Ultrashort pfas: a review of the topic.

Background: Ultrashort perfluoroalkyl substances (UsPFAS), characterized by carbon chain lengths of 2 to 4 atoms, represent a distinct subgroup within the broader PFAS class of chemicals. Despite their lower molecular weight, ultrashort PFAS have gained significant attention due to their widespread presence. This article provides a comprehensive review of the topic. Methods: We analyzed 33 articles published between 2017 and 2024 found on Pubmed using "ultrashort PFAS" as keyword. We compared: 1- environmental matrices in which ultrashort PFAS were found, 2- different distribution patterns, 3- degradation pathways, to better understand whether they may resemble longer-chain PFAS, which are known for their bioaccumulation and persistence as "forever chemicals". Conclusions: The occurrence of ultrashort PFAS has been documented in different environmental matrices (including surface waters, waste waters, precipitations, sediments, soils, and also human serum and urine) indicating widespread environmental exposure. Advanced analytical techniques, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS), have enabled the sensitive detection and quantification of these compounds at trace levels. Studies keep finding new ultrashort PFAS and have focused on elucidating their sources and fate pathways to better understand their behavior in natural systems. The toxicity of ultrashort PFAS remains an area of active in-vestigation. While less is known about their health effects, studies suggest potential adverse impacts on organisms and ecosystems. This underscores the importance of continued research to assess the eco-logical consequences of ultrashort PFAS exposure and bring up risk management strategies.

Application and internal validation of lung ultrasound score in COVID-19 setting: The ECOVITA observational study.

BACKGROUND: The severe acute respiratory syndrome Coronarovirus-2 associated still causes a significant number of deaths and hospitalizations mainly by the development of respiratory failure. We aim to validate lung ultrasound score in order to predict mortality and the severity of the clinical course related to the need of respiratory support. METHODS: In this prospective multicenter hospital-based cohort study, all adult patients with diagnosis of SARS-CoV-2 infection, performed by real-time reverse transcription polymerase chain reaction were included. Upon admission, all patients underwent blood gas analysis and lung ultrasound by expert operators. The acquisition of ultrasound scan was performed on 12 peculiar anatomic landmarks of the chest. Lung ultrasound findings were classified according to a scoring method, ranging 0 to 3: Score 0: normal A-lines. Score 1: multiple separated B-lines. Score 2: coalescent B-lines, alteration of pleural line. Score 3: consolidation area. RESULTS: One thousand and seven patients were included in statistical analysis (male 62.4 %, mean age 66.3). Oxygen support was needed in 811 (80.5 %) patients. The median ultrasound score was 24 and the risk of having more invasive respiratory support increased in relation to higher values score computed. Lung ultrasound score showed negative strong correlation (rho: -0.71) with the P/F ratio and a significant association with in-hospital mortality (OR 1.11, 95 %CI 1.07-1.14; p < 0.001), even after adjustment with the following variables (age, sex, P/F ratio, SpO2, lactate, hypertension, chronic renal failure, diabetes, and obesity). CONCLUSIONS: The novelty of this research corroborates and validates the 12-field lung ultrasound score as tool for predicting mortality and severity clinical course in COVID-19 patients. Baseline lung ultrasound score was associated with in-hospital mortality and requirement of intensive respiratory support and predict the risk of IOT among COVID-19 patients.

Protein kinase C activation inhibits alpha1D L-type Ca channel: a single-channel analysis.

The recently reported alpha1D Ca channel in the heart is known to be regulated by protein kinase C (PKC) at the whole cell level and has been implicated in atrial fibrillation. The biophysical basis of this regulation at the single-channel level is not known. Therefore, the effect of PKC activation was studied on alpha1D Ca channel expressed in tsA201 cells using cell-attached configuration. Unitary currents were recorded in the presence of 70 mM Ba2+ as the charge carrier at room temperature. Under basal condition, channel activity was rare and infrequent; however, Bay K 8644 (1 microM) induced channel openings with a conductance of 22.3 pS. Single channel analysis of open and closed time distributions were best fitted with a single exponential. PKC activation by 4alpha-phorbol 12-myristate 13-acetate (PMA; 10 nM), a phorbol ester derivative, resulted in a decrease in open probability and increase in closed-time without any significant effect on the conductance of the alpha1D Ca channel. This is consistent with a decreased entry of alpha1D Ca channel into open states in the presence of PMA. PMA effects could not be reproduced by 4-alpha Phorbol, an inactive PMA analogue. These data show, for the first time, (1) the alpha1D Ca channel activity at the single-channel level and (2) the biophysical basis by which PKC activation inhibits the alpha1D Ca channel. The shortening of the open-time and the lengthening of the closed-time constants and the increase in blank sweeps may explain the inhibition of the previously reported whole-cell alpha1D Ca current. Altogether, these data are essential for understanding the complex role of alpha1D Ca channel not only in physiological settings but also in pathological settings such as atrial fibrillation.

