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The authors describe the case of a young woman who developed a clinical pictures resembling a septic shock-related multiple organ dysfunction syndrome a couple of months after having been diagnosed suffering from a hemophagocytic lymphohistiocytosis associated with an infectious mononucleosis. Despite the aggressive treatment, which included antibiotics, vasopressors, IV immunoglobulins, and the use of an extracorporeal device aimed to remove mediators released both during sepsis and the cytokine storm determined by the hemophagocytic lymphohistiocytosis, the patient died. At the autopsy, an extremely uncommon aggressive lymphoma of Epstein-Barr virus-positive T-lymphocytes with systemic involvement was discovered.

Purpose and methods: In order to evaluate the rate of missed diagnoses (MD) of tumors in critically ill patients died in our Intensive Care Unit (ICU) and correlate them with the outcome, all the autopsy records from January 1st, 1996 and December 31st, 2014 have been reviewed. When the tumor was not diagnosed during the admission but discovered only at the post-mortem examination, the effect of the MD on the outcome was classified according to the Goldman’s criteria. Results: A total of, 1045 autopsies were examined; a solid or hematological cancer was discovered in 74 cases (7%, 50 M, 24 F, age 75.5, IQR 29-90 years). Major discrepancies occurred in 42 patients, but only in one of them (2.4%) a class 1 error was identified; in the other cases the MD did not influence the outcome (class 2 errors) due to the underlying conditions determining the ICU admission and/or the very short length of stay in the ICU; for another 32 patients the MD were considered without clinical relevance. Conclusions: In our experience, autopsy remains an extremely valuable tool to detect MD and to improve the clinical and diagnostic procedures.

Endocarditis is defined as the inflammation of the endocardium, the inner layer of the heart, mainly affecting heart valve leaflets, The term endocarditis was introduced for the first time in the scientific community by Sir William Osler who studied a series of 209 cardiac infections of different origins and delivered a Lecture at the Royal College of Physicians in London on "Malignant Endocarditis" in March 1885.

Infective endocarditis [IE] results from a wide range of combining factors leading to macroscopic alterations, often found at autopsy. The pathology of IE acknowledges the colonized vegetation as pathognomonic lesion, and the presence of sterile vegetation recalls the different clinical scenario of non-IE ..

Prompt coronary catheterization and revascularization have dramatically improved the outcome of myocardial infarction, but also have resulted in a growing number of survived patients with permanent structural damage of the heart, which frequently leads to heart failure. Finding new treatments for this condition is a largely unmet clinical need 1, especially because of the incapacity of cardiomyocytes to replicate after birth and thus achieve regeneration of the lost contractile tissue 2. Here we show that expression of human microRNA-199a in infarcted pig hearts is capable of stimulating cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, the treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. At longer follow-up, however, persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however this therapy needs to be tightly dosed.

Laser therapy, recently renamed as photobiomodulation, stands as a promising supportive treatment for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. Here we explored the anti-cancer effect of 3 laser protocols, set at the most commonly used wavelengths, in B16F10 melanoma and oral carcinogenesis mouse models. While laser light increased cell metabolism in cultured cells, the in vivo outcome was reduced tumor progression. This striking, unexpected result, was paralleled by the recruitment of immune cells, in particular T lymphocytes and dendritic cells, which secreted type I interferons. Laser light also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, an emerging strategy to control tumor progression. Collectively, these results set photobiomodulation as a safety procedure in oncological patients and open the way to its innovative use for cancer therapy., Highlights • Laser light reduces tumor progression while increasing metabolism of cultured cells • Laser-treated tumors contain mature vessels and less pro-angiogenic macrophages • Tumors treated by photobiomodulation are surrounded by lymphocytes and dendritic cells • Laser light promotes secretion of type I interferons in vitro and in vivo Laser therapy, also named photobiomodulation, is recommended to heal mucositis induced by oncological treatments, raising concerns on its safe use in cancer patients. Ottaviani et al. showed that laser light inhibits tumor progression, induces tumor vessel normalization and stimulates the immune system to produce type I interferons, proving the safety and extending the use of laser-based therapies to cancer.

The authors describe the case of a young woman who developed a clinical pictures resembling a septic shock-related multiple organ dysfunction syndrome a couple of months after having been diagnosed suffering from a hemophagocytic lymphohistiocytosis associated with an infectious mononucleosis. Despite the aggressive treatment, which included antibiotics, vasopressors, IV immunoglobulins, and the use of an extracorporeal device aimed to remove mediators released both during sepsis and the cytokine storm determined by the hemophagocytic lymphohistiocytosis, the patient died. At the autopsy, an extremely uncommon aggressive lymphoma of Epstein-Barr virus-positive T-lymphocytes with systemic involvement was discovered.

