Andrographolide Inhibits Corneal Fibroblast to Myofibroblast Differentiation In Vitro.

Corneal opacification due to fibrosis is a leading cause of blindness worldwide. Fibrosis occurs from many causes including trauma, photorefractive surgery, microbial keratitis (infection of the cornea), and chemical burns, yet there is a paucity of therapeutics to prevent or treat corneal fibrosis. This study aimed to determine if andrographolide, a labdane diterpenoid found in Andrographis paniculate, has anti-fibrotic properties. Furthermore, we evaluated if andrographolide could prevent the differentiation of fibroblasts to myofibroblasts in vitro, given that the transforming growth factor beta-1(TGF-ß1) stimulated persistence of myofibroblasts in the cornea is a primary component of fibrosis. We demonstrated that andrographolide inhibited the upregulation of alpha smooth muscle actin (αSMA) mRNA and protein in rabbit corneal fibroblasts (RCFs), thus, demonstrating a reduction in the transdifferentiation of myofibroblasts. Immunofluorescent staining of TGF-ß1-stimulated RCFs confirmed a dose-dependent decrease in αSMA expression when treated with andrographolide. Additionally, andrographolide was well tolerated in vivo and had no impact on corneal epithelialization in a rat debridement model. These data support future studies investigating the use of andrographolide as an anti-fibrotic in corneal wound healing.

Development of the Bleeding and Pelvic Discomfort Scale for Use in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids.

OBJECTIVES: This study aimed to define a cardinal symptom burden measure based on items from the Uterine Fibroid Symptom and Quality of Life questionnaire for use as a clinical trial endpoint. METHODS: Exploratory factor analysis was computed to assess the Uterine Fibroid Symptom and Quality of Life symptom severity scale factor structure, using phase 2 data. Pooled blinded data from phase 3 studies were used for the confirmatory factor analysis and the psychometric evaluation of the new measure. Exit interviews in 30 patients from phase 3 studies provided additional qualitative evidence. A meaningful change threshold was determined using anchor-based analyses supported by patient feedback in the exit interviews. RESULTS: Three factors emerged from the exploratory factor analysis. Factor 1, called the bleeding and pelvic discomfort (BPD) scale, consists of cardinal symptoms, measuring menstrual distress owing to heavy bleeding, passing blood clots, and feeling tightness or pressure in pelvic area. Patients generally understood the items in the scale and the recall period as intended. The BPD scale had good item performance and internal consistency reliability, strong item-to-total correlations, good item discrimination, known-groups validity, and ability to detect change. A 20-point change on the BPD scale was determined as the clinically meaningful change threshold. CONCLUSIONS: The BPD scale assesses symptom burden owing to bleeding, passing blood clots, and pelvic pressure. The subscale is based on a subset of items selected to measure the cardinal symptoms of uterine fibroids in a clinical trial setting. The responder threshold evaluates whether patients experience a meaningful treatment benefit over the on-treatment period.

Convection-enhanced delivery for high-grade glioma.

Glioblastoma (GBM) is the most common adult primary malignant brain tumor and is associated with a dire prognosis. Despite multi-modality therapies of surgery, radiation, and chemotherapy, its 5-year survival rate is 6.8%. The presence of the blood-brain barrier (BBB) is one factor that has made GBM difficult to treat. Convection-enhanced delivery (CED) is a modality that bypasses the BBB, which allows the intracranial delivery of therapies that would not otherwise cross the BBB and avoids systemic toxicities. This review will summarize prior and ongoing studies and highlights practical considerations related to clinical care to aid providers caring for a high-grade glioma patient being treated with CED. Although not the main scope of this paper, this review also touches upon relevant technical considerations of using CED, an area still under much development.

Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.

Purpose: To describe our population of primary brain tumor (PBT) patients, a subgroup of cancer patients whose intensive care unit (ICU) outcomes are understudied. Methods: Retrospective analysis of PBT patients admitted to an ICU between 2013 to 2018 for an unplanned need. Using descriptive analyses, we characterized our population and their outcomes. Results: Fifty-nine PBT patients were analyzed. ICU mortality was 19% (11/59). The most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies. Further study of a larger population would inform guidelines for triaging PBT patients who would most benefit from ICU-level care.

Lay abstract Purpose: Data are lacking regarding outcomes of patients with primary brain tumors (PBTs) admitted to an intensive care unit (ICU), which may it difficult for ICU providers to know who of these patients will best benefit from ICU-level care. We aimed to describe our patient population to contribute to the limited data. Methods: We performed a retrospective analysis of critically ill PBT patients in our ICU. Results: Of 59 patients analyzed, ICU mortality was 19% (11/59), and the most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies.

Palliative Care Use for Critically Ill Patients With Brain Metastases.

