Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis-1 with Everolimus: A Phase II, Open-Label, Single-Arm Trial.

BACKGROUND: Cutaneous neurofibromas cause disfigurement and discomfort in individuals with neurofibromatosis type 1 (NF-1). METHODS: The primary objective of this phase II, open-label, single-arm trial was to assess whether orally administered everolimus reduced the surface volume of cutaneous neurofibromas in patients with NF-1. RESULTS: Of 22 patients who took the study drug, 17 completed the trial; 5 patients withdrew due to adverse events. Sixteen patients had photographs of sufficient quality for assessment of the primary outcome. A significant reduction in lesion surface volume, defined as an end of trial volume > 2 standard errors (SE) less than baseline volume, was observed for 4/31 lesions (13%) from 3/16 patients (19%). Additionally, a statistically significant absolute change in average height for paired lesions was observed (p = 0.048). Although not a prespecified outcome measure, a dramatic reduction in the size of 3 large plexiform neurofibromas with a cutaneous component was also noted and documented by measurement of maximum circumference or magnetic resonance imaging-based volumetric analysis. Adverse events were common in this trial, but no serious adverse events occurred. CONCLUSIONS: Although this was a small, exploratory trial that was not powered for significance, the reduction in surface volume observed in this study is noteworthy assuming that the natural course for untreated lesions is to maintain or increase in volume. Future studies are needed with larger study populations that incorporate longer durations of treatment and better standardization of volumetric measurements. Trial Registration ClinicalTrials.gov Identifier: NCT02332902.

Morphoproteomics and biomedical analytics confirm the mTORC2/Akt pathway as a resistance signature and activated ERK and STAT3 as concomitant prosurvival/antiapoptotic pathways in metastatic renal cell carcinoma (RCC) progressing on rapalogs: pathogenesis and therapeutic options.

BACKGROUND: It has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due to adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) to mTORC2. OBJECTIVE: To combine phosphoprotein staining and applied biomedical analytics to investigate resistance signatures in patients with metastatic RCC progressing on rapalog therapies. DESIGN: We applied morphoproteomic analysis to biopsy specimens from nine patients with metastatic RCC who continued to show clinical progression of their tumors while being treated with a rapalog. RESULTS: In patients who were on temsirolimus or everolimus at the time of biopsy, a moderate to strong expression of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment with concomitant expression of p-Akt (Ser 473) confirmed the mTORC2 pathway. Concomitant moderate to strong nuclear expression of p-ERK 1/2 (Thr202/Tyr204) and p-STAT3 (Tyr705) was confirmed. Histopathologic changes of hypoxic-type coagulative necrosis in 5 cases as well as identification of insulin-like growth factor-1 receptor (IGF-1R) expression and histone methyltransferase EZH2 in all tumors studied suggested that hypoxia also contributed to the resistance signature. Biomedical analytics provided insight into therapeutic options that could target such adaptive and pathogenetic mechanisms. CONCLUSIONS: Morphoproteomics and biomedical analytics confirm mTORC2/Akt as a resistance signature to rapalog therapy in metastatic RCC and demonstrate activation of the prosurvival ERK and STAT3 pathways and involvement of hypoxic pathways that contribute to pathogenesis of such adaptive resistance. These results highlight the need for a novel combinatorial therapeutic approach in metastatic RCC progressing on rapalogs.

Simple infrared thermometry in fever detection: consideration in mass fever screening.

OBJECTIVE: The need to rapidly screen patients during outbreaks has prompted Cutaneous Infrared Thermometry (CIT) use. Little is known of CIT performance in this context. What are the performance characteristics of simple CIT in detecting fever? DESIGN: Prospective cohort, sequential convenience sample. PARTICIPANTS: All patients presenting to the study Emergency Department for care. INTERVENTION: CIT and oral temperature measurements. MAIN OUTCOMES: Fever defined as oral temperature≥38°C. CIT is measured simultaneously with oral temperatures. Comparisons of temperatures are expressed as means and 95% confidence intervals. Means are compared using Student's t test. Limits of agreement are measured using Bland-Altman. Receiver operating characteristics are determined. RESULTS: There are 548 cases comprising 224 males, 324 females, with mean age 26 years. The mean temperature difference is 12.95°C, (13.18-9.08°C) p≤0.0001. Bland-Altman demonstrates bias at 8.680 (-9.084 to -8.275) p≤0.0001 with upper and lower level bias values of 18.124 (18.819-17.435) and 0.768 (0.076-1.459), respectively. Based on Receiver Operator Characteristics analysis, detection of hyperpyrexia at a CIT of 35.3°C provided sensitivity of 0.236 (0.143-0.359), specificity 0.977 (0.959-0.989), positive predictive value 0.589 (0.325-0.810), negative predictive value 0.904 (0.891-0.919), and accuracy of 0.888 (0.861-0.913). CONCLUSIONS: The use of a readily available CIT measurement device predicted hyperpyrexia about 59 percent of the time and the absence of hyperpyrexia about 90 percent of the time. This is consistent with previous reports of more complex infrared measurement devices. Although commonly used in mass fever screening, the current performance characteristics of CIT are limited and may add little to detection of target diseases in a mass screening context.

Glucocorticoid-induced TNFR-related protein stimulation reverses cardiac allograft acceptance induced by CD40-CD40L blockade.

