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A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group.

The present randomized, prospective study was designed to assess whether alternating induction cyclophosphamide, doxorubicin, vincristine-altretamine (hexamethylmelamine), etoposide, and methotrexate (CAV-HEM) chemotherapy is better than standard chemotherapy (CAV) in improving response, survival, and remission time in 577 evaluable patients having extensive-disease small-cell lung cancer (SCLC). In addition, the study was designed to assess the impact of maintenance chemotherapy following a complete response (CR) on the time to progression and survival. The response rates (CR plus partial response [PR]) for CAV-HEM and CAV were 64% and 61%, respectively, but 23% of the patients on CAV-HEM achieved a CR compared with 16% for CAV alone (P = .03). Among complete responders, the continuation of therapy significantly increased the remission time for patients on CAV, while maintenance therapy for patients on CAV-HEM had no significant impact on remission time. However, the increased remission had little effect on survival. Patients on CAV maintenance therapy survived marginally longer than those patients on no maintenance therapy, whereas patients who received CAV-HEM and no maintenance therapy survived longer than those on maintenance therapy. CAV-HEM was associated with significantly higher severity of complications (ie, mainly myelosuppression) than CAV (P = .01). Maintenance chemotherapy was associated with significantly more complications than no maintenance therapy. Patients on CAV-HEM lived significantly longer than those on CAV alone (45.9 weeks v 42.7 weeks; P = .002). Ten percent of patients treated on CAV-HEM survived at least 2 years, compared with 4% on CAV alone. In our study involving patients with extensive-disease SCLC, the alternating induction chemotherapy significantly increased the CR rates and had a small impact on long-term survival compared with the results achieved with standard induction chemotherapy. Moreover, when the alternating induction chemotherapy was used, long-term maintenance chemotherapy was not needed.

Aged

Effects of continuous or discontinuous maintenance therapy on subsequent remission maintenance in childhood leukemia.

This study was designed to determine if resistance to a standard drug during the second remission of children with acute leukemia was reduced by discontinuation of therapy during the initial remission. The initial maintenance therapy was either 6-mercaptopurine (6-MP), methotrexate (MTX), or cyclophosphamide (CYC) given continuously to relapse or discontinued (at random) at 2 or 6 months. Following the initial relapse and after induction of a second complete remission, 72 evaluable patients received (continuously to relapse) either 6-MP (53 patients) or CYC (19 patients) for the second remission maintenance. Resistance of 6-MP occurred during the second maintenance, regardless of the drug used during the initial maintenance, in that the length of second remissions was significantly shorter than the length of first remissions. However, this resistance was most pronounced in patients who initially relapsed while on continuous 6-MP maintenance (medium duration of remission [MDR] of 9 weeks). Patients whose initial relapse occurred after the discontinuation of 6-MP had a MDR of 23 weeks and patients whose second remission was maintained with CYC (after relapse from initial continuous remission on 6-MP) had a MDR of 25 weeks.

Acute Disease

Intravesical combination chemotherapy with mitomycin C and doxorubicin for superficial bladder cancer: a randomized trial of maintenance versus no maintenance following a complete response.

Between November 1986 and April 1989, 101 patients with superficial bladder cancer were treated with intravesical instillations of mitomycin C on day 1 and doxorubicin on day 2 of each week for 5 consecutive weeks. Of 61 complete responders, 23 patients with carcinoma in situ and 28 with papillary cancer were randomly assigned to a non-maintenance group or to a group receiving maintenance therapy consisting of monthly instillations of the same drugs for 12 months. The 2-year non-recurrence rate calculated for patients with carcinoma in situ was significantly better in the maintenance group than in the non-maintenance group. A similar tendency was observed for patients with papillary cancer, although the difference was not significant. Side effects were considerable, with moderate to severe bladder irritation occurring in approximately half of the patients. In addition to our previous findings, the present results indicate that this intravesical combination chemotherapy is effective in eliminating superficial bladder cancers and that since the effect is not durable, even in complete responders, maintenance therapy is necessary to reduce subsequent tumor recurrence.

Administration, Intravesical

Structural similarities between a mitochondrially encoded polypeptide and a family of prokaryotic respiratory toxins involved in plasmid maintenance suggest a novel mechanism for the evolutionary maintenance of mitochondrial DNA.

