High Proportion Of Responses Research Articles

A Multicenter Phase2 Trial of Linperlisib in Relapsed or Refractory Peripheral T/NK Cell Lymphomas

Introduction Peripheral T/NK cell lymphomas (PTCLs) are a group of aggressive heterogeneous non-Hodgkin's lymphomas where in relapsed or refractory (r/r) disease, the approved standard therapies are limited with a median progression free survival (mPFS) of only 3-4 months. PI3Kdelta inhibitors have demonstrated clinical activities in T-cell and B-cell lymphomas, owing to the multiple cellular activities in the T, B, and myeloid cell tumor microenvironment. However, application of these agents has been hampered by poor tolerabilities, particularly with toxicities such as diarrhea/colitis, hepatotoxicity, pneumonitis, hyperglycemia, and rash. As a new PI3Kdelta-selective oral agent, linperlisib was shown to be efficacious and indicated a favorable safety profile in phase 1 and 2 clinical trials in r/r Follicular Lymphoma (FL) and PTCL. Linperlisib received marketing approval in China in 2022 for r/r FL patients (pts) with 2 prior systemic therapies. Here we report the efficacy and safety findings for linperlisib in a pivotal phase 2 trial in r/r PTCL. Methods Ninety-eight pts were enrolled in the open-label phase 2 registration trial (CTR20210333) from May 2021 to October 2022 at 25 sites in China. The trial had a representation of different PTCL subtypes: AITL (48 pts), PTCL-NOS (24 pts), NKT (8 pts), ALCL (2 pts), MEITL (2 pts), Other (4 pts), and 10pt did not qualify as PTCL confirmed by independent pathology review, yielding a Full Analysis Set (FAS) of 88 pts for efficacy evaluation. Linperlisib was orally dosed at 80 mg QD (RP2D) continuously until disease progression, intolerable toxicity, or study withdrawal. Tumor assessments performed every 2 treatment cycles (28-day cycle) were evaluated with Lugano 2014 criteria by an Independent Review Committee. Safety was evaluated according to CTCAE v5.0. Results In this phase 2 study, the median age was 57 years, ECOG 0-1 (100%). Most patients were diagnosed with Lugano 2014 Stage III (29 pts, 33%), or IV (49pts, 56%) diseases, and were refractory or relapsed to a median of 2 prior systemic therapies. Sixty-four pts (73%) had refractory diseases, 59 pts (67%) had relapsed diseases, and 35 pts (40%) were with both r/r. Treatment related adverse events (TRAE) were observed in 94 pts (95.9%) , with the most common TRAEs (≥10%) being neutropenia (59%), leukopenia (47%), thrombocytopenia (32%), anaemia (24%), elevated alanine aminotransferase (23%), elevated aspartate aminotransferase (20%), pneumonia (20%), lymphocytopenia (17%), hypertriglyceridemia (15%), fever (15%), diarrhea (14%), elevated lipase (13%), hyperuricemia (13%), rash (13%), hypercholesterolemia (12%), hyponatremia (11%), elevated lactate dehydrogenase (10%), elevated creatinine (10%). AEs of ≥Grade 3 (≥5%) were neutropenia (32%), pneumonia (14%), leukopenia (10%), anaemia (6%), thrombocytopenia (5%), upper respiratory tract infection (5%) and lymphocytopenia (5%). The most frequent Serious Adverse Event (drug-related) was pneumonia (11%). Twenty-two pts (22.4%) had dose reductions, and 9 pts (9.2%) discontinued from the study due to AEs. The safety profile was consistent with all previously reported in linperlisib clinical studies. Among the 88 FAS pts, the objective response rate (ORR) was 48%, including 30% (26 pts) complete response, 18% (16 pts) partial response, and 20% (18 pts) stable disease. The disease control rate was 68%. Responses were demonstrated in all subtypes, including AITL, PTCL-NOS, NKT, and others. As of April 24, 2023, the median duration of response had not been reached (95%CI: 7.8, NR), and mPFS was 5.5 months (95%CI: 3.5, 15.6). All pts had ≥6 months of follow-up as of the safety and efficacy analysis data cut off (April 24, 2023); median follow-up was 13.9 months. The 6-month OS rate was 75% (95% CI: 64.51%, 82.74%), the median OS was 14.2 months (95%CI: 7.9, NR), 16 pts continued to receive linperlisib treatment. Conclusions Linperlisib, as a new PI3Kdelta-selective oral agent, showed a well-tolerated safety profile with low levels of severe gastrointestinal and liver toxicities seen with other PI3K agents. In r/r PTCL, linperlisib had promising durable efficacies, with 48% ORR (30% CR) and a median duration of response that was not reached. As in previous lymphoma studies with linperlisib, a high proportion of responses were CRs, and responses were observed across almost all PTCL subtypes. A phase 2 r/r PTCL and CTCL trial in the US/EU is ongoing.

