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Objective The aim of this study was to determine the rate of coronavirus disease-19 (COVID-19) among patients with cancer treated with immune checkpoint inhibitors (ICIs). Materials and Methods This was a retrospective study of 1,545 patients with cancer treated with ICIs between July 1, 2019, and February 29, 2020, and 20,418 age-, sex-, and cancer category-matched controls in a large referral hospital system. Confirmed COVID-19 case and mortality data were obtained with Massachusetts Department of Public Health from March 1 through June 19, 2020. Results The mean age was 66.6 years, and 41.9% were female. There were 22 (1.4%) and 213 (1.0%) COVID-19 cases in the ICI and control groups, respectively. When adjusting for demographics, medical comorbidities, and local infection rates, ICIs did not increase COVID-19 susceptibility. Conclusion ICIs did not increase the rate of COVID-19. This information may assist patients and their oncologists in decision-making surrounding cancer treatment during this pandemic.

Cutaneous reactions are among the most prevalent immune-related adverse events in patients treated with immunotherapy. Given that immunotherapies often act through blocking inhibitory signals on T cells, these treatments also have the potential to generate a host of immune toxicities. We report the case of a 73-year-old woman with a history of non-small cell lung cancer treated with nivolumab 10 months prior to presentation who developed painful nodules, bullae, and a scaly rash on her extremities. Four months after discontinuation of nivolumab, she noted an acute eruption of painful nodules on her extremities, followed by pink papules and tense bullae on her palms and soles. Biopsies were performed of three lesions in sites of varying morphologies. These findings were felt to be consistent with a nivolumab-induced lichenoid reaction. She was initially treated with intralesional steroid injections, topical steroid ointment, and liquid nitrogen cryotherapy with minimal improvement. As the lesions continued to progress, the patient was admitted to the hospital and started on intravenous methylprednisolone. She eventually transitioned to daily oral prednisone with a slow taper with good effect and no recurrence of lesions.

Our collective understanding of melanoma genomics has rapidly expanded in the past decade, bringing great promise to patients affected with the most severe and aggressive cases of melanoma. In this review, we present the practical clinical impact of genetics and genomics on modern melanoma diagnosis and treatment. Characterization of somatic driver mutations, which can be used to distinguish different subtypes of melanoma such as nonacral cutaneous melanoma (NACM), desmoplastic melanoma (DM), acral melanoma (AM), mucosal melanoma (MM) and uveal melanoma (UM), has led to the development of many targeted therapies against these tumours. Although targeted therapies exist for certain mutations, such as BRAF and KIT, other genotypes respond to newer-generation immune therapies such as immune checkpoint inhibitors. Epigenetics also plays a critical role in melanoma pathogenesis and drug resistance, holding promise for new treatment avenues. In this review, special attention is placed on clinical trials and translational research, especially novel genomic tests aimed to benefit patients on an individualized level in the current emerging era of personalized therapy.

Background It is unclear whether treatment with immune checkpoint inhibitors (ICIs) is a risk factor for contracting COVID-19. We investigated whether patients prescribed ICIs were more or less likely to contract COVID-19 than matched controls in a collaboration between a large academic healthcare system and the Massachusetts Department of Health. Methods We performed a retrospective study of 1,577 cancer patients prescribed ICI and 26,241 matched controls. We included all patients infused with an ICI in the Mass General Brigham (MGB) network between 7/1/19 and 2/29/20 and generated an exact match of control patients from the MGB database on age, sex, and Charlson comorbidity index. For both groups, we cross referenced COVID-19 infection data through June 19, 2020 from the Massachusetts Department of Public Health using date of birth, last name, and first four letters of the first name. We calculated odds ratios (OR) for COVID-19 diagnosis using a multivariate logistic regression adjusting for age, sex, race, CCI, zip code income, and local infection rate. Results Twenty-one patients (1.3%) prescribed ICIs and 527 controls (2.0%) were identified as COVID positive in the Massachusetts department of health database. When controlling for local infection rate, age, sex, race, CCI, and zip code income, there were no significant differences in COVID infection between ICI recipients and matched controls (OR: 0.7, 95% CI: 0.45 – 1.09, p=0.1; table 1). Conclusions In our experience, patients who were prescribed ICI were not more likely to contract COVID-19 than matched controls, which may assist in decision-making around continuation of therapy during the pandemic. More research needs to be conducted to determine potential behavioral and testing factors that may affect COVID-19 diagnosis.

