Real-World Treatment Patterns and Clinical Outcomes in Canadian Patients with AML Unfit for First-Line Intensive Chemotherapy.

Acute myeloid leukemia (AML) is a hematological malignancy that predominantly affects the elderly. Prognosis declines with age. For those who cannot tolerate intensive chemotherapy, historically established treatment options have been hypomethylating agents (HMAs), low dose cytarabine (LDAC), and best supportive care (BSC). As the standard of care evolves for those unfit for intensive chemotherapy, there is a need to understand established treatment pathways, clinical outcomes and healthcare resource utilization in Canada. The CURRENT study was a retrospective chart review of AML patients not eligible for intensive chemotherapy who initiated first-line treatment between 1 January 2015 and 31 December 2018. Data were collected from 170 Canadian patients treated at six hematology centers, of whom 118 received systemic therapy and 52 received BSC as first-line treatment. Median overall survival was 8.58 months and varied from 2.96 months for BSC to 13.31 months for HMAs. Over 80% of patients had at least one outpatient visit, and 67% of patients receiving systemic therapy and 71% of those receiving BSC had at least one admission to hospital, during their first line of therapy. A total of 96 (81.4%) patients receiving first line systemic therapy and 39 (75.0%) of those receiving first line BSC had at least one red blood cell or platelet transfusion. These findings highlight the unmet need for novel therapies for patients ineligible for intensive chemotherapy.

Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome.

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9-9.9) months with glasdegib/LDAC and 4.9 (3.5-6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39-0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit-risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Gemcitabine/dexamethasone/cisplatin vs cytarabine/dexamethasone/cisplatin for relapsed or refractory aggressive-histology lymphoma: cost-utility analysis of NCIC CTG LY.12.

BACKGROUND: The NCIC CTG LY.12 study showed that gemcitabine, dexamethasone, and cisplatin (GDP) were noninferior to dexamethasone, cytarabine, and cisplatin (DHAP) in patients with relapsed or refractory aggressive histology lymphoma prior to autologous stem cell transplantation. We conducted an economic evaluation from the perspective of the Canadian public healthcare system based on trial data. METHODS: The primary outcome was an incremental cost utility analysis comparing costs and benefits associated with GDP vs DHAP. Resource utilization data were collected from 519 Canadian patients in the trial. Costs were presented in 2012 Canadian dollars and disaggregated to highlight the major cost drivers of care. Benefit was measured as quality-adjusted life-years (QALYs) based on utilities translated from prospectively collected quality-of-life data. All statistical tests were two-sided. RESULTS: The mean overall costs of treatment per patient in the GDP and DHAP arms were $19 961 (95% confidence interval (CI) = $17 286 to $24 565) and $34 425 (95% CI = $31 901 to $39 520), respectively, with an incremental difference in direct medical costs of $14 464 per patient in favor of GDP (P < .001). The predominant cost driver for both treatment arms was related to hospitalizations. The mean discounted quality-adjusted overall survival with GDP was 0.161 QALYs and 0.152 QALYs for DHAP (difference = 0.01 QALYs, P = .146). In probabilistic sensitivity analysis, GDP was associated with both cost savings and improved quality-adjusted outcomes compared with DHAP in 92.6% of cost-pair simulations. CONCLUSIONS: GDP was associated with both lower costs and similar quality-adjusted outcomes compared with DHAP in patients with relapsed or refractory lymphoma. Considering both costs and outcomes, GDP was the dominant therapy.

[Psychotherapy: Legally recognized in Quebec]. / Psychothérapie - Un encadrement nécessaire et légalement reconnu au Québec.

Until recently, Quebec was the first to have regulated the practice of psychotherapy through law adopted in 2009. The law emerged following 30 years of efforts and inter-professional discussions that led to a consensus by an expert committee presided by Dr Jean-Bernard Trudeau in 2005. In this essay, Dr Jean-Bernard Trudeau, general practitioner, and two psychiatrist and psychologist colleagues, who have participated to the expert committee or have been involved more recently in the implementation of law no 21 in Quebec, relate the main landmarks and moments in the regulation of the practice in psychotherapy following this inter-professional consensus that was translated in the law 21. They relate particularly the last ten years that have led to the adoption of law 21 in 2009, following two parliamentary commission after the Trudeau report. They underline how the practice of psychotherapy is integrated in the professional system and submitted to strict regulation. It includes regulations for obtaining the license of psychotherapist and for maintaining competence. Guidelines emerging from continuous inter-professional discussions for the application of the law and of its regulation in the public and private sectors are produced by the Quebec Professions Office. The definition of psychotherapy that was reached by consensus is not limited to the treatment of mental disorders and is distinguished from other intervention in the area of human relations. Continuous training is mandatory and is implemented on one hand by the Order of the psychologists for the psychologists and other professionals practicing psychotherapy and on the other hand the College of physicians for physician practicing psychotherapy. The authors finally described the interdisciplinary advisory council for the practice of psychotherapy that the legislator has foreseen as an external mechanism to insure the conformity of regulation with the spirit of the law and to give opinions to the various professional orders.