Identifying lifestyle factors associated to co-morbidity of obesity and psychiatric disorders, a pilot study.

Obesity and psychiatric disorders are linked through a bidirectional association. Obesity rates have tripled globally in the past decades, and it is predicted that by 2025, one billion people will be affected by obesity, often with a co-morbidity such as depression. While this co-morbidity seems to be a global health issue, lifestyle factors associated to it differ between countries and are often attributed to more than one factor. Prior obesity studies were performed in Western populations; this is the first study that investigates lifestyle factors relating to obesity and mental health of the diverse population in Qatar, a country that has witnessed tremendous lifestyle change in a short time. In this pilot study, we surveyed 379 respondents to assess and compare the lifestyles of Qatar residents to the global population. However due to the high proportion of responses from the United Kingdom (UK) residents, we have made comparisons between Qatar residents and UK residents. We used chi-square analysis, spearman rank correlation and logistic regression to compare the lifestyle factors of individuals suffering from both increased BMI and mental health conditions. The types of food consumed, stress, exercise frequency and duration, alcohol and tobacco consumption, and sleep duration, were explored and results argue that different lifestyle factors can contribute to the same health condition, suggesting different mechanisms involved. We found that both groups reported similar sleep durations (p = 0.800), but that perception of sleep (p = 0.011), consumption of alcohol (p = 0.001), consumption of takeaway food (p = 0.007), and physical activity significantly varied between the groups (p = 0.0001). The study examined the predictors of comorbidity in Qatar as well as UK populations using multivariate logistic regression analysis. The result of the study showed no statistical association between comorbidity and the predictors drinking habit, smoking, physical activity, vegetable consumption, eat outs, and sleep perception for the Qatar population, and for the combined population. This study, however showed a significant association (p = 0.033) between sleep perception and comorbidity for the UK population. We conclude that further analysis is needed to understand the relationship between specific lifestyle factors and multimorbidity in each country.

The Law: Government Transparency and Public Access

AbstractNational governments regularly balance concerns of transparency and access to information against the need for information security and confidentiality. Increased government transparency can inform the public of the reasons underlying government decisions and can promote the participation of outside parties and actors. However, increased transparency can uncover wrongdoing that can lead to embarrassment or legal action against government actors. This project explores the implementation of the Freedom of Information Act (FOIA) and analyzes how politicization affects aggregate federal executive branch transparency. Utilizing FOIA initial disposition data across the Bush II and Obama administrations, I find a complex relationship between politicization, as indicated by aggregate appointee presence within an agency, and FOIA requests outcomes. I find that increased politicization is associated with a higher proportion of responses, noting that agencies were not able to locate responsive FOIA records. However, I find less evidence that politicization affects the aggregate amount of information released to requesters from retrieved records.

Relating Sensory, Cognitive, and Neural Factors to Older Persons' Perceptions about Happiness: An Exploratory Study.

