Early-stage melanoma, squamous and basal cell carcinomas have local control rates of >90% with wide excision after pathologically clear margins and >95% with Mohs micrographic surgery. Local control rates for these approaches are not well defined in Merkel cell carcinoma (MCC). Herein, we analyzed data from 80 patients (pts) in a Seattle-based IRB-approved registry who had local MCC and underwent surgical excision with pathologically clear margins. Patients who had local radiation therapy after surgery were excluded as radiation affects recurrence rate independent of surgery. We also performed meta-analysis of 13 published studies (846 pts) based on a random-effects model. For the 80 pt cohort, local recurrence rate (LRR; ≤2 cm from the primary tumor) was 10%. In-transit recurrence rate (ITR; >2cm from primary) was 1%. Regional nodal recurrence rate (RRR) was 5%. This cohort had low-risk characteristics with small primary tumors (74% were ≤1 cm, 23% were 1-2, and 4% were >2 cm). No residual tumor was found in 60% of re-excisions while 29% had closest pathologic margins <1 cm. Meta-analysis of 9 published studies (745 pts) who underwent excision with clear pathological margins yielded 16.4% LRR [95% CI 8.3-26.5], 9.5% ITR [95% CI 5.4-14.6], and 32.1% RRR [95% CI 19.1-46.7]. Data from 4 studies (101 pts) who underwent Mohs yielded 3.6% LRR [95% CI 0-16.3], 12.8% ITR [95% CI 6.4-21.1], and 20.7% RRR [95% CI 13.8-38.3]. In each cohort, LRR/IRR following surgical excision with pathologically clear margins was >10%. This suggests MCC is more likely to recur near the excision site than other skin cancers and may reflect biological difference in the MCC local extension pattern (discontinuous spread beyond pathologically clear margins). Even for pathologically negative excisions, higher risk tumors may benefit from adjuvant radiotherapy.

Charged particles in the heliosphere can be continuously accelerated by interplanetary shocks and eventually escape from these shocks without returning to it. Acceleration and escape are highly intertwined and both contribute to the shaping of the particles’ momentum spectrum at the shock. The simplest model which describes this phenomenon is called Diffusive Shock Acceleration (DSA). DSA has been very successful in describing several observations. However, DSA does not include an energy-dependent escape from the foreshock region. We expand upon DSA by presenting a model for interplanetary shock acceleration which includes this energy-dependent particle escape. We analytically solve a one-dimensional transport equation with a diffusion coefficient and an escape time that describes both the turbulence self-generated by the shock and the far upstream pre-existing turbulence. We consider the case where a shock encounters a population of pre-existing charged particles with a power law energy distribution as measured by spacecraft. We find that at lower energies our solution is concave, whereas at higher energies it asymptotically approaches a power law whose slope depends on the original energy spectrum’s power law index and shock parameters. We fitted the solution obtained from this transport equation to shock data measured from multiple shock events collected by ACE/EPAM (the Electron, Proton, and Alpha Monitor aboard the Advanced Composition Explorer spacecraft). We find that for the shock events considered, our model’s best fit parameters match very well with the predicted values, obtained by using the measured shock parameters. From this model, we can better understand the mechanism of interplanetary shock acceleration and how this phenomenon energizes charged particles near the Sun and around other objects (for example, blazars and supernova remnants).

Cystic fibrosis (CF) is a genetic disease characterized by defects in lung host defenses against infection. Chronic lung infections by the bacterium Pseudomonas aeruginosa (Pa) are a major cause of death in CF, and recent work shows that infecting Pa strains can evolve extensive genetic diversity in vivo during infection. A new class of drugs called modulators markedly improves the CF host defense defect and improves symptoms but does not frequently produce infection eradication. We hypothesize that the extent of phenotypic diversity within Pa populations infecting individual subjects will negatively affect Pa clearance after modulator treatment. This hypothesis stems from observations in environmental systems showing that diversity generally increases the stress resistance of populations. To test this hypothesis, we sampled the lungs of 9 subjects with bronchoscopy before and 18 months after they started the most effective modulator currently available and collected ~ 100 Pa isolates from each of the five different lung regions. The collected isolates are being tested for variation in resistance to different classes of antibiotics and their nutritional requirements, motility, capacity to secret virulence factors, and attach to and aggregate on surfaces. These measurements will enable us to compare the phenotypic diversity of Pa populations infecting subjects that do and do not eradicate infection. In my preliminary work examining Pa populations from two subjects, I found much lower levels of diversity in resistance to three antibiotic classes in the subject that cleared infection as compared to the subject that did not (mean variance in resistance of 0.22 vs 75.3, respectively), which is consistent with my hypothesis. Understanding the consequences of Pa diversity in CF infections could shed light on factors causing different infection outcomes and suggest new approaches to treatment.

One of the most common causes of death in people with the genetic disease Cystic fibrosis (CF) is lung infection by the bacterium Pseudomonas aeruginosa (Pa). Despite aggressive treatment, Pa infections persist for years to decades. One factor that could contribute to poor antibiotic responses is drug antagonism: when one drug reduces the efficacy of another drug when drugs are used in combination. Tobramycin (Tob), an antibiotic, is commonly administered to CF patients to decrease Pa density in the lungs. Azithromycin (Azm), an anti-inflammatory drug, is frequently administered to the same patients. Clinical observations suggest that the clinical efficacy of Tob is reduced in some patients co-prescribed Azm. These observations led us to hypothesize that subjects exhibiting poor clinical responses when co-prescribed Tob and Azm are infected by Pa strains exhibiting greater antagonism than subjects that have good clinical responses to combined treatment. I refined an assay to measure Tob and Azm antagonism by growing a laboratory strain of Pa (PAO1) on plates with varying concentrations of Azm and Tob, and found that PAO1 was able to grow on higher Tob concentrations in the presence of Azm than in its absence. This work demonstrates that measuring antagonism is feasible. I have also identified twelve candidate subjects with banked Pa isolates who exhibited good and poor clinical responses when co-prescribed Tob and Azm. Work is underway to measure Tob-Azm antagonism in these isolates. My preliminary work on isolates from one subject showed a similar degree of antagonism as found in PAO1. Findings from this study could lead to changes in antibiotic therapies used to treat CF and help gain a better understanding of antibiotic resistance in chronic CF infections.