Adherence to adjuvant endocrine therapy in estrogen receptor-positive breast cancer patients with regular follow-up.

BACKGROUND: Adjuvant hormonal therapy is crucial in the treatment of estrogen receptor-positive breast cancer. The nonadherence rate to hormonal treatment is reported to be as high as 60%. The goal of this study was to evaluate the factors evoked by the patients as well as the demographic and disease-related factors that could be associated with nonadherence to adjuvant hormonal therapy. METHODS: All consecutive patients treated for an estrogen receptor-positive breast cancer who showed up for regular follow-up with a single breast specialist between November 2008 and April 2009 were included in the study. We assessed adherence to hormonal therapy (either with tamoxifen or aromatase inhibitor). Reasons for adherence and nonadherence were collected. Records were also reviewed for demographic and cancer characteristics and for treatment components. RESULTS: We included 161 patients in the study; 150 (93.2%) adhered to hormonal treatment. Side effects and absence of conviction were the main reasons for nonadherence. The importance of the diagnosis of cancer, fear of recurrence and regular follow-up were reported as the main reasons for adherence. CONCLUSION: Severity of disease and side effects are associated with nonadherence to treatment. Strict follow-up appears to be a necessary adjunct in the adherence to treatment. The association between demographic and cancer characteristics and treatment components needs further investigation. However, these factors may help identify patients at risk of nonadherence and help the oncology team.

CONTEXTE: Le traitement hormonal adjuvant est crucial dans le traitement du cancer du sein avec récepteurs estrogéniques positifs. Le taux d'inobservance au traitement hormonal atteint 60 %. Le but de cette étude consiste à évaluer les facteurs évoqués par les patientes ainsi que les facteurs démographiques et pathologiques pouvant être associés à l'inobservance au traitement hormonal adjuvant. MÉTHODES: Toutes les patientes qui ont été traitées pour cancer du sein avec récepteurs estrogéniques positifs et suivies régulièrement par un spécialiste du cancer du sein de novembre 2008 à avril 2009 ont été incluses dans l'étude. L'adhérence au traitement hormonal (tamoxifène ou inhibiteur de l'aromatase) a été évaluée. Les dossiers des patientes ont aussi été révisés pour colliger les facteurs démographiques, pathologiques et thérapeutiques. RÉSULTATS: Il y a eu 161 patientes; 150 (93,2%) ont suivi le traitement hormonal. Les effets secondaires et l'absence de conviction des patientes face au bénéfice du traitement furent les principales raisons évoquées pour ne pas prendre la médication. L'importance du diagnostic de cancer, la peur de récidive et le suivi régulier furent les principales raisons rapportées pour suivre le traitement. CONCLUSION: La sévérité de la maladie et les effets secondaires sont associés avec l'inobservance au traitement hormonal. Le suivi rigoureux semble s'avérer nécessaire dans l'observance au traitement des patientes. La relation entre les facteurs démographiques, les caractéristiques du cancer et du traitement nécessite une investigation plus approfondie. Cependant, ces facteurs peuvent certainement permettre d'identifier les patients à risque d'inobservance et aider l'équipe d'oncologie à optimiser les discussions.

Measuring dynamic stability requirements during sitting pivot transfers using stabilizing and destabilizing forces in individuals with complete motor paraplegia.

