Cancer survivors' needs during various treatment phases after multimodal treatment for colon cancer - is there a role for eHealth?

BACKGROUND: More colon cancer patients are expected to fully recover after treatment due to earlier detection of cancer and improvements in general health- and cancer care. The objective of this study was to gather participants' experiences with full recovery in the different treatment phases of multimodal treatment and to identify their needs during these phases. The second aim was to propose and evaluate possible solutions for unmet needs by the introduction of eHealth. METHODS: A qualitative study based on two focus group discussions with 22 participants was performed. The validated Supportive Care Needs Survey and the Cancer Treatment Survey were used to form the topic list. The verbatim transcripts were analyzed with Atlas.ti. 7th version comprising open, axial and selective coding. The guidelines of the consolidated criteria for reporting qualitative research (COREQ) were used. RESULTS: Experiences with the treatment for colon cancer were in general positive. Most important unmet needs were 'receiving information about the total duration of side effects', 'receiving information about the minimum amount of chemo needed to overall survival' and 'receiving a longer aftercare period (with additional attention for psychological guidance)'. More provision of information online, a chat function with the oncological nurse specialist via a website, and access to scientific articles regarding the optimal dose of chemotherapy were often mentioned as worthwhile additions to the current health care for colon cancer. CONCLUSIONS: Many of the unmet needs of colon cancer survivors occur during the adjuvant treatment phase and thereafter. To further optimize recovery and cancer care, it is necessary to have more focus on these unmet needs. More attention for identifying patients' problems and side-effects during chemotherapy; and identifying patients' supportive care needs after finishing chemotherapy are necessary. For some of these needs, eHealth in the form of blended care will be a possible solution.

Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours.

Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.

Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered continuously via the oral route. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with R115777 using an interpatient dose escalation scheme starting at 50 mg bid. Pharmacokinetics were assessed on days 1, 28, and 56. RESULTS: Twenty-eight patients were entered onto the study and the median duration of treatment was 55 days. The dose-limiting toxicities were myelosuppression and neurotoxicity. At a dose of 400 mg bid, grade 4 leukocytopenia and neutropenia were seen in two of four patients. Neurotoxicity grade 3 developed in one of five patients at 500 mg bid and in one of 13 at 300 mg bid after 8 weeks of treatment. Common nonhematologic toxicities were nausea, vomiting, and fatigue. The recommended dose for phase II/III testing in this scheme is 300 mg bid. The pharmacokinetic studies indicated dose proportionality. Little accumulation occurred and steady-state levels were reached within 2 to 3 days. Analyses of historic tumor material showed that five of 15 of patients had a K-ras mutation in codon 12. Three patients with pancreatic, colon, and cervix carcinomas had stable disease and one patient with a colon carcinoma had a minor response accompanied by a more than 50% decrease in carcinoembryonic antigen tumor marker. A fifth patient, with platinum-refractory non-small-cell lung cancer, showed a partial response that lasted for 5 months. CONCLUSION: Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.

Evaluation of the bioequivalence of tablets and capsules containing the novel anticancer agent R115777 (Zarnestra) in patients with advanced solid tumors.

R115777 (Zamestra) is a novel anticancer agent, currently undergoing phase III clinical testing. An open, cross-over trial was performed in 24 patients with solid tumors to compare the bioavailability of a new tablet formulation with the standard capsule formulation. Both dosage forms were administered once daily in doses of 300 or 400 mg. Patients received R115777 as a capsule on day I and as a tablet on day 2, or vice versa. Blood samples were drawn up to 24 hours after drug intake and R115777 levels were measured using a validated high performance liquid chromatography (HPLC) method. The following pharmacokinetic parameters were determined and compared for the two formulations: time to maximal plasma concentration (Tmax), half-life (t 1/2), maximal plasma concentration (Cmax) and area under the curve at twenty-four hours (AUC24h). For the latter two parameters, 90% classical confidence intervals of the ratio tablet/capsule were calculated after a log-transformation, using an Analysis of Variance (ANOVA). For t 1/2 and Tmax, no statistically significant differences were found between tablet and capsule. The point estimates of the ratio's of the log-normalized Cmax and AUC24h were 0.94 and 0.92, respectively, and the 90% confidence intervals were 0.81-1.09 and 0.83-1.03, which is within the critical range for bioequivalence of 0.80-1.25. In conclusion, the established pharmacokinetic parameters demonstrate that the capsule and tablet formulations of R115777 are interchangeable.

Ras biochemistry and farnesyl transferase inhibitors: a literature survey.

