Adjacent cartilage tissue structure after successful transplantation: a quantitative MRI study using T2 mapping and texture analysis.

OBJECTIVES: The aim of this study was to assess the texture of repair tissue and tissue adjacent to the repair site after matrix-associated chondrocyte transplantation (MACT) of the knee using gray-level co-occurrence matrix (GLCM) texture analysis of T2 quantitative maps. METHODS: Twenty patients derived from the MRI sub-study of multicenter, single-arm phase III study underwent examination on a 3 T MR scanner, including a T2 mapping sequence 12 and 24 months after MACT. Changes between the time points in mean T2 values and 20 GLCM features were assessed for repair tissue, adjacent tissue, and reference cartilage. Differences in T2 values and selected GLCM features between the three cartilage sites at two time points were analyzed using linear mixed-effect models. RESULTS: A significant decrease in T2 values after MACT, between time points, was observed only in repair cartilage (p < 0.001). Models showed significant differences in GLCM features between repair tissue and reference cartilage, namely, autocorrelation (p < 0.001), correlation (p = 0.015), homogeneity (p = 0.002), contrast (p < 0.001), and difference entropy (p = 0.047). The effect of time was significant in a majority of models with regard to GLCM features (except autocorrelation) (p ≤ 0.001). Values in repair and adjacent tissue became similar to reference tissue over time. CONCLUSIONS: GLCM is a useful add-on to T2 mapping in the evaluation of knee cartilage after MACT by increasing the sensitivity to changes in cartilage structure. The results suggest that cartilage tissue adjacent to the repair site heals along with the cartilage implant. KEY POINTS: • GLCM is a useful add-on to T2 mapping in the evaluation of knee cartilage after MACT by increasing the sensitivity to changes in cartilage structure. • Repair and adjacent tissue became similar to reference tissue over time. • The results suggest that cartilage tissue adjacent to the repair site heals along with the cartilage implant.

IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. METHODS: The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02-positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 µg), with one dose of cyclophosphamide (300 mg/m2) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901. FINDINGS: Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92-35·64). Median overall survival did not differ significantly between the groups (33·17 months [95% CI 27·81-41·36] in the sunitinib plus IMA901 group vs not reached [33·67-not reached] in the sunitinib monotherapy group; hazard ratio 1·34 [0·96-1·86]; p=0·087). 116 (57%) of 202 patients in the sunitinib plus IMA901 group and 62 (47%) of 132 in the sunitinib group had grade 3 or worse adverse events, the most common of which were hypertension, neutropenia, and anaemia in both groups, and mild-to-moderate transient injection-site reactions (eg, erythema, pruritus) were the most frequent IMA901-related side-effect in the sunitinib plus IMA901 group. Serious adverse events leading to death occurred in four (2%) patients (one respiratory failure and circulatory collapse [possibly related to sunitinib], one oesophageal varices haemorrhage [possibly related to sunitinib], one cardiac arrest [possibly related to sunitinib], and one myocardial infarction) and eight (6%) patients in the sunitinib group (one case each of renal failure, oesophageal varices haemorrhage, circulatory collapse, wound infection, ileus, cerebrovascular accident [possibly treatment related], and sepsis). INTERPRETATION: IMA901 did not improve overall survival when added to sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated. FUNDING: Immatics Biotechnologies.

Hydrogel-Based Matrix-Associated Autologous Chondrocyte Implantation Shows Greater Substantial Clinical Benefit at 24 Months Follow-Up than Microfracture: A Propensity Score Matched-Pair Analysis.

