Inclisiran in dyslipidemia.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Hypercholesterolemia has been shown to be one of the most important risk factors for CVD. Statins are currently the standard of care for the management of hypercholesterolemia. However, certain patients on statin therapy fail to achieve the desired low-density lipoprotein cholesterol (LDL-C) goals or are intolerant to statins due to side effects (mostly myalgias). The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the subsequent development of PCSK9 inhibitors provided another route to lower LDL-C levels by increasing recycling of LDL receptors (LDLR) in the hepatocytes. More recently, inclisiran, a small interfering RNA (siRNA) molecule, which increases the number of LDLR in the hepatocyte membranes by halting the transcription of PCSK9, has emerged as a novel promising agent for the management of hypercholesterolemia. Inclisiran received marketing authorization in the European Union in December 2020 for use in adults with primary hypercholesterolemia or mixed dyslipidemia. This review aims to focus on the role of inclisiran in the management of hypercholesterolemia.

Assessing the effectiveness of sustainable land management policies for combating desertification: A data mining approach.

This study investigates the relationship between fine resolution, local-scale biophysical and socioeconomic contexts within which land degradation occurs, and the human responses to it. The research draws on experimental data collected under different territorial and socioeconomic conditions at 586 field sites in five Mediterranean countries (Spain, Greece, Turkey, Tunisia and Morocco). We assess the level of desertification risk under various land management practices (terracing, grazing control, prevention of wildland fires, soil erosion control measures, soil water conservation measures, sustainable farming practices, land protection measures and financial subsidies) taken as possible responses to land degradation. A data mining approach, incorporating principal component analysis, non-parametric correlations, multiple regression and canonical analysis, was developed to identify the spatial relationship between land management conditions, the socioeconomic and environmental context (described using 40 biophysical and socioeconomic indicators) and desertification risk. Our analysis identified a number of distinct relationships between the level of desertification experienced and the underlying socioeconomic context, suggesting that the effectiveness of responses to land degradation is strictly dependent on the local biophysical and socioeconomic context. Assessing the latent relationship between land management practices and the biophysical/socioeconomic attributes characterizing areas exposed to different levels of desertification risk proved to be an indirect measure of the effectiveness of field actions contrasting land degradation.

Evaluation and selection of indicators for land degradation and desertification monitoring: methodological approach.

An approach to derive relationships for defining land degradation and desertification risk and developing appropriate tools for assessing the effectiveness of the various land management practices using indicators is presented in the present paper. In order to investigate which indicators are most effective in assessing the level of desertification risk, a total of 70 candidate indicators was selected providing information for the biophysical environment, socio-economic conditions, and land management characteristics. The indicators were defined in 1,672 field sites located in 17 study areas in the Mediterranean region, Eastern Europe, Latin America, Africa, and Asia. Based on an existing geo-referenced database, classes were designated for each indicator and a sensitivity score to desertification was assigned to each class based on existing research. The obtained data were analyzed for the various processes of land degradation at farm level. The derived methodology was assessed using independent indicators, such as the measured soil erosion rate, and the organic matter content of the soil. Based on regression analyses, the collected indicator set can be reduced to a number of effective indicators ranging from 8 to 17 in the various processes of land degradation. Among the most important indicators identified as affecting land degradation and desertification risk were rain seasonality, slope gradient, plant cover, rate of land abandonment, land-use intensity, and the level of policy implementation.

Evaluation and selection of indicators for land degradation and desertification monitoring: types of degradation, causes, and implications for management.

Indicator-based approaches are often used to monitor land degradation and desertification from the global to the very local scale. However, there is still little agreement on which indicators may best reflect both status and trends of these phenomena. In this study, various processes of land degradation and desertification have been analyzed in 17 study sites around the world using a wide set of biophysical and socioeconomic indicators. The database described earlier in this issue by Kosmas and others (Environ Manage, 2013) for defining desertification risk was further analyzed to define the most important indicators related to the following degradation processes: water erosion in various land uses, tillage erosion, soil salinization, water stress, forest fires, and overgrazing. A correlation analysis was applied to the selected indicators in order to identify the most important variables contributing to each land degradation process. The analysis indicates that the most important indicators are: (i) rain seasonality affecting water erosion, water stress, and forest fires, (ii) slope gradient affecting water erosion, tillage erosion and water stress, and (iii) water scarcity soil salinization, water stress, and forest fires. Implementation of existing regulations or policies concerned with resources development and environmental sustainability was identified as the most important indicator of land protection.

