Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter ...randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation.
Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months.
Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption.
Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.
Summary Background Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone ...is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma. Methods This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18–75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3·5 g/m2 on day 1 (n=40) or methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice a day on days 2–3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00210314. Findings All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6–30) and 46% (31–61), respectively, (p=0·006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25–55) and 69% (55–83), respectively, (p=0·009). Grade 3–4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 92% vs six 15%). Four patients died of toxic effects (three vs one). Interpretation In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone. Funding Swiss Cancer League.
Summary Background Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative ...predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. Methods In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov , number NCT01673022 and is completed and closed. Findings Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0–100), and a negative predictive value of 99·6% (97·9–100). The most common grade 3–4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. Interpretation Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. Funding Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.
SpaceOAR, a Food and Drug Administration–approved hydrogel intended to create a rectal–prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation ...therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years.
Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds.
The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02).
The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.
Several clinical and procedural factors have been identified as predictors of early and midterm events after transcatheter aortic valve implantation (TAVI), but incidence and prognostic impact of ...diabetes mellitus (DM), especially insulin treated, on short- and midterm outcomes remain to be defined. All consecutive patients who underwent TAVI at our institutions were enrolled and stratified according to DM status. All-cause mortality at 30 days or in hospital and at follow-up was the primary end point, whereas periprocedural complications, rates of myocardial infarction, stroke, and reintervention at follow-up were the secondary ones. All end points were adjudicated according to the Valve Academic Research Consortium definitions. In all, 511 patients were enrolled: 361 without DM, 78 with orally treated DM, and 72 with insulin-treated DM. Orally treated DM patients were more frequently women, whereas insulin-treated DM patients were younger. Thirty-day Valve Academic Research Consortium mortality was not significantly higher in patients with orally treated DM and insulin-treated DM compared with patients without diabetes (6.4%, 9.7%, and 4.7%, p = 0.09). Bleedings, vascular complications, postprocedural acute kidney injury, and periprocedural strokes were not significantly different in the 3 groups. At midterm follow-up (median 400 days), patients with insulin-treated DM had a significantly higher mortality rate (33.3% vs 18.6%, p = 0.01) and higher myocardial infarction incidence (8.3% vs 1.4%, p = 0.002) if compared with patients without diabetes. Strokes and reinterventions at follow-up were similar in the 3 groups. After multivariable adjustment, insulin-treated DM was independently correlated with death (hazard ratio 2, 95% confidence interval 1.3 to 3.3) and myocardial infarction (hazard ratio 3.73, 95% confidence interval 1.1 to 13). In conclusion, DM does not significantly affect rates of complications in patients who underwent TAVI. Insulin-treated DM, but not orally treated DM, is independently associated with death and myocardial infarction at midterm follow-up and should be included into future TAVI-dedicated scores.
Objectives The aim of this study was to investigate the relationship between platelet reactivity (PR) after a loading dose (LD) of prasugrel and thrombotic events. Background Post-treatment PR has ...been shown to be strongly associated with the occurrence of major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI) in the clopidogrel era. Prasugrel is a new P2Y12 –adenosine diphosphate receptor with a higher potency on PR. Methods A prospective multicenter study included patients who underwent successful PCI for acute coronary syndromes and received prasugrel therapy. Vasodilator-stimulated phosphoprotein (VASP) index was measured after the prasugrel LD. High on-treatment PR was defined as a VASP index ≥50%. MACE included cardiovascular death, myocardial infarction, and definite stent thrombosis at 1 month. Results Three hundred one patients were enrolled. The mean VASP index after 60 mg of prasugrel was 34.3 ± 23.1%. High on-treatment PR was observed in 76 patients (25.2%). Patients experiencing thrombotic events after PCI had significantly higher VASP indexes compared with those free of events (64.4 ± 14.4% vs. 33.4 ± 22.7%; range: 51% to 64% and 5% to 47.6%, respectively; p = 0.001). Kaplan-Meier analysis comparing good responders and patients with high on-treatment PR demonstrated a significantly higher rate of MACE in patients with suboptimal PR inhibition (log-rank p < 0.001). Receiver-operating characteristic curve analysis found a cutoff value of 53.5% of the VASP index to predict thrombotic events at 1 month (r = 0.86, p < 0.001). Patients with minor or major Thrombolysis In Myocardial Infarction unrelated to coronary artery bypass grafting bleeding and those without had similar VASP indexes (30 ± 17.8% vs. 34.3 ± 23%, p = 0.70). Conclusions Despite the use of prasugrel, a significant number of patients undergoing PCI in the setting of acute coronary syndromes do not achieve optimal PR inhibition. Such patients have a higher risk for MACE after PCI.