Despite increased rates of disease, disability, and social losses with aging, seniors consistently report higher levels of subjective well-being (SWB), a construct closely related to happiness, than younger adults. In this exploratory study, we utilized an available dataset to investigate how aspects of health commonly deteriorating with age, including sensory (i.e., vision and hearing) and cognitive status, relate to variability in self-described contributors to happiness. Community-dwelling seniors (n = 114) responded to a single-item prompt: “name things that make people happy.” 1731 responses were categorized into 13 domains of SWB via structured content analysis. Sensory health and cognition were assessed by Snellen visual acuity, pure-tone audiometry, and in-person administration of the Brief Test of Adult Cognition by Telephone (BTACT) battery. A subset of eligible participants (n = 57) underwent functional magnetic resonance imaging (fMRI) to assess resting state functional connectivity (FC) within a previously described dopaminergic network associated with reward processing. SWB response patterns were relatively stable across gender, sensory status, and cognitive performance with few exceptions. For example, hearing-impaired participants listed fewer determinants of SWB (13.59 vs. 17.16; p < 0.001) and were less likely to name things in the “special events” category. Participants with a higher proportion of responses in the “accomplishments” domain (e.g., winning, getting good grades) demonstrated increased FC between the ventral tegmental area and nucleus accumbens, regions implicated in reward and motivated behavior. While the framework for determinants of happiness among seniors was largely stable across the factors assessed here, our findings suggest that subtle changes in this construct may be linked to sensory loss. The possibility that perceptions about determinants of happiness might relate to differences in intrinsic connectivity within reward-related brain networks also warrants further investigation.

Using predicted Spanish preference to target bilingual mailings in a mail survey with telephone follow-up.

Spanish-preferring Medicare beneficiaries are underrepresented in national patient experience surveys. We test a method for improving their representation via higher response rates. 2009-2010 Medicare CAHPS surveys; Medicare population. We used surname and address to predict Spanish-language preference for a national sample of 177139 beneficiaries. We randomized half of the 10000 non-Puerto Rico beneficiaries with the highest predicted probabilities of Spanish preference (>10 percent) to bilingual mailings (intervention) and half to standard English-only mailings (control). Medicare CAHPS Survey data were collected through mail surveys with telephone follow-up of nonrespondents. Mail response rate was higher for intervention (28.7 percent) than control (23.9 percent) (P<0.0001); phone response rates among mail nonrespondents were similar in intervention and control arms (15.8 percent vs 15.7 percent, P=0.90). Targeted bilingual mailings induced 6.5 percent of those who would not have responded to respond by mail and 54.0 percent of those who would have responded in English to respond in Spanish. Beneficiaries with greater Spanish probabilities showed greater increases in response rates, a higher proportion of responses in Spanish, and lower control response rates among. Targeted bilingual mailing of mixed-mode surveys using commonly available surname and address information can efficiently increase representation of this underrepresented group.

Beyond Cisplatin – I

Roughly 25% of patients at diagnosis of urothelial cancer (UC) have at least muscle invasive disease [1] and about half of these have extravesical extension or more advanced disease at that time. Additionally 10–15% of patients who initially have non-muscle invasive UC will subsequently develop muscle invasive or more advanced cancer. The outlook for patients with advanced or metastatic UC, particularly those who do not respond to Cisplatin-based combination chemotherapy regimens is very poor. Moreover, except in adjuvant and neoadjuvant settings, despite objective response rates to Cisplatin based combination therapies of about 50% [2] median survival is only about 15 months and time to progression far briefer, with 5 year survival only being about 15% [3]. Additionally, because of comorbidities and frailty, many patients with advanced UC cannot receive these Cisplatin containing regimens. Relapsing patients respond poorly to additional treatments with median survival of usually <10 months [4]. However two “new” approaches have appeared on the horizon to treat such patients which take advantage of great advances in molecular biology over the past 15 years which give some reason for optimism. The first is targeted molecular therapies which are tied to our increased understanding of urothelial cancer’s molecular and genetic makeup (as illustrated by The Cancer Genome Atlas [TCGA]) [5], and the second, is the emergence of immune checkpoint inhibitors as viable options for systemic treatment of UC. We will focus on the former in this Paper Alert, and will review new articles on the immune modulators in a later edition.

Comparison of Generic, Condition-Specific, and Mapped Health State Utility Values for Multiple Myeloma Cancer

