Factors associated with axillary conversion after neoadjuvant chemotherapy in initially node positive breast cancer patients: A transSENTINA analysis.

567 Background: Current study concepts in early breast cancer after neoadjuvant chemotherapy (NAT) are aiming at reducing morbidity by omission of axillary surgery in selected patients. Selection criteria for this strategy have to include the probability of conversion from cN1 to ycN0. We analyzed the association of clinical/pathological parameters and axillary conversion with data from arms C and D of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were recruited to Arms C/D of the SENTINA trial in case they presented with clinically positive nodes before NAT. Based on their response to NAT they were then assigned to either arm C (clinically conversion to ycN0) or arm D (no clinical conversion (ycN+). In both the pre- and post-NAT scenarios, clinically involved lymph nodes were defined as palpable and/or suspect by ultrasound. Univariate logistic regression analyses were carried out to evaluate the association between clinical/pathological parameters and axillary conversion after NAT. Results: Of the 892 patients in arms C and D of the SENTINA trial 716 were evaluable for this analysis. After NAT, 593 patients converted to ycN0 and were therefore assigned to arm C; in contrast, 123 patients still had involved lymph nodes after NAT (ycN+) and were assigned to Arm D. Arms C and D were compared regarding the clinical/pathological parameters tumor diameter by ultrasound before and after NAT, grading, multifocality, ER status, PR status, HER2 status, pathological complete remission in the breast (breast pCR), morphology, lymphovascular invasion (LVI) and hemangiosis. Only small tumor diameter after NAT (p = 0.0038), achievement of breast pCR (p = 0.0001) and lack of LVI (p = 0.0009) were positively associated with axillary conversion from cN1 to ycN0 after NAT. Conclusions: Because of the small patient number in arm D, we were not able to identify an association between parameters of tumor biology (ER, PR, HER2 and TN status) and axillary conversion. However, favorable response of the primary tumor (represented both clinically by tumor diameter after NAT and pathologically by pCR in the breast) were positively associated with conversion from cN1 to ycN0. These results justify including patients with clinical and pathological response of the primary tumor in trials investigating de-escalation of axillary surgery after NAT.

How I treat anaplastic glioma without 1p/19q codeletion

Anaplastic astrocytoma without 1p/19q codeletion is a rare primary central nervous system tumour occurring primarily in middle-aged adults and associated with a median survival of 5–10 years. The major corner stone of treatment is maximal safe neurosurgical resection, followed by radiotherapy and chemotherapy. Several clinical trials addressed the optimal adjuvant treatment; however, interpretation has been challenged by the recent molecular marker-based reclassification of tumour. The interim study of the CATNON trial strongly suggests the addition of 12 adjuvant cycles of temozolomide in addition to radiotherapy after maximal safe resection in patients with anaplastic astrocytoma without 1p/19q codeletion. Based on more recently presented data from the second interim analysis of the CATNON trial and from the molecular analysis, benefit from temozolomide during and after radiotherapy is limited to patients with isocitrate dehydrogenase-mutated anaplastic astrocytoma. Given the small patient number in the single subgroups and the so far missing neurocognitive and quality of life data, more mature analyses needs to be awaited to draw final conclusions on the application of concurrent temozolomide treatment for the daily routine in patients who already are scheduled for adjuvant temozolomide. Further molecular analysis is ongoing to define personalised treatment approaches in patients with anaplastic astrocytoma.

Ustekinumab with Intravenous Infusion: Results in Hidradenitis Suppurativa

Adalimumab is the only approved biological therapy for hidradenitis suppurativa (HS). The last published recommendations support the use of other off-label biologic therapies. We report on a multicentric retrospective review of patients with HS treated with an ustekinumab dosing schedule of intravenous infusion adjusted by weight, followed by a subcutaneous maintenance dose of 90 mg every 8 weeks, as recently approved for Crohn’s disease. The minimal follow-up period required for inclusion was 16 weeks. A total of 14 patients from six hospitals were included. In 50% of the treated patients, therapeutic outcomes, measured by means of the Hidradenitis Suppurativa Clinical Response (HiSCR) and decrease of Dermatology Life Quality Index (DLQI) and visual analog scale (VAS) of pain, were reached at week 16. In 71.42% of patients DLQI and VAS of pain improved, irrespective of achievement of HiSCR. Two patients abandoned treatment due to lack of efficacy or patient preferences. No ustekinumab-related adverse effects were reported. The results are limited by the retrospective nature of the study, the short follow-up period, and the small patient number. This therapeutic regime proved to be safe and showed moderate efficacy in treating HS with failure to previous biologic therapy. Ideally, the efficacy of ustekinumab in HS should be tested in randomized and controlled clinical trials.

