A phase II study on the efficacy and safety of procedural analgesia with fentanyl buccal tablet in cancer patients for the placement of indwelling central venous access systems.

BACKGROUND: Pain in cancer patients is often related to oncologic therapies and diagnostic procedures. The placement of fully implantable venous access systems is a very common procedure in oncology patients. Local anaesthesia is the method most commonly used to overcome pain related to this surgical procedure, but the local anaesthetic may be unable to completely eradicate all pain. This study investigates the effectiveness and safety of fentanyl buccal tablet (FBT), administered by OraVescent® technology, in reducing procedural pain related to the placement of indwelling central venous access systems (Ports) in opioid-naïve cancer patients. METHODS: Inpatients who required an indwelling vascular access (Port) were preoperatively assessed with a self-assessment questionnaire on anxiety and pain. A 100 µg FBT was administered 10 min before preparation of the operating field. A self-assessment scale for pain experienced during the procedure was administered at the end of the procedure. Vital signs and the presence of any side effects or bothersome symptoms were monitored during the procedure, at the end, and 4 h later. RESULTS: From October 2012 to June 2014, 65 patients were enrolled in the study. A total of 61 (93.9 %) patients perceived no or a little pain during the procedure. Four patients (6.2 %) reported a lot of pain. No patient reported very severe pain. This data is significant in terms of the lower than expected presence of pain (Fisher test p = 0.0018) as assessed in our previous experience without procedural analgesia. The most common side effects of FBT was drowsiness, experienced by 28 patients at the end of the procedure (43.1 %), significantly reduced (p < 0.01) to 8 patients after 4 h (12.5 %). Nausea was present in 6 cases at the end of the procedure (9.2 %) and in 7 cases 4 h later (10.9 %). Vomiting was present in 3 cases at the end (4.7 %) and in 2 other patients after 4 h (7.8 %). No significant change of vital parameters was observed between the baseline and the subsequent measurements in all patients studied. CONCLUSIONS: The significant improvement in the number of patients experiencing little or no pain, accompanied by a lower number of non-severe side effects, suggests that FBT is a valid, practical and safe method of procedural analgesia. It will be necessary to perform further studies, taking into account the need for standard antiemetic pre-medication to minimise the incidence of nausea and vomiting.

Early and short-term acenocumarine or dalteparin for the prevention of central vein catheter-related thrombosis in cancer patients: a randomized controlled study based on serial venographies.

BACKGROUND: We evaluated efficacy and safety of early and short-term prophylaxis with acenocumarine or dalteparin in the prevention of non-occlusive or occlusive central vein catheter-related thrombosis (CVCrT). PATIENTS AND METHODS: Consecutive cancer patients scheduled for chemotherapy randomly received: acenocumarine 1 mg/day for 3 days before and 8 days after central vein catheter (CVC) insertion; dalteparin 5000 IU 2 h before and daily for 8 days after CVC insertion; no anticoagulant treatment (NT). All patients underwent venography on days 8 and 30, some of them on days 90, 150 and 210 after CVC. RESULTS: A total of 450 patients were randomized, 348 underwent at least two venography. Both acenocumarine and dalteparin reduced venography-detected CVCrT rate [21.9% acenocumarine versus 52.6% NT, odds ratio (OR) 0.3, P < 0.01; 40% dalteparin versus 52.6% NT, OR 0.6, P = 0.05]. Acenocumarine was more effective than dalteparin (OR 0.4, P = 0.01). The rate of occlusive CVCrT was not different in the three groups (0.9% acenocumarine, 3.3% dalteparin, 1.8% NT; P = 0.40). Most CVCrTs (95.6%) were observed on day 8 after CVC insertion and were non-occlusive. CONCLUSIONS: In this study of early and short-term prophylaxis, acenocumarine was more effective than dalteparin on non-occlusive and asymptomatic CVCrT events. The first days following CVC insertion represent the highest risk for CVCrT.

Celiac plexus block: injectate spread and pain relief in patients with regional anatomic distortions.

