Robert Gerring

Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal Function

We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA‐based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy‐eight patients were randomized (Evr n = 52; CsA n = 26). The 1‐year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥3 (estimated glomerular filtration rate <60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.

Current concepts in the pathogenesis and treatment of chronic suppurative otitis media.

Otitis media (OM) is an inflammation of the middle ear associated with infection. Despite appropriate therapy, acute OM (AOM) can progress to chronic suppurative OM (CSOM) associated with ear drum perforation and purulent discharge. The effusion prevents the middle ear ossicles from properly relaying sound vibrations from the ear drum to the oval window of the inner ear, causing conductive hearing loss. In addition, the inflammatory mediators generated during CSOM can penetrate into the inner ear through the round window. This can cause the loss of hair cells in the cochlea, leading to sensorineural hearing loss. Pseudomonas aeruginosa and Staphylococcus aureus are the most predominant pathogens that cause CSOM. Although the pathogenesis of AOM is well studied, very limited research is available in relation to CSOM. With the emergence of antibiotic resistance as well as the ototoxicity of antibiotics and the potential risks of surgery, there is an urgent need to develop effective therapeutic strategies against CSOM. This warrants understanding the role of host immunity in CSOM and how the bacteria evade these potent immune responses. Understanding the molecular mechanisms leading to CSOM will help in designing novel treatment modalities against the disease and hence preventing the hearing loss.

In Vitro Interaction of Pseudomonas aeruginosa with Human Middle Ear Epithelial Cells

Background Otitis media (OM) is an inflammation of the middle ear which can be acute or chronic. Acute OM is caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis whereas Pseudomonas aeruginosa is a leading cause of chronic suppurative otitis media (CSOM). CSOM is a chronic inflammatory disorder of the middle ear characterized by infection and discharge. The survivors often suffer from hearing loss and neurological sequelae. However, no information is available regarding the interaction of P. aeruginosa with human middle ear epithelial cells (HMEECs). Methodology and Findings In the present investigation, we demonstrate that P. aeruginosa is able to enter and survive inside HMEECs via an uptake mechanism that is dependent on microtubule and actin microfilaments. The actin microfilament disrupting agent as well as microtubule inhibitors exhibited significant decrease in invasion of HMEECs by P. aeruginosa. Confocal microscopy demonstrated F-actin condensation associated with bacterial entry. This recruitment of F-actin was transient and returned to normal distribution after bacterial internalization. Scanning electron microscopy demonstrated the presence of bacteria on the surface of HMEECs, and transmission electron microscopy confirmed the internalization of P. aeruginosa located in the plasma membrane-bound vacuoles. We observed a significant decrease in cell invasion of OprF mutant compared to the wild-type strain. P. aeruginosa induced cytotoxicity, as demonstrated by the determination of lactate dehydrogenase levels in culture supernatants of infected HMEECs and by a fluorescent dye-based assay. Interestingly, OprF mutant showed little cell damage compared to wild-type P. aeruginosa. Conclusions and Significance This study deciphered the key events in the interaction of P. aeruginosa with HMEECs in vitro and highlighted the role of bacterial outer membrane protein, OprF, in this process. Understanding the molecular mechanisms in the pathogenesis of CSOM will help in identifying novel targets to design effective therapeutic strategies and to prevent hearing loss.

Immunity Genes and Susceptibility to Otitis Media: A Comprehensive Review

Otitis media (OM) is a middle ear infection associated with inflammation and pain. This disease frequently afflicts humans and is the major cause of hearing loss worldwide. OM continues to be one of the most challenging diseases in the medical field due to its diverse host targets and wide range of clinical manifestations. Substantial morbidity associated with OM is further exacerbated by high frequency of recurrent infections leading to chronic suppurative otitis media (CSOM). Children have greater susceptibility to, and thus, suffer most frequently from OM, which can cause significant deterioration in quality of life. Genetic factors have been demonstrated, in large part by twin and family studies, to be key determinants of OM susceptibility. In this review, we summarize the current knowledge on immunity genes and selected variants that have been associated with predisposition to OM. In particular, polymorphisms in innate immunity and cytokine genes have been strongly linked with the risk of developing OM. Future studies employing state-of-the-art technologies, including next-generation sequencing (NGS), will aid in the identification of novel genes associated with susceptibility to OM. This, in turn, will open up avenues for identifying high-risk individuals and designing novel therapeutic strategies based on precise targeting of these genes.

Early use of mammalian target of rapamycin inhibitors is an independent risk factor for incisional hernia development after liver transplantation

Incisional hernias (IHs) are common complications after liver transplantation (LT) with a reported incidence of 1.7% to 34.3%. The purpose of this retrospective study was to evaluate the risk factors for IH development after LT with a focus on the role of immunosuppressive therapy during the first month after LT. We analyzed 373 patients who underwent LT and divided them into 2 groups according to their postoperative course: an IH group (121 patients or 32.4%) and a no‐IH group (252 patients or 67.6%). A univariate analysis demonstrated that the following were risk factors related to IH development: male sex (P = 0.03), a body mass index ≥ 29 kg/m2 (P = 0.005), LT after 2004 (P = 0.02), a Model for End‐Stage Liver Disease (MELD) score ≥ 22 (P = 0.01), and hepatitis B virus infection (P = 0.01). The highest incidence of IHs was found in patients treated with mammalian target of rapamycin (mTOR) inhibitors (54.5%, P = 0.004). A multivariate analysis revealed male sex (P = 0.03), a pretransplant MELD score ≥ 22 (P = 0.04), and the use of mTOR inhibitors (P = 0.001) to be independent risk factors for IHs after LT. In conclusion, immunosuppressive therapy with mTOR inhibitors is an important independent risk factor for IH development after LT. To reduce the incidence of IHs, mTOR inhibitors should be avoided until the fourth month after LT unless their use is deemed to be strictly necessary. Liver Transpl 18:188–194, 2012.