Background Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and periosteal tissues of the extremities. It can be a rare hereditary disease (pachydermoperiostosis) or can be secondary to various diseases, though mostly lung malignancies. Here, we report an unusual clinical presentation of HOA. Case presentation A 77-year-old man presented with fever, diarrhea, and an oligoarthritis involving the left knee and the ankles. Since left knee synovial fluid aspiration revealed an aseptic synovitis and Clostridium Difficile toxin was detectable in stool samples, a reactive arthritis secondary to a Clostridium Difficile induced colitis was initially suspected. However, the presence of a worsened digital clubbing and the lack of a good clinical response to steroid therapy led us to perform a radionuclide bone scanning, which revealed HOA. This turned out to be associated with a lepidic predominant lung adenocarcinoma, which was clinically and radiologically difficult to distinguish from a relapse of pneumonia. Conclusion Consistent with the literature, HOA tends to have a variable clinical presentation, mimicking that of various rheumatic diseases. This clinical case shows that HOA can present as a presumptive acute reactive arthritis, and it highlights the importance of patient’s follow-up in the differential diagnosis of inflammatory arthritis, especially when a worsened digital clubbing is present.

PURPOSE In a previous pilot study we observed that intra-operative narrow-band imaging (NBI) helps achieve clear superficial resection margins. The aim of this study was to verify if the use of intra-operative NBI can help to obtain tailored resections and if it is influenced by the lesion site, aspects not investigated in our previous study. MATERIALS AND METHODS The resection margins of 39 oral and 22 oropharyngeal squamous cell carcinomas were first set at 1.5cm from the macroscopic lesion boundary (white light, WL, tattoo). Then, the superficial tumor extension was more precisely defined with NBI, giving rise to three possible situations: NBI tattoo larger than the WL tattoo, NBI tattoo coinciding with the WL tattoo, or NBI tattoo smaller than the WL tattoo. For each of these situations the space comprised between the NBI and WL tattoos was defined "NBI positive", "NBI null", and "NBI negative", respectively. Resections were performed following the outer tattoo. The number of clear superficial resection margins, and the pathological response on the "NBI-positive" and the "NBI-negative" areas were recorded. RESULTS We obtained 80.3% negative superficial resection margins. NBI provided a more precise definition of superficial tumor extension in 43 patients. Sensitivity, specificity, positive and negative predictive values were 94.4%, 64%, 79.1% and 88.9%, respectively; a test of proportions demonstrated they were not influenced by tumor site. CONCLUSIONS NBI could allow for real-time definition of superficial tumor extension with possible tailored resections and fewer positive superficial resection margins; it is not influenced by tumor site.

Background: Statins and sildenafil have been shown to exert beneficial effects in cardiac injury. We hypothesized that antenatal maternal administration of simvastatin and/or sildenafil might also promote benefits in cardiac remodeling of congenital diaphragmatic hernia (CDH). Therefore, we performed micro-CT image analysis and histology of the heart after antennal treatment in experimental nitrofen-induced CDH. Methods: At 9.5 days post conception (dpc), pregnant rats were exposed to nitrofen. At 16 and 20 dpc fetuses were treated with simvastatin and/or sildenafil. At 21 dpc postmortem micro-CT and autopsy were performed. Results: All nitrofen-treated fetuses had a lower birth weight compared to controls; in the simvastatin-treated group, a significant improvement in CDH was noted. Impairment of the lung and liver was also noted in CDH. Compared to controls, CDH rats showed lower ventricular mass, with greater left ventricular thickness; simvastatin decreased the ventricular mass and improved wall thickness. CDH rats exhibited myocardial hypotrophy, severe vascular depression in the left ventricle, and intense interstitial edema compared to controls and nitrofen-exposed animals without CDH. In CDH, the cardiac morphology appeared deformed with left ventricular wall verticalization. Simvastatin improved cardiac myocyte appearance and heart morphology. Conclusion: The potential to treat CDH with antenatal simvastatin may improve the management of this malformation.

A girl aged 4 years and 3 months presented to our department for a right breast mass, slowly enlarging since the age of 6 months (figure 1). The mass was tender at the outer and harder at the medial quadrants to palpation, with apparently regular margins. The nipple over the mass was not altered. Figure 1 Right breast swelling without alteration of the skin or nipple. MRI showed a diffuse …

Primary aldosteronism (PA), also known as Conn’s syndrome, is a frequent cause of secondary hypertension. If PA is due to a documented unilateral adrenal adenoma, adrenalectomy is the treatment of choice. Endocrine Society guidelines suggest monitoring potassium after adrenalectomy, while there is no mention of sodium disorders after surgery. Here we report the case of a patient with Conn’s syndrome who developed hyponatremia after surgery. This was an unexpected event in the course of the treatment, which sheds light on the fact that low levels of aldosterone strongly influence sodium concentration, and advises clinicians to monitor sodium after adrenalectomy.

