Higher Probability Of Response Research Articles

Immunosuppressive Treatment Is Associated with Durable Responses and a Survival Advantage in Younger Patients with int-1 Myelodysplastic Syndrome.

Immunosuppressive therapy (IST) can improve cytopenias in selected patients with myelodysplastic syndrome (MDS). Between 1998 and 2004, 129 patients with MDS [94 int-1, 13 int-2, 16 low and 6 high International Prognostic Scoring System (IPSS) stage] were given IST on investigational protocols: 116 received ATG 160mg/kg, 42 with additional cyclosporine (CsA); 13 received CsA alone for up to 6 months. Mean follow-up was 47 (range 0.7–120) months. Previously, we reported a score, using HLA-DR15 type, age and duration of red cell transfusion-dependence to segregate patients into high probability (HP), intermediate probability (IP), and low probability (LP) of hematological response to IST. Here we compare survival, response, and leukemic progression in HP and LP/IP NIH IST-treated patients and in non-IST controls enrolled in the International MDS Risk Analysis Workshop (IMRAW) (Blood 89:2079, 1997). Overall, 29% of NIH IST patients responded: HP patients (median ages for HP and the combined LP/IP] were 49 and 65 yr, respectively) were more likely to respond to IST than LP patients 38/55 (69%) vs 0/71 plus 0/3 IP; p<0.0001) (IP was included in LP group for analysis of survival), with better responses to ATG/CsA than with ATG alone (p=0.015). Neither abnormal cytogenetics nor bone marrow cellularity affected the response rate independent of IPSS int-1 or HP status. Seven of eight (87%) int-1 patients ≤ 60 with trisomy 8 as the sole abnormality and 16/34 with normal cytogenetics (47%) responded to one course of ATG; all 11 int-1 patients with 5q- were >60 years of age and none responded to IST. Marrow cellularity did not influence response to IST. Only two responders relapsed and required re-treatment with ATG; both responded to the second treatment. All but one patient with trisomy 8 increased the percentage of these cells in the marrow following therapy; the two responding monosomy 7 patients showed normal cytogenetics and FISH analysis following response to therapy. Age and IPSS stage were the major factors affecting survival in both treated and untreated patients. The actuarial survival of the 44 IST int-1 patients (median age 54) age ≤ 60 was superior to the untreated 87 int-1 IMRAW patients age ≤ 60 years (median age 48); the projected median survival was >16.4 years for the IST group and 5.2 years for the IMRAW group (p=0.0016), while there was no difference in survival between IST and IMRAW int-1 patients > 60 years of age (p=NS). Leukemic evolution was also decreased in the int-1 IST treated group ≤ 60 years of age compared to the comparable conservatively treated IMRAW group (projected time for 25% pts to develop AML was >16.4 years for IST patients vs 6.9 years for the IMRAW group) (p<0.001). These findings indicate that our IPSS int-1 patients ≤age 60 who received IST had improved survival compared to an untreated historical control group and that combined ATG/CsA gave superior responses compared to ATG alone.

Prospective Targeted Epoietin beta Therapy for Chemotherapy-Associated Anaemia Achieves High Response Rates.