Paclitaxel-ifosfamide-carboplatin combination chemotherapy regimen in advanced uterine and adnexal malignant mixed Mullerian tumours.

BACKGROUND: Malignant mixed Mullerian tumours (MMMTs) of the uterus and adnexa represent aggressive gynaecologic malignancies with a high rate of loco-regional and distant failure. For that reason, we evaluated the paclitaxel-ifosfamide-carboplatin (TICb) combination in patients with advanced MMMTs. METHODS: Female patients with advanced MMMTs, WHO-PS 0-2, no prior chemotherapy for systemic disease, unimpaired haemopoietic and organ function were eligible. Chemotherapy was administered at the following doses; paclitaxel: 175 mg m(-2) on day 1, ifosfamide: 2.0 g m(-2) day(-1)--days 1 and 2, and carboplatin at a target area under the curve 5 on day 2, with prophylactic G-CSF from day 3. RESULTS: Forty patients of a median age 61 (45-72) years, performance status 0-2 with advanced MMMTs of the uterus (n=34), tubes (n=2) or ovary (n=4) have entered and all were evaluable for response and toxicity. Responses were as follows: 27 out of 40 (67.5%) evaluable patients responded, with 11 complete responses and 16 partial responses, while 10 had stable disease, and 3 developed progressive disease. The median response duration was 9 months (range, 4-40 months), median progression-free survival 13 months (range, 3-42 months), while median overall survival 18 months (range, 4-48 months). Grade 3/4 neutropenia was recorded in 22 out of 40 (55%)--with 13 developing grade 4 (≤7 days) and 7 out of 40 (17.5%) of patients at least one episode of febrile neutropenia. CONCLUSION: In this study, it appears that the TICb combination, yielded important activity with manageable toxicity in females with advanced MMMTs warranting further randomised comparison with current standard regimens.

Palliative gastrectomy and other factors affecting overall survival in stage IV gastric adenocarcinoma patients receiving chemotherapy: a retrospective analysis.

OBJECTIVE: Most patients with gastric cancer present with locally advanced or metastatic disease and usually receive palliative therapy. We sought to identify factors influencing overall survival in patients with stage IV gastric cancer receiving palliative chemotherapy. PATIENTS AND METHODS: The records of 311 patients with histological diagnosis of gastric adenocarcinoma were retrospectively reviewed and 17 clinicopathological and therapeutic parameters were evaluated for their influence on overall survival. RESULTS: In multivariate analysis nine factors were found to independently influence survival: no previous palliative gastrectomy [Hazard ratio (HR, 12; CI 7.969-18.099)], single agent chemotherapy instead of combination chemotherapy (HR, 1.35; CI 1.068-1.721), histological grade III (HR, 1.39; 95% CI 1.098-1.782), the presence of hepatic (HR, 1.6; 95% CI 1.246-2.073) and abdominal metastasis (HR, 1.33; 95% CI 1.039-1.715), CA 72-4 > 7 U/L (HR, 1.39; 95% CI 1.026-1.887), LDH > 225 U/L (HR, 1.72; 95% CI 1.336-2.236], need for blood transfusions (HR, 1.58; 95% CI 1.213-2.082), and weight loss > 5% (HR, 1.96; 95% CI 1.352-2.853) at the time of initial diagnosis. Patients were stratified as low (0-2 factors), intermediate (3-6 factors) and high (7-9 factors) risk and the median survival was 76, 40 and 11 weeks, respectively. CONCLUSION: Nine clinical and laboratory factors that adversely affect survival in patients with stage IV gastric cancer who receive chemotherapy were identified. Their concurrent presence seems to have an additive effect as patients with seven to nine factors have the worse prognosis. Palliative gastrectomy and combination chemotherapy appear to be associated with improved survival.

Phase II study of liposomal cisplatin (Lipoplatin) plus gemcitabine versus cisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small cell lung cancer.