ObjectiveResource allocation informed by cost-utility analysis requires that the benefits be comparable across patient groups and interventions. One option is to recommend the use of one generic utility measure, but this raises the issue of comparability when the preferred measure is inappropriate or unavailable. Many cancer trials do not include generic measures such as the EuroQol five-dimensional (EQ-5D) questionnaire and instead include condition-specific measures and use these to generate utility estimates. We analyze the comparability of generic, condition-specific, and mapped utility values for a multiple myeloma cancer patient data set. MethodsGeneric EQ-5D, condition-specific EORTC-8D, and EQ-5D utility values mapped from the EORTC QLQ-C30 were compared by using psychometric and statistical analysis to determine discrimination across severity groups, responsiveness, and agreement. ResultsGeneric, condition-specific, and mapped utility estimates were responsive over time and show discriminative validity. The EQ-5D had higher responsiveness and detected a greater change across severity groups and treatment periods than did the EORTC-8D but has a higher proportion of responses at full health (12.8%). Differences in the EQ-5D and the EORTC-8D were due at least in part to differences in the classification system. Mapped EQ-5D estimates had a smaller SD and do not reflect the severe range of health states reported by using the EQ-5D. ConclusionsOur findings suggest that condition-specific EORTC-8D or mapped EQ-5D utility estimates are broadly comparable to directly obtained EQ-5D utilities for a multiple myeloma patient data set. However, EORTC-8D estimates captured changes in quality of life for patients in mild health states that were not captured by the EQ-5D, but estimated lower utility gains than did the use of the EQ-5D directly.

Bortezomib, melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event-free survival compared with MP alone. In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose-intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28-day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled. After a median follow-up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles. A weekly infusion of bortezomib associated with lower dose-intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM.

P67 Switch to other nucleos(t)ide analogues therapy in chronic hepatitis B cohort on long-term de-novo combination therapy with lamivudine plus adefovir: efficacy and safety

IntroductionLong-term de-novo combination therapy with lamivudine (LAM) 100 mg/d + adefovir (ADV) 10 mg/d is highly efficient, with no/minimal drug resistance and good safety profile. Tenofovir (TDF) 245 mg/d or...

Measuring interobserver variation in a pathology EQA scheme using weighted κ for multiple readers

BackgroundA Urological Pathology External Quality Assurance (EQA) Scheme in the UK has reported observer variation in the diagnosis and grading of adenocarcinoma in prostatic biopsies using basic κ statistics, which...

Does mode of administration matter? Comparison of online and face-to-face administration of a time trade-off task

Developments in electronic data collection methods have allowed researchers to generate larger datasets at lower costs, but relatively little is known about the comparative performance of the new methods. This paper considers the comparability of two modes of administration (face-to-face and remote electronic) for the time trade-off. Data were collected from a convenience sample of adults (n = 135) randomised to either a face-to-face time trade-off or a remote electronic tool. Patterns of responses were considered. For each sample, standard regression analysis was undertaken to generate a valuation set, which were then contrasted. The pattern of responses differed by mode of administration, with the electronic tool yielding larger standard deviations and higher proportions of responses at -1, 0 and 1. The impact of this on the regression was difficult to disentangle from the high variability around individual scores of states, which is a common feature of responses to time trade-off tasks. Under the scoring algorithms generated by mode of administration, the difference between scores exceeded 0.1 for 100 of the 243 EQ-5D health states. This comparison demonstrates that variability arising from mode of administration needs to be considered in developing health state valuations. While electronic administration has considerable cost advantages, particular attention to the design of the task is required. This has wider implications, as all modes of administration may have mode-specific impacts on the distribution of valuation responses.

Combination of Lenalidomide, Melphalan, Prednisone and Thalidomide (RMPT) in Relapsed/Refractory Multiple Myeloma: Results of a Multicenter Phase II Clinical Trial