BACKGROUND: The success of the neurolytic celiac plexus block, despite different approaches and methods used, depends on adequate spread of the injectate in the celiac area. This retrospective study was conducted to evaluate the patterns of alcohol spread and pain relief in patients with cancer or therapy-related anatomic distortion of the celiac area. METHODS: From 177 cancer patients who underwent computed tomography (CT)-guided single-needle neurolytic celiac plexus block via an anterior approach, a radiologist, blind to the aim of the study, retrospectively selected 105 patients with abnormal anatomy of the celiac area as judged by CT images obtained before the block. To evaluate CT patterns of neurolytic (mixed with contrast) spread, the celiac area was divided on the frontal plane into four quadrants: upper right and left and lower right and left, as related to the celiac artery. Results were expressed as the number of quadrants into which contrast spread, ie., four, three, two, or one quadrants with contrast. The patterns of contrast spread according to the number of quadrants with anatomic distortion were analyzed. Patient assessment by visual analog scale was reviewed to evaluate the degree of pain relief. Pain relief 30 days after block was considered long-lasting. Pain relief at 30 days after block was analyzed according to the number of quadrants with contrast. RESULTS: Overall, four, three, two, and one quadrants with contrast were observed in 9 (8%), 21 (20%), 49 (47%), and 26 (25%) patients, respectively. An inverse correlation was observed between the number of quadrants with anatomic distortion and the number of quadrants with contrast (P < 0.001). Long-lasting pain relief was noticed in nine of nine patients (100%; 95% confidence interval, 66-100) with contrast in four-quadrants, and in 10 of 21 patients (48%; 95% confidence interval, 26-70) with contrast in 3 quadrants (P < 0.01). None of the 75 patients with contrast in two quadrants or one quadrant experienced long-lasting pain relief. CONCLUSIONS: These findings suggest that, using the single-needle anterior approach, the neurolytic spread in the celiac area is highly hampered by the regional anatomic alterations. It also appears that only a complete (four quadrants) neurolytic spread in the celiac area can guarantee long-lasting analgesia, and that this picture may be obtained in a very limited fraction of patients with regional anatomic alterations.

Continuous infusion fluorouracil in the management of advanced breast cancer: a phase II study.

AIMS AND BACKGROUND: The evaluation of unconventional schedules of well-known drugs represents a promising avenue in the search for new regimens with a better therapeutic index in metastatic breast cancer. In particular, protracted continuous infusion (PCI) of 5-fluorouracil (5-FU) has yielded interesting results in gastrointestinal malignancies and in breast cancer. METHODS: From March 1996 30 consecutive patients with heavily pretreated breast cancer were treated with PCI 5-FU at a daily dose of 250 mg/m2 by means of disposable elastomeric pumps until progression or toxicity. The median age was 54 years (range, 28-71) and median performance status was 1 (range, 0-3). All patients but four were pretreated with anthracycline-containing regimens or taxanes; the median number of chemotherapy lines was 3 (range, 2-4). Metastatic sites were predominantly visceral in 60% of the patient population. RESULTS: All 30 patients were evaluable for response and toxicity. The median duration of PCI was 20 weeks (range, 2-36 weeks). Two complete responses (7%) and eight partial remissions (26%) were observed, giving an overall response rate of 33%. The median duration of response was six months (range, 4-9 months). Stabilization was observed in seven patients (23%) with a median duration of seven months (range, 3-9 months). The main toxic effects were grade I-II mucositis and hematologic toxicity, while grade 3 hand-foot syndrome was observed in eight patients (27%). CONCLUSIONS: This study confirms the efficacy and safety of 5-FU at this dosage and schedule in heavily pretreated women with advanced breast cancer. In order to improve on these results further studies are needed in a less advanced stage of the disease and together with other active drugs.

Different patterns of postoperative bleeding following cytoreductive surgery for gynecological cancer.

PURPOSE OF INVESTIGATION: To study the possible causes of postoperative bleeding following maximal cytoreductive surgery for gynecological cancers. METHOD: We have retrospectively reviewed all our cases of postoperative bleeding following major abdominal and pelvic cytoreductive surgery within a 48-hour period. In the postoperative period, replacement therapy was ineffective in achieving hemodynamic stability. During re-operation, the entire abdominal cavity was evaluated for bleeding sites that were adequately ligated or electrocoagulated. RESULTS: Of 942 women undergoing major cytoreductive surgery 22 women (2.3%) were re-operated for postoperative bleeding after a mean of 14.2 hours. Bleeding was either localized from a vessel in 9 women (40.9%) or diffuse (capillary oozing) in 13 women (59.1). Operative deaths have been as high as 36.8%. CONCLUSION: Postoperative bleeding following cytoreductive surgery can be from a single group of vessels or a capillary oozing from the edges or denuded areas of excised peritoneum.

Pharmacokinetic and pharmacodynamic effects of high-dose continuous intravenous verapamil infusion: clinical experience in the intensive care unit.