BACKGROUND: Lipoplatin is a new liposomal cisplatin designed to reduce cisplatin toxicities without reducing efficacy. In the present randomized phase II study, we examined the efficacy and safety of a Lipoplatin-gemcitabine versus a cisplatin-gemcitabine combination as first line treatment in advanced NSCLC. PATIENTS AND METHODS: Patients with advanced (stages IIIB-IV) NSCLC received up to six 21-day cycles of Lipoplatin 120 mg/m(2) (days 1, 8, 15) and gemcitabine 1000 mg/m(2) (days 1+8) (arm A; LipoGem) versus cisplatin 100mg/m(2) (day 1) and gemcitabine 1000 mg/m(2) (days 1+8) (arm B; CisGem). The primary objective was objective response rate (ORR). Secondary objectives were disease control rate (DCR), progression-free survival (PFS), duration of response and overall survival (OS). Another secondary objective was safety and tolerability of the LipoGem combination. RESULTS: Eighty-eight patients (n=88) entered the study; 47 patients were treated with LipoGem versus 41 patients treated with CisGem. Efficacy was assessed in patients who completed at least 1 cycle of treatment; ORR was 31.7% in arm A versus 25.6% in arm B and DCR was 70.7% versus 56.4%, respectively. A preliminary efficacy of LipoGem versus CisGem in the adenocarcinoma histological subtype of NSCLC showed 16.7% versus 45.8% PD. Treatment in arm A was better tolerated with myelotoxicity and a transient mild elevation of serum creatinine as the dominant side effects; the only grade 4 adverse event was neutropenia noted in 2% of the patients. There was a significant reduction in nephrotoxicity in the LipoGem arm (0% versus 5% grade III, p-value<0.001) as well as in nausea vomiting (2% versus 12% grade III, p-value<0.001). In addition, less antiemetics and G-CSF were administered in arm A. CONCLUSION: Overall, Lipoplatin appears to have lower toxicity, mainly renal toxicity as well as higher efficacy than cisplatin when combined with gemcitabine in advanced NSCLC.

Evaluation of the paclitaxel-ifosfamide-cisplatin (TIP) combination in relapsed and/or metastatic cervical cancer.

BACKGROUND: Recurrent or metastatic cervical cancer represents an aggressive malignancy with a high rate of locoregional and distant failure. Therefore, we evaluated the three-drug combination of paclitaxel-ifosfamide-cisplatin (TIP). METHODS: Systemic chemotherapy-naive patients with advanced metastatic/relapsed cervical cancer and a World Health Organization (WHO) performance status (PS) of 0-2 were eligible. TIP chemotherapy doses were paclitaxel 175 mg m(-2) on day 1, ifosfamide 2.5 g m(-2) on days 1+2, and cisplatin 40 mg m(-2) on days 1+2, with prophylactic granulocyte-colony stimulating factor. RESULTS: A total of 42 patients with recurrent/metastatic cervical cancer are evaluable for response and toxicity: median age: 56 (25-74) years; PS: 1 (0-2); histologies - squamous: 35, adenosquamous: 5, and adenocarcinoma: 2. Responses were overall response rate (RR): 62% (95% confidence interval (CI): 47.3-76.7%), with complete response (CR): 26% (95% CI: 12.7-39.3%), and partial response (PR): 36% (95% CI: 21.5-49.9%). Responses according to the relapse site were overall RR: 32% (95% CI: 13.7-50.3%) within previously irradiated pelvis vs 75% (95% CI: 57.7-92.3%) in extra-pelvic sites. Median time to progression (TTP) was 7 (range, 2-34+) months and median overall survival (OS) was 16.5 (range, 3-36+) months. Toxicities included grade 3-4 neutropenia: 83% (21% febrile neutropenia), grade 3-4 thrombocytopenia: 9%, no grade 3 neuropathy (35% grade 2), grade 2 asthenia/fatigue 15%, and no treatment-related deaths. CONCLUSION: TIP is an active regimen with acceptable toxicity in advanced/relapsed cervical cancer.

Evaluation of the possible benefits of post-radiotherapy surgery after concomitant chemoradiotherapy with a new radio-sensitizing regimen (irinotecan / CPT-11, interferon A2b and amifostine) for advanced-stage cervical carcinoma. Preliminary results of a pilot phase-II study.