Efficacy of the combination of cisplatin with either gemcitabine and vinorelbine or gemcitabine and paclitaxel in the treatment of locally advanced or metastatic non-small-cell lung cancer: a phase III randomised trial of the Southern Italy Cooperative Oncology Group (SICOG 0101).

BACKGROUND: Triplet regimens were occasionally reported to produce a higher response rate (RR) than doublets in locally advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was conducted to assess (i) whether the addition of cisplatin (CDDP) to either gemcitabine (GEM) and vinorelbine (VNR) or GEM and paclitaxel (PTX) significantly prolongs overall survival (OS) and (ii) to compare the toxicity of PTX-containing and VNR-containing combinations. PATIENTS AND METHODS: Stage III or IV NSCLC patients were randomly assigned to (i) GEM 1000 mg/m(2) and VNR 25 mg/m(2) on days 1 and 8 (GV arm); (ii) GEM 1000 mg/m(2) and PTX 125 mg/m(2) on days 1 and 8 (GT arm); (iii) GV plus CDDP 50 mg/m(2) on days 1 and 8 (PGV arm); and (iv) GT plus CDDP 50 mg/m(2) on days 1 and 8 (PGT arm). Treatments were repeated every 3 weeks for a maximum of six cycles. RESULTS: A total of 433 (stage III, 160; stage IV, 273) patients were randomly allocated to the study. RR was 48% [95% confidence interval (CI), 42% to 54%] for triplets and 35% (95% CI, 32% to 38%) for doublets (P = 0.004). Median progression-free survival (6.1 versus 5.5 months, P = 0.706) and median OS (10.7 versus 10.5 months, P = 0.379) were similar. CDDP significantly increased the occurrence of severe neutropenia (35% versus 13%), thrombocytopenia (14% versus 4%), anaemia (9% versus 3%), vomiting (6% versus 0.5%), and diarrhoea (6% versus 2%). Conversely, frequency of severe neutropenia (30% versus 17%) and thrombocytopenia (11% versus 6%) was significantly higher with VNR-containing regimens. CONCLUSIONS: Adding CDDP to GV or GT significantly increased RR, but did not prolong the OS of patients. Among doublets, the GT regimen should be preferred in view of its better safety profile.

Oxaliplatin plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial.

PURPOSE: The primary end point of this phase III trial was to compare the response rate (RR) of oxaliplatin (OXA) plus levo-folinic acid (l-FA) and 5-fluorouracil (5-FU) bolus with that of irinotecan (IRI) plus l-FA and 5-FU bolus in advanced colorectal carcinoma. PATIENTS AND METHODS: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200 mg/m(2) on day 1, l-FA 250 mg/m(2) intravenously plus 5-FU 850 mg/m(2) on day 2 (IRIFAFU); or OXA 100 mg/m(2) on day 1, l-FA 250 mg/m(2) plus 5-FU 1050 mg/m(2) on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85 mg/m(2) and 5-FU to 850 mg/m(2) [OXAFAFU low dose (ld)]. RESULTS: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P=0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade > or =3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P=0.046) and overall survival of patients (18.9 versus 15.6 months; P=0.032) were significantly prolonged with OXAFAFU. CONCLUSIONS: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred in the first-line treatment of advanced colorectal cancer patients.

Randomised, open-label, phase II trial of paclitaxel, gemcitabine and cisplatin versus gemcitabine and cisplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium.