CONTEXT: Critically ill patients with brain metastases (BM) face significant uncertainty regarding prognosis and survival and can benefit from Palliative care (PC). However, research regarding the role of PC in this population is lacking. OBJECTIVES: We sought to compare BM patients admitted to an intensive care unit who received an inpatient PC consult (PC cohort) to those who did not (Usual Care, UC cohort). METHODS: We performed a single-institution retrospective cohort analysis. Our outcome variables were mortality, time from intensive care unit admission to death, disposition, and change in code status. We also evaluated PC's role in complex medical decision making, symptom management and hospice education. RESULTS: PC consult was placed in 31 of 118 (28%) of patients. The overall mortality rates were not statistically different (78.8% vs. 90.3%, P= 0.15, UC vs. PC cohort). Patients in the PC cohort had a shorter time to death, higher rate of death within 30 days of admission, increased rate of discharge to hospice, and increase percentage of code status change to "do not attempt resuscitation" during the admission. The primary services provided by PC were symptom management (n = 21, 67.7%) and assistance in complex medical decision making (n = 20, 64.5%). CONCLUSION: In our patient cohort, PC is an underutilized service that can assist in complex medical decision making and symptom management of critically ill BM patients. Further prospective studies surveying patient, family and provider experiences could better inform the qualitative impact of PC in this unique patient population.

A Diffuse Leptomeningeal Glioneuronal Tumor Without Diffuse Leptomeningeal Involvement: Detailed Molecular and Clinical Characterization.

Prior to their provisional WHO classification as a distinct entity in 2016, diffuse leptomeningeal glioneuronal tumors (DLGNT) were often regarded as diffuse leptomeningeal presentations of oligodendrogliomas or extraventricular neurocytomas. Their classification as a distinct entity partly relies on their pattern of growth, but DLGNTs without radiological leptomeningeal involvement have been described. In a patient with a DLGNT of the spinal cord without evidence of leptomeningeal involvement, we review in depth the clinical course and the histologic and molecular features of the neoplasm, in the context of other reported cases without diffuse leptomeningeal involvement. Our findings highlight the advantages of molecular analysis in making accurate diagnoses on small spinal tissue samples and underline the need for more long-term clinical follow-up of these rare neoplasms to inform treatment decisions.

Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs.

BACKGROUND: We previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model. METHODOLOGY/PRINCIPAL FINDINGS: MPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed. CONCLUSIONS: PPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.

Novel chemotherapeutics and other therapies for treating high-grade glioma.

INTRODUCTION: Despite extensive research, high-grade glioma (HGG) remains a dire diagnosis with no change in the standard of care in almost a decade. However, recent advancements uncovering molecular biomarkers of brain tumors and tumor-specific antigens targeted by immunotherapies provide opportunities for novel personalized treatment regimens to improve survival. AREAS COVERED: In this review, the authors provide a comprehensive overview of recent therapeutic advancements in HGG. Furthermore, they describe new molecular biomarkers and molecular classifications, in addition to updated research on bevacizumab, targeted molecular therapies, immunotherapy and alternative delivery methods that overcome the blood-brain barrier to reach the target tumor tissue. Challenges regarding each therapy are also outlined. The authors also provide some insight into a novel non-chemotherapeutic treatment for malignant glioma, NovoTTFA, as well as a summary of current treatment options for recurrence. EXPERT OPINION: Current research for treating malignant gliomas are paving the path to personalized therapy, including immunotherapy, that involve integrated genomic and histolopathologic data, as well as a multi-modal treatment regimen. Immunotherapy will potentially be the next addition to the current standard of care, specialized to the antigens presented on the tumors. The results of the current trials of multi-antigen vaccines are eagerly anticipated.

Interpersonal violence screening for ambulatory gynecology patients.

OBJECTIVE: To estimate the effects of patient and health care provider variables on rates of interpersonal violence screening in an ambulatory gynecology practice. METHODS: A cross-sectional study of 300 patients were chosen randomly from annual health care visits during 2007 at a university-affiliated ambulatory gynecology clinic. All encounters were recorded on a standardized health history form, which included questions about abuse history. Data on patient and health care provider characteristics were collected. The association of health care provider screening with selected patient variables was assessed using multivariable logistic regression. RESULTS: The median age of the study population was 29 years (range 15-73 years). The cohort was racially and ethnically diverse, and the majority was on government assistance. Sixty-seven percent (194 of 291) had children living at home, and 57% (164 of 286) were single. Of the 300 patients, 243 (81%) had documentation of abuse screening in their medical records. Variables previously found to be associated with higher rates of partner abuse such as younger age or increased parity did not influence whether patients were screened. Similarly, differences in screening by health care provider type (nurse practitioner or resident) or health care provider gender did not emerge. Patients were, however, significantly more likely to be questioned about partner violence when they received other preventive screening (adjusted odds ratio 2.50, 95% confidence interval 1.26-4.99) or presented with a somatic pain complaint (adjusted odds ratio 2.55, 95% confidence interval 1.12-5.83). CONCLUSION: Ambulatory gynecology patients were more likely to be screened for interpersonal violence when health care providers performed other preventive health screening using a standardized health history form. LEVEL OF EVIDENCE: II.