Inhalant abuse, also known as huffing, is common among teenagers and adolescents in the United States and worldwide. Inhaled aerosols are dangerous due to both the presence of volatile hydrocarbons causing direct organ damage and the risk of the compressed air causing physical trauma (e.g. expansion, barotrauma) or skin trauma from chemical or temperature burn. Here, we present the case of a 35-year-old man who was inhaling multiple canisters of Dust-Off (Falcon Safety Products Inc., Branchburg, NJ) keyboard air duster daily for approximately one month. He presented with intermittent burning chest pains, and was found to have elevated troponin (peak 17 ng/mL, normal range 0-0.5 ng/mL) without ST-segment elevations, concerning for non-ST elevation myocardial infarction (NSTEMI) as well as elevated aminotransferases and elevated serum creatinine. He was treated conservatively with supportive measures, with successful resolution of his laboratory abnormalities as well as his chest pain. Clinicians should be aware of the possible medical complications of inhalant abuse, and the expected clinical course. In this case, we aim to demonstrate the acute onset and self-resolution of significant cardiomyocyte damage in a young male patient abusing duster.

Preterm birth is a leading cause of morbidity and mortality in newborns. Babies born prematurely are at increased risk of lifelong health problems, including neurodevelopmental abnormalities. Cervical shortening precedes preterm birth in many women. Cervical shortening is caused, in part, by excessive softening of the extracellular matrix (ECM) of the cervical stroma. In clinical obstetrics, cervical shortening prompts treatment with supplemental progesterone to prevent preterm birth. However, progesterone-mediated effects on the cervical ECM are not well understood. This research sought to study progesterone-mediated remodeling of ECM produced by human cervical fibroblasts in vitro. A previously developed three-dimensional (3D) engineered model of the cervical ECM was used for experiments. Cervical fibroblasts were seeded on porous scaffolds and cultured in spinner flasks to promote ECM synthesis. Scaffolds were exposed to two conditions: 10(–8) M estradiol versus 10(–8) M estradiol +10(–6) M progesterone for 4 weeks. To measure ECM strength, two scaffolds were mounted end-to-end on a wire and cultured such that ECM filled the gap between the scaffolds. The force required to pull the scaffolds apart was measured. Collagen content and collagen crosslinks were measured with ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry. Whole-transcriptome RNA sequencing (RNA-seq) was used to quantify gene expression between the two experimental conditions. Zymography was used to study the quantity and activity of matrix metalloproteinase-2 (MMP2) in the scaffolds. The study found that exposure to progesterone increased tissue softness of the engineered ECM over 28 days. Increased tissue softness correlated with decreased collagen content. With RNA-seq, progesterone exposure resulted in gene expression changes consistent with known progesterone effects. Pathway analysis of the RNA-seq data suggested MMPs were significantly dysregulated in progesterone-exposed engineered ECM. Increased expression of active MMP2 was confirmed in the progesterone-exposed engineered ECM. In summary, progesterone increased the softness of the ECM, which was correlated with decreased collagen production and altered histology. These results are important for deciphering the role of progesterone in preventing preterm birth.

Pathogenic phenotypes in cutaneous melanoma have been vastly cataloged, although these classifications lack concordance and are confined to either morphological or molecular contexts. In this study, we perform unsupervised k-medoids clustering as a machine learning technique of 2,978 primary cutaneous melanomas at Mass General Brigham and apply this information to elucidate computer-defined subsets within the clinicopathologic domain. We identified five optimally separated clusters of melanoma that occupied two distinct clinicopathologic subspaces: a lower-grade partition associated with common or dysplastic nevi (i.e., nevus-associated melanomas) and a higher-grade partition lacking precursor lesions (i.e., de novo melanomas). Our model found de novo melanomas to be more mitogenic, more ulcerative, and thicker than nevus-associated melanomas, in addition to harboring previously unreported differences in radial and vertical growth phase status. The utilization of mixed clinicopathologic variables, reflective of actual clinical data contained in surgical pathology reports, has the potential to increase the biological relevance of existing melanoma classification schemes and facilitate the discovery of new genomic subtypes.