OBJECTIVE: To compare substantial clinical benefit (SCB) of a hydrogel-based, matrix-associated autologous chondrocyte implantation (M-ACI) method versus microfracture (MFx) in the treatment of knee cartilage defects. DESIGN: Propensity score matched-pair analysis, using the MFx control group of a phase III study as comparator for M-ACI treatment in a single-arm phase III study, resulting in 144 patients in the matched-pair set. RESULTS: Groups were comparable regarding baseline Knee Injury and Osteoarthritis Outcome Score (KOOS), sex, age, body mass index, symptom duration, smoking status, and previous knee surgeries. Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 cm2 vs. 3.7 cm2). Other differences concerned location, number, and etiology of defects that were not considered to influence the interpretation of results. At 24 months, significantly more patients in the M-ACI group achieved SCB in KOOS pain (72.2% vs. 48.6%; P = 0.0108), symptoms (84.7% vs. 61.1%, P = 0.0039), sports/recreation (84.7% vs. 56.9%, P = 0.0008), and quality of life (QoL; 72.2% vs. 44.4%, P = 0.0014). The SCBs for KOOS activities in daily living and International Knee Documentation Committee score were higher for M-ACI but not significantly different from MFx. The SCB rates consistently favored M-ACI from 3 months onward. The highest improvements from baseline at 24 months in patients with SCB were observed for KOOS sports/rec. (M-ACI: 60.8 points, MFx: 55.9 points) and QoL (M-ACI: 58.1, MFx: 57.4). CONCLUSION: Hydrogel-based M-ACI demonstrated superior SCB in KOOS pain, symptoms, sports/rec., and QoL compared with MFx in patients with knee cartilage defects through 2 years follow-up.

Comparison of Hydrogel-Based Autologous Chondrocyte Implantation Versus Microfracture: A Propensity Score Matched-Pair Analysis.

Background: Few studies exist for large defects comparing matrix-associated autologous chondrocyte implantation (M-ACI) with other cartilage repair methods due to the limited availability of suitable comparator treatments. Purpose: To compare the clinical efficacy of a novel hydrogel-based M-ACI method (NOVOCART Inject plus) versus microfracture (MFx) in patients with knee cartilage defects. Study Design: Cohort study; Level of evidence, 3. Methods: Propensity score matched-pair analysis was used to compare the 24-month outcomes between the M-ACI treatment group from a previous single-arm phase 3 study and the MFx control group from another phase 3 study. Patients were matched based on preoperative Knee injury and Osteoarthritis Outcomes Score (KOOS), symptom duration, previous knee surgeries, age, and sex, resulting in 144 patients in the matched-pair set (72 patients per group). The primary endpoint was the change in least-squares means (ΔLSmeans) for the KOOS from baseline to the 24-month assessment. Results: Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 versus 3.7 cm2). Other differences included defect location (no patellar or tibial defects in the MFx group), number of defects (33.3% with 2 defects in the M-ACI group versus 9.7% in the MFx group), and defect cause (more patients with degenerative lesions in the M-ACI group). The M-ACI group had higher posttreatment KOOS (M-ACI versus MFX: 81.8 ± 16.8 versus 73.0 ± 20.6 points) and KOOS ΔLSmeans from baseline to 24 months posttreatment (M-ACI versus MFX: 36.9 versus 26.9 points). Treatment contrasts in KOOS ΔLSmeans from baseline indicated statistical significance in favor of M-ACI from 3 to 24 months posttreatment (P = .0026). Significant and clinically meaningful differences in favor of M-ACI at 24 months were also found regarding International Knee Documentation Committee (IKDC) score ΔLSmeans from baseline (37.8 versus 30.4 points; P = .0334), KOOS responder rates at 24 months (≥10-point improvement from baseline; 94.4% versus 65.3%; P < .0001), IKDC responder rates at 24 months (>20.5-point improvement from baseline; 83.3% versus 61.1%, P = .0126) and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score in a subgroup of patients (LS means, 86.9 versus 69.1; P = .0096). Conclusion: In this exploratory analysis, M-ACI using an in situ crosslinked hydrogel demonstrated superior clinical and structural (MOCART) 24-month outcomes compared with MFx in patients with knee cartilage defects.

Differentiation of Cartilage Repair Techniques Using Texture Analysis from T2 Maps.

OBJECTIVE: The aim of this study was to investigate texture features from T2 maps as a marker for distinguishing the maturation of repair tissue after 2 different cartilage repair procedures. DESIGN: Seventy-nine patients, after either microfracture (MFX) or matrix-associated chondrocyte transplantation (MACT), were examined on a 3-T magnetic resonance (MR) scanner with morphological and quantitative (T2 mapping) MR sequences 2 years after surgery. Twenty-one texture features from a gray-level co-occurrence matrix (GLCM) were extracted. The texture feature difference between 2 repair types was assessed individually for the femoral condyle and trochlea/anterior condyle using linear regression models. The stability and reproducibility of texture features for focal cartilage were calculated using intra-observer variability and area under curve from receiver operating characteristics. RESULTS: There was no statistical significance found between MFX and MACT for T2 values (P = 0.96). There was, however, found a statistical significance between MFX and MACT in femoral condyle in GLCM features autocorrelation (P < 0.001), sum of squares (P = 0.023), sum average (P = 0.005), sum variance (P = 0.0048), and sum entropy (P = 0.05); and in anterior condyle/trochlea homogeneity (P = 0.02) and dissimilarity (P < 0.001). CONCLUSION: Texture analysis using GLCM provides a useful extension to T2 mapping for the characterization of cartilage repair tissue by increasing its sensitivity to tissue structure. Some texture features were able to distinguish between repair tissue after different cartilage repair procedures, as repair tissue texture (and hence, probably collagen organization) 24 months after MACT more closely resembled healthy cartilage than did MFX repair tissue.