Background: EPO for management of chemotherapy-associated anaemia in patients with cancer is recommended by international guidelines. However, the variable response rate to EPO limits its effective deployment. In the UK, a ‘predictive factor testing service (PFTS)' (supported by Roche) ascribes a low, moderate or high probability of response to EPO therapy - based on a two step holostic evaluation: (i) the state of erythropoiesis (serum EPO in relation to Haemoglobin concentration [Hb]; reticulocyte count and %); (ii) the need for IV iron to support erythropoiesis (MCH, reticulocyte Hb and serum ferritin).Aims: To assess the utility of the PFTS and iron supplementation in improving response rates to EPO used for chemotherapy-induced anaemia.Patients and methods: an ASH/ASCO based-guideline for EPO therapy was developed. The criteria were: patients with CLL, myeloma and NHL (excluding diffuse large B-cell NHL); Hb < 10 g/dl; on chemotherapy; a moderate or high PFTS score. EPO dose: 30,000 units s.c. once weekly, increased to 60,000 at 4 weeks if there was no response (NR: Hb increase of < 1g/dl over baseline). EPO was stopped at 8 weeks if NR. Minor (MiR) and major (MaR) responses were defined as: Hb increase of 1 - 2 and > 2 g/dl, respectively. Iron dose: iron sucrose (Venofer) 200mg IV weekly for 3 doses, repeated as indicated. Two successive 6-month, prospective audits (I and II) were performed, which differed only in that audit II, in addition to the PFTS score, also took into account the recommendation for IV iron supplementation. We retrospectively audited a 6-month period preceding the guideline introduction and analysed Hb response and red blood cell transfusion (RBC TX) of those patients who would have been eligible for EPO.Results: Prospective audit (I) - 12 patients received EPO; 8 (66%) responded. Hb levels and RBC Tx are shown in table 1. Prospective audit (II) - 25 patients qualified for EPO; 23 patients (92%) responded, with 17 MaR. Hb levels and RBC Tx are shown in table 1. Iron supplementation: Nine patients received IV iron. Seven patients received IV iron from week 0 and all responded; one patient from week 4, who converted from NR to MaR; and one patient received IV iron at week 8, but failed to maintain a MiR. Thus, 8/9 patients given IV iron responded (7 MaR) and 5 had EPO dose reductions. EPO dosage: Overall, there was a dose reduction of EPO in 8 patients, and a dose increase in 4 (2 responses achieved). The average EPO dose was 340,000 units/patient.The 6-month retrospective audit data is also shown in table 1.Conclusion: an holistic approach, using readily available laboratory parameters, to assess erythropoietic status and the need for IV iron supplementation has increased the response rate to EPO from 66 to 92%. The limited data presented here suggests similar response rates can be achieved in cancer as in renal use of EPO. This approach to targeted EPO therapy warrants further investigation and validation.Hb and RBC Tx outcomes both with and without EPOPatients (n)Mean Hb weeks 0 /4 /8 /12 RespondersMean Hb weeks 0 /4 /8 Non respondersTotal RBC Tx (units /patient)Retro. Audit17#8.0*5.5Prosp. Audit - I (R)88.6 /10.3 /− /−1.1Prosp. Audit – I (NR)48.9 /8.3 /−6.0Prosp. Audit – II (R)239.5 /10.5 /11.6 /11.80.8Prosp. Audit – II (NR)28.9 /8.6 /7.64.5#: patients who would have been eligible for EPO ; *: mean Hb at each visit; Retro. Audit: retrospective audit ; Prosp. Audit: prospective audit; R: responders ; NR: non responders

Antimicrobial Susceptibility Breakpoints

Since the early 1960s, considerable advancements have been made to standardize and provide quality assurance for clinical susceptibility testing procedures of antimicrobial agents. Controversy, however, remains as to the interpretation of clinical laboratory susceptibility test results. While some feel susceptibility breakpoints should only detect resistance mechanisms, others believe they should predict a high probability of clinical response. This has resulted in confusion among clinicians, as it has been apparent for some time that there can be discordance between interpretive test results and clinical response to therapy (generally cures of infections caused by resistant pathogens). Nearly simultaneous with the beginning of the standardization process for clinical susceptibility testing procedures, the first penicillin-resistant Streptococcus pneumoniae isolates were detected. During the ensuing decades, penicillin-resistant pneumococci became a greater clinical concern, resulting in macrolides emerging as safe therapeutic alternatives to beta-lactam agents for the treatment of community-acquired respiratory tract infections. During the last 10 years, the incidence of pneumococcal isolates with elevated macrolide minimum inhibitory concentration (MIC) values has also increased, yet the debate over the clinical meaning of these statistics persists. The youthful science of pharmacokinetics-pharmacodynamics provides a useful platform to determine which pneumococcal strains with elevated MIC values can be treated with contemporary dosing regimens and also facilitates the proper selection of antimicrobial breakpoints for all antimicrobial classes, including the newer macrolides.