Dynamic stability requirements have never been quantified when long-term manual wheelchair users transfer themselves in a seated position from an initial surface to a target surface, a functional task commonly referred to as sitting pivot transfers (SPTs). Ten individuals with spinal cord injury (SCI), who rely on a manual wheelchair for mobility, underwent a comprehensive biomechanical SPT assessment. SPTs performed toward a target seat of same height (even) and a seat 10cm higher than the initial seat (uneven), repeated three times for each task, were assessed. A dynamic equilibrium model, continuously measuring the theoretical forces required to move the center of pressure to the limit of the base of support (destabilizing force) and to neutralize the kinetic energy and stop the displacement of the center of mass at the limit of the base of support (stabilizing force) at each instance during the performance of SPTs, was used to identify the phases of greatest instability during the SPT tasks. The greatest levels of instability were reached around the time the buttocks lost contact with the initial seat and around the time the buttocks landed on the target seat (pre- and post-lift transition phases). These transition periods, characterized by the lowest destabilizing force (424.7-487.1N) and the greatest stabilizing force (24.2-33.2N), confirmed the greatest level of instability. The height of the target seat had no significant effect (p=0.278-0.739) on dynamic postural stability requirements during the SPTs. During SPTs towards even and uneven target seats, the greatest postural instability occurs during the transition phases in individuals with complete motor thoracic SCI.

Addition of AEG35156 XIAP antisense oligonucleotide in reinduction chemotherapy does not improve remission rates in patients with primary refractory acute myeloid leukemia in a randomized phase II study.

BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an inhibitor of caspases 3 and 9 that is overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report an open-label randomized phase II trial of reinduction chemotherapy with and without the XIAP antisense oligonucleotide AEG35156 in patients with AML who did not achieve remission with initial induction chemotherapy. METHODS: Twenty-seven patients with AML who were refractory to initial induction chemotherapy were randomized and treated with AEG35156 (650 mg) in combination with high-dose cytarabine and idarubicin. Thirteen patients were randomized and treated with high-dose cytarabine and idarubicin alone. The rates of response and toxicity were determined. RESULTS: Of the 27 patients assigned to AEG35156 in combination with high-dose cytarabine and idarubicin, 3 died during reinduction chemotherapy, 5 achieved complete remission (CR), and 6 achieved CR with incomplete platelet count recovery (CRp), for an overall response rate of 41%. Of the 13 patients assigned to the control arm of the study, none died during reinduction, 6 achieved CR, and 3 achieved CRp, for an overall response rate of 69%. The differences in response rates between patients in the AEG35156 and control arms were not statistically different (P = 0.18 by the χ(2) test). CONCLUSIONS: The addition of AEG35156 to reinduction chemotherapy was well tolerated but did not improve rates of remission. Therefore alternative therapeutic strategies should be explored in patients with AML refractory to induction chemotherapy.

A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients.

PURPOSE: The tyrosine kinase inhibitor, imatinib, has the potential to indirectly inhibit DNA repair. This mechanism of action has been shown to mediate sensitization to chlorambucil in chronic lymphocytic leukemia (CLL). To evaluate this effect in vivo, we performed a phase I study of chlorambucil combined with imatinib in relapsed CLL patients. METHODS: The three dose levels studied included imatinib at 300, 400, or 600 mg/day. Imatinib was given on days 1-10, and chlorambucil (8 mg/m(2) daily) was given on days 3-7 of a 28-day cycle (up to 6 cycles). RESULTS: Eleven patients participated in this study. Low-grade gastrointestinal toxicities were observed in a dose-dependent manner. Forty-five percent of patients responded (two unconfirmed CRs and three PRs). Two responding patients were fludarabine refractory. The in vitro IC(50) of chlorambucil alone or in the presence of 5 µM imatinib in CLL lymphocytes correlated with the decrease in lymphocyte counts on day 15. Imatinib plasma concentrations achieved in patients were in the range of those effective in in vitro sensitization studies. CONCLUSION: The combination of chlorambucil and imatinib in patients with previously treated CLL was well tolerated and showed evidence of clinical efficacy. Based on our results, we recommend the 400 mg daily dose of imatinib on days 1-10 with 8 mg/m(3) chlorambucil on days 3-7 every 28 days as the phase II dose. This represents the first clinical trial examining the potential synergy between a tyrosine kinase inhibitor and a conventional alkylating agent for the treatment of CLL.

Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial.