The purpose of the study was to evaluate the antitumor activity and the safety of paclitaxel combined with gemcitabine and cisplatin in patients affected by advanced transitional cell carcinoma of the urothelium (TCC). Eighty-five patients affected by advanced TCC and measurable disease were randomized to receive either paclitaxel at dosage of 70 mg/m2, gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks (GCP) or gemcitabine 1000 mg/m2 on days 1, 8, 15 and cisplatin 70 mg/m2 on day 2 every 4 weeks (GC). All enrolled patients were considered evaluable for response and toxicity (intention to treat). The observed response rate was 43% for GCP and 44% for GC combination, respectively. Median time to treatment failure was 32 weeks for GCP and 26 weeks for GC and overall survival 61 vs 49 weeks, respectively (p-value not significant). Grade 3-4 neutropenia was observed in 49% of patients treated with GCP vs 35% of those treated with GC (P=0.05) and grade 3-4 thrombocytopenia was observed in 36% of GCP treated patients as compared to 21% of those treated with GC (P=0.01). Seven patients over 70 years old or with poor PS were removed from the study: 6 patients from GCP group (2 toxic deaths, 2 grade 4 myelotoxicity and 2 grade 3 asthenia) and 1 from GC group was lost to follow-up after the first cycle. The combination of paclitaxel, gemcitabine and cisplatin is effective in the treatment of TCC. However, the addition of paclitaxel to the combination of gemcitabine plus cisplatin seems to increase toxicity, therefore it seems not suitable for poor PS patients and those over 70 years old. Larger and more powered studies are needed to exactly define the role of paclitaxel in this combination.

Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients.

The aim of this study was to assess whether a combination of gemcitabine (GEM) with either paclitaxel (PTX) or vinorelbine (VNR) could be more effective than GEM or PTX alone in elderly or unfit advanced non-small-cell lung cancer (NSCLC) patients. A total of 264 NSCLC patients aged >70 years with ECOG performance status (PS)< or =2, or younger with PS=2, were randomly treated with: GEM 1200 mg m(-2) on days 1, 8 and 15 every 28 days; PTX 100 mg m(-2) on days 1, 8 and 15 every 28 days; GEM 1000 mg m(-2) plus PTX 80 mg m(-2) (GT) on days 1 and 8 every 21 days; GEM 1000 mg m(-2) plus VNR 25 mg m(-2) (GV) on days 1 and 8 every 21 days. In all arms, an intra-patients dose escalation was applied over the first three courses, provided that no toxicity of WHO grade > or =2 had previously occurred. At present time, 217 (82%) patients had died. The median (months) and 1-year survival probability were 5.1 and 29% for GEM, 6.4 and 25% for PTX, 9.2 and 44% for GT, and 9.7 and 32% for GV. Multivariate analysis showed that PS< or =1 (hazard ratio (HR)=0.67; 95% CI 0.51-0.90), and doublet treatments (HR=0.76; 95% CI 0.59-0.99) were significantly associated with longer survival. Doublets produced no more toxicity than single agents. GT should be considered a reference regimen for elderly NSCLC patients with PS< or =1.

Irinotecan plus leucovorin-modulated 5-fluorouracil I.V. bolus every other week may be a suitable therapeutic option also for elderly patients with metastatic colorectal carcinoma.

The aim of this study was to assess the safety and efficacy of biweekly irinotecan plus leucovorin-modulated 5-fluorouracil i.v. bolus in metastatic colorectal carcinoma according to the age of patients. For this purpose, we have analysed 108 patients randomly allocated to receive irinotecan 200 mg m(-2) i.v. (1-h infusion) on day 1, and L-leucovorin 250 mg m(-2) i.v. (1-h infusion) plus 5-fluorouracil 850 mg m(-2) i.v. bolus on day 2 every 2 weeks (IRIFAFU) in our previous SICOG 9801 trial. According to age, patients were retrospectively divided into three groups: younger (/=70 years, n=17). Apart from gender, pretreatment characteristics were well balanced across the three groups. WHO grade >/=3 neutropenia and diarrhoea affected on the whole 46 and 16 patients, respectively, without any significant difference according to age-grouping. Patients aged

Phase I/II study of paclitaxel, gemcitabine and vinorelbine as first-line chemotherapy of non-small-cell lung cancer.