Immunosuppression for Myelodysplastic Syndrome: Association between a Score Based on Presenting Features and Long-Term Survival.

Immunosuppressive therapy (IST) can improve cytopenias in selected patients with myelodysplastic syndrome (MDS). Between 1998 and 2004, 133 patients with MDS (FAB classification RA, RA, or RARS ) were enrolled in NHLBI IST protocols: 74 received ATG (Pharmacia, 40mg/kg x 4 days); 43 received a combination of ATG and CsA Fourteen received cyclosporine (CsA) to maintain levels above 100 ng/ml for up to 6 months. Average follow-up was 41 months (range 1 week to 10 years). Previously, we reported that responses to ATG alone were most likely in HLA DR15 individuals of younger age and with a shorter duration of red cell transfusion-dependence. We applied a score based on these factors to assign patients into high probability (HP) and low probability (LP) of response to immunosuppression. Here, we use the score to analyze effectiveness of different IST and compare survival, response, and leukemic progression in HP and LP patients. Patients with HP were more likely to respond to any IST schedule than were patients with LP (85% vs 8%; p<0.0001) and they had longer survival when compared to LP patients (90% vs 38% alive at 3 years; P<0.0001). There were no differences in response or survival between HP patients treated with ATG or with ATG/CsA; CsA-alone treated patients were too few for survival evaluation. Other factors positively affecting survival were response to therapy (p=.0004) and female sex (p=0.03). Neither bone marrow cellularity nor cytogenetics independently affected response or survival; patients with monosomy 7 and 5q- were in the LP group while patients with trisomy 8 predominated in the HP group. In general, patients with trisomy 8 and 5q- survived comparably to patients with normal cytogenetics, but patients with monosomy 7 had statistically shorter survival (p=0.007) than patients with normal cytogenetics or trisomy 8. The scoring system further segregated 95 patients within IPSS int-1 into a HP group with 92% 3 year survival vs 39% for LP patients (p<.0001). Mortality in the HP group was a consequence of cytopenias, while most deaths in the LP were from leukemia: only 2/50 (4%) of patients in the HP group developed leukemia compared with 30% of LP patients followed for a mean of 57 months (hazard ratio = 11; 95% CI 2.566 to 12.18; p< P<0.0001). These findings suggest that immunological characteristics may be independent factors determining the outcome of IST in patients with MDS. [Display omitted]

Serotonin transporter gene polymorphism and response to lithium augmentation in patients with treatment-refractory depression

The promoter region of the serotonin transporter gene (5HTTLPR) displays a polymorphism, which consists in the presence or absence of a 44 base-pair segment producing either a long (l), or short (s) allele. Previous studies have suggested a superior response of l-allele carriers to selective serotonin reuptake inhibitors (1). We examined the association of the 5HTTLPR polymorphism with the response to lithium augmentation, which is thought to enhance serotoninergic activity (2). Posthoc genotyping was performed in 46 patients with treatment-resistant depression who had undergone a 4-week lithium augmentation treatment. One subgroup was treated according to a stepwise treatment algorithm (SSTR) [n=28], the other was treated as usual (TAU) [n=18]. Survival analysis revealed a significantly more rapid response and a higher probability of response in carriers of the ss-genotype, but only in TAU patients (p<0,01). Ss-carriers might more than others profit by early lithium augmentation. The absence of this difference in SSTR patients may be due to factors selecting a higher degree of refractoriness throughout the highly standardized treatment procedure before reaching the lithium augmentation step.