PURPOSE: This phase II pilot study was conducted to evaluate the results of a three-modality approach (which included post-chemoradiotherapy surgery) in advanced-stage cervical carcinomas. PATIENTS AND METHODS: Thirty-six patients underwent either surgery or were put on follow-up after having received radical cervical radiotherapy (RT) combined with radiosensitizing chemoimmunotherapy with irinotecan (CPT-11), interferon (IFN) A2b, and amifostine. The last selection (surgery or follow-up) was based on clinical evaluation (downstaged or not). Feasibility, morbidity, surgical outcome and survival were evaluated. RESULTS: Twenty-six patients had stage IIb and 10 IIIb disease at diagnosis. Sixteen (44%) were clinically downstaged, thus becoming eligible for surgery. Twelve (33%) were operated and the others were put on follow-up. There was no significant increase in treatment-related morbidity of the group of patients receiving three-modality therapy, since only one intraoperative complication had occurred. In 58% of the operated patients, chemoradiotherapy-resistant tumor was found on pathology of the cervical specimens, while 29% of them had lymph nodes infiltrated by the tumor. After a median follow-up of 42.5 months, overall survival (OS) of operated vs. non-operated patients (88 vs. 56%, respectively) show only a trend toward significance (p=0.10). The overall recurrence/metastasis rate was 36.1% and the disease-free survival (DFS) 56% for operated vs. 76% for non-operated patients, respectively (p=0.63). CONCLUSION: These results indicate that post-chemoradiotherapy surgery is justified because of the high rate of residual disease found. Morbidity can be effectively limited with proper patient selection. A considerable survival benefit is expected, although this remains to be confirmed with phase III studies.

CEA and CA-19.9 serum tumor markers as prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

Most pancreatic adenocarcinoma patients present with locally advanced or metastatic disease at diagnosis. in this retrospective study the authors evaluated the prognostic significance of the CEA and CA-19.9 serum tumor markers in advanced (unresectable) pancreatic cancer in correlation to other prognostic factors (demographic data, clinical parameters, treatment modality) and survival time using univariate and multivariate methods, in 215 patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma. median survival was 29.0 weeks, with 21.9% of patients surviving 36 weeks. Among 24 potential prognostic variables, 19 were associated with shorter survival. Multivariate analysis indicated that ten factors had a significant independent effect on survival: chemotherapy, surgery, tumor localization, elevated C-reactive protein, elevated CeA, CA 19-9 (>30 x nl), jaundice at diagnosis, weight loss >10%, distant metastases, and Karnofsky performance status. Patients who had only palliative therapy had a hazard ratio of 8.94 versus those who underwent palliative surgery and chemotherapy. Although certain clinical, biochemical and biological factors remain important predictors of survival in patients with advanced pancreatic cancer, CA-19.9 serum tumor marker levels retain independent prognostic value for poor survival.

Efficacy of tropisetron in patients with advanced non-small-cell lung cancer receiving adjuvant chemotherapy with carboplatin and taxanes.

Even though significant progress has been made, chemotherapy-induced emesis remains a challenging problem. Few studies focus on emesis in patients treated with carboplatin and the observation period is limited to the initial 24 h following chemotherapy. Thus, we investigated if tropisetron (T) monotherapy can adequately prevent acute and delayed emesis in non-small-cell lung cancer (NSCLC) patients receiving a moderately emetogenic chemotherapy (MEC) (carboplatin-containing) regimen. Furthermore, we explored the merits of adding dexamethasone (D) or alprazolam (A) to T, especially in the setting of a pre-existing high level of stress. We studied 60 patients with advanced NSCLC receiving carboplatin and taxanes in three consecutive cycles. During the first cycle, patients received 5 mg of T intravenously before chemotherapy and the same dose per os on each of the following 3 days. In the second cycle, T was co-administered with 8 mg of D once a day, while, during the third cycle, T was combined with per os A 0.25 mg every 12 h and continued over the following 3 days. Finally, we evaluated the impact of stress on the anti-emetic response achieved with the previously described regimens. The combination of T + A was superior to T monotherapy and the combination of T + D, regarding the prevention of acute and delayed emesis. Both T + A and T + D combinations led to appetite improvement, while patients receiving T + A experienced sedation more frequently. Interestingly, subgroup analysis revealed that patients without underlying stress obtained no further benefit by the addition of A or D, while both T + A and T + D combinations led to a better anti-emetic response in patients with stress. In conclusion, T monotherapy provides a satisfactory result in controlling nausea and emesis caused by a MEC regimen in patients without stress. However, the addition of D and, mainly, A improves its anti-emetic effect in patients with obvious stress.