BACKGROUND: The aim of our study was to determine the maximum tolerated dose of paclitaxel combined with a fixed dose of gemcitabine and vinorelbine in the treatment of non-small-cell lung cancer (NSCLC) and to evaluate in a phase II trial the efficacy of this combination. PATIENTS AND METHODS: Sixty-two patients with stage IIIB/IV NSCLC were treated with paclitaxel in escalating doses from 40-80 mg/m(2) combined with gemcitabine and vinorelbine at fixed doses of 1000 mg/m(2) and 25 mg/m(2), respectively. All drugs were given intravenously on day 1 and 8 every 3 weeks. RESULTS: In a phase I trial, carried out on 21 patients, grade 4 neutropenia, as dose-limiting toxicity, occurred at the dosage level of paclitaxel 80 mg/m(2). In a phase II trial, with paclitaxel administered at 70 mg/m(2), 27 out of 41 (66%) assessable patients responded (10% complete responses and 56% partial responses). Objective response was observed in 13 of 16 patients (81%) with stage IIIB disease and in 14 of 25 (56%) with stage IV disease. The median time to treatment failure was 26 weeks (range 3-72 weeks; 32 weeks and 20 weeks for stages IIIB and IV, respectively) and median survival 62 weeks (range 4-176 weeks; 72 weeks and 56 weeks for stages IIIB and IV, respectively). One-year survival was 64% for all patients (72% for patients with stage IIIB and 52% for those with stage IV). Grade 3 and 4 neutropenia were observed in 11 (27%) and seven (17%) cases, respectively; grade 3 thrombocytopenia was observed in three patients (7%) and grade 3 anemia in four patients (10%). The most relevant non-hematological toxicity was grade 2/3 asthenia, which was observed in 12 patients (29%). Alopecia was almost universal, whereas nausea and vomiting were absent. CONCLUSIONS: The combination of paclitaxel, gemcitabine and vinorelbine is effective and tolerable in the treatment of NSCLC. The high activity and low toxicity of this regimen warrant randomized studies with platinum-containing combinations.

Addition of either irinotecan or methotrexate to bolus 5-fluorouracil and high-dose folinic acid every 2 weeks in advanced colorectal carcinoma: a randomised study by the Southern Italy Cooperative Oncology Group.

PURPOSE: The purpose of this study was to compare the activity and toxicity of the combination of irinotecan (IRI) plus folinic acid (FA)-modulated 5-fluorouracil (5-FU) i.v. bolus with a regimen of double modulation of 5-FU with methotrexate (MTX) and FA in patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Two-hundred and thirty-four patients were enrolled: 118 patients received IRI 200 mg/m2 (90-min i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and 5-FU 850 mg/m2 (i.v. bolus) on day 2 (IRIFAFU), and 116 patients received MTX 750 mg/m2 (2-h i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and FU 800 mg/m2 (i.v. bolus) on day 2 (MTXFAFU). Both cycles were repeated every 2 weeks until progression or to a maximum of 16 cycles. Response rate (RR) was the main end point of the study; responses were assessed every four cycles and confirmed after 2 additional months of treatment. RESULTS: RR was significantly greater with IRIFAFU (36%) than with MTXFAFU (20%) (P <0.001). Multivariate analysis showed that IRIFAFU was significantly associated with a greater activity (P = 0.028). Median progression-free survival was longer with IRIFAFU than with MTXFAFU (7.2 months compared with 4.8 months; P = 0.048). Median survival time (MST) did not differ between the two arms (14.7 months compared with 14.8 months, respectively). Patients not receiving second-line chemotherapy, however, lived longer when treated in the first-line with IRIFAFU (MST 11.9 months compared with 6.4 months; P = 0.038). IRIFAFU caused a significantly greater occurrence of grade 3 or 4 neutropenia (40% compared with 9%; P = 0.001) and diarrhoea (13% compared with 4%; P = 0.024), but a significantly lower incidence of stomatitis (3% compared with 12%; P = 0.007), than the comparative regimen. CONCLUSIONS: IRIFAFU appeared comparable in terms of activity and toxicity with other weekly or biweekly bolus or infusional combination regimens. IRIFAFU, however, seems easier to administer, because it does not require infusional catheter or pump devices, and it is less expensive. It may represent a new option for treating advanced colorectal carcinoma.