Once‐weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production

Once‐weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production

Maintenance of High-Frequency Transmission at Purkinje to Cerebellar Nuclear Synapses by Spillover from Boutons with Multiple Release Sites

Cerebellar Purkinje neurons maintain high firing rates but their synaptic terminals depress only moderately, raising the question of how vesicle depletion is minimized. To identify mechanisms that limit synaptic depression, we evoked 100 Hz trains of GABAergic inhibitory postsynaptic currents (IPSCs) in cerebellar nuclear neurons by stimulating Purkinje axons in mouse brain slices. The paired-pulse ratio (IPSC 2/IPSC 1) of the total IPSC was ∼1 and the steady-state ratio (IPSC 20/IPSC 1) was ∼0.5, suggesting a high response probability of postsynaptic receptors, without an unusually high release probability. Three-dimensional electron microscopic reconstructions of Purkinje boutons revealed multiple active zones without intervening transporters, suggestive of “spillover”-mediated transmission. Simulations of boutons with 10–16 release sites, in which transmitter from any site can reach all receptors opposite the bouton, replicated multiple-pulse depression during normal, high, and low presynaptic Ca influx. These results suggest that release from multiple-site boutons limits depletion-based depression, permitting prolonged, high-frequency inhibition at corticonuclear synapses.

Radiotherapy and oral capecitabine in the preoperative treatment of patients with rectal cancer: rationale, preliminary results and perspectives.

Preoperative radiotherapy alone or combined with chemotherapy increases the chances of tumor down-staging and down-sizing and facilitates sphincter-sparing surgical procedures, thereby improving survival and quality of life. Though several innovative agents are being investigated in combination with radiotherapy, 5-fluorouracil in continuous infusion remains the common schedule used in the preoperative chemoradiation setting. However, the protracted venous infusion of 5-fluorouracil requires specialized pumps and long-term venous access, which makes patients susceptible to infections or thrombosis. To overcome the 5-fluorouracil infusion-related problems, oral 5-fluorouracil precursors and inhibitors of 5-fluorouracil degradation have been developed and explored. These include oral fluoropyrimidines such as tegafur (ftorafur), uracil plus tegafur (UFT), S-1, eniluracil and the oral carbamate capecitabine. Phase I trials have demonstrated the feasibility of the capecitabine-radiotherapy combination with respect to the bolus or infusion 5-fluorouracil-radiation approach and have defined the optimal dose of capecitabine during radiotherapy (825 mg/m2/day through a bid administration). Severe hand-foot syndrome occurred in 7-15% of patients, representing the most commonly observed toxicity. It is noteworthy that severe diarrhea with capecitabine during radiotherapy was not common. Leukopenia frequently occurred but was mild and reversible. Phase II trials, although limited in number, have evidenced a high probability of pathological complete response (up to 31%) with capecitabine and radiation, with an increased probability of sphincter-sparing surgical procedures. Although it is too early to assess whether oral capecitabine will be able to replace iv 5-fluorouracil in combination with preoperative radiotherapy, the NSABP will address this question in a large randomized trial. Finally, phase I-II trials evaluating escalating doses of capecitabine associated with oxaliplatin or irinotecan with radiotherapy are being carried out to assess the maximum-dose tolerance and efficacy in the preoperative setting. It is likely that these new chemoradiation associations might increase rectal cancer clearance, hopefully without increasing toxicity.

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life.

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo </= 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S-Epo > 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

The Costs and Efficacy of Liposomal Doxorubicin in Platinum-Refractory Ovarian Cancer in Heavily Pretreated Patients

