Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Acral keratoses and leucocytoclastic vasculitis occurring during treatment of essential thrombocythaemia with hydroxyurea.

Hydroxyurea is used in essential thrombocythaemia to lower thromboembolic risk. Cutaneous adverse effects from hydroxyurea are diverse. Small vessel vasculitis has been rarely reported, and the coexistence of several different morphologies has not been described. We report a case of acral keratoses, psoriasiform plaques and leucocytoclastic vasculitis (LCV) in a patient with essential thrombocythaemia. A 69-year-old woman developed a confusing array of skin lesions including keratotic papules, psoriasiform plaques and keratoderma 4 years after commencing hydroxyurea therapy. The initial diagnosis was hand and foot psoriasis, but lesions were resistant to therapy. With an increase in the dose of hydroxyurea, the lesions ulcerated. Skin biopsies taken from different sites indicated different diagnoses, including LCV. Discontinuation of hydroxyurea yielded rapid improvement. Although the most commonly reported cutaneous adverse effect from hydroxyurea is leg ulceration, this can be preceded or accompanied by less dramatic skin lesions. Unless recognized, delayed diagnosis and lesion progression can occur.

Kinetic-dependent Killing of Oral Pathogens with Nitric Oxide.

Nitric oxide (NO)-releasing silica nanoparticles were synthesized via the co-condensation of tetramethyl orthosilicate with aminosilanes and subsequent conversion of secondary amines to N-diazeniumdiolate NO donors. A series of ~150 nm NO-releasing particles with different NO totals and release kinetics (i.e., half-lives) were achieved by altering both the identity and mol% composition of the aminosilane precursors. Independent of identical 2 h NO-release totals, enhanced antibacterial action was observed against the periodontopathogens Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis with extended NO-release kinetics at pH 7.4. Negligible bactericidal effect was observed against cariogenic Streptococcus mutans at pH 7.4, even when using NO-releasing silica particles with greater NO-release totals. However, antibacterial activity was observed against S. mutans at lower pH (6.4). This result was attributed to more rapid proton-initiated decomposition of the N-diazeniumdiolate NO donors and greater NO-release payloads. The data suggest a differential sensitivity to NO between cariogenic and periodontopathogenic bacteria with implications for the future development of NO-releasing oral care therapeutics.

Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations.

Synovial sarcoma (SS), clear cell sarcoma (CCS), and desmoplastic small round cell tumor (DSRCT) are soft-tissue malignancies occurring primarily in adolescents and young adults. These tumors contain specific chromosomal translocations that fuse the 5' region of one gene with the 3' region of another, resulting in the formation of characteristic fusion proteins. These translocations are unique to tumor cells and may be required for persistence, thereby serving as targets for immunotherapy. It was hypothesized that the fusion breakpoint sequences associated with SS, CCS, and DSRCT can serve as tumor-specific neoantigens. To test this, peptides corresponding to the fusion breakpoints were designed and assessed for ability to bind to various class I HLA molecules. Two peptides derived from the SS breakpoint specifically bind the HLA-B7 antigen, and a 10-amino acid minimal epitope was identified for this interaction. Specific binding of a SS peptide and a CCS peptide to HLA-B27 molecule was also observed. Finally, a peptide designed from the DSRCT breakpoint specifically binds the HLA-A3 molecule, and a 9-amino acid optimal epitope was identified for this interaction. The physiological/immunological relevance of these peptide/MHC interactions was demonstrated by the induction of SS-specific CTLs from normal donor lymphocytes using in vitro stimulation with autologous, peptide-pulsed dendritic cells and by the ability of these CTLs to lyse human SS tumor cells endogenously expressing the full-length fusion protein. These results suggest that sequences in the fusion region of sarcoma-associated chimeras can bind class I HLA molecules and serve as neoantigens. These may be useful for the development of novel immunotherapies for sarcoma patients with appropriate HLA molecules and tumors bearing these translocations.

Soluble leukocyte selectin in the analysis of pleural effusions.

STUDY OBJECTIVES: To determine if soluble leukocyte selectin (sL-selectin) levels in serum and pleural fluid (PF) are an inflammatory marker that differentiates pleural effusion transudates from exudates. DESIGN: sL-selectin PF and serum levels were measured in consecutive patients and compared to established criteria. SETTING: A tertiary-care military medical center. PATIENTS: One hundred twenty patients undergoing diagnostic or therapeutic thoracentesis. INTERVENTIONS: PF and serum samples were collected during thoracentesis and analyzed separately for sL-selectin levels. Results were compared with clinical diagnosis and established PF criteria including the criteria of Light et al, cholesterol ratio, total bilirubin ratio, and albumin gradient. MEASUREMENTS AND RESULTS: sL-selectin levels in PF and serum were determined in 109 patients. By clinical diagnosis, mean +/- SD PF sL-selectin levels were 200.2 +/- 124.3 ng/mL in transudates and 496.8 +/- 379.2 ng/mL in exudates (p < 0.001). By the criteria of Light et al, mean PF sL-selectin levels were 195.7 +/- 105.2 ng/mL in transudates and 448.2 +/- 367.6 ng/mL in exudates (p < 0.001). Mean sL-selectin PF to serum ratios were 0.31 +/- 0.17 in transudates and 0.72 +/- 0.31 in exudates (p < 0.001) by clinical criteria, and 0.31 +/- 0.18 in transudates and 0.64 +/- 0.33 in exudates (p < 0.001) by the criteria of Light et al. No significant difference was noted with serum sL-selectin levels between groups. CONCLUSIONS: sL-selectin is an inflammatory marker that differentiates transudates from exudates in pleural effusions and is a sensitive indicator for PF analysis.

Richter's transformation presenting as an obstructing endobronchial lesion.

A 60-year-old man with chronic lymphocytic leukemia presented to our institution with a recurring lingular pneumonia. On fiberoptic bronchoscopy, the patient was found to have an endobronchial mass obstructing the lingula and left upper lobe. Biopsy specimens of the mass demonstrated anaplastic large cell lymphoma consistent with Richter's transformation. Only one case of endobronchial Richter's transformation has been previously reported in the literature. This was described as peribronchial and endobronchial leukemic infiltrates within the bronchial mucosa. We report the first case of an obstructive endobronchial mass secondary to Richter's transformation. The endobronchial mass was treated with a Nd-YAG laser to maintain airway patency while the patient underwent chemotherapy, resulting in complete resolution of the mass within the airway.

A comparative evaluation of pulmonary artery balloon counterpulsation and a centrifugal flow pump in an experimental model of right ventricular infarction.

To compare the efficiency of pulmonary artery balloon counterpulsation and a centrifugal flow pump in reversing the hemodynamic consequences of acute right-sided heart failure, we employed both devices in 14 Yorkshire pigs in which right ventricular infarction was created via surgical ligation of branches of the right coronary artery. Pulmonary artery balloon counterpulsation improved some of the indicators of right heart failure, as manifested by significantly decreased right atrial pressure and increased mean systemic blood pressure. In contrast, the centrifugal flow pump consistently and significantly reversed all of the hemodynamic consequences of right ventricular infarction. In comparison to pulmonary artery balloon counterpulsation, the centrifugal flow pump resulted in lower right atrial pressures (p=0.020), lower mean pulmonary pressures (p less than 0.0001), increased left atrial pressures (p=0.026), increased cardiac output (p less than 0.0001), and increased mean systemic blood pressures (p less than 0.0001). Possible mechanisms to explain the superiority of the centrifugal flow pump include better hemodynamic unloading of the failing myocardium and independence from right ventricular output.