Role of innate immunity in the pathogenesis of otitis media.

Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects.

Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survival

PurposeTo describe prognostic factors and survival outcomes in patients who underwent orbital exenteration for periocular non-melanoma cutaneous malignancies.MethodsThe authors performed an institutional review board-approved retrospective review of all patients who underwent orbital exenteration for non-melanoma periocular cutaneous malignancies at a tertiary care hospital system over a 10-year period. Patient demographics, tumor, and treatment data were recorded. Survival outcomes included disease-free survival (DFS) and overall survival (OS). Log-rank tests were used to test for difference in survival curves among various potential prognostic indicators, and multivariate analysis was performed using Cox’s proportional hazards model.ResultsForty-nine patients with an average age of 70.3 years were followed with a median follow-up of 17.5 months. At 2 years the OS was 78% while the DFS was 61%. The mean DFS for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC) were 52.6, 39.2 and 28.1 months, respectively. Multivariate analysis demonstrated that only positive final surgical margin was predictive of worse outcome (P=0.002). Recurrences were most frequent in the first 2 years.ConclusionsDespite the relatively more aggressive nature of periocular malignancies that have invaded the orbit, orbital exenteration offers an overall 2-year DFS of ~60%. BCC had the greatest mean survival time, however this was not statistically significant. We found worse prognosis with positive final surgical margins and recommend a multidisciplinary surgical approach to achieve complete resection when indicated.

Liver transplantation in patients aged 65 and over: a case–control study

Montalti R, Rompianesi G, Di Benedetto F, Ballarin R, Gerring RC, Busani S, De Pietri L, De Ruvo N, Iemmolo RM, Guerrini GP, Smerieri N, Gerunda GE. Liver transplantation in patients aged 65 and over: a case–control study.
Clin Transplant 2010 DOI: 10.1111/j.1399‐0012.2010.01230.x.
© 2010 John Wiley & Sons A/S.

Parotid and Temporal Bone Resection for Skull Base Malignancies: Outcome

We reviewed the outcome of and determined prognostic factors for patients undergoing combined lateral skull base resection for advanced lateral skull base malignancies. We performed a retrospective, single-institution case series in an academic tertiary care hospital. Seventy-nine patients with combined temporal bone resection and parotidectomy for advanced lateral skull base malignancy were included. Main outcome measures were overall survival and disease-free survival. The mean follow-up time was 18.3 months, with an overall survival of 64.5 months and disease-free survival of 42.6 months. Disease-free survival was 36.2 months for skin tumors, 42.7 months for salivary glands tumors, and 8.5 months for tumors of mesenchymal origin. Log-rank tests for prognostic indicators demonstrated that temporal bone erosion on computed tomography (CT) scan (p = 0.009) and histology (p = 0.045) were statistically significant predictors of poor outcome. Subtotal resection of the facial nerve and positive lymph nodes were associated with poor outcome in tumors arising from skin. Advanced malignancies of the lateral skull base are best managed using a combined lateral temporal bone resection and parotidectomy, with a 50% disease-specific survival of 32 months. Malignant mesenchymal tumors as well as presence of temporal bone erosion on preoperative CT scan are associated with poor prognosis.

Orbital Exenteration for Advanced Peri-orbital Skin Cancer: Prognostic Factors and Survival

Objectives: Orbital exenteration for advanced periorbital malignancies is a relatively rare but highly morbid procedure, often done for cancers arising from periorbital skin. The purpose of this research is to investigate and describe cases of cutaneous malignancy of the periorbital skin for which orbital exenteration was done. Methods: This is a retrospective single institution case series at a tertiary care university hospital, including all cases of orbital exenteration for advanced periorbital malignancies performed between January 2002 and January 2012 at the University of Miami/Bascom Palmer Eye Institute/Jackson Memorial Hospital. Patient demographics, tumor characteristics, operative reports, histologic, radiologic and clinical follow-up data were recorded. Outcome measures were overall survival and disease free survival, univariate analysis for multiple clinical factors including prior surgery, bony erosion on pre-operative CT scan, intracranial involvement, and surgical margins. Results: There were 64 patients with a mean age of 70 years (41 male, 23 female) who underwent orbital exenteration for periorbital skin cancers. Of these, 24 patients had squamous cell carcinoma, 24 basal cell carcinoma, 11 sebaceous carcinoma, and 5 cases of malignant melanoma. The most common sites of origin were facial skin (17), medial canthus (14), inferior lid (14), and upper lid (11). Conclusions: Surgical outcome and survival were reviewed with relation to significant prognostic variables.