The impact of agricultural soil erosion on the global carbon cycle.

Agricultural soil erosion is thought to perturb the global carbon cycle, but estimates of its effect range from a source of 1 petagram per year(-1) to a sink of the same magnitude. By using caesium-137 and carbon inventory measurements from a large-scale survey, we found consistent evidence for an erosion-induced sink of atmospheric carbon equivalent to approximately 26% of the carbon transported by erosion. Based on this relationship, we estimated a global carbon sink of 0.12 (range 0.06 to 0.27) petagrams of carbon per year(-1) resulting from erosion in the world's agricultural landscapes. Our analysis directly challenges the view that agricultural erosion represents an important source or sink for atmospheric CO2.

Integration of novel targeted therapies into the systemic treatment of breast cancer--a review.

Over the last few years it has been anticipated that molecularly targeted agents can provide substantial improvement in the treatment of breast cancer. The most illustrative paradigm has been that of trastuzumab (Herceptin), a humanized monoclonal antibody against the HER2 oncoprotein overexpressed in 25% of breast cancers. Trastuzumab when combined with standard cytotoxic chemotherapy improved the outcome and survival in patients with metastatic breast cancer, whereas, over the last 2 years studies incorporating trastuzumab in sequence to or concurrently with taxane-based chemotherapy in the adjuvant setting demonstrated a considerable benefi t in this subset, with the results of longer follow-up regarding long-term outcome and late toxicities expected over the forthcoming years. Moreover, the prognostic and predictive value of topoisomerase IIa (Topo IIa) overexpression in these subgroups with respect to anthracycline treatment has been extensively discussed and analysed. Other inhibitors of both HER1/HER2 have recently been introduced with promising results and results of ongoing studies are awaited with great interest. A recently anticipated target in advanced breast cancer has been the pathway of angiogenesis; first a humanized monoclonal antibody-bevacizumab (Avastin)- has demonstrated encouraging results when combined with chemotherapy in pretreated HER2-negative advanced breast cancer, while combinations with trastuzumab+/-chemotherapy are currently examined in HER2-overexpressing breast cancer. Furthermore, as novel molecular pathways relevant to breast cancer biology are explored, it is expected that a whole array of targeted agents will be tested in combination or in sequence to standard chemotherapy with the aim to improve outcome of high-risk breast cancer patients.

Successful treatment with cyclosporine of thymoma-related aplastic anemia.

Aplastic anemia is a rare immune-mediated complication of thymoma. Thymomas, especially of the cortical type, have the capacity to generate mature T-cells from their immature precursors. Furthermore, mature intratumorous T-cells have an increased autoantigen-specific potential. We present the case of a 75-year-old patient with an inoperable cortical thymoma who developed aplastic anemia 7 years after the initial diagnosis. The infiltration of the bone marrow by these cells was accompanied by the production of cytokines such as tumor necrosis factor alpha (TNF-alpha) in the microenvironment of bone marrow and in the serum sample. The patient was successfully treated with oral cyclosporine A for 14 months and when she died due to progression of the thymoma, 9 months after the discontinuation of cyclosporine, the aplastic anemia had not recurred.

Docetaxel-ifosfamide combination in patients with advanced breast cancer failing prior anthracycline-based regimens: results of a phase I-II study.