The “Apple-Bite-Fracture”: ACL rupture combined with posterolateral tibia plateau fracture

Aims and Objectives: Anterior cruciate ligament (ACL) ruptures are often concomitated by posterolateral bone bruise in the MRI. This is caused by a ventral subluxation of the tibia and impact of the femur in the posterolateral tibia plateau. In some cases, this impact causes a fracture of the posterolateral tibia plateau, the so-called Apple-Bite-Fracture. The increased posterior slope can cause additional instability and has to be considered as a risk factor for ACL failure. In this study we investigated the short term clinical outcomes of patients with this combined injury. Materials and Methods: Retrospective study of 14 patients (mean age 46 ± 12,3) (8 male, 6 female) with a mean follow up of 23,75 months. Different treatment strategies were analyzed. The clinical evaluation included visual analog score (VAS) increasing from 0-10 for Pain, IKDC Score, Rasmussen score as well as a clinical evaluation. Results: First analysis of the treatment options revealed a non-uniformed therapy strategy. In three patients the ACL tear was treated nonsurgical. In 11 patients the ACL tear was addressed surgical: six times the ACL was reconstructed with hamstring tendon graft, two times the ACL was sutured. Two patients treated with a non-reconstructive technique to promote healing (“healing response”). In one patient a tibial eminence fracture was fixated with a screw. The fracture of the posterolateral tibia plateau was in nine cases minimally invasive reduced and fixated with a screw osteosynthesis in jail technique. Two patients needed posterior buttress plate. Three times the large bone defect has been augmented with autologous bone graft from the pelvis. The postoperative clinical testing did not reveal any persisting knee instabilities. All patient had a non-limited ROM. No significant differences in ROM in comparison to the contralateral knee was seen. One patient reported persisting knee pain (VAS 3). All other patients reported no pain (VAS 0). Subjective IKDC score was 78,18 (71,3 - 83,9; ± 5,68). Clinical Rasmussen scores ranged from 27 to 30 (mean 27, ± 3,0). Rasmussen radiological results ranged from 16 to 18, mean 16,67 (± 1,15). Conclusion: Despite a very small patient number and leck of statistical power the new patient-spedific mini-metal implant seems to be a good options fort he treatment of middle-aged patients who already underwent frustane cartilage surgery. In these relatively rare caes early unicompartimental arthroplasty can be prevented. Further clinical studies with larger patient collectives have to prove the effectiveness of this new technique.

Clinical 2 years results after implantation of patient-specific mini-metal implants in middle-aged patients alfter previous frustrane cartilage surgery

Aims and Objectives: The treatment of focal (osteo-)chondral lesions of the knee in middle-aged patients with previous frustane cartilage regeneration is challenging. This prospective study presents clinical 2 years results after implantation of patient-specific mini-metal implants. Materials and Methods: Based on a three dimensional MRI planing 7 patient-specific mini-metal implants (Episealer, Episurf, Stockholm, Sweden) were produced for 4 patients (2 men, 2 women). In one patient a single implant was implanted to the trochlea, the other 3 patients received each a trochlea and a medial condyle implant. Corresponding cartilage lesions in the tibia plateau or retropatellar surface were excluded by a detailed specific MRI resulting in a so called “damage report”. MRI data was used to manufacture patient-specific implants and guide instruments, to fit the unique anatomy of each individual knee. Demographic, operative and clinical scores (VAS of pain and patient satisfaction, KOOS and Forgotten Joint Score) were collected preop and at 6 months, 1 and 2 years postoperatively. Results: Mean age was 51.5 (47-57) years. All patients had failed previous cartilage surgery. All mean KOOS domain scores were improved at 1 and 2 years. Mean preoperative aggregated KOOS (35) improved to 60 at 12 months and remained at 60 also at 24 months. Mean VAS score (pain) improved from 7.4 preoperatively to 2.1 at 24 months, mean VAS score (patient satisfaction) improved from 3.1 to 8.5 postoperatively at 24 months. The forgotten joint score reached a mean of 24 points. No revisions or complications were detected. Conclusion: Despite a very small patient number and leck of statistical power the new patient-spedific mini-metal implant seems to be a good options fort he treatment of middle-aged patients who already underwent frustane cartilage surgery. In these relatively rare caes early unicompartimental arthroplasty can be prevented. Further clinical studies with larger patient collectives have to prove the effectiveness of this new technique.

A phase Ib/IIa study of combination therapy with gemcitabine and Atu027 in patients with locally advanced or metastatic pancreatic adenocarcinoma.