Hemispherectomy in a premature neonate with linear sebaceous nevus syndrome.

A male neonate with seizures, linear sebaceous nevus syndrome and hemimegalencephaly underwent hemispherectomy at 36 weeks' gestational age. He has had no clinical seizures in the 13 months since surgery but continues to have sharp wave activity over some parts of the intact hemisphere. He has moderate developmental delay and a mild hemiparesis but is making developmental progress.

Structurally colored thiol chitosan thin films as a platform for aqueous heavy metal ion detection.

Thin films of the polysaccharide chitosan and several chitosan derivatives, including conjugates of l-cysteine, thioglycolic acid, and 2-iminothiolane, were produced from dilute acidic solutions. Attempts to produce a fourth conjugate using lipoic acid resulted in the synthesis of partially N-acetylated chitosan ethanoate. These biopolymer films were exposed to solutions containing 50 ppm concentrations of various metal ion and counterion analytes. Analyte-induced changes in film thicknesses and refractive indices were measured using a spectroscopic ellipsometer, and shifts in film color were quantified using a reflectance spectrometer. The modified chitosans were generally more sensitive to change in response to pure water but also showed varied response to several ions of interest, including Cr(III) and Cr(VI), Hg(II), Ni(II), and others. The potential for tuning film response was demonstrated by varying the concentration of sulfur groups in the thioglycolic acid conjugate, leading to increased specificity for Hg(II).

The burden of radiation-induced central nervous system tumors: a single institution s experience.

Radiation-induced tumors of the central and peripheral nervous systems are becoming a noticeable subset of tumors seen at referral institutions. This paper outlines a single institution s experience with 22 examples of secondary meningiomas, gliomas, and sarcomas that developed in adults. These tumors are being increasingly encountered by physicians, but the greatest burden is on the patients themselves, who not only experience the life-altering effects of the original tumor and the subsequent delayed cognitive effects of radiotherapy, but later develop a second intracranial neoplasm. We detail a particularly poignant example of a 34-year-old man who developed a high-grade sarcoma with rhabdomyosarcomatous and osteogenic elements. Local control was difficult over the next year, and he eventually developed cerebrospinal fluid dissemination and succumbed. Although radiation-induced neoplasm remain relatively infrequent numerically, each case reminds us of the need for new, less toxic, and more targeted therapies for brain neoplasms.

Proximal nerve root capillary hemangioma presenting as a lung mass with bandlike chest pain: case report and review of literature.

BACKGROUND: Capillary hemangiomas occasionally occur in the peripheral nervous system (PNS), presenting as mass lesions causing proximal nerve root symptoms, thus prompting neurosurgical intervention. In contrast to cavernous angiomas, which may also occasionally involve the PNS, capillary hemangiomas have little or no tendency for acute or chronic bleeding and, hence, lack the apoplectic symptomatic onset and neuroimaging features of hemosiderin deposition as seen in cavernous angiomas. CASE DESCRIPTION: A 56-year-old man presented with chronic, radiating, bandlike, chest wall pain. Chest radiograph revealed an apical lung mass suspicious for malignancy. Subsequent magnetic resonance imaging revealed an enhancing dumbbell-shaped mass extending into the spinal canal and chest cavity at T3, causing a slight degree of lung compression. Differential diagnostic considerations included schwannoma, neurofibroma, and meningioma. At operation, the spongy, reddish purple vascular tumor was easily separated from dura but had to be excised en bloc, with the T3 nerve root at the neural foramen. The large intrathoracic portion measuring 37 x 41 mm was left behind. Pathology was consistent with a capillary hemangioma. CONCLUSIONS: We present the second case in the English language literature of a dumbbell-shaped, epidural capillary hemangioma with intrathoracic extension. We review the literature on proximal nerve capillary hemangiomas and contrast these with cavernous angiomas and capillary hemangioblastomas, both of which occasionally involve proximal nerves. Unlike capillary hemangioblastomas, which may be multiple and associated with von Hippel-Lindau (VHL) syndrome, capillary hemangiomas are solitary lesions and have not been associated with an inherited disorder.

Multifocal papillary-cystic neoplasm of the pancreas.

This case report describes the second known instance of a multifocal capillary pancreatic neoplasm. Both cases occurred in young African American females. A less-than-total pancreatectomy was performed to maintain endocrine function.