Preliminary experimental IRE trials safely ablated healthy canine and cancerous human prostates, as examined in the short- and medium-term. IRE-relevant prostate properties are now experimentally and numerically defined. Importantly, the electric field required to kill healthy prostate tissue is substantially higher than previously characterized tissues. These findings can be applied to optimize IRE prostate cancer treatment protocols.

No abstract

Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill-defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, a mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients.

We read with great interest the recent study by Beilfuss et al, 1 which found vitamin D supplementation to ameliorate transforming growth factor-β-induced fibrogenesis in human hepatic stellate cells.Vitamin D is an important secosteroid hormone with pleiotropic effects that extend well beyond its established regulatory role in calcium and bone homeostasis. These include its recently described involvement in the regulation of immunomodulation, cell proliferation and differentiation, as well as anti-inflammatory and anti-fibrotic properties. 2 Subjects with non-alcoholic fatty liver disease (NAFLD) have a lower 25-hydroxyvitamin D [25 (OH)D] level, 3 which is reported to be independently associated with the histological severity of non-alcoholic steatohepatitis (NASH). 4 We recently undertook a prospective pilot study evaluating the impact of high-dose oral vitamin D 3 supplementation (25 000 IU/week) over 24 weeks on liver histology and metabolic profile in 12 non-cirrhotic patients with biopsy-proven NASH, defined as a NAFLD Activity Score of ≥4. Five patients (42%) had vitamin D deficiency, defined as a 25(OH)D level <50 nmol/L (<20 ng/mL) and 8 (67%) had a 25(OH) D level <75 nmol/L (<30 ng/mL). All patients underwent repeat liver biopsy at the end of the study period. Mean liver biopsy length was 14.9±3.8 mm including a mean portal tract number of 11.7±4.4. The mean NAFLD Activity Score was 5.6 ±0.9 and hepatocellular ballooning score was 1.8±0.4. Fibrosis stage prevalence was F1 58.3% (n=7), F2 8.3% (n=1) and F3 33.3% (n=4). Neither weight ( p=0.43) nor HbA1c ( p=0.52) significantly changed during therapy. We found that high-dose vitamin D supplementation had no impact on NAFLD Activity Score ( p=0.93), ALT ( p=0.78), HOMA-IR ( p=0.78), leptin ( p=0.53) or adiponectin ( p=0.20), as shown in table 1. Mean 25 (OH)D level increased from 63.3±31.6 to 109.8±15.6 nmol/L ( p=0.001) and no clinical or laboratory safety issues were observed.Although our pilot study found 24 weeks high-dose oral vitamin D 3 supplementation had no impact on liver histology, liver biochemistry, insulin resistance or adipocytokine profile in patients with biopsy-proven NASH, the potential therapeutic anti-fibrotic effect of vitamin D requires further clinical evaluation. 5 Such an effect would likely require an intervention of at least 2 years, and a prospective, randomised controlled trial of high-dose vitamin D supplementation is warranted to evaluate for any in vivo anti-fibrotic effect of vitamin D supplementation in NASH. The burgeoning incidence and prevalence of diseases that are a direct consequence of high levels of childhood and adult obesity, and/or a sedentary lifestyle are placing an increasing demand on limited healthcare resources. Simple, safe and cost-effective prevention and therapeutic strategies in this area such as vitamin D supplementation are urgently needed.

A 42-year-old woman presented with a rapidly enlarging right-sided thyroid mass and underwent hemithyroidectomy. Riedel's thyroiditis was only diagnosed upon surgical decompression of the right carotid artery 2 years later. She became more symptomatic as Riedel's thyroiditis progressed, and mediastinal fibrosclerosis developed over the next 12 months. Oral prednisolone failed to improve her condition, and she was commenced on tamoxifen. Despite initial improvement, her symptoms recurred 2 years later, mainly arising from compression of the trachea and esophagus at the thoracic inlet. Fluorodeoxyglucose positron emission tomographic scan showed locally advanced active invasive fibrosclerosis in the neck and mediastinum. An elevated activin-A level of 218 pg/mL was consistent with active inflammation. IgG subtypes (including IgG4) were normal. Two courses of iv methylprednisolone were given but only produced transient improvement. Subsequently, the patient received 3 doses of i.v. rituximab at monthly intervals and had prompt sustained symptomatic improvement. Activin-A level decreased to 122 pg/mL 10 months after rituximab therapy. Fluorodeoxyglucose positron emission tomographic scan 6 weeks after therapy showed reduction in inflammation. A further scan at 10 months demonstrated ongoing response to rituximab. This is a case of refractory Riedel's thyroiditis with symptomatic, biochemical, and radiological improvement that has persisted 14 months after rituximab. The likelihood and duration of response to rituximab in Riedel's thyroiditis requires further study.

Mucormycosis carries a high mortality rate with few therapeutic options available. We describe a man with pulmonary/splenic mucormycosis complicating hypoplastic myelodysplastic syndrome on a background of chronic kidney disease, who achieved a complete response with salvage isavuconazole therapy following intolerance of consecutive courses of liposomal amphotericin and posaconazole therapy.

Cutaneous endometriosis that arises de novo, without a prior history of surgery, is a rare phenomenon. The clinical diagnosis of cutaneous endometriosis remains challenging due to the variable clinical appearance and symptoms of the condition, and therefore must be considered in the differential diagnosis of any umbilical lesion. We report a 31-year-old woman who presented with spontaneous cutaneous endometriosis of the umbilicus.

Spontaneous hair repigmentation of physiologically white or gray hair is a rare occurrence that may be associated with melanoma in elderly individuals. We present the first case of this phenomenon in a man. A gray-haired, 80-year-old man presented to dermatology clinic with a 3-cm lock of black hair on his vertex scalp that developed over 1 year. Punch biopsies showed an increase in junctional dendritic melanocytes with rare pagetoid cells and extension along the follicular outer root sheath epithelium and interfollicular epidermis, associated with prominent dendritic melanocytic hyperplasia and pigment-containing melanocytes within the hair bulbs. Although the findings on the biopsies were not diagnostic of melanoma in situ, an irregular interfollicular distribution of melanocytes was concerning for an adjacent atypical process. A complete excision was performed and revealed melanoma in situ, lentigo maligna type. Rare reports describe spontaneous hair repigmentation as a harbinger of lentigo maligna in women. Repigmentation can occur in the setting of proliferation of malignant pigment-producing melanocytes or by paracrine stimulation of benign bulbar melanocytes through receptor tyrosine kinase KIT activation. Presence of prominent dendritic melanocytic hyperplasia and pigment-containing melanocytes within the hair bulbs in our patient's biopsies was suggestive of paracrine or physiologic stimulation of bulbar melanocytes. Given the importance of early melanoma detection and the low visibility of the scalp, this report raises awareness of an extraordinary presentation of lentigo maligna and exemplifies the importance of close clinicopathologic correlation to ensure optimal clinical management and patient outcome.