Uveal malignant melanoma (UMM), the most common primary adult intraocular tumor with a marked metastatic potential, is genetically unique and has unfortunately had few treatment breakthroughs. In this study, we subjected a UMM cell line to high-throughput library screening with 1,018 FDA-approved compounds to identify potential UMM-selective cytotoxic agents. Amlodipine, a dihydropyridine calcium channel blocker (CCB), ranked no. 2 and no. 8 of the most cytotoxic compounds. Thus, we further characterized the differential effects of calcium blockade on UMM and cutaneous malignant melanoma (CMM) lines in vitro using growth inhibition, cell cycle progression, apoptosis and senescence assays. Amlodipine had a significantly higher growth inhibitory potency in UMM (IC50=13.1 µM) than CMM (IC50=15.9 µM, P

Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others. To study the link between mutational burden and survival, we analyzed survival effects of tumor exonic missense mutation burden (TEMMB) across 6947 specimens spanning 31 cancers which have undergone whole exome sequencing as part of TCGA. We adjusted TEMMB for age, sex, stage, and recruitment center, and computed Cox-proportional models of TEMMB survival effects. We assigned a recurrence score (RS) to each cohort, defining RS as the burden of recurrent mutations exceeding 1% population prevalence. High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60–0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59–0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70–0.93], p = 0.003. High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00–1.74], p

During the ongoing coronavirus disease 2019 (COVID-19) crisis, data on risks of immunomodulatory biologics have been limited, causing uncertainty for patients and providers whether to continue biologic therapy for chronic skin disease We aimed to investigate if patients treated with biologics were at an increased risk for COVID-19 infection and all-cause mortality once infected We performed a retrospective study of 7,361 patients prescribed biologics and 74,910 matched controls, cross-referenced with the Massachusetts Department of Public Health COVID-19 infection and all-cause mortality data through June 19, 2020 We included patients in the Mass General Brigham system with at least 1 prescription for a biologic between July 1, 2019 and February 29, 2020 Multivariable logistic regression was used on matched data to calculate the odds ratio (OR) for COVID-19 infection between patients on biologics and controls, adjusting for age, gender, race, Charlson Comorbidity Index (CCI) severity grade, median income, and local infection rate Multivariate Poisson regression was performed on COVID-19 positive patients to compare all-cause mortality, adjusting for gender, CCI severity, income, and local COVID-19 rate 7,361 patients treated with biologics and 74,910 matched controls were included in the analysis (mean age, 50 6 years;56 0% women, 84 5% white;mean age adjusted CCI 2 8) There were 87 (1 2%) infections and 7 deaths (8 0%) in patients treated with biologics and 1063 (1 4%) infections and 71 deaths (6 7%) in the control group Patients treated with immunosuppressive biologics were not at increased risk of COVID-19 diagnosis (OR 0 88, 95% CI 0 71-1 09, p=0 25) or subsequent mortality (OR 1 38, 95% CI 0 62-3 07, p=0 43) Given an absence of evidence that patients treated with biologics are more susceptible to COVID-19, patients should be encouraged to continue their therapy to prevent disease progression during this pandemic

Importance: It is unclear if systemic immunosuppression for chronic conditions modifies patients’ risk of contracting COVID-19, leading to uncertainty among patients and dermatologists treating immune-mediated skin conditions during the pandemic Methods: We partnered with the Massachusetts Department of Public Health to identify COVID-19 positivity and mortality for patients treated at the Mass General Brigham who were prescribed a systemic immunosuppressant from 07/01/19-02/29/20 We excluded biologics, steroids, and antirheumatic drugs from the analysis Patients were compared with exact matched controls using a multivariable logistic regression for infection and multivariable Poisson regression for mortality, adjusting for demographics, comorbidity score, and local infection rate Results: The most common medications identified were Methotrexate (23 5%), Mesalamine (19 2%), Paclitaxel (8 3%), Mycophenolate (7 8%), Hydroxyurea (6 0%), and Tacrolimus (5 3%) 218 of 14,865 (1 5%) patients prescribed systemic immunosuppressants and 1,368 of 80,318 (1 7%) controls were identified as COVID-19 positive Of these, 26 (0 2%) patients prescribed immunosuppressants and 162 (0 2%) controls died after diagnosis Patients prescribed immunosuppressants were not more likely to have a COVID-19 diagnosis (OR 0 91, 95% CI 0 79-1 05, p=0 22) or die after diagnosis (OR 0 95, 95% CI 0 62-1 44, p=0 80) after adjusting for demographics, comorbidity score, and local infection rate Conclusions and Relevance: We found no evidence that systemic immunosuppression preceding the COVID-19 pandemic increased risk of contracting COVID-19 or risk of mortality among COVID-19 positive patients