Subunit 8 of mitochondrial ATP synthase (A8), a mitochondrially encoded polypeptide, has no known homologue in any prokaryotic or plastid ATP synthase, suggesting that it has been recruited to its present role in the enzyme from an extraneous source. The polypeptide is poorly conserved at the primary sequence level, but shows a well-conserved hydropathy profile. The hydropathy profiles of A8 from diverse taxa were compared with those of the hok family of prokaryotic respiratory toxins, some of whose members are involved in plasmid maintenance, through postsegregational killing of cells that lose the plasmid at cell division. Such comparisons revealed a highly significant degree of similarity, suggesting a functional relationship. Based on these findings, it is proposed that A8 evolved from a hok-like protein, whose original role was the maintenance of an extrachromosomal replicon in the endosymbiont ancestor of mitochondria. An aggressive mechanism for the evolutionary maintenance of mitochondrial DNA overcomes many of the failings of traditional explanations for its retention as a separate genome.

Biological Evolution

Post-remission therapy in acute myeloblastic leukemia. A randomized trial comparing early consolidation plus maintenance versus maintenance therapy alone.

During a 5-year period 203 previously untreated patients with acute myeloblastic leukemia entered an intensive induction chemotherapy regimen with daunorubicin, cytosine arabinoside, 6-thioguanine, vincristine and prednisone (DATOP). The complete remission rate was 64%. Patients in complete remission were randomly assigned to 3 courses of early consolidation with DATOP at lower dosage followed by maintenance chemotherapy, or to the same maintenance regimen in the absence of any consolidation courses. No significant differences were found between these options concerning disease-free survival (median 7.0 vs. 9.8 months; p greater than 0.10) or survival (median 15.8 vs. 19.4 months; p greater than 0.10). This study, in addition to the few previously reported randomized trials, suggests that early low-dose consolidation adds no benefit to maintenance chemotherapy in acute myeloblastic leukemia once complete remission has been achieved.

Adolescent

Randomized prospective trial of ganciclovir maintenance therapy for cytomegalovirus retinitis.

We report the first randomized prospective comparative study of long-term maintenance ganciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine, BW759U, DHPG) therapy for cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Eleven retinitis patients who received a 10-day course of ganciclovir induction therapy and then were randomized to receive either immediate daily ganciclovir maintenance therapy or deferred maintenance (eight deferred maintenance, three immediate maintenance) were evaluated for drug efficacy. Median time to retinitis progression was 42 days for the immediate maintenance group compared with 16 days for the deferred maintenance group, (P = 0.07). After crossing over to maintenance therapy, patients in the deferred group had a median time to retinitis progression of 58 days compared to 16 days while not on maintenance therapy (P = 0.13). Only 9% of cultures obtained while patients received maintenance therapy were positive for cytomegalovirus, vs 40% of those obtained off maintenance (P less than 0.001). We can state then that maintenance therapy with ganciclovir delays, but does not halt, progression of cytomegalovirus retinitis and suppresses, but does not eradicate, cytomegalovirus shedding in patients with AIDS.

Acquired Immunodeficiency Syndrome

Nine years of maintenance treatment with ranitidine for patients with duodenal ulcer disease.

Four hundred and sixty-four patients with duodenal ulcer disease received continuous maintenance treatment with ranitidine for up to 9 years. Treatment failure was defined as either the first symptomatic recurrence of ulcer or the first ulcer recurrence accompanied by haemorrhage. Life tables were constructed using the Kaplan-Meier product-limit method; comparisons of survival curves were performed using the log-rank test; and multivariate analysis was carried out using the Cox proportional hazards model. Results. The proportion of patients remaining free from symptomatic recurrence of ulcer during maintenance treatment with either 150 mg/day or 300 mg/day ranitidine was: 95% at 1 year; 88% at 3 years; 86% at 5 years; and 81% at 7 and 9 years (95% C.I. 76-86%). Young age and the absence of exposure to non-steroidal anti-inflammatory drugs (NSAIDs) at the time of diagnosis of ulcer were shown to increase the likelihood of developing ulcer recurrence. The rate of ulcer recurrence after 9 years of maintenance treatment (17%) was significantly less than that after 5 years without active anti-ulcer therapy (80%), P = 0.0001. The proportion of patients who remained free from ulcer haemorrhage during maintenance treatment was: 99.1% at 1 year and 98.1% at 5 and 9 years (95% C.I. 96.7-99.6%). The risk of haemorrhage was significantly greater in patients who were not receiving active treatment (12.4% at 5 years) than in patients receiving maintenance treatment (less than 2% at 9 years), P = 0.0001 (log-rank test). Patients who had originally presented with haemorrhage had an increased risk of further ulcer bleeding compared with patients who presented with pain (P = 0.0013). A significantly greater proportion of patients with NSAID-associated duodenal ulcers remained free from ulcer recurrence during maintenance treatment compared with patients suffering from 'idiopathic' ulcers (P = 0.0238), although there was no difference between the two groups in respect of haemorrhage during maintenance treatment. Conclusions. (a) Continuous maintenance treatment with ranitidine for up to nine years successfully prevents ulcer recurrence in more than 80% of patients with duodenal ulcer disease. (b) Young age increases the risk of ulcer recurrence during maintenance treatment with ranitidine. Ulcers associated with NSAID-intake at the time of diagnosis have a lesser risk of recurrence during maintenance treatment. (c) The risk of haemorrhage in patients with ulcer disease receiving maintenance treatment with ranitidine for nine years was less than 2% compared with greater than 12% in untreated patients observed for 5 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult

Maintenance therapy of duodenal and gastric ulcer with H2-receptor antagonists.

Maintenance therapy with either ranitidine or cimetidine has been administered for up to 5 years to several hundred patients suffering from duodenal or gastric ulcer disease. Maintenance treatment prevented symptomatic ulcer relapse in approximately three-quarters of patients over this period of time. About half of symptomatic ulcer relapses occurred during the 1st year of maintenance therapy, and thereafter the symptomatic recurrence rate was extremely low. Potentially the most important effect of maintenance therapy was to reduce the incidence of ulcer complications, particularly haemorrhage (from 6.2% to 0.4% during the 1st year of duodenal ulcer maintenance). Maintenance therapy is therefore likely to reduce ulcer morbidity and to be cost-beneficial in patients who have previously experienced an ulcer complication and are at an increased risk of the same complication in the future. Maintenance therapy with 300 mg ranitidine daily was more effective than 150 mg ranitidine at night in smokers and may be a useful therapeutic option for smokers who relapse during maintenance therapy with 150 mg ranitidine at night or for smokers in whom it is mandatory to prevent ulcer recurrence because of a previous complication. Asymptomatic ulcers occurring during maintenance therapy are clinically benign, and rehealing such ulcers does not alter the subsequent clinical course. Point prevalences of asymptomatic reulceration should not be used when assessing the clinical value of maintenance therapy.

Anti-Inflammatory Agents, Non-Steroidal

Predictors of Efficacy Maintenance After Vunakizumab Discontinuation in Patients With Moderate-to-Severe Plaque Psoriasis: A Post Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Efficacy cannot be maintained in some psoriasis patients after biological discontinuation. This study aimed to explore predictors of efficacy maintenance after vunakizumab discontinuation in patients with moderate-to-severe plaque psoriasis. METHODS: This post hoc analysis used data from a phase III trial (NCT04839016); 291 patients with moderate-to-severe plaque psoriasis who achieved 100% improvement in Psoriasis Area and Severity Index (PASI) score at Week 52 were enrolled. Efficacy maintenance was defined as patients who maintained PASI 90 or PASI 100 after 20&#x2009;weeks of vunakizumab discontinuation. RESULTS: There were 44.7% and 72.5% of patients with PASI 100 and PASI 90 maintenance, respectively. In the multivariate logistic regression model, body mass index (BMI) (odds ratio [OR]&#x2009;=&#x2009;0.922, p&#x2009;=&#x2009;0.024) and treatment interruption (OR&#x2009;=&#x2009;0.550, p&#x2009;=&#x2009;0.020) were independently associated with a lower possibility of PASI 100 maintenance; however, the association of family history of psoriasis and the first time of PASI 100 achievement with PASI 100 maintenance did not achieve statistical significance. Duration of psoriasis (OR&#x2009;=&#x2009;0.972, p&#x2009;=&#x2009;0.049) and treatment interruption (OR&#x2009;=&#x2009;0.257, p&#x2009;<&#x2009;0.001) were independently associated with a lower possibility of PASI 90 maintenance. Two nomograms for predicting PASI 90 and PASI 100 maintenance were constructed based on the multivariate models, which disclosed good calibration performance. CONCLUSIONS: PASI 90 and PASI 100 maintenance rates are 72.5% and 44.7% after 20&#x2009;weeks of vunakizumab discontinuation in patients with moderate-to-severe plaque psoriasis. BMI, treatment interruption, and duration of psoriasis predict a lower possibility of efficacy maintenance after vunakizumab discontinuation.