Retinoids induce fibroblast growth factor-2 production in endothelial cells via retinoic acid receptor alpha activation and stimulate angiogenesis in vitro and in vivo.

The effect of retinoic acid (RA) on endothelial cells is still controversial and was examined in the present study. In bovine aortic endothelial cells (BAECs), all-trans RA (ATRA) and 9-cis RA (9CRA), but not 13-cis RA (13CRA), induced fibroblast growth factor-2 (FGF-2) production and exhibited a biphasic dose-dependent effect to enhance BAEC proliferation and differentiation into tubular structures on reconstituted basement membrane proteins (Matrigel); both processes were inhibited by FGF-2-neutralizing antibody. The pan RA receptor (RAR)-selective ligand (E)-4-[2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphtalenyl)-1-propenyl] benzoic acid and the RARalpha-selective ligand 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-ethenyl] benzoic acid stimulated the production of FGF-2, whereas the addition of the RARalpha-antagonist RO 41-5253 inhibited this effect. In BAECs, the forced expression of RARalpha, but not RARbeta or RARgamma, enhanced FGF-2 production, whereas the RARalpha-dominant negative, Delta403, blocked this effect. Furthermore, RARalpha overexpression directly stimulated BAEC differentiation on Matrigel and potentiated the effects of ATRA in this assay. Finally, ATRA-treated BAECs coinjected with Matrigel subcutaneously in mice induced neovascularization within the Matrigel plug, and ATRA also enhanced angiogenesis in the chicken chorioallantoic membrane assay. In conclusion, RA can stimulate endothelial cell proliferation and differentiation in vitro via enhanced RARalpha-dependent FGF-2 production, and it can also induce angiogenesis in vivo. The full text of this article is available at http://www.circresaha.org.

Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial.

PURPOSE: The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex) (TOM + LFA-5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU). PATIENTS AND METHODS: One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 850 mg/m2 s i.v. bolus (arm A); TOM, 3 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 1050 mg/m2 i.v. bolus (arm B); or MTX, 750 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 800 mg/m2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more. RESULTS: The RRs were: 34% (95% confidence interval (95%, CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs, in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA 5-FU. Median relative dose intensity over eight cycles (DI8) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA-5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI8 was 93% for TOM, and 82% for 5-FU. CONCLUSIONS: CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.

Phase II study of vinorelbine with protracted fluorouracil infusion as a second- or third-line approach for advanced breast cancer patients previously treated with anthracyclines.

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m(2) administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m(2)/d given continuously over a 24-hour period. RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

Interim analysis of a phase III trial comparing cisplatin, gemcitabine, and vinorelbine vs. either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non small-cell lung cancer. A Southern Italy Cooperative Oncology Group Study.

In a previous phase II randomized study, a cisplatin/gemcitabine/vinorelbine (PGV) regimen produced a 50-week median survival time (MST) in advanced non small-cell lung cancer (NSCLC) patients. The present trial was planned to randomly compare the outcome of patients treated with this new triplet regimen with those of patients receiving either cisplatin plus vinorelbine (PV) or cisplatin plus gemcitabine (PG) doublet combinations. One hundred eighty patients with stage IIIB (76) or IV (104) disease, aged

Mitoxantrone, L-leucovorin and 5-fluorouracil: an effective and well tolerated first-line treatment for advanced breast cancer.

