Summary Background Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of ...the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. Methods For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day short infusion, days 1 and 2 plus ifosfamide 3 g/m2 per day days 1, 2, and 3, repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2 , given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov , number NCT01710176 , and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010–023484–17, and is closed to patient entry. Findings Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 34% with undifferentiated pleomorphic sarcoma; 64 22% with high-grade myxoid liposarcoma; 70 24% with synovial sarcoma; 27 9% with malignant peripheral nerve sheath tumour; and 28 10% with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75–28·20), the projected disease-free survival at 46 months was 62% (95% CI 48–77) in the standard chemotherapy group and 38% (22–55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22–3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 86%), anaemia (24 19%), and thrombocytopenia (21 17%); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 26%). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. Interpretation In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. Funding European Union grant (Eurosarc FP7 278472).
Summary Background Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of ...leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. Methods In a phase I–II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per μL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00423124. Findings From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17–66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25–73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Interpretation Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. Funding MolMed SpA, Italian Association for Cancer Research.
Summary Background A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI ...lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis. Methods We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R2 value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses. Findings We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0·52; R2 =0·71), much the same as was previously estimated (pinteraction =0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6–9 months) can also predict the effects on relapses over longer follow-up periods (12–24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials. Interpretation Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults. Funding None.
Transaortic Chordal Cutting Ferrazzi, Paolo, MD; Spirito, Paolo, MD; Iacovoni, Attilio, MD ...
Journal of the American College of Cardiology,
10/2015, Letnik:
66, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) and mild septal hypertrophy, mitral valve (MV) abnormalities may play an important role in MV ...displacement into the left ventricular (LV) outflow tract. Therefore, isolated myectomy may not relieve outflow obstruction and symptoms, and MV replacement is often the surgical alternative. Objectives This study sought to assess the clinical and hemodynamic results of cutting thickened secondary MV chordae combined with a shallow septal muscular resection in severely symptomatic patients with obstructive HCM and mild septal hypertrophy. Methods Clinical features were compared before surgery and at most recent clinical evaluation in 39 consecutive patients with obstructive HCM. Results Over a 23 ± 2 months follow-up, New York Heart Association functional class decreased from 2.9 ± 0.5 pre-operatively to 1.1 ± 1.1 post-operatively (p < 0.001), with no patient in class III at most recent evaluation. The resting outflow gradient decreased from 82 ± 43 mm Hg to 9 ± 5 mm Hg (p < 0.001) and septal thickness decreased from 17 ± 1 mm to 14 ± 2 mm (p < 0.001). No patient had MV prolapse or flail and 1 had residual moderate-to-severe MV regurgitation at most recent evaluation. MV geometry before and after surgery was compared with that of 25 consecutive patients with similar clinical profile and septal thickness that underwent isolated myectomy. After adjustment for differences in pre-operative values between the groups, the post-operative anterior MV leaflet-annulus ratio was 17% greater and tenting area 24% smaller in patients with chordal cutting, indicating that MV apparatus had moved to a more normal posterior position within the LV cavity, preventing MV systolic displacement into the outflow tract and outflow obstruction. Conclusions This procedure relieves heart failure symptoms, abolishes LV outflow gradient, and avoids MV replacement in patients with obstructive HCM and mild septal thickness.
Summary Background Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is ...controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. Methods In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18–70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov , number NCT00433420. Findings Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range IQR 4·5–6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79–84) in patients treated every 2 weeks and 76% (74–79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65–0·92; p=0·004); overall survival rates at 5 years were 94% (93–96) and 89% (87–91; HR 0·65, 0·51–0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75–81) in the FEC-P groups and 79% (76–82) in the EC-P groups (HR 1·06, 0·89–1·25; p=0·561); overall survival rates at 5 years were 91% (89–93) and 92% (90–94; 1·16, 0·91–1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3–4 of anaemia (14 1·4% of 988 patients vs two 0·2% of 984 patients; p=0·002); transaminitis (19 1·9% vs four 0·4%; p=0·001), and myalgias (31 3·1% vs 16 1·6%; p=0·019), and decreased rates of grade 3–4 neutropenia (147 14·9% vs 433 44·0%; p<0·0001). Addition of fluorouracil led to increased rates of grade 3–4 neutropenia (354 34·5% of 1025 patients on FEC-P vs 250 24·2% of 1032 patients on EC-P; p<0·0001), fever (nine 0·9% vs two 0·2%), nausea (47 4·6% vs 28 2·7%), and vomiting (32 3·1% vs 15 1·4%). Interpretation In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome. Funding Bristol-Myers Squibb, Pharmacia, and Dompè Biotec.
Objective The role of surgery in the treatment of preoperatively diagnosed N2 non–small cell lung cancer remains controversial. This study sought significant prognostic factors to select candidates ...for surgery and assess prognosis. Methods The study population included 277 patients who underwent primary resection (192) or induction chemotherapy followed by surgery (85) for preoperatively diagnosed, potentially resectable N2 non–small cell lung cancer. N2 descriptors were prospectively recorded. Kaplan–Meier curves were used to evaluate survival, and statistical significance of differences between curves was assessed by log-rank test. Cox regression was used for multivariate analyses. Results Preoperative significant prognostic factors were number of mediastinal node levels involved ( P < .001), symptom severity ( P = .013), clinical T ( P = .041), and induction chemotherapy ( P = .001). Three groups with different prognoses were based on individual prognostic score. The group that did best had a median survival of 29.6 months. Postoperative predictors of survival were pathologic T ( P = .003), tumor residue ( P = .034), and number of mediastinal nodes involved ( P < .001). Of 3 groups with different prognoses, the most favorable had a median survival as long as 42 months. Conclusion This study provides a practical tool that uses significant prognostic factors to predict which patients with preoperatively diagnosed N2 non–small cell lung cancer have better prognoses. Because patients with the favorable prognostic factors showed good long-term survival and excellent local disease control, surgery should still play an important role in the multimodality treatment of these patients.
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