Treatment algorithm for the comprehensive management of severe lichen sclerosus in boys based on the pathophysiology of the disease.

INTRODUCTION: It is estimated that approximately one out of 200 boys has the diagnosis of lichen sclerosus (LS), previously referred to as BXO (balanitis xerotica obliterans). Severe progressive disease is rare however, mismanagement of urethral tissues may contribute to progression of LS. STUDY DESIGN: The current literature regarding the management of severe lichen sclerosus was reviewed alongside our management of seven patients with ages ranging from six to ten years of age with severe lichen sclerosus who required surgical intervention. These patients were identified out of a busy pediatric practice that saw 5507 patients during the four-year span. Based on the pathophysiology of lichen sclerosus, urethral anatomy, and our management an algorithm was developed for medical and surgical management. RESULTS: All patients received initial medical treatment with topical steroids. Three patients underwent urethral mobilization and serial biopsy. One of these patients with severe disease required a second distal urethral mobilization. Three patients were treated with circumcision, and one is responding well to topical steroids after complex reconstruction. None developed postoperative urethral disease. DISCUSSION: Lichen sclerosus affects squamous epithelium but can extend to unaffected tissue if traumatized via the Koebner phenomenon. There are no randomized control trials for the management of the disease. Thus, appropriate early management with avoidance of urethral dilation or incision may prevent extension down the urethra that can lead to severe stricture disease. Several authors identified this as one of the worst forms of stricture diseases to manage. Based on the pathophysiology of the disease and our 4-year experience treating patients, we propose an algorithm for management of severe lichen sclerosus in boys. The diagnosis of lichen sclerosus in boys requires a high level of suspicion, and early biopsies should be obtained if suspected. If identified before circumcision or meatotomy, initial treatment should be medical. If the patient fails topical steroid therapy, circumcision and biopsy are the initial recommended surgical approach. Optimally, a biopsy with the first meatotomy establishes the diagnosis. If the disease persists, urethral mobilization may represent a curative treatment as it advances healthy urethra and allows complete removal of distal squamous epithelium instead of traumatic repeated dilations or incisions. CONCLUSION: This paper summarizes the available literature on the management of severe LS and provides a flow diagram based on the pathophysiology of the disease and our experience sever cases.

Outcomes of extensive stage extrapulmonary small cell cancer.

BACKGROUND: Extrapulmonary small cell cancer (EPSCC) is a rare malignancy with an incidence of approximately 0.1%-0.4% of all cancers. Treatment of this disease is often based on small cell lung cancer. AIMS: We aimed to investigate real-world clinical outcomes of patients with extensive-stage (ES) ESPCC. METHODS: Patients diagnosed with ES EPSCC between 2010 and 2020 from multiple centres in New South Wales were identified. Patient, disease and treatment characteristics were collected and presented using descriptive statistics. Survival was analysed using the Kaplan-Meier method. Univariate and multivariate Cox regression hazard models were used to identify potential prognostic factors. RESULTS: Sixty eligible ES EPSCC patients were identified, including 65% male and 35% female. The mean age was 69 years (range 37-88). Forty-five per cent were never smokers, 42% ex-smokers and 13% current smokers, and 17% of patients had limited-stage disease prior to development of ES disease. The most common primary sites were genitourinary (42%; mainly prostate (n = 14) and bladder (n = 10)), gastrointestinal (28%; mainly oesophagus (n = 5) and colon (n = 4)) and unknown primary (22%). Treatments received included palliative chemotherapy (67%), palliative radiotherapy (53%), palliative surgery (13%) and best supportive care alone (13%). The median overall survival (OS) was 8.0 months. The median progression-free survival was 5.4 months, and response rate to first-line chemotherapy was 65%. Platinum-based chemotherapy was prognostic of longer OS (HR 0.27, CI 0.12-0.60, P = 0.001). CONCLUSIONS: Patients with ES EPSCC had good response to palliative chemotherapy, but OS remained poor. Further research is required to improve the prognosis in this population.