Objective. In clinical practice, chemotherapy agents demonstrating modest second-line activity against platinum-refractory epithelial ovarian cancer (PROC) are frequently used in patients who have received multiple prior chemotherapy agents. Whether the response rates reported in selected patients can be expected in heavily pretreated patients is not known. Similarly, the costs of palliative chemotherapy are not known. We sought to determine the response, survival, and predictors of response in an unselected cohort of PROC patients receiving liposomal doxorubicin (LD) for relapsed disease, and the overall costs of delivering liposomal doxorubicin in this setting.Methods. In a cohort of 62 consecutive patients who initiated LD as second- or greater-line therapy for PROC, the following variables were examined: age, number of prior regimens for relapse disease, duration of first clinical remission, time from last prior treatment, dose intensity of LD received, response/clinical benefit, time to progression, toxic effects, and survival. Multivariate analyses were used to identify predictors of clinical benefit and overall survival. Direct medical charges were calculated and converted to costs, and major cost drivers determined.Results. Sixty-two patients received a total of 174 cycles of LD. The mean number of cycles per patient was 2 (range, 1–8); the median number of prior regimens for recurrent PROC was 2 (range, 0–8); and the median duration of the first clinical remission was 6 months. Median dose intensity of LD delivered was 11.4 mg/m2/week (range, 2.8–16.7 mg/m2/week). Nine of sixty-two patients (14.5%) had an objective clinical response by CA-125 and/or CT scan (95% confidence interval, 6–23%). Grade 3/4 toxicity occurred in 11% of patients. In the full cohort, median time to progression was 2.2 months, and median overall survival, 9.6 months (range, 0.2–26 months). Dose intensity was the only independent predictor of overall response. Duration of first clinical remission and number of prior salvage regimens were associated with longer overall survival. The mean total direct medical cost per cycle of LD was $5763, and the major cost drivers were hospitalizations and drug acquisition/delivery costs.Conclusion. LD is an active agent in PROC, even when used as greater-than-second-line therapy. Among heavily pretreated patients, delivering a dose intensity of at least 9.0 mg/m2/week was associated with a higher probability of response. The cost per cycle of LD is driven by hospitalizations and drug acquisition/delivery costs.

Early versus delayed inpatient stroke rehabilitation: A matched comparison conducted in Italy

Objective: To assess the specific influence of onset-admission interval (OAI) on rehabilitation results.Design: A case-control study in consecutive stroke inpatients, enrolled in homogeneous subgroups, matched for age (within 1 year) and Barthel Index (BI) score at admission, and different for OAI to the rehabilitation ward. The short OAI group began rehabilitation treatment within the first 20 days from stroke, medium OAI group between days 21 and 40, and long OAI between days 41 and 60.Setting: Rehabilitation hospital.Patients: One hundred forty-five patients with sequelae of first stroke.Main Outcome Measures: Efficiency (average increase in BI per day), effectiveness (proportion of potential improvement achieved during rehabilitation) of treatment, and percentage of low- and high-response patients, calculated on BI, were evaluated. Odds ratios (ORs) of dropouts and of poor and excellent therapeutic response were also quantified.Results: The short OAI subgroup had significantly higher effectiveness of treatment than did the medium (p < .05) and the long OAI groups (p < .005). Beginning treatment within the first 20 days was associated with a significantly high probability of excellent therapeutic response (OR = 6.11; 95% confidence interval [CI], 2.03–18.36), and beginning later was associated with a similar risk of poor response (OR = 5.18; 95% CI, 1.07–25.00). On the other hand, early intervention was associated with a five times greater risk of dropout than that of patients with delayed start of treatment (OR = 4.99; 95% CI, 1.38–18.03). The three subgroups were significantly (p < .05) different regarding the percentage of low and high responders.Conclusion: Our results showed a strong association between OAI and functional outcome.

Monitoring individual response to hormone replacement therapy with bone markers

Hormone replacement therapy (HRT) induces a rapid decrease in biochemical markers of bone turnover that correlate with a subsequent increase in bone mineral density (BMD). To determine the utility of bone markers in the management of postmenopausal women receiving HRT, we analyzed the relationship between changes in four markers (serum osteocalcin and bone alkaline phosphatase [BAP], serum and urinary C-telopeptide of type I collagen [CTX]) and changes in spine BMD in 569 women treated for 2 years with different doses of a matrix transdermal 17β-estradiol patch in two placebo-controlled trials. Using a logistic regression model, we found that both the percent change from baseline and the actual value of resorption markers at 3 and 6 months of treatment were predictive of BMD response at 2 years. Comparable results were obtained with formation markers at 6 months only. We determined the sensitivity, probably of positive BMD response, and corresponding cutoff value of markers at 3 and 6 months with a specificity set at a level of 0.90, so that <10% of women classified with markers as responders, i.e., as having a subsequent increase in BMD at 2 years ≥2.26%, would be false positive. All markers provided a high probability of positive BMD response ranging from 0.82 to 0.91, with a sensitivity higher for resorption than for formation markers, and sometimes improved in a model combining the percent change and the actual value of marker under HRT. For example, a decrease in serum CTX ≥ 33% at 3 months of HRT provided a 68% sensitivity and 87% probability of positive BMD response at 2 years for a 90% specificity. At 6 months, a decrease in urinary CTX ≥ 53% provided a 68% sensitivity and 91% probability of a positive BMD response for a 90% specificity. Half of false-negative cases at 3 months will be correctly identified by a subsequent urinary CTX measurement at 6 months. We conclude that the short-term change in bone markers reflects long-term changes of BMD in postmenopausal women treated with HRT. Our data suggest that bone turnover markers can be used to monitor the BMD response to HRT at the individual level. Whether such monitoring could improve long-term compliance to HRT should be tested prospectively.

