizing. the impossibility of achieving surgical revascularisation in advanced peripheral arteriosclerosis enhances the role of CT-guided percutaneous sympathectomy in relieving rest pain and healing ulcers in order to postpone the amputation.

Carboplatin, doxorubicin and etoposide in the treatment of tumours of unknown primary site.

The aim of this study was to assess the activity and toxicity of a platinum-based treatment on a group of patients with unknown primary tumours (UPTs). Patients with a diagnosis of UPT underwent a standard diagnostic procedure. Treatment was started within 2 weeks from diagnosis and consisted of carboplatin 400 mg m(-2) day 1, doxorubicin 50 mg m(-2) day 1, etoposide 100 mg m(-2) days 1-3, every 21 days. Response was evaluated after three courses and treatment continued in case of objective response (OR) or symptom control. A total of 102 patients were eligible. The median age was 59 years, sex male/female 54/48, histology was mainly adenocarcinoma or poorly differentiated carcinoma. Nodes, bone, liver and lung were the most frequently involved sites. In all, 79 patients received at least three courses of treatment; 26 patients received six courses or more. Six complete responses and 21 partial responses were observed, for a total of 27 of 102 ORs or 26.5% (95% confidence interval 18.2-36.1%). The median survival was 9 months and median progression-free survival was 4 months. Toxicity was moderate to severe, with 57.8% of patients experiencing grade III-IV haematological toxicity, mainly leucopenia. The regimen employed has shown activity in tumours of unknown primary site, but was associated with significant toxicity. Such toxicity may be considered unjustified, given the large proportion of patients with tumours not likely to respond. Efforts should therefore be addressed to identify predictors of response to chemotherapy, thus limiting aggressive treatment to those patients who could benefit from it.

Efficacy of anthracyclines and paclitaxel as first line chemotherapy in patients with visceral metastases of breast cancer.

BACKGROUND: Anthracyclines combined with paclitaxel are one of the most active schedules in patients with advanced breast cancer: response rates range from 40 to 80%, considering all metastatic sites (visceral and soft tissues). We performed a non-randomized phase II trial with anthracyclines/paclitaxel combination to evaluate response and toxicity only in patients with visceral metastases. METHODS: Twenty-seven patients (median age 50 years; range 30-72) with visceral metastases of breast cancer were enrolled in this study. Overall, 11 patients had lung metastases (41%), 10 liver (37%), 4 liver-lung metastases (15%) and 2 peritoneal carcinosis (7%). 7 patients had received adjuvant anthracycline-based chemotherapy (26%) and 10 patients adjuvant CMF combination chemotherapy (37%); 10 patients (37%) received hormonal therapy for advanced disease. Treatment schedules were: group A) 17 patients, Adriamicyn 50 mg/m2 on day 1 i.v. bolus and Paclitaxel 175 mg/m2 on day 2 i.v. 3 hours infusion, every 3 weeks; group B) 10 patients, epirubicin 90 mg/m2 on day 1 i.v. bolus and paclitaxel 200 mg/m2 on day 2 i.v., 3 hours infusion, every 3 weeks. The number of cycles administered was 141 with a median of 5 (range 3-9). RESULTS: All patients were evaluable for response and toxicity. The objective response rate was 59% - 16 patients - (15% complete and 44% partial remission), 95% C.I. 40.7-77%; 10/17 in group A and 7/10 in group B. Stable disease 30% (8 patients) and progressive disease 11% (3 patients). The median duration of response was 5 months (range 1-16); median time to progression 13 months (range 3-18) and median survival 17 months (range 4-24). The main toxicity was neutropenia, occurred in 16 patients (59%; grade IV in 7 patients, of whom 2 febrile neutropenia, and grade III in 9 patients); grade III gastrointestinal toxicity in 2 patients; grade III neurological toxicity in 1 patient; grade III stomatitis in 2 patients. No congestive hearth failure or treatment death related was observed. CONCLUSIONS: These schedules of anthracyclines and paclitaxel confirmed their efficacy in metastatic breast cancer even in patients with visceral disease. Neutropenia was the main toxicity; grade IV neutropenia was more frequently observed in epirubicin/paclitaxel arm.

A new cisplatin/gemcitabine schedule in locally advanced (IIIB) and metastatic (IV) non-small cell lung cancer: relationship between dose-intensity and efficacy. A phase II study.