CD40-CD40L blockade has potent immunosuppressive effects in cardiac allograft rejection but is less effective in the presence of inflammatory signals. To better understand the factors that mediate CD40-CD40L blockade-resistant rejection, we studied the effects of stimulation through glucocorticoid-induced TNFR-related protein (GITR), a costimulatory protein expressed by regulatory and effector T cells. Stimulation of CD40-/- or wild-type recipient mice treated with anti-CD40L mAb (WT+anti-CD40L) and with agonistic anti-GITR mAb resulted in cardiac allograft rejection. GITR stimulation did not induce rejection once long-term graft acceptance was established. In vitro, GITR stimulation increased proliferation of effector T cells and decreased regulatory T cell (Treg) differentiation in both treatment groups. GITR-stimulated CD40-/- recipients rejected their allografts more rapidly compared to GITR-stimulated WT+anti-CD40L recipients, and this rejection, characterized by a robust Th2 response and significant eosinophilic infiltrate, could be mediated by CD4+ T cells alone. In contrast, both CD4+ and CD8+ T cells were required to induce rejection in GITR-stimulated WT+anti-CD40L-treated recipients, and the pathology of rejection was less severe. Hence, early GITR stimulation could initiate graft rejection despite CD40 deficiency or anti-CD40L mAb treatment, though the recipient response was dependent on the mechanism of CD40-CD40L disruption.

Phase III Study of Silver Leaf Nylon Dressing vs Standard Care for Reduction of Inframammary Moist Desquamation in Patients Undergoing Adjuvant Whole Breast Radiation Therapy.

AIMS: The primary objective of this study was to assess silver leaf nylon dressings as a prophylactic measure in reducing inframammary fold radiation induced dermatitis in women receiving adjuvant whole breast radiotherapy compared with standard skin care. A secondary objective was to assess if the dressing influenced breast skin-related pain, itching and burning resulting from whole breast radiotherapy. MATERIAL AND METHODS: A prospective randomized trial compared silver leaf nylon dressing worn continuously from the sixth fraction of whole breast radiotherapy until 14 days after therapy completion to standard skin care in patients deemed to be at risk of inframammary radiation induced dermatitis by virtue of a large breast volume or a significant inframammary skin fold in the treatment position. Stratification before randomization was for anthracycline chemotherapy and fractionation scheme. Digital photos of the inframammary region were taken at one week before, the last day of whole breast radiotherapy, and one week after treatment completion. Three observers blinded to treatment arm assessed the images for the presence of moist desquamation and the Radiation Therapy Oncology Group (RTOG) skin toxicity score. Patients completed questionnaires comprising visual analogue scales for pain, itching and burning sensation, and questions regarding which topical skin cream was being used, at the before-mentioned times as well as at baseline and two weeks after completing whole breast radiotherapy. RESULTS: A total of 196 patients completed the study. Moist desquamation occurred in 38% of patients. No difference in incidence or maximum size of moist desquamation or RTOG skin toxicity scores was seen between the treatment arms. However, on the last day of radiation treatment and one week after completion of treatment, patient reports of itching decreased in the experimental arm. At one week before whole breast radiotherapy completion, patients using Glaxal Base cream reported worse burning, those using aloe vera reported worse pain and burning, whereas patients who had not used a moisturizing cream reported less pain. CONCLUSION: Silver leaf nylon dressing use did not demonstrate a decrease in the incidence of inframammary moist desquamation, but did decrease itching in the last week of radiation and one week after treatment completion.

Covalent inactivation of factor VIII antibodies from hemophilia A patients by an electrophilic FVIII Analog.

The antigen-binding sites of antibodies (Abs) can express enzyme-like nucleophiles that react covalently with electrophilic compounds. We examined the irreversible and specific inactivation of antibodies (Abs) to Factor VIII (FVIII) responsible for failure of FVIII replacement therapy in hemophilia A (HA) patients. Electrophilic analogs of FVIII (E-FVIII) and its C2 domain (E-C2) were prepared by placing the strongly electrophilic phosphonate groups at surface-exposed Lys side chains of diverse antigenic epitopes. IgG Abs to FVIII from HA patients formed stable immune complexes with E-FVIII and E-C2 that were refractory to dissociation by SDS treatment and boiling, procedures that dissociate noncovalent Ab-antigen complexes. The rate-limiting step in the reaction was formation of the initial noncovalent complexes. Conversion of the initial complexes to the irreversible state occurred rapidly. The antigenic epitopes of E-FVIII were largely intact, and most of the Abs were consumed covalently. E-FVIII expressed poor FVIII cofactor activity in clotting factor assays. Nonspecific interference by E-FVIII in clotting factor function was not evident. Treatment with E-FVIII, and to a lesser extent E-C2, irreversibly relieved the FVIII inhibitory effect of HA IgG in clotting factor assays. Small FVIII peptides did not display useful reactivity, highlighting the diverse epitope specificities of the Abs and the conformational character of FVIII epitopes. E-FVIII is a prototype reagent able to attain irreversible and specific inactivation of pathogenic Abs.

Pectus excavatum. More than meets the eye.

Pectus excavatum is an anterior chest deformity that is characterized by a depressed sternum. Physical examination is the primary means of diagnosis. Common surgical operations to correct this malformation include the Ravitch and Nuss procedures, both of which have favorable postoperative outcomes. This deformity affects physical, emotional and psychological well-being. In addition, there are several important nursing interventions that need to be considered when caring for patients who have undergone surgical repair for pectus excavatum.