BACKGROUND AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy. Between June 5, 2000, and February 6, 2006, 379 eligible patients were enrolled in community and academic oncology centers across the United States and Canada. In February 2006, the trial was closed to new patient entry before meeting the target sample size because of insufficient accrual. All subjects received induction chemotherapy followed by concurrent chemotherapy with chest radiotherapy. Each participating center administered one of the two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. The primary endpoint was overall survival, and secondary endpoints were time to progression, progression-free survival, tumor response rate, and toxic effects. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS There was no statistically significant difference in overall survival between the chemoradiotherapy plus AE-941 group (n = 188; median survival = 14.4 months, 95% confidence interval = 12.6 to 17.9 months) and the chemoradiotherapy plus placebo group (n = 191; median survival = 15.6 months, 95% confidence interval = 13.8 to 18.1 months) (P = .73). Time to progression, progression-free survival, and tumor response rates were not statistically significantly different between the AE-941 and the placebo groups. No differences between the two groups were observed in common grade 3 or higher toxic effects attributable to chemoradiotherapy. CONCLUSIONS The addition of AE-941 to chemoradiotherapy did not improve overall survival in patients with unresectable stage III NSCLC. This study does not support the use of shark cartilage-derived products as therapy for lung cancer.

Biomechanical assessment of sitting pivot transfer tasks using a newly developed instrumented transfer system among long-term wheelchair users.

This paper describes the technical characteristics of a transfer assessment system, along with details on three-dimensional (3D) upper extremity (U/E) kinematics required to compute U/E joint forces and moments using inverse dynamics during a displacement of the body in a sitting position from an initial surface to a target one (sitting pivot transfer (SPT)). This system includes five instrumented surfaces designed to measure position (center of pressure (COP)), magnitude and direction of the tri-axial force components underneath the feet, hands (leading and trailing) and buttocks (initial and target seats) during SPTs. Linearity, COP position and natural frequency tests were performed to confirm the accuracy of the transfer assessment system outcomes. Preliminary data of one person with spinal cord injury performing SPTs toward a target seat of same height (50 cm) and additional ones toward a raised target seat (60 cm) are presented. The transfer assessment system was found to be safe, versatile in terms of height- and width-adjustment ranges, portable within a laboratory environment, easy for experienced rehabilitation scientists to use, and allowed for valid quantification of reaction forces during SPTs as confirmed by the overall accuracy test results. Combined with the 3D U/E kinematic and anthropometric parameters, the transfer assessment system outcomes allowed for the quantification of U/E joint forces and moments. Preliminary results highlight the kinematic and kinetic specificities of the leading and trailing shoulders and elbows during SPTs. The impact of modifying target seat heights on the kinematic and kinetic outcomes during SPTs is explored. The transfer assessment framework proposed is useful for research and offers a wide spectrum of possibilities for acquiring new biomechanical knowledge on SPTs that may strengthen clinical practice guidelines, targeting the preservation of U/E integrity following SCI.

Oral versus intravenous administration of vinorelbine as a single agent for the first-line treatment of metastatic nonsmall cell lung carcinoma (NSCLC): A randomized phase II trial.

OBJECTIVES: Many patients with metastatic nonsmall cell lung carcinoma (NSCLC) cannot tolerate intravenous chemotherapy. Orally active agents would be more convenient and thus could improve their quality of life. METHODS: A total of 189 patients were randomized 2:1, 181 patients received treatment, 120 PO and 61 IV vinorelbine, 158 patients had stage IV and 31 stage IIIB disease. Among patients who received PO vinorelbine, the median age was 72 years, 62% were males; the Karnofski Performance Status (KPS) was 80-100 in 71%. These compare with a median age of 70 years, 56% male, and KPS of 80-100 in 65% of patients who received IV vinorelbine. Oral vinorelbine 60 mg/m2 was to be dose-escalated to 70 mg/m2 after the initial 3-weekly doses if there was no unacceptable toxicity. Intravenous vinorelbine was to be given 30 mg/m2 weekly. RESULTS: Five patients (4%) on PO and 8 (13%) on IV vinorelbine had a confirmed partial response, 56 (44%) and 29 (46%) had stable disease, respectively. Median time-to-disease-progression was 16.6 weeks (PO) versus 23.9 weeks (IV), and the median survival was 26 weeks (PO) versus 40.9 weeks IV vinorelbine. Median survival on PO vinorelbine for patients with KPS 60-70 was 8.3 weeks versus 43 weeks (IV). On PO vinorelbine 59 patients (57%) were dose escalated, 9 (7.5%) were dose reduced, and 10 (8.3%) did not receive PO vinorelbine at week 4. Pharmacokinetic studies confirmed PO vinorelbine exposure was significantly less than IV exposure. CONCLUSION: The inability to escalate the dose of PO vinorelbine above 60 mg/m2 weekly resulted in inferiority to IV vinorelbine at 30 mg/m2 weekly, especially in patients with poor performance status.