Background: In newly diagnosed multiple myeloma (MM) patients the addition of lenalidomide or thalidomide or bortezomib to the standard oral melphalan and prednisone (MP) combination significantly increased response rate and event-free survival. In advanced MM, the 4 drug combination VMPT further improves response rate. In this multicenter open label phase I/II trial the safety/efficacy profile of the 4 drug combination, lenalidomide, melphalan, prednisone and thalidomide (RMPT) was evaluated in patients with relapsed/refractory myeloma.Methods: Oral lenalidomide was administered at 10 mg/day on days 1–21, oral melphalan at 0.18 mg/kg on days 1–4, oral prednisone at 2 mg/kg on days 1–4. Thalidomide was administered at 50 mg/day (Arm A) or 100 mg/day (Arm B) on days 1–28. Each course was repeated every 28 days for a total of 6 courses. Aspirin 100 mg/day was given as a prophylaxis for thrombosis. Maintenance therapy included lenalidomide alone at 10 mg/day on days 1–21.Results: Forthy-four patients, median age 69 years (range 47–80), with relapsed or refractory MM were enrolled. Twenty-six patients received RMPT as second line of therapy, 18 as third line. Twenty patients received prior autologous transplant, 10 thalidomide-based regimen, 9 bortezomib-based regimen and 3 allogeneic stem cell transplant. After a median of 2 courses, 75.8% of patients achieved at least a partial response (PR), including 30% very good partial response (VGPR). Among patients who received RMPT as second line therapy the PR rate was 81.8%, including VGPR 36.4%.Among patients who received thalidomide 100 mg, the PR rate was 93.3% (including VGPR 46.7%) compared to 64.7% of thalidomide 50 mg. The 1-year-progressionfree survival was 48.6% and the 1-year survival from study entry was 90%. Grade 3–4 hematologic adverse events included: neutropenia (66.6%), thrombocytopenia (36.3%) and anemia (30.2%). Grade 3–4 non hematologic adverse events included: infections (21.2%), neurological toxicity (6%) and fatigue (9%). No thromboembolic events were reported.Conclusion: Initial results showed that RMPT is an effective salvage therapy with a high proportion of responses. Toxicities were manageable. No thromboembolic complications were reported.

Factors predictive of outcome in relapsed, refractory multiple myeloma patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)

8048 Background: In relapsed/refractory multiple myeloma (MM) patients, the addition of thalidomide and bortezomib to the standard oral melphalan/prednisone (VMPT) significantly increased response rate and progression-free survival (PFS) (Blood. 2006 Dec 5; [Epub ahead of print]). Baseline parameters which may predict outcome after VMPT have been investigated to identify which patient subgroups most benefit from this drug combination. Methods: Thirty patients with relapsed or refractory MM after 1 or 2 lines of treatment, were treated with six 35-days courses of bortezomib (3 dose levels: 1.0,1.3 and 1.6 mg/m2) on days 1,4,15,22, plus melphalan (6 mg/m2) and prednisone (60 mg/m2) on days 1–5 and thalidomide (50 mg) on days 1–35. Several parameters such as age, β2-microglobulin, C-reactive protein, chromosome 13 abnormalities, albumin, haemoglobin, stage, creatinine, bone marrow plasmacytosis, line of therapy and dosage of bortezomib were analyzed in association with response rate and PFS, using χ2 and Cox model. Results: At least a very good partial response was achieved in 43% of patients and at least a partial response in 67%. The 1-year PFS was 61%, and the 1- year overall survival was 84%. Subgroup analyses did not show any statistical difference between responses and either age, β2 microglobulin, C-reactive protein, chromosome 13 abnormalities, line of treatment or dosage of bortezomib. Serum albumin &lt;3.5 mg/dL was loosely associated with a lower response rate (p=0.09). Factors predictive of shorter PFS were C-reactive protein = 6 mg/L (p=0.02) and 3rd line of therapy (p=0.009). Factors loosely associated with shorter PFS were β2-microglobulin = 3.5 mg/L (p=0.06) and creatinine = 2 mg/dL (p=0.09). No difference in PFS was observed between patients with or without chromosome 13 abnormalities. Conclusions: VMPT induced a high proportion of responses and appeared to overcome the poor prognosis of patients with chromosome 13q deletion. [Table: see text]

Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma

AbstractIn multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

Combination of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) for Relapsed Multiple Myeloma: Results of a Phase I/II Clinical Trial.

BACKGROUND: In newly diagnosed patients, the addition of thalidomide or bortezomib (Velcade™) to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter, open-label, non randomized, phase I/II trial, the safety/efficacy profile of the 4 drug combination, bortezomib (Velcade™), melphalan, prednisone, and thalidomide (VMPT) was evaluated in patients with relapsed/refractory myeloma.METHODS: Bortezomib was administered by IV bolus on days 1, 4, 15, 22 at three dose levels: in the first cohort (10 patients) at 1.0 mg/m2; in the second cohort (10 patients) at 1.3 mg/m2and in the third cohort (10 patients) at 1.6 mg/m2. Oral melphalan was administered at 6 mg/m2 on days 1–5, oral prednisone at 60 mg/m2 on days 1–5. Thalidomide was delivered at 50 mg on days 1–35. Each course was repeated every 35 days for a total of 6 courses.RESULTS: Thirty patients, median age 66 years (range 38–79), with relapsed or refractory myeloma were enrolled. Fourteen patients received VMPT as second line of therapy, 16 as third line. Twenty patients received prior autologous transplant, 10 conventional chemotherapy and 9 thalidomide-based regimens. After a median of 6 courses, 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good partial response (VGPR). Among patients who received VMPT as second line treatment, the PR rate was 79%, and the immunofixation negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 non-hematological adverse events included: infections (5 patients), fatigue (1), vasculitis (1) and peripheral neuropathy (2); no grade 4 toxicities were recorded.CONCLUSIONS: Initial results showed that VMPT is an effective salvage therapy with a high proportion of responses. Toxicities were manageable. The incidence of neurotoxicities was unexpectedly low.