AIMS AND BACKGROUND: The combination of mitoxantrone plus leucovorin/fluorouracil in heavily pretreated patients with advanced breast cancer has shown significant activity and extremely good tolerability. The aim of this study was to evaluate the activity of this combination in patients not previously submitted to chemotherapy. METHODS: From May 1993 to December 1995 we treated 80 patients with advanced breast cancer with a combination of mitoxantrone, l-leucovorin and 5-fluorouracil. All patients had histologically or cytologically proven breast cancer, WHO performance status 0-3, normal hematological parameters and normal serum bilirubin. Prior chemotherapy for metastatic disease was not allowed, whereas adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) or adjuvant anthracycline (doxorubicin or epirubicin) therapy was allowed; a single prior hormone treatment was permitted. Chemotherapy consisted of mitoxantrone 12 mg/m2 i.v. day 1, l-leucovorin 150 mg/m2 i.v. days 1, 2 and 3 and 5-fluorouracil 350 mg/m2 i.v. days 1, 2 and 3. The courses were repeated every 3 weeks. RESULTS: Objective response (CR + PR) was observed in 46/80 (57%) patients (95% CI, 46%-68%). Complete response (CR) was observed in 21/80 cases (26%). Response was observed in 14/24 (58%) patients with soft tissues as the dominant site of disease, in 22/34 (65%) patients with visceral involvement and in 10/22 (45%) of those with bone as the dominant site of disease. The median duration of response and survival was 9 months (range, 3-16) and 22 months (range, 2-48+), respectively. Toxicity was very manageable, with grade 4 leukopenia and thrombocytopenia in 6/80 (7.5%) and 1/80 (1.25%) patients, respectively, and negligible non-hematological toxicity. CONCLUSIONS: The combination of mitoxantrone, 5-fluorouracil and high-dose l-leucovorin is a safe and effective regimen for first-line treatment of advanced breast cancer.

Concurrent modulation of 5-fluorouracil with methotrexate and L-leucovorin: an effective and moderately toxic regimen for the treatment of advanced colorectal carcinoma. A multicenter phase II study of the Southern Italy Cooperative Oncology Group.

AIMS AND BACKGROUND: Methotrexate (MTX) and leucovorin (LV) can enhance the cytotoxicity of 5-fluorouracil (5FU) by modifying its metabolic pathway inside target cells. Some preclinical studies and clinical trials have suggested that the concurrent or sequential double modulation of 5FU by means of MTX and LV may give a higher activity than single biochemical modulations. The purpose of our phase II study was to assess the activity and toxicity of a biweekly regimen including MTX, levo-LV and 5FU in colorectal cancer patients. METHODS: From July 1994 to May 1997, 100 consecutive patients affected by advanced or metastatic colorectal carcinoma were given MTX, 750 mg/m2 iv (2-h infusion) on day 1, and levo-LV, 250 mg/m2 iv (2-h infusion) followed by 5FU, 800 mg/m2 iv bolus on day 2, every two weeks. Patients were treated until complete response or progressive disease was documented, or for a maximum of 16 courses. RESULTS: Among 97 eligible patients, 5 complete and 25 partial responses were obtained, giving an overall response rate of 31% (95% exact confidence limits, 22-41%). Response rate was significantly higher in patients with a good (ECOG scale 0) than with a poor (ECOG scale 1 or 2) performance status (40% versus 17%, P <0.02). Median time to treatment failure was 27 weeks, median survival time was 63 (95% confidence limits, 54-71) weeks, and 2- and 3-year probability of survival were 34% and 12%, respectively. Performance status was the only pretreatment characteristic significantly affecting the outcome of patients. Indeed, median survival time was 94 weeks for patients with a performance status = 0 and 37 weeks for patients with a performance status > or = 1 (P<0.05). Toxicity of the treatment was low and manageable; grade 3 to 4 leukopenia affected 8% of patients, whereas grade 3 diarrhea and mucositis occurred in 5% and 4%, respectively. CONCLUSIONS: The double biochemical modulation of 5FU by MTX and levo-LV is at least as effective as, and probably more effective than, the single modulation by MTX or by LV. It may therefore represent a therapeutic option for the palliative treatment of patients with advanced colorectal carcinoma.

Complete response to chemotherapy in intra-abdominal desmoplastic small round cell carcinoma. A case report.

AIMS AND BACKGROUND: The authors report the case of a 23-year-old woman affected by intra-abdominal desmoplastic small round cell tumor (DSRCT) who obtained a complete response to multiagent chemotherapy. DSRCT is a rare, highly aggressive neoplasm generally arising in young people and seldom in females (about 20 cases described in the literature). METHODS: The patient underwent surgical resection of a large 15 x 15 cm mass located in the right lower abdominal quadrant, but after only 2 months later, two liver metastasis were noted. Thus, she was subjected to an aggressive antineoplastic treatment consisting of three groups of alternating non-cross resistant multiagent regimens administered every 21 days (cis-platin-etoposide-adriamycin-bleomicin; gemcitabine-ifosfamide-dacarbazine; methotrexate-5-fluorouracil-folinic acid) for a total of 9 administrations. RESULTS: After one cycle of treatment including the administration of all the three alternated schemes of chemotherapy, a complete disappearance of liver disease was noted. The treatment was relatively well-tolerated and the toxicity was acceptable. At present, after 15 months from diagnosis and 12 months after starting chemotherapy, the patient is disease-free and in good health. CONCLUSIONS: Even though this study regards only a single patient, it is noteworthy because of the rarity of this neoplasm and because of the infrequent complete responses reported in the literature. The efficacy and manageability of the treatment, suggests that both the timing and schedule used could constitute an important therapeutical option for this aggressive and poorly chemo-responsive tumor.