Song recognition in female bushcrickets Phaneroptera nana.

Unlike most acoustic systems evolved for pair formation, in which only males signal, in many species of phaneropterine bushcrickets both sexes sing, producing a duet. We used the duetting species Phaneroptera nana as a model to explore the cues in the male's song that elicit the female's phonoresponse. Different synthetic male songs (chirps containing 2-6 pulses) were presented to Ph. nana females, and their acoustic responses were recorded. The threshold of the female response is lowest at 16 kHz (best frequency), coinciding with the dominant frequency of the male song. The specific amplitude pattern of consecutive pulses in the song of the male is not a critical factor in his signal. That is, songs with both a normal and a reversed order of pulses equally elicit a female response. By systematically deleting pulses from the synthetic male chirp, we found that at least two pulses are needed to elicit a female reply. Under no-choice conditions, increasing the number of pulses did not result in a higher probability of response and did not change the latency of the response; i.e. two pulses are necessary and sufficient to elicit a female response. The range of pulse duration that elicits a female response is 0.2-25 ms, and the inter-pulse silent interval ranges from 5 to 30 ms.

Serum level of soluble intercellular adhesion molecule 1 in patients with chronic liver disease related to hepatitis C virus: A prognostic marker for responses to interferon treatment.

Intercellular adhesion molecule 1 (ICAM-1) is a marker of inflammation and tissue damage. Levels of soluble ICAM-1 (sICAM-1) were measured in 71 patients with chronic C hepatitis treated with interferon (IFN)-alpha-2a, at baseline and at every 3 months of therapy, and in 42 normal control subjects. The levels of sICAM-1 were significantly higher in the patient than in the control subject group, particularly among cirrhotics. Baseline sICAM-1 levels were similar in responders and nonresponders. By contrast, the concentration of sICAM-1 decreased significantly only in responders during the first 3 months of therapy. The probability of response to treatment, analyzed by Kaplan-Meier analysis, was much higher in the group showing a decrease of sICAM-1 than in the patients who did not show such a decrease. In conclusion, a "longitudinal" evaluation of serum levels of sICAM-1 in the first period of treatment is particularly useful in the identification of patients with high significant probability of response to treatment.

Ambamustine in the Second-Line Treatment of Patients With Small-Cell Lung Cancer

Despite a high probability of response to first-line chemotherapy, most patients with small-cell lung cancer (SCLC) will eventually have progression of their disease because of the development of resistant disease. Second-line testing of new drugs is an accepted research strategy in SCLC. In this context, the Italian Lung Cancer Task Force (FONICAP) has tested a new synthetic bifunctional alkylating agent, Ambamustine, with preliminary evidence of activity in other solid tumors. Patients with measurable SCLC, progressive after one first-line chemotherapy regimen (either "sensitive" or "refractory"), were eligible for the study. Ambamustine was administered at the dose of 2 mg/kg as a 1-hour intravenous infusion on day 1 every 21 days. The dose was to be increased to 3 mg/kg if no grade IV toxicity and complete hematologic recovery had occurred by day 22. Sample size was calculated according to a two-stage optimal Simon's design. Seventeen patients were entered into the study. Twelve patients were refractory to prior chemotherapy; 12 had extensive disease; the median age was 64 years (range: 46-75 years) and the median performance status was 1. Among 13 patients who received more than one cycle, 9 patients could increase Ambamustine dose from 2 to 3 mg/kg. No objective response was observed: one patient obtained a 50% regression of the primary tumor with contemporary disease progression in the liver and was qualified as having progressive disease. The treatment was well tolerated: grade IV leukopenia occurred in only 1 patient; grade III anemia occurred in 17.6%, grade III leukopenia in 11.8%, and grade III thrombocytopenia in 23.5%. Nonhematologic toxicity was minimal. Ambamustine, at the dose and schedule used in this study, is well tolerated in pretreated patients with SCLC but has no significant antitumor activity in this unfavorable group of patients.