Summary Background Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the ...best treatment for the disease. We assessed the safety and efficacy of siltuximab—a chimeric monoclonal antibody against interleukin 6—in HIV-negative patients with multicentric Castleman's disease. Methods We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov , number NCT01024036. Findings We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1–54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 47% vs 14 54%) and serious adverse events (12 23% vs five 19%) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days range 1–1031 vs 152 days 23–666). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). Interpretation Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. Funding Janssen Research & Development.
Summary Background Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every ...21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. Methods REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60–80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II–IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0–2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1–14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m2 intravenous rituximab, 750 mg/m2 intravenous cyclophosphamide, 50 mg/m2 intravenous doxorubicin, and 1·4 mg/m2 intravenous vincristine on day 1, and 40 mg/m2 oral prednisone on days 1–5). The primary endpoint was frequency of overall response (complete response CR and partial response PR), which was assessed by18 F-fluorodeoxyglucose (18 F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00907348. Findings 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81–97) achieved a response (42 86% CR; three 6% PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3–4 neutropenia was reported in 87 cycles (31%), grade 3–4 leukopenia in 77 (28%), and grade 3–4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. Interpretation Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. Funding Fondazione Italiana Linfomi and Celgene.
Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A ...retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.
Abstract Objectives The aim of this study was to investigate the individual and combined accuracy of dynamic computed tomography (CT) myocardial perfusion imaging (MPI) and computed tomography ...angiography (CTA) fractional flow reserve (FFR) for the identification of functionally relevant coronary artery disease (CAD). Background Coronary CTA has become an established diagnostic test for ruling out CAD, but it does not allow interpretation of the hemodynamic severity of stenotic lesions. Two recently introduced functional CT techniques are dynamic MPI and CTA FFR using computational fluid dynamics. Methods From 2 institutions, 74 patients (n = 62 men, mean age 61 years) planned for invasive angiography with invasive FFR measurement in 142 vessels underwent CTA imaging and dynamic CT MPI during adenosine vasodilation. A patient-specific myocardial blood flow index was calculated, normalized to remote myocardial global left ventricular blood flow. CTA FFR was computed using an on-site, clinician-operated application. Using binary regression, a single functional CT variable was created combining both CT MPI and CTA FFR. Finally, stepwise diagnostic work-up of CTA FFR with selective use of CT MPI was simulated. The diagnostic performance of CT MPI, CTA FFR, and CT MPI integrated with CTA FFR was evaluated using C statistics with invasive FFR, with a threshold of 0.80 as a reference. Results Sensitivity, specificity, and accuracy were 73% (95% confidence interval CI: 61% to 86%), 68% (95% CI: 56% to 80%), and 70% (95% CI: 62% to 79%) for CT MPI and 82% (95% CI: 72% to 92%), 60% (95% CI: 48% to 72%), and 70% (63% to 80%) for CTA FFR. For CT MPI integrated with CTA FFR, diagnostic accuracy was 79% (95% CI: 71% to 87%), with improvement of the area under the curve from 0.78 to 0.85 (p < 0.05). Accuracy of the stepwise approach was 77%. Conclusions CT MPI and CTA FFR both identify functionally significant CAD, with comparable accuracy. Diagnostic performance can be improved by combining the techniques. A stepwise approach, reserving CT MPI for intermediate CTA FFR results, also improves diagnostic performance while omitting nearly one-half of the population from CT MPI examinations.
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