Changes in Ascitic Fluid Polymorphonuclear Cell Count After Antibiotics Are Associated With Mortality in Spontaneous Bacterial Peritonitis.

Spontaneous bacterial peritonitis (SBP) is a feared complication of ascites that affects 10%-30% of hospitalized patients with cirrhosis with an associated mortality rate of approximately 20%.1-3 Although efforts have been undertaken to encourage prompt evaluation and treatment of SBP, outcomes have generally remained dismal.3 There is significant interest in identifying factors that can reliably predict mortality among individuals with SBP.

Newer approaches in diagnosis of diarrhea in immunocompromised patients.

PURPOSE OF REVIEW: This review will focus on the epidemiology and cause of diarrheal illness in solid organ transplant and stem-cell transplant population recipients with a specific focus on the role of advanced multiplex technology in the diagnosis of diarrhea within this patient population. RECENT FINDINGS: A wide range of infectious and noninfectious causes of diarrhea have been described in immunocompromised patients. The most common infections noted are Clostridioides difficile, norovirus, and cytomegalovirus, whereas immunosuppressive drugs and mucositis are the most common noninfectious causes of diarrhea. Historically, diagnostic evaluation has been limited to an array of single pathogen assays. Newer multiplex assays have become available that allow rapid, sensitive detection of a wide range of pathogens in a single assay. These assays have improved the number of patients with a diagnosed pathogen but may identify colonizing pathogens that are not pathogenic. Studies are needed to inform the discrimination and optimal use of these newer assays. SUMMARY: Diarrhea is a common complication in immunocompromised patients and is associated with greater morbidity and rare mortality. New diagnostics facilitate detection of recognized pathogens and may allow for improved outcomes through the use of pathogen-targeted therapy.

Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Several factors prognostic for survival have been identified including the presence of certain lymphocyte markers. Tumor-infiltrating lymphocytes (TILs), particularly cytotoxic CD8+ TILs, have been shown to be most favorable for prognosis in ovarian cancer, although other immune cells including CD3+ T-cells, CD4+ T-cells, and B-cells have also demonstrated survival benefits. Although data for these markers exists, results are not uniform in the literature. Furthermore, other immunomodulatory protein markers that have been targeted in effective immunotherapies for other malignancies may prove to be favorable in ovarian cancer. METHODS: Here, extensive immunohistochemical analysis was performed on a tissue microarray, containing 135 ovarian cancer cases obtained during tumor debulking detecting 15 key lymphocyte markers such as CD3, CD4, and CD20, as well as activation and immunomodulatory molecules such as TIA-1 and PD-L1. Samples were analyzed for expression of markers in tumor islets or stroma and expression was correlated with overall survival, histotype, stage, age, debulking grade, and response to chemotherapy. RESULTS: Our results confirm the presence of CD8+ and CD20+ TILs is positively correlated with overall survival, with further multivariate modeling replicating that prognostic benefit. Additional markers of significant prognostic importance, including TIA-1, CD103 and HLA Class-II were also revealed. CONCLUSIONS: Our results further support the vital role of cytotoxic T-cells in defense against ovarian cancer and reveals new questions as to the role of B-cells in tumor control as well as the potential benefits of immunotherapy involving other immune modulating molecules.

A rare anaerobic cause of vertebral osteomyelitis and psoas abscess: A case study.

Parvimonas micra is an obligate anaerobe that forms part of the normal gastrointestinal flora. The advent of matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF) and 16s ribosomal RNA gene sequencing has led to increased detection of many rare anaerobic isolates, including Parvimonas micra. Typical risk factors for Parvimonas micra bacteremia include dental procedures or spinal instrumentation. Here, we report a case of Parvimonas micra spondylodiscitis and psoas abscess in a patient with no obvious antecedent risk factors and explore the challenges in isolation of the organism from tissue samples.

Role of Therapeutic Drug Monitoring in the Treatment of Persistent Mycobacterium abscessus Central Nervous System Infection: A Case Report and Review of the Literature.

A patient presenting with recurrent ventriculoperitoneal shunt infection was found to have Mycobacterium abscessus growing from cerebrospinal fluid (CSF), which remained persistently positive. Therapeutic monitoring of clarithromycin, imipenem, and linezolid in CSF and plasma revealed lower than expected concentrations, prompting alternative therapy and culture clearance on hospital day 42.

A Case of Drug-Induced Liver Injury Secondary to Natalizumab.

A 33-year-old Caucasian female with relapsing-remitting multiple sclerosis presented with abdominal pain, nausea, and vomiting and was found to have acute liver injury. After thorough investigation, she was diagnosed with drug-induced liver injury (DILI) thought secondary to redosing of Natalizumab therapy.

An unusual case of Staphylococcus pasteuri osteomyelitis.