The role of repeat transplantation of haemopoietic stem cells and adoptive immunotherapy in treatment of leukaemia relapsing following allogeneic transplantation.

The role of repeat transplantation of haemopoietic stem cells and adoptive immunotherapy in treatment of leukaemia relapsing following allogeneic transplantation.

Recombinant human erythropoietin (rhEPO) in the management of anemia and fatigue associated with hematologic malignancies and the myelodysplastic syndromes

Anemia is a common complication in patients with chronic lymphocytic leukemia, non- Hodgkin's lymphoma, multiple myeloma, and the myelodysplastic syndromes (MDS). Al though an inappropriately low serum erythro poietin level often correlates with anemia in these malignancies, this is not always the case. Nevertheless, recombinant human erythropoie tin (rhEPO) has been studied in various hemato logic malignancies and in MDS to correct the anemia and avoid the use of red blood cell transfusions. Clinical benefit has been demon strated in most hematologic malignancies or disorders; however, patients with refractory anemia with ringed sideroblasts, a subset of MDS, are resistant to rhEPO therapy. Interest ingly, the combined use of rhEPO and granulo cyte colony-stimulating factor appears to en hance the response in this subset of patients. Most studies did not include extensive phar macoeconomic or quality of life analyses. Thus, it will be important to define more clearly the lowest effective dose and to identify patients with a high probability of response.

Donor Leukocyte Infusions Are Effective in Relapsed Multiple Myeloma After Allogeneic Bone Marrow Transplantation

AbstractDonor leukocyte infusions (DLI) can induce sustained remissions in patients with acute and chronic myeloid leukemia who relapse after allogeneic bone marrow transplantation (allo-BMT). Also, in multiple myeloma (MM), incidental reports have indicated the existence of a graft-versus-myeloma effect (GVM) induced by allo-reactive T cells. We performed a retrospective study in a larger group of MM patients to characterize better the effect, prognostic factors, and toxicity of this new treatment modality. Thirteen patients with relapsed MM after allo-BMT were studied. Patients received a total of 29 DLI with T-cell doses ranging from 1 × 106/kg to 33 × 107/kg. Repetitive courses, sometimes with escalated cell doses, were undertaken in case of no response to or relapse after DLI. Eight of 13 patients responded: 4 patients achieved a partial remission and 4 patients achieved a complete remission. Dose escalation was effective in 3 patients. The time to response was median 6 weeks (range, 4 to 10 weeks). Major toxicities were secondary to acute and chronic graft-versus-host disease (GVHD), which occurred in 66% and 56% of all patients and in 87% and 85% of the responders, respectively. Two responding patients developed fatal BM aplasia. The only prognostic factors for response were a T-cell dose greater than 1 × 108/kg and the occurrence of GVHD. Seven of nine patients developing acute GVHD responded, as compared with only 1 response in the 4 patients without GVHD and 6 of 7 patients with chronic GVHD responded, whereas no response was observed in the 5 patients without chronic GVHD. DLI are effective in a high percentage of patients with relapsed MM after allo-BMT, although it is associated with a high treatment-related toxicity. The dose of T cells used may be important in determining the GVM effect, with the highest probability of response after infusion of more than 1 × 108 T cells. Because the optimal individual dose may vary, patient-adapted therapy consisting of repeated infusions with escalating dose of donor leukocytes until maximum response is achieved may therefore be preferable.