The established clinical activity of docetaxel and ifosfamide as single agents in anthracycline pre-treated breast cancer, led us to conduct a phase I-II study to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and clinical activity of the docetaxel+ifosfamide combination in this setting. Patients with histologically confirmed metastatic breast cancer, after failure on prior anthracycline-based chemotherapy, were treated at successive dose levels (DLs) in cohorts of 3-6 with escalated doses of docetaxel 70-100 mg/m(2) over 1 h on day 1 followed by ifosfamide 5-6 g/m(2) divided over days 1+2 (2.5-3.0 g/m(2)/day over 1 h), every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. Between March 1997 and December 2002, 65 patients with a median age of 57 years (range, 32-72) and performance status (WHO) of 1 (range, 0-2) were treated at 5 DLs as follows; 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were: 56%; (95% CI, 42.2-69.7%); 4 CRs, 24 PRs, 10 SD and 12 PD. The median response duration was 7 mo (3-24 mo), median TTP 6.5 mo (0.1-26 mo), and median OS 13 mo (0.1-33 mo). Grade 3/4 toxicities included: neutropenia in 72% of patients, with 60% developing grade 4 neutropenia (

Methotrexate-paclitaxel-epirubicin-carboplatin (M-TEC) combination chemotherapy in patients with advanced bladder cancer: an open label phase II study.

The present phase II study aimed to define the application of a novel regimen incorporating methotrexate, paclitaxel, epirubicin, and carboplatin (M-TEC) in advanced bladder cancer, essentially as an M-VAC-like regimen, by substitution of cisplatin by carboplatin, doxorubicin by epirubicin and vinblastine by paclitaxel. Forty patients with advanced bladder cancer entered the study; 34 males/6 females, median age: 68 (range, 59-76), median PS (Karnovsky): 80, without receiving prior chemotherapy. Disease extention was as follows; 11/40 had local recurrence, 6/40 liver metastases, 14/40 lung metastases, bone and lymph node 8/40, bones-lymph node-lung metastases 4, lymph node and liver 4/40, lymph node-liver and lung metastases 2/40. Drug schedule and doses were as follows: paclitaxel 180 mg/m2, carboplatin AUC = 5 (according to creatinine clearance, based on Calvert's formula), and epirubicin 40 mg/m2 were administered during day 1, whereas methotrexate 30 mg/m2 and epirubicin 40 mg/m2 were administered on day 14. All patients were evaluable for response with 24/40 responding [response rate (RR) 60%]; 10/40 (25%) CR, 14/40 (35%) PR, 9/40 (22.5%) SD, and 7/40 (17.5%) PD. Symptomatic improvement was observed in 50% of patients. The median duration of response was 22 (14-32) weeks, median time-to-progression (TTP) 33 (12-44) weeks, and median survival was 56 (20-84) weeks. Toxicity was well accepted and was mainly neutropenia > grade 3: 17%, anemia >grade 3: 16%, thrombocytopenia > grade 2: 6%, nausea & vomiting mainly > grade 2: 31%, according to the administered chemotherapy cycles, whereas fatigue grade 2-3: 19%, neurotoxicity grade 1-2 13% of patients, and alopecia grade 2 was observed in all patients. The present pilot study indicates the feasibility of the M-TEC combination for bladder cancer with acceptable toxicity.

Leucovorin and 5-fluorouracil versus levamisole and 5-fluorouracil as adjuvant chemotherapy in rectal cancer.

PURPOSE: To evaluate the effectiveness of 6-month therapy with leucovorin (LV)+5-fluorouracil (5-FU) versus 12-month therapy with levamisole (LVS)+5-FU, as adjuvant chemotherapy in patients with completely resected Aster-Coller stage B(2) or C(1)/C(2) rectal cancer (RC). PATIENTS AND METHODS: One hundred and fifty patients with surgically resected RC were enrolled. Seventy patients with stage B(2) and 80 with stage C were randomly assigned to adjuvant chemotherapy with 5-FU+LXx6 months or 5-FU+LVSx12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant chemotherapy consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v. bolus every week plus LVS tablets 50 mg t.i.dx3 days every 2 weeks for 1 year. RESULTS: After a median follow up for survivors of 8.7 years (range 1.8-10.5), all of the patients were evaluable. There were no significant differences between the two treatment groups with respect to the recurrence rates (p=0.821). Moreover, there were no significant differences between the two tratment groups in disease-free survival (DFS) (p=0.84) [B(2)(p=0.805) and C (p=0.978)] and overall survival (OS) rates for patients of either stage B(2) or C (p=0.78). Toxicities were more frequent in the 5-FU+LVS versus 5-FU+LV group: myelosuppression (grade 3 leucopenia, 12 versus 4%, p<0.04), diarrhea (grade 0, 60 versus 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients versus 2, p<0.03.). No patient stopped chemotherapy because of toxicity, and there were no treatment-related deaths. CONCLUSION: Adjuvant chemotherapy in RC with LV+5-FU for 6 months is equally effective and less toxic than LVS+5-FU for 12 months.