The lung alveoli slowly self-renew pneumocytes, but their facultative regeneration capacity is rapidly efficient after an injury, so fibrosis infrequently occurs. We recently observed Keratin 14 (KRT14) expression during diffuse alveolar damage (DAD), but not in controls. We wonder if KRT14 may be a marker of pneumocyte transition from quiescence to regeneration. Quantitative PCR and Western blot analyses highlighted the presence of KRT14 (mRNA and protein) only in human lung samples with DAD or interstitial lung disease (ILD). In the exponentially growing cell lines A549 and H441, the mRNA and protein levels of KRT14 peaked at day one after cell seeding and decreased at day two, opposite to what observed for the proliferation marker E2F1. The inverse relation of KRT14 versus E2F1 expression holds true also for other proliferative markers, such as cyclin E1 and cyclin D1. Of interest, we also found that E2F1 silencing caused cell cycle arrest and increased KRT14 expression, whilst E2F1 stimulation induced cell cycle progression and decreased KRT14. KRT14 also increased in proliferative pneumocytes (HPAEpiC) just before transdifferentiation. Overall, our results suggest that KRT14 is a viable biomarker of pneumocyte activation, and repair/regeneration. The involvement of KRT14 in regenerative process may suggest a novel pharmaceutical target to accelerate lung repair.

Objective Prenatal heart adaptations to congenital diaphragmatic hernia (CDH) could help define postnatal outcome. Methods We retrospectively analyzed post-mortem tissues from fetuses with severe CDH (n = 7). Histology and immunohistochemical distribution of desmin, muscle actin [HHF35], endothelin-1 [ET-1] and TGF-β were evaluated. Results In the atrium, desmin, HHF35, ET-1, TGF-β were found expressed only in preterm CDH. Dishomogeneous ventricular distribution of cardiac growth factors were detected in term CDH. The cardiomyocyte nucleus/cytoplasmatic ratio in CDH was higher compared with controls (p = 0.01). Small intramyocardial artery density and vascular wall thickness was increased in CDH compared with controls (p = 0.03 and p < 0.01). In comparison with the ventricles, the interventricular septum showed a greater vessel density (p = 0.01) and a greater vascular wall thickness, particularly compared with the CDH right ventricle (p = 0.02). Conclusion Left ventricle immaturity seems to be a cardiac adaptive response of severe CDH in utero.

Papillary fibroelastoma is the second most frequent primary tumor of the heart. We report the case of a cardiac papillary fibroelastoma, arising from the interatrial septum, symptomatic from distal embolization to lower limb arteries. Such a clinical presentation is extremely infrequent for cardiac papillary fibroelastomas. Moreover, the site of origin not from cardiac valves and the pathogenetic mechanism underlying the clinical manifestation both represent peculiar additional findings of our case.

Diffuse alveolar damage (DAD) is the chief pathological basis of life- threatening acute pulmonary conditions like the acute respiratory distress syndrome (ARDS). It may be considered as a model of lung regeneration and wound-repair, because the natural history of ARDS may include the resolution of diffuse alveolar damage (DAD) and a complete function recovery. Recent murine models of ARDS due to H1N1 infection suggested p63+/Krt5+ basal cells as tissue precursors for both airways and alveoli, but no human confirmation have been provided to date. Objectives: To investigate in human biopsy/autopsy samples of ARDS if p63+/Krt5+ cells have a pivotal role in lung regeneration following DAD. Secondarily, we challenged other possible markers of human lung regenerative process activation. Methods: We immunohistochemically analyzed a series of stem-cell related markers in 15 lung specimens of patients with ARDS/diffuse alveolar damage (DAD), comparing them with normal lung samples. Measurements and Main Results: Bronchiolar proliferation was not observed in regenerating parenchyma, where hyperplastic type-II pneumocytes did not express basal-cell markers Krt5 and ∆N-p63 (only scattered pneumocytes exhibited TA-p63 immunoreactivity revealed by a pan-p63 antibody). A striking finding in our study was a diffuse high percentage of Krt14+ pneumocytes in all DAD cases, at variance with normal controls where Krt14 expression was entirely negative. Variable Krt14 expression was evidenced in bronchiolar epithelium. A high proliferating index was observed in Krt14-expressing pneumocytes on double-stain Ki67/Krt14 preparations. No correlation was found between Krt14+ cells and clinical outcome (p>1.00). Conclusions: Our study suggests that basal cells are not involved in alveolar epithelial regeneration/repair and that Krt14 might be considered as a marker of alveolar regeneration/repair.