Over the last decades, knowledge on the genetic defects involved in tumor formation and growth has increased rapidly. This has launched the development of novel anticancer agents, interfering with the proteins encoded by the identified mutated genes. One gene of particular interest is ras, which is found mutated at high frequency in a number of malignancies. The Ras protein is involved in signal transduction: it passes on stimuli from extracellular factors to the cell nucleus, thereby changing the expression of a number of growth regulating genes. Mutated Ras proteins remain longer in their active form than normal Ras proteins, resulting in an overstimulation of the proliferative pathway. In order to function, Ras proteins must undergo a series of post-translational modifications, the most important of which is farnesylation. Inhibition of Ras can be accomplished through inhibition of farnesyl transferase, the enzyme responsible for this modification. With this aim, a number of agents, designated farnesyl transferase inhibitors (FTIs), have been developed that possess antineoplastic activity. Several of them have recently entered clinical trials. Even though clinical testing is still at an early stage, antitumor activity has been observed. At the same time, knowledge on the biochemical mechanisms through which these drugs exert their activity is expanding. Apart from Ras, they also target other cellular proteins that require farnesylation to become activated, e.g. RhoB. Inhibition of the farnesylation of RhoB results in growth blockade of the exposed tumor cells as well as an increase in the rate of apoptosis. In conclusion, FTIs present a promising class of anticancer agents, acting through biochemical modulation of the tumor cells.

A randomised, multicentre study of ceftriaxone versus standard therapy in the treatment of lower respiratory tract infections.

In this study the efficacy and cost-effectiveness of i.v. ceftriaxone 1 g once daily (CTX) was compared with standard i.v. antibiotic treatment (STD) for lower respiratory tract infections (LRTI). STD was given according to the guidelines of the American Thoracic Society and consisted of either cefuroxime 1500 mg three times daily (q8h), amoxicillin/clavulanic acid 1200 mg q8h or ceftriaxone 2 g once daily; each with or without a macrolide. After a minimum of 5 days i.v. therapy, patients could be switched to oral therapy. One hundred patients were enrolled in the study; 52 patients received CTX and 48 STD. Groups were comparable with respect to demographic and baseline characteristics. Seventy patients had a confirmed diagnosis of pneumonia. Twenty-nine patients had a severe type I exacerbation of chronic bronchitis. In one patient the diagnosis of LRTI could not be confirmed. In approximately 50% of the patients a microbiological diagnosis could be made. The most important isolated pathogens from sputum and blood were (positive blood cultures in brackets): Streptococcus pneumoniae 14 (9) and Haemophilus influenzae 16. Mean duration of i.v. therapy was 7.4 days in both groups. Average duration of hospitalisation was 15.0 days for CTX patients and 15.9 days for STD patients. Overall cure and improvement rate at the end of treatment was 47 (90%) for patients receiving ceftriaxone 1 g compared to 37 (77%) for patients receiving standard therapy. Pathogens were eradicated or presumed to be eradicated in 84% of the CTX patients and in 76% of the STD patients. Mean total costs per treatment were lower for CTX than for STD treatment: NLG 169 versus 458. These results show, that i.v. ceftriaxone 1 g once daily is as effective as standard therapy in the treatment of LRTI and that its use reduces treatment costs, in view of the multiple daily dosing regimens of most standard therapies.

Amylolytic activity in germinated Agrostemma githago L. seeds.

The perisperm of seeds of Agrostemma githago contains starch reserves which constitute 40% of the dry weight of the mature seed. These starch reserves were mostly broken down between 48 and 96 h after initiation of imbibition. (Germination occurred after 24 h.) The mode of starch degradation showed close parallels with the breakdown of the starchy endosperm in cereals. Thus, between 24 and 96 h the cotyledons secreted α-amylase (EC 3.2.1.1) whereas other degradative enzymes in the perisperm, ß-amylase (EC 3.2.1.2) and maltase (EC 3.2.1.20), appeared to originate in the perisperm itself. Cotyledons secreted similar levels of α-amylase in the presence and absence of exogenous starch, indicating that secretion is an internal developmental event of the embryo. By isoelectric focussing the secreted α-amylase was separated into two isoenzymes. In the cotyledons, several other starch-degrading isoenzymes were present but were not secreted.

Assembly of Agrostemma githago (corn-cockle) storage proteins and their precursor proteins into oligomers.

The major fraction of seed storage proteins of Agrostemma githago (corn-cockle), a non-leguminous dicot, occurs as material with S20,w values of approximately 11S and approximately 2S, and a minor fraction as oligomers with S20,w values of approximately 6.5S. The 11S proteins are of the legumin type and consist of disulphide-linked alpha- and beta-subunits of Mr approximately 39 000 and approximately 23 000 respectively. The oligomeric assembly of the precursor polypeptides of the 11S proteins was examined. The approximately 65 000-Mr precursor polypeptides of two 11S proteins, which consist of 38 000-25 000-Mr subunits and 36 000-22 000-Mr subunits respectively, were assembled into oligomers of approximately 7S and subsequently cleaved. Thereafter the 11S oligomer was formed. The 88 000-Mr precursor of a third 11S protein, which consists of 41 000-23 000-Mr subunits, was assembled into an approximately 8S oligomer and then cleaved, yielding two disulphide-linked intermediates of Mr 59 000 and 24 000. Thereafter, the 11S oligomer was formed. Processing of the 59 000-Mr to the 41 000-Mr polypeptide occurred both in the 8S and in the 11S form.

Protein Synthesis in Embryos of Dormant and Germinating Agrostemma githago L. seeds.