In a recent publication (Ind. Eng. Chem. Res. 2013, 52 (35), 12369) we generalized the classic design of experiments (DoE) methodology by introducing the Design of Dynamic Experiments (DoDE), allowing for the systematic design of experiments involving time-varying inputs. Here, we expand the response surface model (RSM) methodology, used in DoE and DoDE problems, so that it describes the time-evolution of the process, not just the results at the end of the experiment. We apply this generalized type of RSM model, to be denoted by DRSM, to three example processes; a nonisothermal batch reactor with a simple reaction, an isothermal semibatch reactor with several reactions, and a semibatch penicillin fermentation process. Using a limited number of online measurements at prespecified equidistant time instants, we are able to quickly and accurately represent the time evolution of the process output through these simple interpolative data-driven models. The ever-increasing availability of time-resolved measureme...

Current Optimization and Model Predictive Control practices for batch processes are implemented using two models, one for determining the optimal trajectories and another identified around those trajectories for control purposes. Here we use the recently developed Dynamic Response Surface Modeling methodology from which the optimal trajectories and the local linear or nonlinear state-space models for control purposes are obtained. Because concentration measurements at each batch run are very infrequent, this might be the most attractive way to obtain a dynamic model for control purposes.

In contemporary medical practice, approaches to infectious disease management have been primarily rooted in a pathogen-centered model. However, host genetics also contribute significantly to infectious disease burden. The fast expansion of bioinformatics techniques and the popularization of the genome-wide association study (GWAS) in recent decades have allowed for rapid and affordable high-throughput genomic analyses. This review focuses on the host model of infectious disease with particular emphasis placed on the genetic variations underlying observed infectious disease predisposition. First, we introduce observational twin-twin concordance studies of diseases such as poliomyelitis, tuberculosis, and hepatitis which suggest the important role of host genetics. We review the well-established links between specific genetic alterations and predisposition to malaria (P. falciparum and P. vivax), Creutzfeldt-Jacob disease (CJD), human immunodeficiency virus (HIV), and Norwalk virus. Finally, we discuss the novel findings yielded by modern GWAS studies, which suggest the strong contribution of immunologic variation in the major histocompatibility complex (MHC) to host genetic infectious disease susceptibility. Future large-scale genomic studies hold promise in providing insights into immunology-pathogen links and may allow for the development of personalized genomic approaches to infectious disease prevention and treatment.

Background Melanoma can mimic other cutaneous lesions, but the full spectrum and prevalence of these morphologic variants remain largely unknown. Objective To classify nonacral cutaneous melanomas into distinct morphologic clusters and characterize clusters’ clinicopathologic features. Methods All pathologic melanoma diagnoses (occurring during 2011-2016) were reviewed for routine prebiopsy digital photographs (n = 400). Six dermatologists independently assigned lesions into 1 of 14 diagnostic classes on the basis of morphology. Image consensus clusters were generated by K-means; clinicopathologic features were compared with analysis of variance and χ2. Results Five morphologic clusters were identified: typical (n = 136), nevus-like (n = 81), amelanotic/nonmelanoma skin cancer (NMSC)–like (n = 70), seborrheic keratosis (SK)–like (n = 68), and lentigo/lentigo maligna (LM)–like (n = 45) melanomas. Nevus-like melanomas were found in younger patients. Nevus-like and lentigo/LM-like melanomas tended to be thinner and more likely identified on routine dermatologic examinations. NMSC-like melanomas were tender, thicker, more mitotically active, and associated with prior NMSC. Typical and SK-like melanomas had similar clinicopathologic features. Limitations Cluster subdivision yielded diminished sample sizes. Visual assignment was performed without clinical context. Conclusion When primary cutaneous melanomas were assigned into diagnostic groups and subjected to novel consensus clustering, recurrent morphologic patterns emerged. The spectrum of these morphologies was unexpectedly diverse, which might have implications for visual training and possibly clinical diagnosis.

