Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, we curated 1547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 acute myeloid leukemia (AML) patients (13.6%) in 34 genes, including 6.39% (25/391) of patients harboring P/LP variants in genes considered clinically actionable (tier 1). 41.5% of the 53 patients with P/LP variants were in genes associated with the DNA damage response. The most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, and SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, 6 patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in silico approach that applies ACMG curation in an automated manner using the tool for assessment and (TAPES) prioritization in exome studies, which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

Trends in utilization of first-line palliative treatments for anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma patients often present with significant symptoms, including pain, bleeding, and obstructive symptoms. This requires palliation-directed therapy as a first-line treatment to alleviate symptoms. The proportion of patients receiving first-line palliative treatments is unknown. We aimed to study the factors associated with the use of first-line palliative treatments in stage II-IV anal squamous cell carcinoma patients. METHODS: We used the National Cancer Database to identify adult patients diagnosed with stage II-IV anal squamous cell carcinoma between 2004 and 2016. We performed univariable and multivariable logistic regression analysis to determine the clinical and sociodemographic variables associated with the utilization of palliative treatment in the first-line setting, including palliative radiotherapy, chemotherapy, surgery, and pain management. RESULTS: Among 16,944 patients diagnosed with stage II-IV anal squamous cell carcinoma, only a small proportion of 492 (2.9%) required first-line palliative treatments to control symptoms. The majority of these patients received palliative radiotherapy (32%), followed by palliative surgery (25%), palliative chemotherapy (19%), combination therapies (14%), and pain management (10%). On multivariable analysis, higher stage disease, lower income, Medicare and Medicaid insurance, and life expectancy <6 months were associated with higher odds of use of first-line palliative therapy. CONCLUSIONS: First-line use of palliative treatments to control symptoms is needed in a small proportion of anal squamous cell cancer patients. It was utilized in all stages, but it was most frequently observed in patients with stage IV disease and patients with <6 months life expectancy. First-line palliative therapy was also more frequent in lower-income patients and patients with Medicare and Medicaid insurance which highlights the disparities in anal cancer management.

Photocontrolled nanoparticles for on-demand release of proteins.

We describe here light-regulated swelling and degradation features of polymeric nanoparticles that are produced using an inverse microemulsion polymerization method. We demonstrate the phototriggered release characteristics of the nanoparticles by sequestering protein molecules and releasing them using light as a trigger. Furthermore, the intracellular translocation of the nanoparticles, along with its fluorescent protein payload, was achieved using a cell-penetrating peptide-based surface modification. We expect that the noncovalent encapsulation of proteins using nanoparticles and their photo triggered release using an external light would provide opportunities for achieving intracellular release of molecular therapeutics for on-demand requirements.

Near-complete vision recovery from bilateral serous retinal detachment associated with thrombotic thrombocytopenic purpura.

Ocular manifestations of thrombotic thrombocytopenic purpura (TTP) are uncommon, and bilateral retinal detachment is a rare presentation of TTP. We report a rare case of bilateral retinal detachment from underlying TTP in a patient presenting with vision loss. A 56-year-old man presented with a 4-day history of bilateral vision loss. Bilateral serous retinal detachment was confirmed using dilated ophthalmoscope examination. Laboratory results were significant for severe thrombocytopenia, peripheral smear revealed numerous schistocytes and ADAMTS13 activity of less than 1%. The patient was treated with plasma exchange (PLEX), prednisone, rituximab and caplacizumab. This case report highlights that prompt treatment of TTP with PLEX, prednisone, rituximab and caplacizumab could result in significant vision recovery.

Postoperative infections in women undergoing hysterectomy for benign indications: a cohort study.

BACKGROUND: There is limited data on the incidence of postoperative infections following hysterectomy by route of surgery. We hypothesize that vaginal hysterectomy has lower rates of postoperative infection than laparoscopic and abdominal hysterectomies. METHODS: A retrospective cohort study and independent hand review of charts of participants undergoing hysterectomy at five hospitals from September 2011 through May 2015 was performed. Cases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and were reviewed by the investigators. The primary outcome was the development of Clostridium difficile infection, urinary tract infection, surgical site infection, or yeast vaginitis within 60 days following surgery. RESULTS: In total, 2742 women underwent hysterectomy: abdominal 17.5% (AH), laparoscopic 65.8% (LH), and vaginal 16.7% (VH). The composite postoperative infection rate for the four specified variables was 8.5% (232). In comparing surgical route, AH was most commonly associated with CDI (0.6%, p <0.001), SSI (6.0%, P=0.001), and yeast vaginitis (1.9%, p <0.001), while VH was most commonly associated with UTI (8.1%, P=0.002). After controlling for demographic and operative factors, multivariable analysis showed that hysterectomy route was not associated with infection. Independent predictors for postoperative infection were increasing age, American Society of Anesthesiologists physical status classification, operative time, and hospital type. CONCLUSIONS: Infectious complications after hysterectomy are uncommon, accounting for 8.5% of cases. Multivariable analysis showed that demographic and operative variables were more likely to serve as independent predictors of development of infection than hysterectomy route.