Humans

Quizartinib for patients with newly diagnosed FLT3-ITD-positive AML who received maintenance therapy in QuANTUM-First.

QuANTUM-First demonstrated improved overall survival (OS) in patients with newly diagnosed acute myeloid leukemia with FMS-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD) treated with quizartinib + standard chemotherapy. Herein, we evaluated the impact of postconsolidation/posttransplant single-agent maintenance therapy on clinical outcomes in patients receiving maintenance, focusing on measurable residual disease (MRD) status at maintenance onset. OS, event-free survival, and relapse-free survival were prespecified exploratory analyses. Cumulative incidence of relapse, analyses by allogeneic hematopoietic cell transplant (allo-HCT), and analyses by MRD status were post hoc and not powered for statistical significance. Samples for FLT3-ITD MRD analysis were collected from patients with composite complete remission &#x2264;30 days before receiving maintenance and assessed using an ultrasensitive amplicon-based assay. More patients who had received an allo-HCT and quizartinib treatment received maintenance (71%) vs placebo (55%); OS benefit was not demonstrated among these patients. In patients who did not undergo allo-HCT, quizartinib maintenance was associated with a significant OS benefit (hazard ratio [HR], 0.401; 95% confidence interval [CI], 0.192-0.838), including a benefit in patients who were MRD negative at the start of maintenance (OS HR, 0.194; 95% CI, 0.056-0.676). Patients who were MRD negative at the completion of consolidation achieved 89.1% (95% CI, 70.0-96.4) survival at 3 years with quizartinib maintenance in the absence of allo-HCT. These data suggest that for patients who achieve FLT3-ITD MRD negativity after induction and consolidation with quizartinib, maintenance with quizartinib provides a significant survival benefit and, in some patients, may eliminate the need for allo-HCT. This trial was registered at www.clinicaltrials.gov as NCT02668653.

Humans

Correlates of maintenance of a low-fat diet among women in the Women's Health Trial.

BACKGROUND: The Women's Health Trial (WHT) was a feasibility study for a randomized controlled trial designed to test the hypothesis that a reduction in dietary fat reduces breast cancer incidence among women age 45 to 69. Between 1984 and 1988, 2,064 women participated in its two phases. METHODS: A follow-up study of 525 women who were randomized to receive the WHT dietary intervention program was conducted to assess maintenance of the diet 1 year on average after the trial ended. Among 448 participants, the mean percentage of energy from fat as measured by a food frequency questionnaire was 40.0% at baseline, 26.3% at the end of the trial, and 27.7% at follow-up. Based on 408 women with complete data, a recursive model was estimated, describing the influence of baseline characteristics of the women on attendance at intervention program sessions, adherence to the diet during the trial, and long-term maintenance of the diet after the trial ended. The effects of women's experiences during the trial on adherence and long-term maintenance were investigated as well. RESULTS: Attendance at the educational sessions was strongly related to adherence to the diet during the trial (P less than 0.001), and adherence was the most important predictor of long-term maintenance (P less than 0.001). The percentage of energy from dietary fat at baseline was an important correlate of both adherence (P less than 0.001) and long-term maintenance (P less than 0.001). College-educated women were more likely to adhere to the diet during the trial (P less than 0.001). Feelings of deprivation adversely affected long-term maintenance (P less than 0.01), primarily through their effect on adherence during the trial (P = 0.01). Costliness of the diet in time and money negatively influenced long-term maintenance (P less than 0.05). Development of a distaste for fat encouraged adherence (P = 0.06). CONCLUSIONS: The low-fat dietary pattern established during the WHT was maintained for as long as 20 months after the trial ended. A recursive model was useful in analyzing the process and correlates of long-term maintenance of dietary behavior change. Both predisposing variables and women's experiences while on a low-fat diet were associated with long-term maintenance. The results suggest that feelings of deprivation should be avoided, perhaps by use of low-fat substitutes, by those attempting to lower their dietary fat and that more research is needed on the development of a distaste for fat among individuals who adopt low-fat diets.