Mathematical model and tool to explore shorter multi-drug therapy options for active pulmonary tuberculosis.

Standard treatment for active tuberculosis (TB) requires drug treatment with at least four drugs over six months. Shorter-duration therapy would mean less need for strict adherence, and reduced risk of bacterial resistance. A system pharmacology model of TB infection, and drug therapy was developed and used to simulate the outcome of different drug therapy scenarios. The model incorporated human immune response, granuloma lesions, multi-drug antimicrobial chemotherapy, and bacterial resistance. A dynamic population pharmacokinetic/pharmacodynamic (PK/PD) simulation model including rifampin, isoniazid, pyrazinamide, and ethambutol was developed and parameters aligned with previous experimental data. Population therapy outcomes for simulations were found to be generally consistent with summary results from previous clinical trials, for a range of drug dose and duration scenarios. An online tool developed from this model is released as open source software. The TB simulation tool could support analysis of new therapy options, novel drug types, and combinations, incorporating factors such as patient adherence behavior.

Non-Invasive Buccal Swab Gene Testing for Skin Cancer Risk

Background: Studies have identified numerous genetic polymorphisms associated with increased risk of melanoma and non-melanoma skin cancer (NMSC). In this pilot study, we aimed to examine whether previously identified melanoma and non-melanoma associated single nucleotide polymorphisms (SNPs) which were found to be associated with cutaneous malignancy were also present in a relatively heterogeneous population with a history of skin cancer versus an age and environmental matched controls. The undertaking of this project serves to further the current understanding of the genetic profile for those at higher risk for developing skin cancer. Methods: Nineteen NMSC patients and their age-matched and environmental controls underwent genotyping of 7 previously discovered SNPs associated with melanoma and NMSC. Results: In a random, heterogeneous population in Southern California, SNP's Chr1, PAD16, PIGU, TDG had a similar association with NMSC previously reported in prior studies. Due to small trial size, no conclusions or observable associations could be drawn from the SNPs MC1R, TP53, and XRCC1. Conclusion: This data supports that 4 of the 7 SNP's studied had similar associations and could potentially be predictive tool of NMSC risk in this patient population. The remaining three SNP's did not have a definitive association with malignancy. Larger studies are needed to further elucidate the specific roles of these SNPs collectively and ultimately to develop a genetic profile for those patients at increased risk of developing skin cancer. J Drugs Dermatol. 2019;18(5):448-453.

Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Imaging Assessment of Partial Liquid Ventilation in Bronchopulmonary Dysplasia.

Partial liquid ventilation is proposed as an alternative ventilation strategy to reduce surface tension, increase alveolar recruitment, and decrease inflammation. Studied in acute respiratory distress and other indications, liquid ventilation is being revisited for infants with bronchopulmonary dysplasia. Perfluorooctyl bromide used for liquid ventilation is radiopaque, allowing radiographic visualization of lung liquid ventilation patterns that may provide additional insight into pulmonary pathophysiology. Current protocols utilize reduced liquid dosing, resulting in unique imaging features. We discuss optimal radiographic technique and report initial ultrasound evaluation results. With renewed interest in partial liquid ventilation, it may be helpful for pediatric radiologists to familiarize themselves with the clinical use and radiographic appearance of liquid ventilation material.

Blue Vision (Cyanopsia) Associated With TURP Syndrome: A Case Report.

There have been many complications associated with transurethral resection of the prostate (TURP), known as TURP syndrome. Of the various irrigation fluids used for TURP, glycine irrigant has been historically popular given its relatively low cost. It is also a nonconductive solution and only slightly hypoosmolar, reducing the risk of burn injury or significant hemolysis. However, there have been many case reports of central nervous system toxicity such as transient blindness and encephalopathy related to glycine toxicity. Here, we report blue vision (cyanopsia), which has never been reported as a symptom of TURP syndrome.

