Intraductal Tissue Sampling Device Designed for the Biliary Tract.

Clinical sampling of tissue that is read by a pathologist is currently the gold standard for making a disease diagnosis, but the few minimally invasive techniques available for small duct biopsies have low sensitivity, increasing the likelihood of false negative diagnoses. We propose a novel biopsy device designed to accurately sample tissue in a biliary stricture under fluoroscopy or endoscopic guidance. The device consists of thin blades organized around the circumference of a cylinder that are deployed into a cutting annulus capable of comprehensively sampling tissue from a stricture. A parametric study of the device performance was done using finite element analysis; this includes the blade deployment under combined axial compression and torsion followed by an axial 'cutting' step. The clinical feasibility of the device is determined by considering maximum deployment forces, the radial expansion achieved and the cutting stiffness. We find practical parameters for the device operation to be an overall length of 10 mm and a diameter of 3.5 mm for a [Formula: see text] blade thickness, which allow the device to be safely deployed with a force of 10N and achieve an expansion over 3x its original diameter. A model device was fabricated with these parameters and a [Formula: see text] thickness out of a NiTi superalloy and tested to validate the performance. The device showed strong agreement with an equivalent numerical model, reaching a peak force within 2% of that predicted numerically and fully recovering after compression to 20% of its length. Clinical and Translational Impact Statement -This pre-clinical research conceptually demonstrates a novel expandable device to biopsy tissue in narrow strictures during an ERCP procedure. It can greatly improve diagnostic tissue yield compared to existing methods.

Sanctuary site central nervous system relapse-refractory DLBCL responding to nivolumab and lenalidomide.

Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. In diffuse large B-cell lymphoma (DLBCL), the incidence of CNS relapse is only ∼5% in unselected cohorts. Immunotherapy is the treatment that either boosts the patient's own immune system or uses man-made versions of the normal parts of the immune system to kill lymphoma cells or slow their growth. We are presenting a thirty-eight year old man who, presented with neck nodes, axillary nodes, altered sensorium, abnormal body movements, unconsciousness, weight loss and, fever, with a past history of DLBCL in May 2008, treated with 6 cycles of CHOP and completed in November 2008. After 9 years in April 2018, the patient developed similar symptoms and treated with salvage chemotherapy with R-DHAP which was completed in September 2018. Post-treatment PET-CT showed partial metabolic response and we started external beam radiotherapy to initial bulky disease. After completion of radiotherapy, the patient was very reluctant for any type of therapy and went home. After one month he presented to us with persistent vomiting, abnormal body movements and, altered sensorium. On examination, his Glasgow Coma Scale (GCS) was E2V3M2 and he was admitted in Intensive Care Unit. The patient was managed with mannitol, dexamethasone, antiepileptics, antibiotics and other supportive care medicines. His brain magnetic resonance imaging (MRI) was showing multiple heterogeneously enhancing lesions with surrounding vasogenic oedema and his cerebrospinal fluid analysis was positive for malignant cells. He was managed with triple intrathecal chemotherapy with methotrexate 12 mg, Cytarabine 50 mg, and Hydrocortisone 50 mg along with other supportive care medicines, and after 4-5 days he regained consciousness and he was able to talk and understand verbal commands. In view of improvement in general condition and performance status, we started biweekly triple intra-thecal therapy, and Inj. Nivolumab 3 mg per kg q 2 weekly. From the second cycle, we started Lenalidomide 10 mg once a day for 21 days with 7 days gap along with 2 weekly nivolumab and biweekly triple IT chemotherapy. After one month his CSF analysis was negative for malignant cells. Now he is on regular treatment with weekly IT chemotherapy, 2 weekly nivolumab and 3 weeks on and one week off lenalidomide. After 2 months of treatment, his MRI Brain was showing. At the time of submission of this article, he has completed the fifth cycle of immunotherapy and two cycles of lenalidomide. He was able to manage his daily ADL and able to walk with a stick. The patient tolerated immunotherapy, triple IT therapy and lenalidomide very well without much intolerable side effects. Therefore, we concluded that nivolumab and lenalidomide was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory sanctuary site CNS B- cell lymphomas. Additional studies of Nivolumab and lenalidomide in these diseases are ongoing.

Isolated acrometastasis: A rare presenting feature of endometrial carcinoma.