Partial substitution of cisplatin with carboplatin in combination with etoposide in advanced non-small cell lung cancer (NSCLC): a multicentric randomised Phase II trial

Seventy previously untreated patients with advanced NSCLC were randomised, after stratification for stage (IIIB vs. IV) and Performance Status (0–1 vs. 2), to receive either treatment A: CDDP 40 mg/m 2 + VP16 100 mg/m 2 day 1–3 (37 patients); or treatment B: CBDCA 250 mg/m 2 day 1 + CDDP 30 mg/m 2 day 2, 3 + VP16 100 mg/m 2 day 1–3 (33 patients). Therapy was recycled on day 29 in both arms. The two arms were well balanced for the main pretreatment characteristics. Sixty-six patients (32 with Stage IIIB and 34 with Stage IV disease) were evaluable for toxicity and response (arm A = 34, arm B = 32), while four ineligible patients were excluded from analysis. Acute toxicity was assessed at recycling. Non-hematologic toxicity was higher in arm A. However, the reduction of nephrotoxicity (9% vs. 23%) in arm B was lower than expected. Leukopenia (15 vs. 5 patients) or thrombocytopenia (7 vs. 0 patients) of any grade affected more patients of arm B. Moreover, Grade 3–4 leukopenia (six patients) or thrombocytopenia (four patients) was observed only in arm B. Seventeen patients responded: 11 34 (32%; 95% C.I. = 17–50%) in arm A, and 6 32 (19%; 95% C.I. = 7–36%) in arm B. Median survival times of 40 and 34 weeks, respectively, were reported in arm A and B. Stage IIIB and squamous cell histology were associated with a higher probability of response. In conclusion, the partial replacement of CDDP with CBDCA in combination with VP16 slightly improves the tolerance of the treatment in terms of nephro- and neurotoxicity; however, it induces a significant increase in hematologic toxicity. In view of this unfavourable toxicologic profile and of the discouraging response rate observed, this regimen cannot be recommended as standard treatment in advanced NSCLC.

Proper sequence of endocrine therapies in advanced breast cancer.

Tamoxifen (TAM) is widely used as therapy in early breast cancer and first-line endocrine therapy in metastatic disease. Despite this therapy, many patients relapse and an important question is: What is the preferred sequence of endocrine therapies in metastatic breast cancer (MBC). While treatment with oophorectomy, aminoglutethimide or progestins have been a logical choice after failure to Tamoxifen recent research has extended the options for endocrine therapy of MBC. New selective aromatase inhibitors (AI) are now in clinical use. The first commercially available of these inhibitors is LENTARON. The active ingredient of LENTARON is a steroidal compound 4-OH-androstenedione: Formestane. It is presented as a depot formulation and applied as an i.m. injection of 250 mg every second week. Previous findings from phase II trials have indicated similar activity as other endocrine treatment modalities. Clinical investigations in properly conducted phase III trials have revealed that the efficacy of LENTARON matches the results which can be obtained with TAM and Megace in trials of first and second-line endocrine therapy. Fifty-four and 51% of MBC patients, respectively, did benefit from therapy with LENTARON in these phase III trials by achieving objective responses or stable disease. Moreover, similar overall survival was seen. The systemic tolerability of LENTARON is comparable to that of TAM, and LENTARON seems less systemically toxic than Megace. Local side effects occured in approximately 7% of the patients giving rise mainly to pain or inflammation at the injection site. In elderly patients, LENTARON therapy assures compliance and no interference with other oral medications has been observed. In conclusion, since the endocrine treatment modalities are comparable in terms of efficacy the optimal sequence of these treatments is based upon differences in tolerability. Patients previously treated with Tamoxifen and with a high probability of a further endocrine response could preferably be treated with a selective AI like LENTARON as second-line endocrine therapy followed by a progestin upon progression in responders.