Characterization of infections and hypogammaglobulinemia treated with the combination of pertuzumab and trastuzumab

We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem. Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.     

Evaluation of two-dimensional lateral cephalogram and three-dimensional cone beam computed tomography superimpositions: a comparative study

Superimposition of radiographic imaging is used to evaluate patient growth and the effects of surgical and/or orthodontic treatment. The purpose of this study was to compare the outcomes of superimposition between two-dimensional (2D) and three-dimensional (3D) superimpositions. 2D lateral cephalograms were generated from the initial and final cone beam computed tomography scans (CBCT) of 18 patients and superimposed. Both 3D CBCT and 2D CBCT generated lateral cephalograms were oriented to the Frankfort horizontal plane and superimposed according to the American Board of Orthodontics recommendations. Changes in landmark position were quantified from the resulting superimposition outcomes via linear measurements made with Dolphin software. Differences between the two methods were analyzed using paired t-tests. Measurements were repeated twice for 10 randomly selected scans to assess reliability by intra-class correlation coefficient (ICC) analysis. Intra-examiner reliability was high for all measurements (ICC > 0.84). Agreement between 2D and 3D superimposition outcomes, as measured by P-values, was low for ANS (P = 0.026), B-point (P < 0.001), ST Upper lip (P = 0.019), U1 tip (P = 0.010), and U1 apex (P = 0.026). 2D measurements were significantly higher than 3D measurements for ANS, B-point, ST Upper lip, U1 tip, and U1 apex. Findings indicated that both methods of superimposition (2D and 3D) are highly reliable. Statistical differences between 2D and 3D superimposition outcomes were below the threshold of clinical significance.     

Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies

Background Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.Methods This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20.Results We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively).Conclusion Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.Subject terms: Cancer, Cancer therapy     

Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T‐cell lymphoma?

Secukinumab is an interleukin (IL)‐17 monoclonal antibody inhibiting T‐helper (Th)1‐mediated immune response. It has proven high efficacy for moderate to severe psoriasis but data on its long‐term toxicities are limited. We describe two patients who received secukinumab for clinically presumed psoriasis, but were subsequently diagnosed with mycosis fungoides (MF) following skin biopsies triggered by skin deterioration while on secukinumab. Previous studies suggested decreased numbers of regulatory T cells (Tregs) with increasing stage of MF, which may lead to the shift in the Treg/Th17 balance towards the Th17 pathway. Theoretically, the use of IL‐17 monoclonal antibodies to inhibit Th17 pathway may lead to further immunosuppression and disease progression in cutaneous T‐cell lymphoma (CTCL) by shifting the balance towards Tregs, although this hypothesis has not been proven. With uncertainty over the role of IL‐17 and Treg/Th17 as well as diagnostic challenges in CTCL, we recommend that patients should have a confirmatory skin biopsy prior to the commencement of biologic therapy.