Gastrointestinal and Hepatic Manifestations of COVID-19: Evolving Recognition and Need for Increased Understanding in Vulnerable Populations

The novel coronavirus, SARS-CoV-2, has caused a global pandemic with high morbidity and mortality. It was first observed to cause a severe acute respiratory syndrome. However, gastrointestinal and hepatic manifestations have been increasingly recognized.Gastrointestinal symptoms include diarrhea, epigastric pain, nausea, and vomiting. Diarrhea is the most common GI manifestation of SARS-CoV-2 and can present without or without respiratory symptoms. Patients with GI symptoms have been associated with longer duration of illness and may be associated with more severe illness. Mechanism of diarrhea is thought to be related to direct viral cytotoxicity occurring when the SARS-CoV-3 enters GI cells via the ACE-2 receptor. Inflammatory response and cytokine release likely contributes to symptoms.SARS-CoV-2 can cause hepatic injury. Studies have shown mild to moderate elevation of liver enzymes. The pattern of liver abnormalities can be hepatocellular, cholestatic or mixed. Patients with severe infection have significantly higher rates of liver injury and worse outcomes. Proposed mechanisms for injury include immune mediated systemic inflammatory response, direct cytotoxicity from viral replication and hypoxia-reperfusion dysfunction.Recent data suggests that GI and hepatic injury may be under-recognized manifestation of SARS-CoV-2 infection. Patients with diarrhea and liver disease may have a worse prognosis. The rapidly evolving literature continues to reveal a growing body of information which enables updated guidance for management. More investigation is needed which focuses on vulnerable patients, including the elderly, those with underlying illness, as well as, racial and ethnic minorities.     

Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis

Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is controversial. Current recommendations contraindicate aggressive surgery because its results are unpredictable and may trigger disease progression. In this prospective study, we assessed the effectiveness of surgical resection of the jaws in cancer patients with BRONJ. Between June 2004 and July 2009, 30 cancer patients with refractory BRONJ underwent surgical resection of the jaws at our Units. They were followed-up weekly for the first month, at 3-month intervals up to 1 year, and at 6-month intervals up to 2 years. Panoramic radiographs and CT-scan were obtained at 3, 6, 12, 18 and 24 months. Primary outcomes were the 24-month recurrence rate of BRONJ and the 24-month mortality rate. Secondary outcomes were post-operative complications, duration of hospital stay after surgery, time to return to oral diet, and degree of oral pain. The 30 patients had a median age of 66 years and were mostly females (80%). Twenty-eight underwent a single resection and two had both jaws resected, for a total of 32 resected jaws. The cumulative recurrence rate of BRONJ in resected jaws 3.1% and 9.4% at 3 and 6 months, respectively. All the jaws with recurrent BRONJ had osteomyelitis at the margins of bone resection. The cumulative incidence of death was 3%, 12% and 16% at 12, 18 and 24 months. Surgical resection of BRONJ was highly effective, with few post-operative complications and were not associated with long-term mortality.     

NHERF1/EBP50 in Breast Cancer: Clinical Perspectives

Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) is a postsynaptic density 95/disc-large/zona occludens (PDZ) domain-containing protein that recruits membrane receptors/transporters and cytoplasmic signaling proteins into functional complexes. NHERF1 expression has been demonstrated to be altered in breast cancer, but its role in mammary cancerogenesis and progression remains still undefined. In this paper, we review what is known on the pathological role and the potential clinical application of NHERF1 protein in breast cancer. Recent evidence shows that an increased cytoplasmic expression of NHERF1 suggests a key role of its localization/compartmentalization in defining cancerogenesis, progression, and invasion. NHERF1 overexpression is associated with increasing tumor cytohistological grade, aggressive clinical behavior, unfavorable prognosis, and increased tumor hypoxia. Moreover, NHERF1 co-localizes with the oncogenic receptor HER2/neu in HER2/neu-overexpressing carcinoma and in distant metastases. These data make NHERF1 also a potential candidate of clinical relevance for anti-HER2/neu therapy.     

Oral Administration of the p75 Neurotrophin Receptor Modulator,LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury

BackgroundRadical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI), but also causes cavernous hypoxia and cavernous structural changes, which lead to a poor response to phosphodiesterase 5 inhibitors.AimTo investigate the therapeutic effect of oral administration of LM11A-31, a small molecule p75 neurotrophin receptor (p75^NTR) ligand and proNGF antagonist, in a mouse model of bilateral CNI, which mimics nerve injury–induced erectile dysfunction after radical prostatectomy.Methods8-week-old male C57BL/6 mice were divided into sham operation and CNI groups. Each group was divided into 2 subgroups: phosphate-buffered saline and LM11A-31 (50 mg/kg/day) being administered once daily starting 3 days before CNI via oral gavage. 2 weeks after CNI, we measured erectile function by electrical stimulation of the bilateral cavernous nerve. The penis was harvested for histologic examination and Western blot analysis. The major pelvic ganglia was harvested and cultured for assays of ex vivo neurite outgrowth.OutcomesIntracavernous pressure, neurovascular regeneration in the penis, in vivo or ex vivo functional evaluation, and cell survival signaling were measured.ResultsErectile function was decreased in the CNI group (44% of the sham operation group), while administration of LM11A-31 led to a significant improvement of erectile function (70% of the sham operation group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal processes. Immunohistochemical and Western blot analyses showed significantly increased p75^NTR expression in the dorsal nerve of CNI mice, which was attenuated by LM11A-31 treatment. Protein expression of active PI3K, AKT, and endothelial nitric oxide synthase was increased, and cell death and c-Jun N-terminal kinase signaling was significantly attenuated after LM11A-31 treatment. Furthermore, LM11A-31 promoted neurite sprouting in cultured major pelvic ganglia after lipopolysaccharide exposure.Clinical ImplicationsLM11A-31 may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases.Strengths & LimitationsUnlike biological therapeutics, such as proteins, gene therapies, or stem cells, the clinical application of LM11A-31 would likely be relatively less complex and low cost. Our study has some limitations. Future studies will assess the optimal dosing and duration of the compound. Given its plasma half-life of approximately 1 hour, it is possible that dosing more than once per day will provide added efficacy.ConclusionSpecific inhibition of the proNGF-p75^NTR degenerative signaling via oral administration of LM11A-31 represents a novel therapeutic strategy for erectile dysfunction induced by nerve injury.Yin GN, Ock J, Limanjaya A, et al. Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2021;18:17–28.     

Laser in treatment of laryngeal amyloidosis: A case report

Amyloidosis is the extracellular deposition of the fibrinous protein amyloid in one or more body sites. Amyloidosis may broadly be classified as either primary or secondary. Primary amyloidosis is idiopathic (56%), whereas the secondary form is associated with a chronic inflammatory or infectious process (5%), Amyloidosis is also related to multiple myeloma (26%). senescence (5%) and where tumor like deposits occur in isolated organs without systemic involvement (8%). Laryngeal amyloidosis is a rare discase. Surgery has been the mainstay of treatment either endoscopically or by an external neck approach. One case of laryngeal amyloidosis, treated with endolaryngeal microsurgery and carbon dioxide laser is presented with a follow up of 8 years.     

Aggressive histiocytic disorders that can involve the skin

Histiocytoses are a heterogeneous group of disorders that are characterized by the proliferation and accumulation of reactive or neoplastic histiocytes. Three classes of histiocytoses have been defined: class I, Langerhans cell disease; class II, non-Langerhans cell histiocytic disease without features of malignancy; and class III, malignant histiocytic disorders. Although the disorders in classes I and II usually have a benign appearance on histology and are commonly non-aggressive and self-healing, some can cause debilitating or even fatal outcomes. Such cases beg the question: what stimulates aggressive behavior of a classically benign disease? New molecular information may now provide insight into the driving force behind many of the aggressive histiocytoses. In this article, we review Langerhans cell disease and seven aggressive histiocytoses that can involve skin, discuss histologic features that may forecast a poor prognosis, and discuss the molecular findings that help to explain the pathophysiology of these aggressive histiocytic disorders.     

Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the biologically active ligand for the vitamin D receptor (VDR). VDR(-/-) mice have a hair follicle-cycling defect resulting in alopecia. However, mice lacking 25-hydroxyvitamin D(3) 1alpha-hydroxylase (CYP27B1(-/-)), and having no circulating 1,25(OH)(2)D(3), have normal follicular function. These mouse models indicate that VDR functions independently of 1,25(OH)(2)D(3) in regulating hair-follicle cycling. Here, we show that VDR(-/-) mice rapidly develop chemically induced skin tumors, whereas CYP27B1(-/-) and wild-type mice do not, indicating that VDR, and not the 1,25(OH)(2)D(3) ligand, is essential for protection against skin tumorigenesis. Because the majority of human skin cancer results from exposure to UV, the susceptibility of VDR(-/-) mice to this carcinogen was also evaluated. VDR(-/-) mice developed UV-induced tumors more rapidly and with greater penetrance than did VDR(+/+) mice. p53 protein levels were upregulated at similar rates in UV-treated keratinocytes of VDR(-/-) and VDR(+/+) mice. However, rates of thymine-dimer repair and UV-induced apoptosis were significantly lower in VDR(-/-) epidermis compared with the wild type epidermis. UV-induced epidermal thickening was also attenuated in VDR(-/-) skin, indicating that VDR plays a critical role in the repair and removal of severely damaged keratinocytes and adaptation of the skin to chronic UV exposure.