Staphylococcus pasteuri is a gram-positive organism found in food products as well as naturally occurring in air and on surfaces. We present the first known case of Staphylococcus pasteuri osteomyelitis caused by machine injection injury. The patient was treated with emergent surgical debridement as well as doxycycline for a soft tissue infection. Despite targeted therapy, the infection progressed to osteomyelitis and was treated successfully with additional surgical debridement and trimethoprim-sulfamethoxazole. There is sparse information on both infections and treatment of Staphylococcus pasteuri. We present our case report as well as a review of the literature on the epidemiology, susceptibility and treatment recommendations for Staphylococcus pasteuri infections.

The human GCOM1 complex gene interacts with the NMDA receptor and internexin-alpha.

The known functions of the human GCOM1 complex hub gene include transcription elongation and the intercalated disk of cardiac myocytes. However, in all likelihood, the gene's most interesting, and thus far least understood, roles will be found in the central nervous system. To investigate the functions of the GCOM1 gene in the CNS, we have cloned human and rat brain cDNAs encoding novel, 105 kDa GCOM1 combined (Gcom) proteins, designated Gcom15, and identified a new group of GCOM1 interacting genes, termed Gints, from yeast two-hybrid (Y2H) screens. We showed that Gcom15 interacts with the NR1 subunit of the NMDA receptor by co-expression in heterologous cells, in which we observed bi-directional co-immunoprecipitation of human Gcom15 and murine NR1. Our Y2H screens revealed 27 novel GCOM1 interacting genes, many of which are synaptic proteins and/or play roles in neurologic diseases. Finally, we showed, using rat brain protein preparations, that the Gint internexin-alpha (INA), a known interactor of the NMDAR, co-IPs with GCOM1 proteins, suggesting a GCOM1-GRIN1-INA interaction and a novel pathway that may be relevant to neuroprotection.

Low yield for non-targeted biopsies of the stomach and esophagus during elective esophagogastroduodenoscopy.

BACKGROUND AND STUDY AIMS: Biopsies of non-specific mucosal findings are often performed during esophagogastroduodenoscopy (EGD). We sought to determine the prevalence and clinical utility of non-targeted biopsies of the stomach and esophagus. PATIENTS AND METHODS: We conducted a retrospective review of 949 outpatient EGDs performed at a US tertiary referral center. Non-targeted biopsies of the stomach were defined as either "normal" or "mild" to "moderate" "erythema" or "inflammation" without other endoscopic features. Non-targeted biopsies of the esophagus and gastroesophageal junction (GEJ) were defined as endoscopically "normal" mucosa. The primary outcome was the proportion of non-targeted biopsies resulting in "definite management change." Secondary outcomes included histopathologic diagnoses of Helicobacter pylori, intestinal metaplasia and esophageal eosinophilia. RESULTS: Of 949 EGDs, 332 (35.0 %, 95 % CI 31.9 - 38.1 %) had a non-targeted biopsy taken at any site. Erythema in the gastric body and antrum was biopsied at a rate of 83 - 86 %, while biopsies of "normal"-appearing mucosa occurred at rates from 3 % (GEJ) to 15 % (body and antrum). The percentage of non-targeted biopsies that led to definite management change ranged from 5 % in the GEJ and esophagus to 9 % in the antrum, but did not significantly differ by mucosal appearance. Multivariable regression analyses suggested associations of language and age > 50 with management change from non-targeted gastric biopsy. CONCLUSIONS: Non-targeted biopsies of the stomach and esophagus led to definite management change in a small proportion of patients. Further studies are needed to identify patient and/or endoscopic characteristics and techniques to improve the yield of this practice.

Tumor infiltrating lymphocytes in ovarian cancer.

The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.

Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

An integrated method for reproducible and accurate image-guided stereotactic cranial irradiation of brain tumors using the small animal radiation research platform.

Preclinical studies of cranial radiation therapy (RT) using animal brain tumor models have been hampered by technical limitations in the delivery of clinically relevant RT. We established a bioimageable mouse model of glioblastoma multiforme (GBM) and an image-guided radiation delivery system that facilitated precise tumor localization and treatment and which closely resembled clinical RT. Our novel radiation system makes use of magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) to define tumor volumes, computed tomographic (CT) imaging for accurate treatment planning, a novel mouse immobilization system, and precise treatments delivered with the Small Animal Radiation Research Platform. We demonstrated that, in vivo, BLI correlated well with MRI for defining tumor volumes. Our novel restraint system enhanced setup reproducibility and precision, was atraumatic, and minimized artifacts on CT imaging used for treatment planning. We confirmed precise radiation delivery through immunofluorescent analysis of the phosphorylation of histone H2AX in irradiated brains and brain tumors. Assays with an intravenous near-infrared fluorescent probe confirmed that radiation of orthografts increased disruption of the tumor blood-brain barrier (BBB). This integrated model system, which facilitated delivery of precise, reproducible, stereotactic cranial RT in mice and confirmed RT's resultant histologic and BBB changes, may aid future brain tumor research.