The most common presenting feature of endometrial carcinoma (EC) is abnormal uterine bleeding. Bone metastasis, as a presenting feature of EC, is very unusual which is usually restricted to pelvis and vertebrae. The occurrence of foot metastasis is exceedingly rare. We report a case of a postmenopausal female presented with pain and swelling involving right foot. Biopsy revealed metastatic adenocarcinoma. The patient denied any history of vaginal bleeding or other gynecological symptoms. Bone scan suggested increased uptake in multiple tarsal bones. Uterine curettage confirmed the diagnosis of endometrial adenocarcinoma. The patient was successfully treated with debulking surgery, palliative radiotherapy to the right foot, bisphosphonates, and systemic chemotherapy with marked improvement in local symptoms and is under follow-up for the last 6 months after completion of the treatment. An extensive review of the literature, to the best of our knowledge, did not reveal many cases of acrometastasis as a presenting feature of EC.

Effectiveness of anti-osteoporotic drugs to prevent secondary fragility fractures: systematic review and meta-analysis.

Patients with osteoporotic fractures have an increased risk for secondary fractures. However, a rigorous study that assesses the effectiveness of individual osteoporotic drugs in preventing subsequent fractures is lacking. The purpose of this review was to analyze the effectiveness of anti-osteoporotic drugs in preventing secondary fractures. We searched for randomized controlled trials that showed the incidence of secondary fractures while using anti-osteoporotic drugs (bisphosphonates, selective estrogen receptor modulators, parathyroid hormone (PTH), or calcitonin) in MEDLINE, Embase.com , and Cochrane Central Register databases. We estimated risk ratios (RR) and numbers needed to treat (NNT) to prevent secondary fractures. Twenty-six studies met our eligibility criteria. There was a significant reduction in RR (0.38-0.77) after the use of anti-osteoporotic drugs for secondary vertebral fractures. Bisphosphonates and PTH significantly reduced the risk of a secondary non-vertebral fracture (RR 0.59 and 0.64). PTH needed the fewest number of patients to be treated to prevent a secondary vertebral fracture (NNT: 56). Our study demonstrated the effectiveness of anti-osteoporotic agents included in our systematic review in preventing secondary vertebral fractures. Bisphosphonates and PTH were most effective in preventing non-vertebral fractures. We suggest that clinicians should prescribe these drugs to prevent secondary vertebral/non-vertebral fractures.

A systematic review of the management of acute pyogenic flexor tenosynovitis.

UNLABELLED: Pyogenic flexor tenosynovitis (PFT) is an aggressive closed-space infection that can result in severe morbidity. Although surgical treatment of pyogenic flexor tenosynovitis has been widely described, the role of antibiotic therapy is inadequately understood. We conducted a literature review of studies reporting on acute pyogenic flexor tenosynovitis management. A total of 28 case series articles were obtained, all of which used surgical intervention with varied use of antibiotics. Inconsistencies among the studies limited summative statistical analysis. Our results showed that use of antibiotics as a component of therapy resulted in improved range of motion outcomes (54% excellent vs. 14% excellent), as did using catheter irrigation rather than open washout (71% excellent vs. 26% excellent). These studies showed benefits of early treatment of pyogenic flexor tenosynovitis and of systemic antibiotic use. As broad-spectrum antibiotics have changed the management of other infectious conditions, we must more closely evaluate consistent antibiotic use in pyogenic flexor tenosynovitis management. LEVEL OF EVIDENCE: Therapeutic, Level III.

Magnetic resonance-guided laser ablation improves local control for postradiosurgery recurrence and/or radiation necrosis.