BACKGROUND: Cisplatin/gemcitabine are one of the "standard" chemotherapy schedules in locally advanced and metastatic NSCLC cancer. A number of trials documented that omission of gemcitabine on day 15 and reduction of cisplatin up to 70 mg/mq are equivalent in term of response rates to "classic" administrations on days 1, 8 and 15 with cisplatin 100 mg/mq. The aim of this study was to confirm this evidence and to demonstrate that a further reduction of gemcitabine dose-intensity may be performed with the same efficacy on response. PATIENTS AND METHODS: Fifty untreated patients with locally advanced and metastatic NSCLC entered the study: 24 stage IIIB and 26 stage IV. The median age was 65 years (range 32-76); 44 males and 6 females Genicitabine was administered 1000 mg/mq weekly on days 1 and 8 followed by a 2-week rest and cisplatin 80 mg/mq on day 2 of each 28-day-cycle. RESULTS: Forty-five patients were evaluable for response and all for toxicity. The overall response rates were 35.5% with 16 partial responses (95% Confidence Interval: 32%-61%). Most of the objective responses were seen in IIIB patients (56% of the stage IIIB and 44% of the stage IV patients responded). According to the intent-to-treat-principle, the response rates were 32% (16 out of 50 patients). The median dose-intensity of gemcitabine and cisplatin was respectively 477.6 mg/mq/week (481.4 for responders) and 19.5 mg/mq/week (19.9 mg/mq for responders). The median response duration was 5 months (range 1-18) and the median time to progression was 5 months (1-21); median survival was 9 months (range 2-31). The main toxicity was haematological: thrombocytopenia grade IV in 5 patients (10%) and grade III in 11 patients (22%); neutropenia grade III-IV in 4 patients (8%); grade III anemia in 3 (6%). Asthenia was the most significant non-haematological toxicity and was observed in 19 patients (38%). CONCLUSION: This trial confirmed the efficacy of a schedule with 2 administrations of gemcitabine (on days 1, 8) and a cisplatin dose on day 2 lower than 100 mg/mq. Moreover, the same efficacy was obtained with a median-dose intensity of cisplatin and gemcitabine lower than planned in a 21-day-schedule. For safety and low toxicity, we think that this schedule provides another chance to treat patients with non-small cell lung cancer, especially the elderly or patients with coexistent medical illnesses.

Feasibility of a cell kinetic-based adjuvant chemotherapy trial in axillary node-negative breast cancer.

AIMS AND BACKGROUND: Accumulated information on biologic prognostic indicators and predictors of response to different types of treatment in patients with different tumor characteristics has made it possible to design clinical protocols on biologic bases. Among cell proliferation indices, the thymidine labelling index (TLI) has proved to be an independent and consistent prognostic indicator over time. Moreover, experimental and retrospective analyses of clinical studies have revealed a direct relation between TLI and response to chemotherapy. On the basis of the results, a prospective clinical protocol on axillary node-negative breast cancer was activated in Italy in 1989. METHODS: Patients with low TLI tumors were treated with local-regional therapy alone, whereas patients with high TLI tumors were randomized to receive local-regional therapy followed or not by adjuvant chemotherapy consisting of 6 cycles of CMF. RESULTS AND CONCLUSIONS: The present paper reports on the feasibility of a prospective clinical protocol based on a subgroup of patients with specific pathologic (node negative) and biologic (rapidly proliferating) breast cancers. However, patient eligibility was only 11%.

Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis.

Recently, a randomised study demonstrated the utility of oral cooling (cryotherapy) in the prevention of 5-fluorouracil (5FU)-induced stomatitis. In order to verify these results a confirmatory study, using identical treatment regimen, was initiated. 84 patients treated with a 5-FU-containing regimen were randomised to a control arm or to receive oral cryotherapy. End point evaluation was obtained by a global assessment of the physician's judgement and patients' description of mucositis severity graded 0-4. Mucositis was significantly reduced by cryotherapy considering both the first cycle of therapy (the mean toxicity score for cryotherapy was 0.59 and it was 1.1 for the control group, P < or = 0.05) and all the chemotherapeutic courses (the mean toxicity score for cryotherapy was 0.36 when it was 0.69 for the control group, P < or = 0.05). In conclusion, the present study confirms that cryotherapy can decrease 5FU-induced stomatitis and should be recommended for patients receiving bolus 5FU-containing regimens.

Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo.