OBJECTIVE: Our study aimed at evaluating the pharmacokinetic, cardiovascular, and metabolic effects of high-dose verapamil continuous intravenous infusion in cancer patients. DESIGN: Prospective clinical and pharmacokinetic study. SETTING: Intensive care unit of a Cancer Research Institute. PATIENTS: Nine patients (age range 31 to 57 yrs) with progressive cancer disease and without cardiovascular, renal, or hepatic dysfunctions. INTERVENTIONS: After a loading dose (0.15 mg/kg followed by 12 hrs of continuous intravenous infusion at 0.20 mg/kg/hr), the infusion rate of verapamil was increased every 24 hrs (0.25, 0.30, 0.35, and 0.40 mg/kg/hr). The highest rate was maintained for 48 hrs. Doxorubicin was given from the 60 th to the 108 th hr. Hydrochlorothiazide (25 mg/day) and potassium (36 mmol/day) were given orally. Altogether, 17 courses were completed. MEASUREMENTS AND MAIN RESULTS: Steady state concentration (C(SS) and systemic clearance of verapamil and nor-verapamil (active metabolite) for each infusion rate were calculated. Mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), PR, QT and QTc intervals, and left ventricular ejection fraction (LVEF) were measured, as well as daily body weight, blood glucose and potassium. C(SS) of verapamil and nor-verapamil increased more than proportionally to the infusion rate (p<.001). Systemic clearance of verapamil decreased over the range of the infusion rate (p<.005). MAP and HR decreased at the 12th hr (p<.001) and then plateaued. CVP increased (p<.01). The relationship between MAP, HR, CVP, and verapamil plasma concentrations was significant (r2 = .25, .14, and .35, respectively; p<.0001). LVEF did not change. Six patients (11 courses) developed junctional rhythm. Three patients (six courses) showed a PR interval increase (p<.05). Patients with junctional rhythm had higher Css of verapamil (p<.009). Overall, QT and QTc intervals increased (p<.01). A linear relationship was observed between verapamil plasma concentrations and QT intervals (r2 = .09, p<.01). Cardiovascular side effects did not determine treatment withdrawal in any patient. Body weight, blood glucose, and potassium did not show significant changes. CONCLUSIONS: Our data suggest a capacity-limited clearance of high-dose verapamil. In the absence of heart disease, following a step by step increase of the dosage, the high plasma verapamil concentrations (617 to 2970 ng/mL) produce frequent but well tolerated hemodynamic and electrocardiogram changes.

Non-linear pharmacokinetics of high-dose intravenous verapamil.

AIMS: In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil. METHODS: We studied nine patients [seven males, two females; median age 46 years (range, 31-57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg-1 followed by 12 h continuous i.v. infusion at 0.20 mg kg-1 h-1), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg-1 h-1). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n = 4) or 60 to 108 h (n = 5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL = ko/Css) and renal clearance (CLr) of verapamil and nor-verapamil. The Css vs rate relationship was fitted to a Michaelis-Menten equation: Css = ko. (K(m)+Css)/(V.Vm). RESULTS: CL was dose-dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL +/- s.d. were 0.51 +/- 0.31, 0.38 +/- 0.16, 0.32 +/- 0.18, and 0.27 +/- 0.11 l h-1 kg-1, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg-1 h-1; P = 0.0001). Css increased more than proportionally to the dose rate and the Css vs rate relationship was best defined by a Michaelis-Menten equation (K(m) = 730 micrograms l-1; V.Vm = 0.55 mg kg-1 h-1), (r = 0.994; P = 0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose. CONCLUSIONS: These findings suggest a non-linear, capacity-limited metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500-2500 ng ml-1) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.

Cytoplasmic free Ca2+ in Arabidopsis roots changes in response to touch but not gravity.

Changes in cytoplasmic Ca2+ concentration ([Ca2+]i) have been proposed to be involved in signal transduction pathways in response to a number of stimuli, including gravity and touch. The current hypothesis proposes that the development of gravitropic bending is correlated with a redistribution of [Ca2+]i in gravistimulated roots. However, no study has demonstrated clearly the development of an asymmetry of this ion during root curvature. We tested this hypothesis by quantifying the temporal and spatial changes in [Ca2+]i in roots of living Arabidopsis seedlings using ultraviolet-confocal Ca(2+)-ratio imaging and vertical stage fluorescence microscopy to visualize root [Ca2+]i. We observed no changes in [Ca2+]i associated with the graviresponse whether monitored at the whole organ level or in individual cells in different regions of the root for up to 12 h after gravistimulation. However, touch stimulation led to transient increases in [Ca2+]i in all cell types monitored. The increases induced in the cap cells were larger and longer-lived than in cells in the meristematic or elongation zone. One millimolar La3+ and 100 microM verapamil did not prevent these responses, whereas 5 mM EGTA or 50 microM ruthenium red inhibited the transients, indicating an intracellular origin of the Ca2+ increase. These results suggest that although touch responses of roots may be mediated through a Ca(2+)-dependent pathway, the gravitropic response is not associated with detectable changes in [Ca2+]i.

Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter. A prospective study.

Studies on catheter-related central venous thrombosis (CRCVT) have been focused mainly on clinically evident CRCVT due to occlusive thrombi, underestimating therefore the actual thrombosis prevalence. This prospective study was aimed at evaluating prevalence, timing and evolution of thrombosis, and identifying involved veins and risk factors in cancer patients (pts) undergoing percutaneous subclavian central venous catheterization (CVC) for chemotherapy, parenteral nutrition or both. We enrolled 127 consecutive pts requiring partially or totally implanted central venous silastic catheters. The study protocol included peripheral phlebography (P) at day 8, 30 and every two months following CVC and/or when clinically indicated, along with peripheral and pullout P on catheter withdrawal. A quantitative scale was developed to evaluate thrombus grading in subclavian, innominate and cava veins. Age, sex, coagulation profile tumor histotype, metastases, therapy, catheter type, and catheter insertion side were also investigated. Only pts who underwent at least two P were evaluated, and chi 2 test was adopted for statistical analysis. Altogether, 95 pts were evaluable. CRCVT was observed in 63/95 (66%) pts. At day 8, 30 and 105 (representing the median days in which first, second and last P were performed) CRCVT was evidenced in 64%, 65% and 66% of the pts, respectively. Thrombus grading did not differ among first, second and last P. CRCVT was symptomatic in 4/63 (6%) pts. Thrombosis prevalence was higher in subclavian (97%) with respect to innominate (60%) or cava (13%) veins (p < 0.001). Thrombosis was higher in left subclavian catheters (14/16; 87.5%) than in right ones (49/79; 62%), p < 0.01. No associations were established between CRCVT and other investigated parameters. Our data show a very high actual frequency of CRCVT in cancer pts, and emphasize that first days following CVC are at the highest risk for CRCVT development. Based on our results, a study on short-term antithrombotic prophylaxis in cancer pts requiring CVC is warranted. Finally, our data indicate that left subclavian vein catheterization represents a risk factor for CRCVT.

Time-dependent efficacy of bacterial filters and infection risk in long-term epidural catheterization.

BACKGROUND: Epidural infection represents a serious albeit infrequent complication of long-term epidural catheterization. The catheter hub is regarded as the main point of entry for microorganisms among the three possible routes (hematogenous, insertion site, hub) of microbial colonization of the inserted catheter. The current study was aimed at evaluating whether frequent changing of antimicrobial filters carries an increased risk of catheter hub contamination and the time-dependent efficacy of commonly used antimicrobial filters after prolonged use. METHODS: In the first part of the study, a microbiologic survey (skin, filter, hub, and catheter tip) was performed weekly in a group of 47 patients with cancer bearing subcutaneously tunneled catheters managed at home. Subsequently, the time-dependent efficacy of 96 micropore filters (32 Portex, 32 Sterifix-Braun, 32 Encapsulon TFX-Medical) differing in surface areas and/or composition of the filtering membrane was evaluated in a laboratory study. Filters were perfused, under the usual conditions of clinical use (flow resistance, injection pressure, temperature), every 8 h up to 60 days, with 5 ml of two different analgesic solutions, either sterile or containing 1.5 x 10(5)/ml of Streptococcus milleri I. Eight filters of each type subsequently were flushed with a S. milleri suspension (0.5 McFarland) after 7, 14, 28, and 60 days of continuous perfusion, and the resulting filtrates were cultured. RESULTS: In 16 of 19 positive hub cultures, the same microorganisms (species, biotype, antibiotype) were cultured from skin and filters. A statistically significant positive trend was found between the number of filter changes and the rate of positive hub cultures (chi 1(2) trend 5.11; P = 0.02). A high correlation coefficient was found between number of positive skin cultures and number of positive filtrates (r = 0.88; P = 0.01) and between number of positive filtrates and number of positive hub cultures (r = 0.93; P = 0.003). Cultures obtained from Portex and Sterifix-Braun filters yielded no bacterial growth (64/64) throughout the study period. Cultures from Encapsulon TFX-Medical filters showed bacterial growth 2/8 at seventh day, 7/8 at the 14th day, and 16/16 from the 28th day onward. CONCLUSIONS: Our data indicate significant correlation between the incidence of catheter hub colonization and the filter-change frequency, when the skin close to the filter-hub connection is contaminated. Our results also show that Portex and Sterifix-Braun bacterial filters, when perfused with reduced volumes at low injection pressures, maintain an unmodified antimicrobial function for at least 60 days. Based on these data, it appears clinically feasible to reduce the frequency of filter changes during long-term epidural catheterization, with a consequent possible decrease of epidural catheter colonization.