Breast cancer following curative chemotherapy for non-Hodgkin's lymphoma and the effect of drug resistance proteins to the final outcome. A retrospective study.

PURPOSE: To investigate the overall survival (OS) of patients developing breast cancer (BC) after curative chemotherapy for non-Hodgkin's lymphoma (NHL) and to evaluate the possible effect on the patients' outcome of the expression of drug resistance-related proteins (P-glycoprotein-Pgp, multidrug resistance-associated protein-MRP, and multidrug resistance-related vault lung resistance protein-LRP) in BC issue. STUDY GROUP: 25 female patients (median age 60 years, range 37-70) who developed BC after chemotherapy for high/intermediate grade B-cell NHL, treated with CHOP and achieving complete remission (CR). This group was further subdivided in subgroups A and B, according to the time interval between NHL and BC development ( 24 months, respectively). A matched-pair group of de novo BC patients formed the control group. BC tissue was immuno-histochemically stained for Pgp, MRP and LRP. RESULTS: The median interval between NHL diagnosis and BC development was 26 months (range 9-49). In both groups 14 patients had tumor grade II; 16 were negative for steroid receptors; 17 overexpressed c-erbB-2; 14 were stage IIIA/B, and 11 stage IV. CMF or CNF (mitoxantrone instead of doxorubicin) were given for BC. Early progression was noticed in all study group patients for which second-line chemotherapy was instituted. There was a better response for stage IV patients in the control versus the study group (p=0.07). More prolonged OS was demonstrate for patients with stage III in the control group (median 51 months) and in subgroup B (median 47 months) than in subgroup A (median 16 months; p=0.00012), as well as for patients with advanced disease (p=0.0045). Development of BC < 24 months after NHL resulted in reduced OS (p=0.017). No difference was noticed in the expression of drug resistance proteins between the study and control group or between subgroups A and B. CONCLUSION: BC developing shortly after a CR to NHL is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of Pgp, MRP and LRP failed to demonstrate significant difference between the study and control group, although indications exist that drug resistance mechanisms might be part of the aggressive disease phenotype, contributing to the poor outcome.

5-fluorouracil cardiotoxicity is a rare, dose and schedule-dependent adverse event: a prospective study.

PURPOSE: Cardiotoxicity associated with 5-fluorouracil (5FU) administration is infrequently reported in the literature, albeit case reports of acute coronary syndromes have been published. In the present study, patients undergoing 5FU chemotherapy were tested for the development of cardiac-related symptoms during its administration. PATIENTS AND METHODS: Five hundred twenty-two patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion were subjected to electrocardiogram (ECG) and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion was interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with >2-fold enzyme elevation were admitted into a coronary care unit for at least 72 hours. Cases with acute myocardial infarction had to discontinue 5FU treatment. RESULTS: Overall 20 (3.8%) patients developed symptoms and/or ECG abnormalities due to 5FU. Patients with continuous 5FU infusion had a trend for higher incidence of cardiotoxicity (13/205, 6.3%) than the remaining (7/317, 2.2%; p=0.067). More specifically, increased toxicity was encountered in patients with continuous 24 h 5FU+ leucovorin (LV) infusion for 5 days compared to patients with the same schedule without LV (p <0.027) and patients with short 5FU+LV administration as well (p=0.024). Seven out of the 20 patients suffered acute myocardial infarction, 6 developed only ischemia, while ECG findings consistent with coronary vasospasm were detected in 4 patients and conduction disturbances in 3 patients (one subsequently died). CONCLUSION: The present study indicates a toxic effect of 5FU on myocardium, which is largely schedule-dependent. High level of alert is required when using this drug, while its toxic effect on the coronary endothelium and myocardium merits further investigation.