The time course of protein synthesis in embryos of dormant and afterripened Agrostemma githago seeds was studied. In embryos of afterripened geminating seeds, protein synthesis increased in three successive stages: (a) concurrent with swelling; (b) during the lag phase between the completion of water uptake and the onset of growth; and (c) immediately after protrusion through the seed coat. Embryos of dormant seeds showed the first increase but not the second unless dormancy was broken by imbibition at 4 degrees C. This indicates that dormancy affects processes prior to the onset of growth. The third increase was largely due to higher oxygen availability after the rupture of the seed coat and not to actual growth. It could also be elicited in dormant embryos by isolating them from the seeds.Electrophoretic analysis of the newly synthesized proteins demonstrated that the patterns of dormant and afterripened embryos became significantly different in both axes and cotyledons only just prior to the onset of axis elongation. Thereafter, the differences became larger.When afterripened or dormant seeds were transferred from a low, germination-permitting to a high, germination-inhibiting temperature, the seeds germinated at the high temperature if they had completed the lag phase to a sufficient extent at the low temperature. This shows that the processes during the lag phase were inhibited by the high temperature while the onset of growth was not affected.

Biosynthesis of Storage Proteins in Ripening Agrostemma githago L. Seeds.

The synthesis of storage proteins in ripening Agrostemma githago seeds was studied by in vivo pulse and pulse-chase experiments with labeled amino acids and labeled glucosamine. It was found that storage proteins were not synthesized directly, but via cleavage of several large precursor proteins. Two disulfide-linked proteins of 38 and 25 kilodaltons were synthesized via a single large precursor protein. This precursor protein contained internal disulfide bridges, at least one of which is involved in holding the subunit structure together following cleavage of the precursor. A similar mode of biosynthesis was noted for two other disulfide-linked proteins of 36 and 22 kilodaltons. The half-life of the precursors was about 2 hours. This mode of processing is analogous to the synthesis of legumin in legumes and globulin in oats. A third pair of disulfide-bonded proteins (41 and 23 kilodaltons) was synthesized from a precursor protein in several steps. These included a legumin-like cleavage, whereafter the subunits remained disulfide-bonded. Then, from the largest subunit, a part was cleaved off, probably a storage protein of 17 kilodaltons. This 17-kilodalton protein was not disulfide-bonded to the 41 and 23-kilodalton complex. The first processing step was fast, the second slow: The half-lives of the precursors were about 3 and 10 hours, respectively. Finally, a group of 16- and 17-kilodalton proteins was synthesized by cleavage of large precursor proteins, likely in two steps. After cleavage, the proteins were not disulfide-bonded. The half-life of the precursors was short, less than 1 hour. In addition, for the 38-, 23-, and one of the 17-kilodalton proteins, a small decrease of relative molecular weight was observed as a last processing step. This was likely due to deglycosylation.

Increase of protein synthesis after isolation in dormant and afterripened Agrostemma githago L. embryos.

Isolated embryos are more suitable for in vivo study of protein synthesis than non-isolated embryos because, after isolation, the uptake of labeled amino acids is about 1000 times higher. However, isolation also stimulates protein synthesis: Up to 4 h after isolation, the capacity to incorporate labeled amino acids increased 7 times. Therefore, data on incorporation obtained with isolated embryos cannot be extended to non-isolated embryos. The increase of protein synthesis was not due to synthesis of specific proteins, but was a general increase. Furthermore, ripening, dormant, and afterripened embryos showed the same degree of increase. Isolation therefore stimulates protein synthesis nonspecifically. When embryos were kept under anaerobic conditions after isolation, protein synthesis did not increase. Therefore, higher oxygen consumption after removal of the seedcoat is probably the cause of the higher incorporation capacity. Furthermore, the activation of protein synthesis lagged several hours behind the increase of oxygen consumption.

The metabolism of applied gibberellic acid in Pharbitis nil choisy: tentative identification of its sole metabolite as gibberellic acid glucoside and some of its properties.

Radioactive gibberellic acid ([(14)C]GA3) applied to seedlings of Pharbitis nil strain Violet is converted to one single metabolite (R-[(14)C]GA3), which has been tentatively identified as GA3-glucoside. As with authentic GA3-glucoside, R-[(14)C]GA3 can be hydrolysed to some extent with cellulase and ß-glucuronidase, but hardly at all with ß-glucosidase. Acid hydrolysis, which is more effective than enzymatic hydrolysis, yielded GA3 as well as a biological inactive compound. The latter represents a degradation product of GA3 due to the sensitivity of GA3 to acidic conditions.The R-[(14)C]GA3, like authentic GA3-glucoside, possesses little or no biological activity. R-[(14)C]GA3 applied to developing seeds is partly hydrolysed during imbibition of the mature seed but is, however, reconverted to R-[(14)C]GA3 during subsequent germination. Applied R-[(14)C]GA3 is strongly accumulated in the cotyledons of Pharbitis seedlings, to a greater extent than [(14)C]GA3. However, unlike [(14)C]GA3 it is not accumulated in the apical regions of the hypocotyl. Furthermore no competition was observed between R-[(14)C]GA3 and [(14)C]GA3, which suggests that they do not compete for the same sites.