Introduction Damage to the posterior interosseous nerve (PIN) is a known complication when using a cortical button during distal biceps tendon repair. Prior studies show that the trajectory of the drill through the biceps tuberosity can affect the distance from the PIN. We develop a mathematical model to predict the location of the tuberosity based on a palpable bony landmark and patient demographic factors. Methods The medical charts and elbow radiographs of (n = 82) adult patients were retrospectively reviewed. Using standard radiographic software, two observers measured the distance from the olecranon tip to the center of the biceps tuberosity. Multivariate regression analysis was used to build a linear model. The model was cross-validated with five arms from three distinct cadavers. A surgical wire was guided into the volar aspect of each forearm using the model, and a dissection was then performed to assess the proximity of the surgical wire to the insertion of the biceps tendon on the radial tuberosity. Results Olecranon-tuberosity distance (OTD) ranged from 52.3 mm to 77.2 mm (mean 66.5 mm). Univariate analyses revealed males had significantly longer OTD (mean 69.3 mm) compared to females (mean 61.2 mm, t-test, p < 0.001). Increased body mass index (BMI) weakly correlated with increased distance (Pearson’s r = 0.22, p = 0.048). Height showed strong positive correlation with increased distance (r = 0.77, p < 0.001). Multivariate regression revealed that significant predictive factors for olecranon-tuberosity distance were height (coefficient = 35.8, p < 0.001), BMI (coefficient = 0.14, p = 0.032), and male sex (coefficient = 3.17, p = 0.0039). The average error in the cadaveric validation, measured as distance from the surgical wire to the distal biceps insertion was 1.8 mm. Conclusion A highly accurate mathematical model can be used to predict the location of the biceps tuberosity in relation to the palpable tip of the olecranon, based only on height, BMI, and sex of the patient. Knowledge of this distance can guide accurate placement of the skin incision when a transverse single-incision approach is utilized for repair of the distal biceps tendon using a cortical button. Diagnostics showed the model to be less accurate near the extremes of the measurement. Since patients with a target incision point far removed from average would most benefit from such a model, we will continue by identifying and enrolling patients at the low and high ends of the range. We further hypothesize that the technique described above could be similarly applied to benefit other procedures.

Pleomorphic dermal sarcoma (PDS) is a rare mesenchymal tissue tumor. Distinguishing PDS from similar conditions, such as atypical fibroxanthoma (AFX), its less aggressive tumor counterpart, is difficult, as they are clinically and histologically similar. We present a case of a 77-year-old man presenting with a large nodular scalp lesion of three weeks duration. Pathology revealed a 3.3 cm invasive pleomorphic dermal sarcoma. Surgical excision with 2 cm margins was performed with successful healing of the graft. This case highlights a rare case of a large pleomorphic dermal sarcoma and discusses the histological features and management of PDS.

The underlying forces that shape mutational patterns within any type of cancer have been poorly characterized. One of the best preserved exclusionary relationships is that between BRAF(V600E) and NRAS(Q61) in melanomas. To explore possible mechanisms which could explain this phenomenon, we overexpressed NRAS(Q61) in a set of BRAF(V600E) melanoma lines and vice versa. Controlled expression of a second activating oncogene led to growth arrest ("synthetic suppression") in a subset of cells, which was accompanied by cell cycle arrest and senescence in several melanoma cell lines along with apoptosis. Through differential gene expression analysis, we identified SPRY4 as the potential mediator of this synthetic response to dual oncogene suppression. Ectopic introduction of SPRY4 recapitulated the growth arrest phenotype of dual BRAF(V600E)/NRAS(Q61) expression while SPRY4 depletion led to a partial rescue from oncogenic antagonism. This study thus defined SPRY4 as a potential mediator of synthetic suppression, which is likely to contribute to the observed exclusivity between BRAF(V600E) and NRAS(Q61R) mutations in melanoma. Further leverage of the SPRY4 pathway may also hold therapeutic promise for NRAS(Q61) melanomas.

Intravesical therapy with Bacillus Calmette-Guerin (BCG) is a common and effective therapy for bladder carcinoma in situ. The risks associated with intravesical BCG therapy are significant and rare. Accurate diagnosis and prompt initiation of management significantly reduce the morbidity associated with these risks. Here, we discuss a case of BCG orchitis, a rare but treatable complication of intravesical BCG therapy. We present the case of a 55-year-old Puerto Rican incarcerated male who was diagnosed with high-grade Stage T1 urothelial carcinoma after presenting with hematuria, treated with transurethral resection of bladder tumor (TURBT), mitomycin, and intravesical BCG. He presented with left testicular pain and swelling after a failed course of ciprofloxacin with ultrasound findings characteristic of BCG orchitis. The patient received a combination therapy of levofloxacin, rifampin, isoniazid, and ethambutol, which resulted in symptom resolution. Combination therapy was initiated in this patient based on a high index of clinical suspicion, and in the absence of positive cultures. Competing diagnoses were considered and excluded based on the history, imaging findings, and observed response to therapy. As this is an uncommon diagnosis, and as routine infectious workup is often inconclusive, we emphasize that early anti-tuberculous treatment should be considered given a high degree of clinical suspicion based on history and patient presentation.