Oral Revlimid® Plus Melphalan and Prednisone (R-MP) for Newly Diagnosed Multiple Myeloma: Results of a Multicenter Phase I/II Study.

Background. Lenalidomide (Revlimid® ) is a novel, orally active immunomodulatory drug, effective in multiple myeloma (MM) patients. In newly diagnosed patients the addition of Thalidomide to the standard oral melphalan and prednisone (MP) significantly increase response rate and event free-survival compared with MP. No data are available on the clinical use of Revlimid® in combination with MP. In this multicenter phase I/II trial, we evaluate the dosing, safety and efficacy of the combination Revlimid® , melphalan and prednisone (R-MP).Methods. Patients (pts) with newly diagnosed symptomatic MM older than 65 years were treated with 9 courses of Revlimid® (5–10 mg/day for 21days every 4–6 weeks) plus MP (melphalan 0.18–0.25 mg/kg and prednisone 2 mg/kg for 4 days every 4–6 weeks) followed by maintenance therapy with Revlimid® alone (10 mg/day for 21days every 4–6 weeks). Four different dose-levels were tested: 1.melphalan 0.18 mg/kg + Revlimid® 5 mg/day; 2.melphalan 0.25 mg/kg + Revlimid® 5 mg/day; 3.melphalan 0.18 mg/kg + Revlimid® 10 mg/day; 4.melphalan 0.25 mg/kg + Revlimid® 10 mg/day. Each cohort included 6 pts, with additional 15 pts enrolled at dose level 3 and 4. All pts received ciprofloxacin and aspirin (100 mg/day) as prophylaxis.Results. Between January and October 2005, 54 pts (median age 71) were enrolled in the study. No DLTs were observed in the first 2 dose-levels. In dose-level 3, one pt experienced DLT (grade 4 neutropenia lasting>7 days). In dose-level 4, three pts showed DLTs (neutropenic fever, grade 3 cutaneous toxicity, pulmonary embolism, delay in the start of cycle 2) during the first cycle. The MTD was defined at dose-level 3 (melphalan 0.18 mg/kg+Revlimid® 10 mg/day).In the dose-levels 3 and 4, after a median of 7 cycles, all patients showed at least a minimal response and 85.4% of patients showed at least a partial response (PR); 41.5% of patients achieved at least a very good partial response (VGPR) and 17.1% of patients reached immunofixation negative complete remission (CR). In the dose-level 3, defined as MTD, 85.6% of patients showed at least a PR, including 52.3% of patients who achieved at least a VGPR and 23.8% who showed immunofixation negative CR. After a median follow up of 9.6 months, the progression free survival (PFS) was 87% at 16 months. FISH informations on chromosome 13q deletion were available in 42 patients (79%): no difference in response rate and PFS was observed between patients with or without 13q deletion.Toxicity was manageable, and occurred more frequently during early cycles. Major grade 3–4 adverse events consisted of hematological toxicities (neutropenia 66%, thrombocytopenia 34% and anemia 17%); major grade 3–4 non-hematological toxicities were cutaneous eruption (10%) and febrile neutropenia (8%). Three cases of tromboembolic events occurred: two of them after aspirin discontinuation, at cycle 7 and during maintenance.Conclusions. R-MP induced a high proportion of responses and appeared to overcome the poor prognosis of patients with chromosome 13q deletion. It was well tolerated, toxicities were predictable and manageable. An update of these data will be presented.

Modification of slot-machine preferences through the use of a conditional discrimination paradigm.