[Coexistence of renovascular hypertension and pheochromocytoma. Description of 2 clinical cases]. / Coesistenza di ipertensione nefrovascolare e feocromocitoma. Descrizione di due casi clinici.

The two unusual clinical cases described here illustrate the importance of correct application of clinical methodology. Two patients, a 55-year-old man and a 50-year-old woman, presented with severe hypertension due to the coexistence of renal artery stenosis and pheochromocytoma. Their symptoms were indicative of renovascular hypertension which was verified by the finding of extremely elevated plasma renin activity and angiographic detection of critical renal artery stenosis. Further consideration of specific clinical findings led to the suspicion of coexisting pathologies: the detection of elevated plasma catecholamine levels and abdominal computed tomography and iodobenzylguanidine imaging confirmed the presence of pheochromocytoma. The first patient repeatedly refused surgical treatment and died after 9 months; the second patient recovered after undergoing combined nephrectomy and tumor removal. These cases underscore the importance of a carefully planned sequence of studies in patients presenting with uncommon or equivocal clinical manifestations, particularly when conclusive diagnosis is essential to successful treatment.

[Prospective evaluation of the captopril test in diagnosing renal artery stenosis in hypertensive patients]. / Valutazione prospettica del test al captopril nella diagnosi di stenosi di arteria renale in soggetti ipertesi.

In order to verify the utility of the captopril test (CT) in diagnosing renal artery stenosis we performed a prospective study in 94 consecutive patients (40 females, 54 males, mean age 52.4 +/- 12.3 years) suspected of having renovascular hypertension and with a serum level of creatinine < 2 mg/dl. Antihypertensive drugs were withdrawn one week before the CT or, if this was considered unsafe, patients were treated with nifedipine or diltiazem (53 subjects; 56.4%). We used renal angiography and the Muller criteria to interpret the CT. Our results were as follows: sensitivity, 92%; specificity, 96%; positive predictive value, 88%; and negative predictive value, 97%. In our study a simplified criterion for positive CT-postcaptopril plasma renin activity > 10 ng/mL/h-provided a similar diagnostic value. We conclude that the captopril test is a useful screening test for the detection of renal artery stenosis in selected hypertensive patients and that it can also be reliably performed in patients who are taking calcium antagonists.

[Comparison of the efficacy of monotherapy with a beta-blocker, a diuretic, and ACE inhibitors in the control of blood pressure during stress]. / Confronto dell'efficacia delle monoterapie con beta-bloccante, diuretico, ACE-inibitore nel controllo dei valori pressori durante stress.

In order to compare the efficacy of beta-blocking, diuretics and ACE-inhibiting monotherapy in controlling the blood pressure increase to stress, a study was conducted on 30 subjects (10 treated with atenolol, 10 with hydrochlorothiazide/amiloride combination, 10 with enalapril) with mild or moderate essential hypertension whose resting blood pressures were normalised by therapy. In the 3 groups of subjects blood pressure values at rest, during mental stress, static and dynamic exercise did not significantly differ before antihypertensive therapy. Atenolol and enalapril significantly reduced systolic and diastolic pressure below pretreatment values throughout and immediately after each test, differing from diuretic therapy which did not show any significant reduction in diastolic rises at the peak of hand-grip or in both systolic and diastolic pressures at the highest work-loads during dynamic exercise. In the recovery period of the exercise cycle test diuretics also produced a later normalisation of diastolic pressure. In conclusion, beta-blockers and ACE-inhibitors seem to be more effective than diuretics in the control of the blood pressure response to stress in hypertensive patients, suggesting that these drugs are the first choice treatment of mild to moderate hypertension.