Malignant pleural mesothelioma is a rare neoplasm of mesodermal origin. Cutaneous involvement of malignant pleural mesothelioma is a very rare entity, with only 11 cases reported in the literature. Here, we describe the case of a 75-year-old man with stage IV epithelioid pleural mesothelioma, presenting with a cutaneous eruption 5 months after initial diagnosis, which revealed sarcomatoid features on skin biopsy. Histological analysis of malignancy progression through immunohistochemical staining of the pleural, lymph node, and skin tissue revealed gradual loss of calretinin and gain of desmin, supporting a transformation from epithelioid to sarcomatoid tissue. To our knowledge, this is the first reported case of an epithelioid to sarcomatoid transformation of malignant pleural mesothelioma manifesting in a cutaneous presentation.

To evaluate the biocompatibility of silk gel for cervical injection.Silk gel was injected into the cervix of pregnant rats on day 13 (n = 11) and harvested at day 17. Histology of silk gel was compared with suture controls. Also, human cervical fibroblasts were cultured on silk gel and tissue culture plastic (TCP) in vitro. Cell viability, proliferation, metabolic activity, gene expression (COL1A1, COL3A1, and COX2), and release of proinflammatory mediators (interleukin [IL] 6 and IL-8) were evaluated.In vivo, a mild foreign body response was seen surrounding the silk gel and suture controls. In vitro, cervical fibroblasts were viable, metabolically active, and proliferating at 72 hours. Release of IL-6 and IL-8 was similar on silk gel and TCP. Collagen and COX2 gene expression was similar or slightly decreased compared with TCP.Silk gel was well tolerated in vivo and in vitro, which supports continuing efforts to develop silk gels as an alternative to cervical cerclage.

Importance Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures Identification of somatic mutations associated with cherry angiomas. Results In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.

For molecules to be used as components in molecular machines, methods that couple individual molecules to external energy sources and that selectively excite motion in a given direction are required1,2,3,4,5,6. Significant progress has been made in the construction of molecular motors powered by light1,2,7 and by chemical reactions3,4,5,8, but electrically driven motors have not yet been built, despite several theoretical proposals for such motors9,10,11,12,13. Here we report that a butyl methyl sulphide molecule adsorbed on a copper surface can be operated as a single-molecule electric motor. Electrons from a scanning tunnelling microscope are used to drive the directional motion of the molecule in a two-terminal setup. Moreover, the temperature and electron flux can be adjusted to allow each rotational event to be monitored at the molecular scale in real time. The direction and rate of the rotation are related to the chiralities of both the molecule and the tip of the microscope (which serves as the electrode), illustrating the importance of the symmetry of the metal contacts in atomic-scale electrical devices14. Tunnelling electrons can be used to simultaneously drive and quantitatively monitor a single-molecule electric motor.

Current methods for treatment of high-risk neuroblastoma patients include surgical intervention, in addition to systemic chemotherapy. However, only limited therapeutic tools are available to pediatric surgeons involved in neuroblastoma care, so the development of intraoperative treatment modalities is highly desirable. This study presents a silk film library generated for focal therapy of neuroblastoma; these films were loaded with either the chemotherapeutic agent doxorubicin or the targeted drug crizotinib. Drug release kinetics from the silk films were fine-tuned by changing the amount and physical crosslinking of silk; doxorubicin loaded films were further refined by applying a gold nanocoating. Doxorubicin-loaded, physically crosslinked silk films showed the best in vitro activity and superior in vivo activity in orthotopic neuroblastoma studies when compared to the doxorubicin-equivalent dose administered intravenously. Silk films were also suitable for delivery of the targeted drug crizotinib, as crizotinib-loaded silk films showed an extended release profile and an improved response both in vitro and in vivo when compared to freely diffusible crizotinib. These findings, when combined with prior in vivo data on silk, support a viable future for silk-based anticancer drug delivery systems.