A method to evaluate contractures effects during the gait of children with Duchenne dystrophy.

Joint contractures are the second major impairment affecting the locomotor system of children with Duchenne muscular dystrophy (DMD). While the negative influence of joint contractures has been documented, the passive moments produced by joint contractures could benefit the gait of patients with muscle weakness. We describe a biomechanical model that quantifies the mechanical contribution of ankle and hip flexion contractures to the gait of DMD children. Kinematic and kinetic parameters were measured under the same experimental conditions during the gait and passive resistance assessment of two subjects: one healthy child as a control, and one child with DMD. The child with DMD had a plantar flexion contracture and a greater ankle stiffness coefficient than the control child. During gait, the contribution of the ankle passive moment to the net moment was more important for the child with DMD than for the control child. At the hip, passive joint moments and passive moment contribution were more important for the control child but this was not related to the presence of hip flexion contracture. These preliminary results suggest the model might be used to evaluate contractures effect on a larger cohort of subjects.

Manual materials handling in mining: the effect of rod heights and foot positions when lifting "in-the-hole" drill rods.

There is a paucity of studies focusing on the lifting of rods or long awkward heavy objects. In-the-hole (ITH) drilling is a heavy repetitive mining task, which has been identified as having a relatively high incidence and severity rate of musculoskeletal injuries. The purpose of this study was to examine how the load experienced by ITH drill operators changed when lifting a vertical drilling rod (1.61m, 35kg) using two rod heights and four different foot positions. In addition, a symmetrical lift with a lifting index (LI) of 1.4 also served as a comparison to determine possible risk of low back injury. Eleven experienced ITH drill operators participated in the study. Each subject was required to lift a vertical drilling rod until the upper body was in an erect posture using four different foot positions (0 degrees =subject facing the rod, 45 degrees =subject oblique to the rod, 90 degrees =subject right side to the rod and freestyle). In addition, two rod height conditions were studied where the base of the vertical rod was supported either (1) at ground level (height of rod CG=0.83m) or (2) on a 20cm rack (height of rod CG=1.03m). Finally, each subject lifted a 21.5kg box in the sagittal plane, which corresponded to an LI of 1.4 in the NIOSH lifting equation. Reflective markers were placed on the subjects, and three video cameras and one force plate were used to record the forces and the motion of the subjects' segments. Two surface electrodes were applied on the right and the left erector spinae (ES) at the level of L3. Back loading was defined by the level of the peak moments, the mechanical work and erector spinae muscle activity (EMG). It was found that the vertical height of the rod had the most significant impact on back loading, while the effect of the initial foot positioning relative to the rod was limited by the technique adopted by the drillers. Moreover, it was found that some of the subjects used techniques less strenuous for the back than others. Finally, the asymmetrical lifting component was found to be the most negative aspect of lifting an ITH drill rod compared to a standard symmetrical lift (NIOSH).

Optically reconfigurable azobenzene polymer-based fiber Bragg filter.

Optically writable, thermally erasable surface relief gratings in thin Disperse Red 1 polymethyl methacrylate azopolymer films were used to demonstrate an arbitrarily reconfigurable fiber Bragg filter. Gratings were optically written on azopolymer-coated side-polished fiber blocks, and a write-erase-write cycle was demonstrated. Finite difference time domain simulations reveal that this optically reconfigurable device concept can be optimized in a silicon-on-insulator waveguide platform.

Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial.

BACKGROUND: High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population. METHODS: Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received Vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by Gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on Vinorelbine or Gemcitabine according to the patient's preference. RESULTS: A total of 126 cycles of Vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of Gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on Vinorelbine, 5 patients on Gemcitabine; 12 patients (26%) had stable disease, 7 patients on Vinorelbine, 5 patients on Gemcitabine. Of 24 patients with progressive disease on Vinorelbine, 3 patients (12.5%) responded to Gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. CONCLUSION: This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.

Weekly paclitaxel and gemcitabine chemotherapy for metastatic non-small cell lung carcinoma (NSCLC): a dose-optimizing phase II trial.