Concanavalin A application to the olfactory epithelium reveals different sensory neuron populations for the odour pair D- and L-carvone.

Carvone enantiomers (D and L optical isomers) have been shown to be discriminable by humans even though the odor qualities are quite similar. Our experiment is based on a finding (J. Steroid Biochem. Molec. Biol. 1991;39(4B):621) that Concanavalin A (ConA) applied to a frog olfactory epithelium preparation blocks cAMP transduction induced by D- but not by L-carvone. We used standard operant conditioning methods to train animals to discriminate low odor concentrations of D-carvone from clean air, to discriminate L-carvone from clean air; or to discriminate between clean air and the odors of D-carvone, L-carvone, ethyl acetate and methacrylic acid. After perfusion of the nasal cavity with ConA, rats did not respond to D-carvone above or near chance level, while the L-carvone response was not affected at the same or higher ConA doses. However, for rats trained on both enantiomers and the two other unrelated odorants, the D-carvone response remained unaffected by ConA. These results suggest to us that: (1) ConA blocks at least one chiral receptor selective for D-carvone; (2) D-carvone odor quality is modified by ConA so that it is no longer recognized by rats trained on D-carvone only, while rats trained to generalize odors still respond to D-carvone.

IMA901: a multi-peptide cancer vaccine for treatment of renal cell cancer.

Despite a major improvement in the treatment of advanced kidney cancer by the recent introduction of targeted agents such as multi-kinase inhibitors, long-term benefits are still limited and a significant unmet medical need remains for this disease. Cancer immunotherapy has shown its potential by the induction of long-lasting responses in a small subset of patients, however, the unspecific immune interventions with (high dose) cytokines used so far are associated with significant side effects. Specific cancer immunotherapy may circumvent these problems by attacking tumor cells while sparing normal tissue with the use of multi-peptide vaccination being one of the most promising strategies. We here summarize the clinical and translational data from phase I and II trials investigating IMA901. Significant associations of clinical benefit with detectable T cell responses against the IMA901 peptides and encouraging survival data in treated patients has prompted the start of a randomized, controlled phase III trial in 1st line advanced RCC with survival results expected toward the end of 2015. Potential combination strategies with the recently discovered so-called checkpoint inhibitors are also discussed.

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

Rapid and sustained influence of intravenous zoledronic Acid on course of pain and analgesics consumption in patients with cancer with bone metastases: a multicenter open-label study over 1 year.

BACKGROUND: Bone metastases might lead to severe bone pain, pathologic fractures, and hypercalcemia. Osteolytic destruction is caused by the activation of osteoclasts by release of tumor-derived stimulating factors. Bisphosphonates are known to inhibit osteoclast function and, therefore, to alleviate the adverse effects of tumor-induced bone resorption. PATIENTS AND METHODS: We investigated the effects of zoledronic acid on bone pain and use of analgesic medication in 604 patients with cancer with bone metastases in an openlabel multicenter study over 1 year. Patients were treated with a maximum of 12 infusions (4 mg) every 3 or 4 weeks. RESULTS: During treatment, the mean visual analog score value for pain (mm) decreased by 13.9 +/- 32.3 from 37.1 +/- 28.2 to 23.3 +/- 24.2 (P < .0001, t test, intent-to-treat population, n = 410) and the mean analgesic score decreased by 0.56 +/- 1.42 from 1.84 +/- 1.53 to 1.28 +/- 1.63 (P < .0001, t test). A statistically significant reduction in visual analog score pain could be observed within 1 week after initiation of treatment. Application of zoledronic acid was safe and well tolerated. CONCLUSION: Treatment with zoledronic acid in patients with cancer with bone metastases in a broad range of tumor types provides substantial benefit in terms of pain relief.