An Undiagnosed Paraganglioma in a 58-Year-Old Female Who Underwent Tumor Resection.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors that can have high morbidity and mortality if undiagnosed. Here we report a case of an undiagnosed paraganglioma in a 58-year-old female who underwent tumor resection. The patient became severely hypertensive intraoperatively with paroxysmal swings in blood pressure and then later became acutely hypotensive after tumor removal. She was managed in the surgical intensive care unit (SICU) postoperatively and discharged from the hospital without acute complications. We briefly discuss the epidemiology, clinical presentation, perioperative management, and possible complications of these tumors to assist healthcare providers if one were to encounter them.

Non-dysbaric arterial gas embolism associated with chronic necrotizing pneumonia, bullae and coughing: a case report.

Arterial gas embolism (AGE) can be clinically devastating, and is most often associated with exposure to changes in ambient pressure, medical procedure or congenital malformation. Here we report a case of AGE in a 78-year-old male without these traditional risk factors. Rather, the patient's history included chronic obstructive pulmonary disease, necrotizing pneumonia, bullous disease and coughing. He was safely treated with hyperbaric oxygen (HBO2) therapy for AGE, with initial clinical improvement, but ultimately died from his underlying condition. Pathophysiology is discussed. This case illustrates the possibility that AGE can occur due to rupture of lung tissue in the absence of traditional risk factors. HBO2 therapy should be considered in the management of such patients.

Handheld optical coherence tomography-reflectance confocal microscopy probe for detection of basal cell carcinoma and delineation of margins.

We present a hand-held implementation and preliminary evaluation of a combined optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) probe for detecting and delineating the margins of basal cell carcinomas (BCCs) in human skin

Treatment and survival of osseous renal cell carcinoma metastases.

BACKGROUND: Renal cell carcinoma is the seventh leading cause of cancer deaths. Studies have shown patients with solitary osseous metastases have a better prognosis; however, methods of resection are not well defined. The purpose of this study was to review factors associated with survival and assess the impact of wide versus intralesional management on function and disease-specific outcomes in patients with renal cell carcinoma metastases. METHODS: Sixty-nine patients with 86 osseous renal cell metastases were reviewed. Potential factors associated with survival were evaluated with Kaplan-Meier curves. ANOVA was performed to compare means between groups. RESULTS: One year survival for the group was 77% and 32.5% at 5 years. The absence of metastatic disease at presentation, nephrectomy, and pre-operative status were associated with improved survival. There was a lower rate of local recurrence with wide resection (5%) versus intralesional procedures (27%). CONCLUSIONS: Improved pre-operative status, nephrectomy, and metachronous lesions had better overall survival. Wide resection results in decreased local recurrence and revision surgeries. However, it did not reliably predict improved survival. Our recommendation is for individual evaluation of each patient with osseous renal cell carcinoma metastases. Wide excision may be used for resectable lesions to prevent local progression and subsequent surgeries.

Ron receptor tyrosine kinase negatively regulates TNFalpha production in alveolar macrophages by inhibiting NF-kappaB activity and Adam17 production.

The Ron receptor tyrosine kinase (TK) plays a regulatory role in the inflammatory response to acute lung injury induced by intranasal administration of bacterial LPS. Previously, we have shown that mice with a targeted deletion of the TK signaling domain of the Ron receptor exhibited more severe lung injury in response to intranasal LPS administration as evidenced by an increased leakage of albumin in the lungs and a greater thickening of the alveolar septa compared with wild-type mice. In addition, lung injury in the Ron TK-deficient (TK(-/-)) mice was associated with increased activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), and significantly increased intrapulmonary expression of TNFalpha. TNFalpha, a multifunctional proinflammatory cytokine, is a central mediator in several disease states, including rheumatoid arthritis and sepsis. On the basis of the observation that TNFalpha production is increased in the Ron TK-/- mice and that macrophages are a major source of this cytokine, we hypothesized that the alterations observed in the Ron TK(-/-) mice may be due, in part, to Ron signaling, specifically in alveolar macrophages. To test this hypothesis, we used the wild-type and Ron TK(-/-) primary alveolar macrophages and the murine alveolar macrophage cell line, MH-S, to examine the effects of Ron activation on LPS-induced TNFalpha production and NF-kappaB activity. Here, we reported that Ron is expressed on alveolar macrophages and MH-S cells. Activation of Ron by its ligand, hepatocyte growth factor-like protein, decreases TNFalpha production in alveolar macrophages after LPS challenge. Decreased TNFalpha is associated with hepatocyte growth factor-like protein-induced decreases in NF-kappaB activation and increases in the NF-kappaB inhibitory protein, IkappaB. We also provided the first evidence for Ron as a negative regulator of Adam17, the metalloprotease involved in TNFalpha processing. These results indicate that Ron plays a critical role in regulation of alveolar macrophage signaling and validates this receptor as a target in TNFalpha-mediated pulmonary pathologies.