Parenteral nutrition in cancer patients receiving chemotherapy: effects on toxicity and nutritional status.

The role of total parenteral nutrition (TPN) in reducing toxicity related to cancer chemotherapy (CT) is presently a controversial issue. To evaluate the effectiveness of TPN in reducing CT-associated toxicity and correcting and preventing CT-related impairments of nutritional status, a prospective crossover controlled study was performed in 43 cancer patients (19 normally nourished and 24 malnourished) randomly divided into two groups (A and B). Group A patients received TPN concomitantly with the first course of chemotherapy, and the second course was administered 21 to 28 days later without TPN support; group B patients were treated in the opposite sequence. The rates of myelotoxicities and gastrointestinal toxicities after CT courses with or without TPN were essentially similar in normally nourished and malnourished patients. No changes in nutritional indexes were detected in normally nourished subjects after each course. Conversely, in undernourished subjects, prealbumin, retinol-binding protein, and nitrogen balance increased in CT+TPN courses (p < .02). In CT-only courses, undernourished subjects showed a decrease in prealbumin and nitrogen balance. Significant changes of nitrogen balance in CT vs CT+TPN courses were detected in malnourished subjects. TPN appears to be unable to reduce CT-associated toxicity. CT administration does not result in any impairment of the nutritional status in normally nourished cancer patients. From our study, it appears that TPN should be limited to severely malnourished neoplastic patients undergoing CT, because of its ability to prevent further impairment of nutritional status and to improve the nitrogen balance and the levels of fast-turnover visceral proteins.

Role of phospholipid fatty acids on the kinetics of high and low affinity sites of cytochrome c oxidase.

The nature of the interactions between cytochrome c oxidase and the phospholipids in mitochondrial membranes has been investigated by varying the nature of the fatty acyl components of Saccharomyces cerevisiae. A double fatty acid yeast mutant, FAI-4C, grown in combinations of unsaturated (oleic, linoleic, linolenic, and eicosenoic) and saturated (lauric and palmitic) fatty acids, was employed to modify mitochondrial membranes. The supplemented fatty acids constituted a unique combination of different acyl chain lengths with varying degrees of unsaturation which were subsequently incorporated into mitochondrial phospholipids. Phosphatidylethanolamine and cardiolipin, the predominant phospholipids of the inner mitochondrial membrane, were characterized by their high levels of supplemented unsaturated fatty acids. Increasing the chain length or the degree of unsaturation of mitochondrial membrane phospholipids had no effect on altering the nature of the phospholipid polar head group but did result in a profound change on the specific activity of cytochrome c oxidase. When studied under conditions of different ionic strengths and pHs the enzyme's activity, as documented by Eadie-Hofstee plots, showed biphasic kinetics. The kinetic parameters for the low affinity reaction were greatly influenced by the changes in the membrane fatty acids and only marginal effects were noted at the high affinity reaction site. The discontinuities in the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene, monitored at increasing temperatures, suggested that changes in membrane fluidity were conditioned by alterations in mitochondrial membrane fatty acid constituents. These results indicate that the lipid changes affecting the low affinity binding site of cytochrome c oxidase may be the result of lipid-protein interactions which lead to enzyme conformational changes or may be due to gross changes in membrane fluidity. It may, therefore, follow that this enzyme site may be embedded in or be juxtaposed to the outer surface of the inner mitochondrial membrane bilayer in contrast to the high affinity site which has been shown to be significantly above the membrane plane.

Saccharomyces cerevisiae as a model eukaryote for studies on mitochondriogenesis.

A great deal of progress has been made in elucidating the underlying mechanisms which control the interplay between the nuclear and mitochondrial genomes during biogenesis of mitochondria. The advantage of using the yeast Saccharomyces cerevisiae in these studies over other eukaryotic cells will be discussed.