The present experiment investigated the impact of contextually trained discriminations on gambling behavior. Nine recreational slot-machine players were initially exposed to concurrently available computerized slot machines that were each programmed on random-ratio schedules of reinforcement and differed only in color. All participants distributed responding equally across the two slot machines. A conditional discrimination procedure was then used to teach the contextual cues representing the arbitrary relations of "greater than" and "less than." Following contextual cue training, participants were reexposed to the concurrent slot-machine task. After training of the contextual cues, a higher proportion of responses were made to the slot machine that shared formal properties (i.e., color) with the contextual cue representing "greater than."

Longitudinal comparison of factors influencing choice of dental treatment by private general practitioners

Service rate variations and appropriateness of care issues have focused attention on factors that influence treatment decisions. The aims of this study were to examine what factors dentists consider in choosing alternative treatments, the stability of these factors over time and whether stability of treatment choice was related to age of dentist. Baseline data were collected by mailed self-complete questionnaires from a random sample of Australian dentists (response rate = 60.3 per cent, n = 345 private general practitioners provided service data from a typical day) in 1997-1998 and follow-up data were collected in 2004 (response rate = 76.8 per cent, n = 177 matched longitudinal cases). The most frequent factors considered important across six alternative treatment pair choice scenarios were caries rate for 'exam v. x-ray', age of patient for 'preventive v. restorative intervention', cost of treatment for 'crown v. build-up', 'root canal v. extraction' and 'bridge v. denture', and calculus for 'prophylaxis v. scaling'. The only differences over time were (t-test, P < 0.05): higher proportions of responses in the mouth status group at follow-up for 'exam v. x-ray'; higher proportions of responses in the visit history group at follow-up for 'preventive v. restorative intervention'; a lower proportion of responses in the caries group at follow-up for 'crown v. build-up'; and a higher proportion of responses in the treatment constraints group at follow-up for 'prophylaxis v. scaling'. While a wide range of responses were offered as factors influencing the choice of alternative treatments, cost of treatment was a major consideration in situations where significantly cheaper alternatives existed, while patient preference was commonly included as a secondary consideration across a wide range of treatment choice scenarios. The treatment choice responses showed a high degree of stability over time across all age groups of dentists, suggesting that if routines are developed these are established before or soon after graduation as a dentist.

Discourse and Sex as Correlates of Adults' Judgments of Children

This study explored the influence of a child's sex and discourse behavior on the way he is judged by adults. Nine adults listened to 29 5-min. samples of the speech of children, aged 102 to 129 mo., conversing with an adult. They rated each child on 12 7-point bipolar adjective scales (e.g., bad/good, superior/inferior). The associations between the ratings on each scale and the child's sex and discourse behavior were then estimated. The aspects of discourse examined were amount of conversational participation, topic maintenance, and use of three types of speech acts (responses, acknowledgments, and assertions). Children who produced higher proportions of responses were judged as more timid and “bad.” Children who participated more in the conversation and who could maintain a topic for a longer series of turns were judged as more intelligent, above average, and superior. Sex was also associated with the judgments on seven scales.

CONCURRENT RATIO SCHEDULES: FIXED vs. VARIABLE RESPONSE REQUIREMENTS1

Rats were trained on concurrent fixed-ratio variable-ratio or concurrent fixed-ratio mixed-ratio schedules of food reinforcement. The variable-ratio schedule was composed of an arithmetic sequence of 11 ratios that averaged 50; the mixed-ratio schedule consisted of equiprobable ratios of 1 and 99. Fixed-ratio values, varied over experimental conditions, included 25, 35, 50, 60, and 99. The proportion of responses and time allocated to the variable- or mixed-ratio schedule increased as the size of the fixed ratio increased. For most subjects, higher proportions of responses and time were maintained on the fixed-ratio schedule at fixed-ratio values of 25 and 35; higher proportions of responses and time were maintained on the variable- or mixed-ratio schedule at fixed-ratio values of 50 or higher. On concurrent variable-ratio fixed-ratio schedules, the tendency for responding to be maintained exclusively by one schedule was related to the difference in local reinforcement rates obtained from those schedules. Exclusive responding was approximated when the difference in local reinforcement rates obtained from those schedules was large; responding was more evenly distributed between the schedules as the difference in the rates at which reinforcement was obtained from each decreased.