BACKGROUND: The current dose-optimizing Phase II study evaluated the effect of weekly paclitaxel and gemcitabine on the response rate and survival of patients with non-small cell lung carcinoma (NSCLC) using dose modifications that permitted optimal treatment intensity. METHODS: Forty-five patients (40 with TNM Stage IV and 5 with TNM Stage IIIB NSCLC) were treated with gemcitabine at 1000 mg/m(2) via a 30-minute intravenous (i.v.) infusion and with paclitaxel at 100 mg/m(2) via a 60-minute i.v. infusion. The first 3 patients received chemotherapy on Days 1, 8, and 15 every 4 weeks; the next 42 patients, participating in the Phase II trial, received chemotherapy on Days 1 and 8 every 3 weeks. RESULTS: The 3 patients who received paclitaxel and gemcitabine on Days 1, 8, and 15 every 4 weeks tolerated the treatment poorly. One patient died suddenly after Day 15 treatment during the first cycle, and the other 2 patients discontinued the treatment because of unacceptable toxicity before the third cycle of chemotherapy. The next 42 patients, 40 of whom were evaluable, entered this trial between May 2000 and April 2001. They received paclitaxel at 100 mg/m(2) i.v. followed by gemcitabine at 1000 mg/m(2) i.v. on Days 1 and 8 every 3 weeks. Two patients (5%) achieved complete response, 20 (50%) achieved partial response, and 8 (20%) had stable disease. Median survival (MS) was 9.8 months; and 1-year survival was 35%. The 32 patients with performance status (PS) 0 or 1 had an MS of 11 months; the 8 patients with PS 2 had an MS of 3 months. Toxicity (especially hematologic toxicity, neuropathy, and alopecia) was minimal. CONCLUSION: A weekly paclitaxel and gemcitabine regimen that incorporated the authors' dose modifications resulted in good efficacy with minimal toxicity.

Knee flexion and base of support in asymmetrical handling: effects on the worker's dynamic stability and the moments of the L(5)/S(1) and knee joints.

OBJECTIVE: To investigate the effects of knee flexion and of the variations of feet lateral spacing on dynamic stability and on the net joint moments distribution between the back and knees. BACKGROUND: The width of the base of support and knee flexion effects on joint moments in asymmetric handling and especially on the worker's stability have rarely been studied. METHODS: Fourteen healthy male subjects performed an asymmetrical lifting task, using four different techniques: two imposed lateral feet spacings (41 and 57 cm) and two knee flexion amplitudes (slightly and deeply flexed knees). A tridimensional dynamic rigid body model was used to estimate the triaxial net reaction moments at L(5)/S(1) and at the knees, using two force platforms. New developments have been undertaken to characterize workers' stability while handling: the horizontal force required to destabilize the worker was calculated as a measure of dynamic stability. RESULTS: The width of the base of support had little effect on L(5)/S(1) and knee moments; however, the subjects were less stable with the narrow base of support. Using the slightly flexed knees technique, trunk maximal resultant moments were slightly smaller (202 vs. 216 Nm), and maximal resultant knee moments were larger (96 vs. 62 Nm). Furthermore, asymmetric moments at the trunk and the asymmetric position of the knees were reduced with this technique, but subjects were less stable. CONCLUSIONS: The use of a slightly flexed knees technique in asymmetrical handling of low-lying loads appears advantageous because it reduces L(5)/S(1) moments while increasing the knees' flexing moments, although this may compromise workers' stability. RELEVANCE: Handling methods used by workers in asymmetrical handling have rarely been studied. Optimizing the safety of a handling method can involve many parameters, such as reducing joint moments and maximizing stability. The evaluation of the worker's stability while handling in conjunction with joint moments is an interesting alternative to study the safety of handling methods.

Load Acceleration and Footstep Strategies in Asymmetrical Lifting and Lowering.

Accelerated execution effects for lifting and lowering a 12-kg box using two footstep strategies associated with experienced workers were studied. Eight healthy male participants performed a normal and an accelerated execution of a lifting task and a lowering task, using a minimal feet displacement strategy (oblique-step) and a strategy with a step (crossed-step). It was hypothesized that the accelerated executions, as compared to the normal executions, would have a different effect on L5/S1 resultant moment, body posture, and other kinematic variables. A tridimensional dynamic rigid body model was used to compute L5/S1 resultant moments. Results showed that the accelerated condition did not reduce body asymmetry of posture, but it reduced the length of the path of the global center of gravity and the duration of the supporting phase of the box, and it did not significantly affect L5/S1 maximal resultant moments for lifting but increased them for lowering. These results indicate that the net work production for accelerated strategies might be smaller, which may represent an economy of energy. Furthermore, the results showed that the use of an accelerated strategy for lowering should be avoided.