BACKGROUND: Enhancing lesions that progress after stereotactic radiosurgery are often tumor recurrence or radiation necrosis. Magnetic resonance-guided laser-induced thermal therapy (LITT) is currently being explored for minimally invasive treatment of intracranial neoplasms. OBJECTIVE: To report the largest series to date of local control with LITT for the treatment of recurrent enhancing lesions after stereotactic radiosurgery for brain metastases. METHODS: Patients with recurrent metastatic intracranial tumors or radiation necrosis who had previously undergone radiosurgery and had a Karnofsky performance status of >70 were eligible for LITT. Sixteen patients underwent a total of 17 procedures. The primary end point was local control using magnetic resonance imaging scans at intervals of >4 weeks. Radiographic outcomes were followed up prospectively until death or local recurrence (defined as >25% increase in volume compared with the 24-hour postprocedural scan). RESULTS: Fifteen patients (age, 46-82 years) were available for follow-up. Primary tumor histology was non-small-cell lung cancer (n = 12) and adenocarcinoma (n = 3). On average, the lesion size measured 3.66 cm (range, 0.46-25.45 cm); there were 3.3 ablations per treatment (range, 2-6), with 7.73-cm depth to target (range, 5.5-14.1 cm), ablation dose of 9.85 W (range, 8.2-12.0 W), and total ablation time of 7.43 minutes (range, 2-15 minutes). At a median follow-up of 24 weeks (range, 4-84 weeks), local control was 75.8% (13 of 15 lesions), median progression-free survival was 37 weeks, and overall survival was 57% (8 of 14 patients). Two patients experience recurrence at 6 and 18 weeks after the procedure. Five patients died of extracranial disease progression; 1 patient died of neurological progression elsewhere in the brain. CONCLUSION: Magnetic resonance imaging-guided LITT is a well-tolerated procedure and may be effective in treating tumor recurrence/radiation necrosis.

Cellular and molecular pathways to myocardial necrosis and replacement fibrosis.

Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signal-transducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca2+ overloading and subsequent induction of oxidative stress, predominantly confined within its mitochondria, to be followed by the opening of the mitochondrial permeability transition pore that leads to the destruction of these organelles and cells. It is now further recognized that Ca2+ overloading of cardiac myocytes and mitochondria serves as a prooxidant and which is counterbalanced by an intrinsically coupled Zn2+ entry serving as antioxidant. The prospect of raising antioxidant defenses by increasing intracellular Zn2+ with adjuvant nutriceuticals can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca2+ - Zn2+ dyshomeostasis. Hence, novel yet simple cardioprotective strategies may be at hand that deserve to be further explored.

Evaluation of acute locoregional toxicity in patients with breast cancer treated with adjuvant radiotherapy in combination with bevacizumab.

PURPOSE: Preclinical studies have shown that bevacizumab combined with radiotherapy (RT) induces a radiosensitizing effect. Published reports regarding the safety of combination therapy involving bevacizumab and RT are lacking. The purpose of this study was to analyze acute locoregional toxicity in patients with breast cancer receiving concurrent bevacizumab plus RT. METHODS AND MATERIALS: After institutional review board approval was obtained, patients with breast cancer who received bevacizumab were identified; these patients were then cross-referenced with patients receiving RT. Toxicity was scored by the Common Terminology Criteria for Adverse Events. Patients were matched 1:1 with those who did not receive bevacizumab. Statistical analysis was performed to analyze toxicity between the two groups. RESULTS: Fourteen patients were identified to have received bevacizumab plus RT. All patients received bevacizumab during RT without delay or treatment breaks; there were no RT treatment breaks in all patients. No patient receiving bevacizumab plus RT experienced ≥Grade 3 toxicity; 3 matched control patients experienced a Grade 3 skin reaction. There was no difference in fatigue, radiation fibrosis, pneumonitis, or lymphedema between the two groups. Five patients (35%) developed reduction in ejection fraction; 2 with right-sided and 3 with left-sided treatment. Patients with left-sided treatment experienced a persistent reduction in ejection fraction compared with those receiving right-sided treatment. CONCLUSION: Concurrent bevacizumab and RT did not increase acute locoregional toxicity in comparison with matched control patients who did not receive RT alone. The addition of concurrent RT when treating the intact breast, chest wall, and associated nodal regions in breast cancer seems to be safe and well tolerated.

Myocardial remodeling in low-renin hypertension: molecular pathways to cellular injury in relative aldosteronism.

The pathologic hypertrophy of hypertensive heart disease is related to the quality, not the quantity, of myocardium; the presence of fibrosis is inevitably linked to structural and functional insufficiencies with increased cardiovascular risk. Elevations in plasma aldosterone that are inappropriate relative to dietary sodium, or relative aldosteronism, are accompanied by suppressed plasma renin activity, elevation in arterial pressure, and dyshomeostasis of divalent cations. The accompanying hypocalcemia, hypomagnesemia, and hypozincemia of aldosteronism contribute to the appearance of secondary hyperparathyroidism. Parathyroid hormone-mediated intracellular calcium overloading of cardiac myocytes and mitochondria leads to the induction of oxidative stress and molecular pathways associated with cardiomyocyte necrosis and scarring of myocardium, whereas the dyshomeostasis of zinc compromises antioxidant defenses. This dys-homeostasis of calcium and zinc, intrinsically coupling prooxidant calcium and antioxidant zinc, raises the prospect for therapeutic strategies designed to mitigate intracellular calcium overloading while enhancing zinc-mediated antioxidant defenses, thus preventing adverse myocardial remodeling with fibrosis, associated diastolic dysfunction, and cardiac arrhythmias.