Aged

Metabolic indices for evaluating the in vitro maintenance of Hymenolepis diminuta in the presence and absence of various additives.

An in vitro maintenance system for H. diminuta was devised by modifying the cultivation procedure of Schiller (1965). In this diphasic maintenance system, tissue culture medium (Triple Eagle's or NCTC-135) was used, in lieu of whole blood, as the 30% supplement to the agar phase. This provides a more defined system suitable for studying the effects of various additives. Morphological criteria were established which aided in assessing the efficacy of media used for the maintenance of 6- and 8-day-old H. diminuta. When successfully maintained, worms exhibited an intact scolex and neck region, undulatory movements along the strobila as well as integumentary and strobilar integrity. A more sensitive method for evaluating the maintenance of 8-day-old worms employed metabolic indices. Wet weight, protein and glycogen levels for 8-day-old H. diminuta served as base-line data allowing estimation of protein and glycogen contents of each worm prior to maintenance. Following maintenance, ratio of final to initial protein and final to initial glycogen levels (metabolic indices). A metabolic index approaching or exceeding unity suggested a reasonably intact metabolism. The addition of sodium taurocholate to the maintenance media appeared beneficial to the worms by prolonging the retention of normal signs. A combination of additives, taurocholate-nucleosides-lipids, improved the maintenance of H. diminuta for periods exceeding 24 hr as determined by observational criteria and metabolic indices. However, addition of a lipid mixture, or a lipid mixture prepared with a low concentration of taurocholate was not beneficial over a 24 hr period. The maintenance system, observational criteria, base-line data and metabolic indices should be useful for future in vitro studies requiring long-term incubation.

Animals

Maintenance of cooling towers following two outbreaks of Legionnaires' disease in a city.

This survey assessed the maintenance of evaporative cooling towers in Glasgow, following two Legionnaires' disease outbreaks. Information was obtained from 76 of 81 premises and a maintenance score was calculated for each of 174 towers. The quality of maintenance was extremely varied (range of maintenance scores, 8-30; mean, 22 (S.D., 5.0); median, 23; maximum possible, 33) and some towers were neglected. Breaches of maintenance principles were mainly structural and organizational, e.g. inadequate drift control, rather than failure to use chemicals. Low maintenance scores were associated with no log book, no guidelines, no change in procedures in last 5 years, solitary cooling towers, and towers on industrial premises. Despite intense publicity the standard of cooling tower maintenance in Glasgow remained a concern. Information campaigns directed at those responsible for cooling-tower maintenance are necessary.

Air Conditioning

[Effect of the nutrition level and sex on the energy maintenance requirement of broilers and rats].

In 3 experiments young broiler chickens were supplied on various feeding levels in the growth range between 200 and 2500 g live weight (2.8 and 2.0 in experiment 1, 2.8, 2.3 and 1.8 in experiments 2 and 4, maintenance = feeding level 1.0). In experiments 1 and 2 short-time measurings (30 min) of heat production by means of gas exchange were made at 500, 1000, 1500 and 2000 g live weight in the post-absorptive state and on the maintenance level of feeding. In experiment 1 the heat production of the restrictively fed chickens was in 3 out of the 4 stages of development studied significantly lower by 10-14% than that of the intensively fed ones. In experiment 2 such an effect could not be observed. Fed on the level of energy maintenance, broilers weighing approximately 2000 g (experiment 3) did not show a significant influence of the sex on heat production as a result of 30-minute gas exchange measurings in the post-absorptive state. In experiment 4 24-hour measurings of the energy metabolism were carried out in the growth development in periods of feeding on the maintenance level by means of indirect calorimetry. In the live weight range between 0.9 and 1.3 kg there was only a low, non-significant decrease of the energy maintenance requirement of 4-6% of the highly restrictively fed chickens in comparison to the intensively fed ones. After continued feed restriction (live weight range 1.7-2.2 kg) an energy maintenance requirement reduced by 17% was measured. In an analogously arranged experiment with 24-hour energy metabolism measurings (experiment 5) male Wistar rats in the growth range between 70 and 280 g were supplied on the feeding levels 1.8 and 1.4 resp. In all three periods studied on the feeding level maintenance--beginning at 140-150 g live weight--the highly restrictively fed animals showed a slightly reduced energy maintenance requirement by 8%, 3% (non-significant) and 6% in comparison with the intensively fed animals.

Animal Feed