Oncologic and functional outcome following sacrectomy for sacral chordoma.

BACKGROUND: Sacral chordoma is a rare, low to intermediate-grade tumor that poses substantial challenges in terms of timely diagnosis and adequate treatment. Few studies have examined the oncologic and functional outcomes of patients treated for sacral chordoma. METHODS: The clinical records of sixteen patients who had undergone sacrectomy for chordoma between 1985 and 2001 were evaluated retrospectively. All patients underwent resection by means of a sequential combined anterior and posterior approach. Patients were followed clinically at six-month intervals following recovery from the index surgical procedure. The disease onset, treatment, hospital stay, recurrence rates, survival, adjuvant therapy, functional outcome measures, and complications were evaluated. RESULTS: The average age at the time of diagnosis was sixty-one years. The mean tumor size was 15.2 cm in diameter, and all patients had a resection involving S1 or S2. The mean duration of follow-up was sixty-six months, and the tumor recurred in twelve of the sixteen patients. The mean time to metastasis was fifty months. Four patients were clinically disease-free at a mean follow-up of 94.5 months, while five patients died as a result of progressive local or metastatic disease at a mean follow-up of 31.4 months. Only one patient had normal bowel and bladder control postoperatively, and only three were able to walk without assistive devices. Eight patients had wound complications, and one patient had a deep-vein thrombosis. With the numbers available, neither negative margins at the time of initial tumor resection nor adjuvant radiation therapy had a significant impact on survival or local recurrence. More cephalad levels of resection were associated with significantly worse bowel (p = 0.01) and bladder (p = 0.01) control. Complications were frequent and were more common with a larger tumor size at the time of presentation (p = 0.034). CONCLUSIONS: The treatment of sacral chordoma is an arduous clinical undertaking that requires a multidisciplinary approach and attention to detail from the outset. Despite aggressive well-planned surgical management and adherence to strict surveillance protocols, frequent recurrence and the late onset of metastatic disease are to be expected in a substantial proportion of patients, especially those with a very large chordoma or one at a more cephalad level. Adequate surgical treatment results in substantial functional impairment and numerous complications; however, it does offer the possibility of long-term disease-free survival. We advocate an attempt at complete resection, when there is still a possibility of cure, and aggressive treatment of local recurrences. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

CVS-3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts.

BACKGROUND: Matriptase, a type-II transmembrane serine protease, is expressed by cancers of epithelial origin including breast, colon, and prostate carcinomas and has been implicated in tumor growth and progression. We studied the effects of CVS-3983, a selective small molecule matriptase inhibitor, on the growth of the androgen independent (AI) CWR22R and CWRSA6 human prostate cancer xenograft models. METHODS: CVS-3983 was administered i.p. twice-daily 7-days per week for 2-3 weeks to mice with established tumors. Measurements of tumor volume were made twice weekly. The effect of CVS-3983 on CWR22RV1 cell invasion through a reconstituted basement membrane matrix of proteins was also evaluated. Matriptase expression across the tumor lines was assessed by RT-PCR and Western blotting. RESULTS: CVS-3983 inhibited final mean tumor volume by 65.5% (n = 10, P = 0.0002) in the CWR22R model and by 56.2% (n = 8, P = 0.0017) in the CWRSA6 tumor model compared with vehicle-treated tumors. CVS-3983 did not inhibit the proliferation of CWR22RV1 cells in vitro; however, the small molecule did significantly reduce by 30.2% the invasion of these cells in vitro through a reconstituted basement membrane matrix. Molecular analysis of the xenograft tumors demonstrated high expression levels of matriptase at the RNA and protein levels, which were not affected by CVS-3983 treatment. CONCLUSIONS: These results identify CVS-3983 as a potent inhibitor of AI prostate cancer cell invasion in vitro and established xenograft tumor growth in vivo.