Coupled calcium and zinc dyshomeostasis and oxidative stress in cardiac myocytes and mitochondria of rats with chronic aldosteronism.

A dyshomeostasis of extra- and intracellular Ca(2+) and Zn(2+) occurs in rats receiving chronic aldosterone/salt treatment (ALDOST). Herein, we hypothesized that the dyshomeostasis of intracellular Ca(2+) and Zn(2+) is intrinsically coupled that alters the redox state of cardiac myocytes and mitochondria, with Ca(2+) serving as a pro-oxidant and Zn(2+) as an antioxidant. Toward this end, we harvested hearts from rats receiving 4 weeks of ALDOST alone or cotreatment with either spironolactone (Spiro), an aldosterone receptor antagonist, or amlodipine (Amlod), an L-type Ca(2+) channel blocker, and from age/sex-matched untreated controls. In each group, we monitored cardiomyocyte [Ca(2+)]i and [Zn(2+)]i and mitochondrial [Ca(2+)]m and [Zn(2+)]m; biomarkers of oxidative stress and antioxidant defenses; expression of Zn transporters, Zip1 and ZnT-1; metallothionein-1, a Zn(2+)-binding protein; and metal response element transcription factor-1, a [Zn(2+)]i sensor and regulator of antioxidant defenses. Compared with controls, at 4-week ALDOST, we found the following: (a) increased [Ca(2+)]i and [Zn(2+)]i, together with increased [Ca(2+)]m and [Zn(2+)]m, each of which could be prevented by Spiro and attenuated with Amlod; (b) increased levels of 3-nitrotyrosine and 4-hydroxy-2-nonenal in cardiomyocytes, together with increased H(2)O(2) production, malondialdehyde, and oxidized glutathione in mitochondria that were coincident with increased activities of Cu/Zn superoxide dismutase and glutathione peroxidase; and (c) increased expression of metallothionein-1, Zip1 and ZnT-1, and metal response element transcription factor-1, attenuated by Spiro. Thus, an intrinsically coupled dyshomeostasis of intracellular Ca(2+) and Zn(2+) occurs in cardiac myocytes and mitochondria in rats receiving ALDOST, where it serves to alter their redox state through a respective induction of oxidative stress and generation of antioxidant defenses. The importance of therapeutic strategies that can uncouple these two divalent cations and modulate their ratio in favor of sustained antioxidant defenses is therefore suggested.

Causes and consequences of zinc dyshomeostasis in rats with chronic aldosteronism.

Iterations in Ca2+ and Mg2+ balance accompany aldosteronism (inappropriate for dietary Na+ intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined. (1) To study the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO3 excretion. (2) To assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn2+]i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress were examined. (3) Oxidative stress and cardiac pathology in response to ZnSO4 supplement (40 mg/d) were also studied. Comparison of controls and rats receiving 4 weeks ALDOST revealed the following: (1) an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; (2) a rise in cardiac Zn, including increased [Zn2+]i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91(phox), coupled with oxidative stress in plasma and urine; (3) ZnSO4 prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO4 attenuated cardiomyocyte necrosis; however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contributes to cardiac pathology.

Bilateral pleural effusions in congestive heart failure.

The salt-avid state that accounts for the clinical syndrome congestive heart failure (CHF) leads to an initial expansion of intra- and subsequent rise in extravascular volumes that can include the appearance of pleural effusion. Herein, we present a 54-year-old man with a dilated cardiomyopathy who was hospitalized because of his CHF, which included bilateral pleural effusions, right hydrothorax greater than left. The pathophysiology of pleural fluid formation in CHF, previously debated, has now reached consensus, albeit not frequently reviewed. This index case offers such an opportunity.

Current update of pediatric hepatitis vaccine use.

Vaccines are now available for the prevention of hepatitis A and hepatitis B. In this article, biologics are reviewed with special attention to their use in the pediatric patient. Special attention is paid to issues that developed in 1999. For hepatitis A vaccine, it is the change in US recommendations regarding increased use in higher-risk US locations. For hepatitis B vaccine, it is the concern about toxicity, real or imagined.