PURPOSE: To evaluate the effect of exogenous recombinant human erythropoietin (rHuEPO) on the increase of hemoglobin levels and on the transfusion requirements in patients with cisplatin (CDDP)-induced anemia, we performed a double-blind randomized trial with placebo. PATIENTS AND METHODS: One hundred patients with CDDP-associated anemia (hemoglobin level < 90 g/L) were randomized to receive either placebo (saline solution) or rHuEPO (100 U/kg body weight subcutaneously) three times per week. The end points of this study were the increase in hemoglobin levels to greater than 100 g/L after 3, 6, and 9 weeks and the effect on transfusion requirements. RESULTS: Ninety-nine of 100 patients were assessable for response and toxicity. In the rHuEPO arm, mean hemoglobin levels were statistically significantly increased after the third, sixth, and ninth weeks of therapy (101.1 +/- 9.0, 102.4 +/- 6.6, and 105.1 +/- 9.4 g/L, respectively) compared with the mean baseline value (86.3 +/- 6.2 g/L). In the placebo arm, there were no increases in mean hemoglobin levels at the third, sixth, and ninth weeks (81.0 +/- 5.2, 81.3 +/- 9.2, and 81.2 +/- 11 g/L, respectively) compared with the mean baseline value (87.3 +/- 5.2 g/L). Furthermore only 20% of patients required blood transfusions in the rHuEPO arm versus 56% of patients in the placebo arm (P = .01), with a mean units of blood transfused per patient of 0.30 in the rHuEPO arm and 1.8 in the placebo arm (P = .01). Treatment was well tolerated, with no significant side effects. CONCLUSION: CDDP-induced anemia is corrected by rHuEPO, which results in reduced blood transfusion requirements.

Cisplatin, 5-fluorouracil and interferon alpha 2b for recurrent or metastatic head and neck cancer.

On the basis of preclinical data suggesting the possibility of maximising the efficacy of 5-fluorouracil and cisplatin by interferon, a pilot clinical trial was initiated in recurrent and/or metastatic head and neck cancer. Thirty-four patients were treated with cisplatin at 100 mg m-2, followed by 5-fluorouracil at 1,000 mg m-2 by continuous infusion for 5 days. Interferon alpha 2b was administered at the dose of 3 million U i.m. daily for 7 days, beginning the day before chemotherapy. Courses were repeated every 3 weeks. Two patients achieved a complete remission, six a partial response, 14 had stable disease and 12 progressed on therapy, for an overall response rate of 23% (95% confidence interval 10-36%). Median survival time was 5 months. Toxicity was severe. Stomatitis, diarrhoea and myelosuppression were the most common side-effects. Because of the poor response rate and the presence of severe toxicity, in our opinion further clinical trials in head and neck cancer should be attempted only after a better definition in preclinical studies of interactions among 5-fluorouracil, cisplatin and interferon.

Control of chemotherapy-induced diarrhea with octreotide. A randomized trial with placebo in patients receiving cisplatin.

Cisplatin-related diarrhea is a relatively common complication in the clinical management of cancer patients and until now no treatment for this condition has been identified. Octreotide has been reported effective in the treatment of 5-fluorouracil-related diarrhea. To assess the safety and efficacy of octreotide in controlling diarrhea caused by cisplatin, 43 patients who had already had diarrhea during the 24-hour period following a previous cisplating administration were randomized to receive either octreotide or placebo during the next cisplatin course. The patients given octreotide experienced less diarrhea (5 vs. 75%, p = 0.01). There were no side effects. We conclude that octreotide is more effective than placebo in controlling diarrhea following cisplatin chemotherapy.

Carboplatin associated anemia treated with subcutaneous erythropoietin - a pilot-study.

In nineteen patients with carboplatin-induced anemia (hemoglobin less than 90 g/l), recombinant human erythropoietin was administered subcutaneously three times a week on an outpatient basis. The initial dose was 50 Units/kg of body weight. If response was not achieved within 3 weeks, dose was increased to 75 Units/kg. Using the same criteria further escalations to 100 and 150 Units/kg were performed. If there was no response erythropoietin was terminated. Two patients obtained an increase of hemoglobin levels greater than 100 g/l, which was considered as a clinical response in this study, with a dose of 75 U/kg; eleven patients needed an erythropoietin dose of 100 U/kg and three a dose of 150 U/kg. The other three patients required hemotransfusions and were considered non responders. Hemoglobin increases occurred despite continuation of carboplatin chemotherapy. In conclusion, subcutaneous eryhtropoietin is effective and safe in the treatment of carboplatin-induced anemia.