Inhibition of HER-kinase activation prevents ERK-mediated degradation of PPARgamma.

R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer xenograft growth through downregulation of cyclin D1 expression via the PPARgamma pathway. PPARgamma protein degradation, observed post-R-etodolac treatment, resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively regulating PPARgamma function. Negative regulation of PPARgamma was overcome by a combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4, which demonstrated an additive antitumor effect. We further show that the inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit PPARgamma protein degradation. This study introduces a novel concept of an in vivo crosstalk between the HER-kinase axis and PPARgamma pathways, ultimately leading to negative regulation of PPARgamma activity and tumor growth inhibition.

Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer.

PURPOSE: Human tumors are dependent on angiogenesis for growth, and vascular endothelial growth factor (VEGF) is a major regulator of this process. We aimed to study clinical utility of a recombinant humanized monoclonal anti-VEGF antibody (rhu alpha VEGF) in the treatment of the CWR22R androgen-independent xenograft model of prostate cancer. EXPERIMENTAL DESIGN: rhu alpha VEGF has previously shown clinical activity in several xenograft cancer models. We administered 5 mg/kg rhu alpha VEGF i.p. twice weekly as a single agent and together with paclitaxel to established CWR22R xenografts. RESULTS: rhu alphaVEGF inhibited established tumor growth by 85% (P < 0.01 for trajectories of the average tumor volumes of the groups) at 3 weeks, but after cessation of rhu alpha VEGF treatment, tumor regrowth ensued. A paclitaxel dosage of 6.25 mg/kg s.c. five times/week slowed tumor growth (72% compared with controls at 3 weeks, P = 0.02). The combination of paclitaxel and rhu alpha VEGF resulted in greater inhibition of tumor growth than that observed with either agent alone (98% growth inhibition, P = 0.024 versus rhualpha VEGF alone and P = 0.02 versus paclitaxel alone). Paclitaxel alone had no antiangiogenic effects at the dosage studied, whereas rhu alpha VEGF had significant inhibition of angiogenesis, noted by microvessel density and CD34 staining. CONCLUSIONS: rhu alpha VEGF has cytostatic clinical activity in this androgen-independent prostate cancer xenograft model, and the addition of paclitaxel demonstrates increased clinical activity.

Use of intercostal bupivacaine with epinephrine after surgery to decrease use of narcotics and duration of intubation.

BACKGROUND: Postoperative pain plays a significant part in the recovery of patients after open heart surgery. OBJECTIVE: To determine if the use of intercostal bupivacaine with epinephrine is associated with decreases in use of narcotics and intubation times after open heart surgery. METHODS: A randomly selected experimental group of 25 patients received injections of bupivacaine with epinephrine in the intercostal tissues before chest closure in open heart surgery. A control group of 22 patients received no bupivacaine, only standard care. Postoperative use of narcotics and intubation times were determined for both groups. RESULTS: Compared with the control group, the group given bupivacaine with epinephrine used significantly less narcotics (P=.008) and had significantly shorter intubation times (P=.003). CONCLUSION: Injection of intercostal bupivacaine with epinephrine before chest closure in open heart surgery decreases use of narcotics and length of intubation postoperatively, thus speeding up recovery times.