385 Background: Atu027 is a liposomally formulated short interfering RNA with anti-metastatic activity, which silences expression of protein kinase N3 (PKN3) in the vascular endothelium. PKN3 acts as a Rho effector downstream of PI3K. This trial was designed to assess safety, pharmacokinetics and efficacy of Atu027 in combination with gemcitabine in advanced pancreatic carcinoma (APC). Methods: 23 patients (pts) with APC stage 3 or 4 were enrolled and randomly assigned to different Atu027 dosing schedules (arm 1: 0.253mg/kg once weekly, n = 11; arm 2: 0.253mg/kg twice-weekly, n = 12) but identical gemcitabine regimen. Response was evaluated according to RECIST 1.1. Quality of life was assessed with EORTC questionnaire QLQ-C30. Results: Combination therapy with Atu027 and gemcitabine was given up to 7.8 months until progression. Grade 3 adverse events (AEs) were reported by 9/11 pts (82%) in arm 1 and 11/12 pts (92%) in arm 2. Grade 4 AEs were reported by two pts in each arm. Interestingly, there was a difference in median progression free survival (mPFS) between the two treatment arms. Arm 1 showed an mPFS of 1.8 [95%CI: 0.4-5.5] months vs. 5.3 [95%CI: 1.5-6.0] months in arm 2, p= 0.399. In a post-hoc analysis of metastatic disease only, the difference in mPFS between the two arms reached statistical significance (1.6 [95%CI:0.4-2.1] vs 2.9 [95%CI:1.0-7.3] months, n = 9 vs 10, p= 0.025). Disease control during treatment was achieved in 4/11 (36%) pts in arm 1 and in 7/12 (58%) pts in arm 2. New lesions occurred in all (6/6) pts in arm 1 who had at least one RECIST re-evaluation but only 5/10 pts (50%) in arm 2. In quality of life analysis, pts in the once-weekly arm showed a stable global health status while pts in the twice-weekly arm reported an improvement (0-100 score change from baseline: -2.3 vs +21.6 after one cycle, N = 7 vs 7). Conclusions: Combination of Atu027 with gemcitabine for the treatment of APC is safe and was well tolerated. Despite the small patient number, there is a clear signal that twice-weekly Atu027 dosing might be superior to the once-weekly regimen. These results suggest efficacy of Atu027 and warrant further investigation with Atu027 added to standard of care in APC. Clinical trial information: NCT01808638.

Clinical Outcome of the Treatment of Adult Acute Lymphoblastic Leukemia (ALL) with the Hyper-CVAD Protocol.

Hyper-CVAD represents an intensified program for the treatment of acute and chronic lymphoid malignancies. This protocol has been proposed as a highly efficient treatment for adult ALL with acceptable toxicity profile. Purpose: In our Institution, Hyper-CVAD was initiated in September 1999 and used as the primary treatment of adult ALL. We analyse and report here our results focusing on the efficacy and the toxicity of the program. Patients and methods: Patient population consisted of 24 de novo ALL (7 T-cell, 17 B-cell). M/F ratio was 11/13, median age 39 yrs,mean age 42,1 yrs (range 18–68 yrs). 7/24(29,1%) patients were older than 50yrs. Hyperleukocytosis of more than 100x109/L was present in 6/24(25%) cases (3 T-cell,3 B-cell), while splenomegaly, hepatomegaly and bulky disease were documented in 19/24, 17/24 and 1/24 cases respectively. Cytogenetic analysis was performed in 23/24 patients: in 11/23 it was normal, in 1/23 showed del(12), in 1/23 revealed just polyploidy and failed in 10/23 cases. Bcr-abl transcripts were detected in three cases. None of our patients presented with CNS disease (morphology & immunophenotyping). Median follow up was 12,5 months (range 1–65 mo). Treatment consisted of four cycles of Hyper-CVAD (including fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) alternating with four cycles of methotrexate and cytarabine. All patients received intrathecal CNS prophylaxis and granulocyte stimulating factor support. Maintenance therapy consisted of two years of treatment with mercaptopurine, methotrexate, vincristine and prednisone (POMP). Imatinib was added in bcr-abl(+) cases. Results: Hematological complete remission was achieved in 21/24 (87,5%) de novo ALL cases: (11pts <4wk, 10pts >4wk ). Primary resistance was documented in 2/24 cases which subsequently received other therapeutic protocols and eventually deceased. One patient died in early induction. From the group of remmiters 11/21 are alive in CR after median DFS of 21mo (mean DFS 32mo, range 3–57). Another 7/21 remitters-including one post autologous transplantation- relapsed after median of 4,5 mo and six of them deceased. 6/21 patients underwent allogeneic transplantation (4 alive in CR, 2 deceased from complications). Regimen-related toxic deaths occurred in 4/23 cases whilst in remission status. 6/8 Τ-ALLs entered CR but half of them latter relapsed (two in consolidation and one in maintenance). CNS involvement during therapy on hyper-CVAD was not detected in the subgroup of resistant/progressive patients. Conclusions: Within the limitations of the small patient number and relatively short follow up we confirm the effectiveness of hyper-CVAD in de novo ALL, albeight at a lower than expected magnitude. Furthermore, we are unable to confirm the reported excellent outcome in T-ALL. Infectious complications were significant despite the administration of growth factors and prophylactic antibiotics. Hyper-CVAD can prevent leukemia extention to CNS in both responders and non responders.