Clinical course of Coronavirus Disease-19 in patients with haematological malignancies is characterized by a longer time to respiratory deterioration compared to non-haematological ones: results from a case-control study.

BACKGROUND: We evaluated clinical features and risk factors for mortality in patients with haematological malignancies and COVID-19. METHODS: Retrospective, case-control (1:3) study in hospitalized patients with COVID-19. Cases were patients with haematological malignancies and COVID-19, controls had COVID-19 without haematological malignancies. Patients were matched for sex, age and time of hospitalization. RESULTS: Overall, 66 cases and 198 controls were included in the study. Cases had higher prior corticosteroid use, infection rates, thrombocytopenia and neutropenia and more likely received corticosteroids and antibiotics than controls. Cases had higher respiratory deterioration than controls (78.7% vs 65.5%, p = 0.04). Notably, 29% of cases developed respiratory worsening > 10 days after hospital admission, compared to only 5% in controls. Intensive Care Unit admission and mortality were higher in cases than in controls (27% vs 8%, p = 0.002, and 35% vs 10%, p < 0.001). At multivariable analysis, having haematological malignancy [OR4.76, p < 0.001], chronic corticosteroid therapy [OR3.65, p = 0.004], prior infections [OR57.7, p = 0.006], thrombocytopenia [OR3.03, p < 0.001] and neutropenia [OR31.1, p = 0.001], low albumin levels [OR3.1, p = 0.001] and ≥ 10 days from hospital admission to respiratory worsening [OR3.3, p = 0.002] were independently associated with mortality. In cases, neutropenia [OR3.1, p < 0.001], prior infections [OR7.7, p < 0.001], ≥ 10 days to respiratory worsening [OR4.1, p < 0.001], multiple myeloma [OR1.5, p = 0.044], the variation of the CT lung score during hospitalization [OR2.6, p = 0.006] and active treatment [OR 4.4, p < 0.001] all were associated with a worse outcome. CONCLUSION: An underlying haematological malignancy was associated with a worse clinical outcome in COVID-19 patients. A prolonged clinical monitoring is needed, since respiratory worsening may occur later during hospitalization.

The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study.

INTRODUCTION AND AIM: A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS: We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS: LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS: LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

A Single-Center 10-Year Experience with Pasireotide in Cushing's Disease: Patients' Characteristics and Outcome.

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing's disease (CD). Our 10-year experience with pasireotide in CD is reported here. Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor(®); Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months). Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients. Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

Bone complications in patients with Cushing's syndrome: looking for clinical, biochemical, and genetic determinants.

SUMMARY: This is the first study examining the impact of both clinical, biochemical, and genetic determinants in the occurrence of bone complications in patients with overt Cushing's syndrome (CS). It demonstrates that the degree and duration of hypercortisolism seem to play a major role in bone loss and fractures development in these patients. INTRODUCTION: Bone loss and fractures are a common complication of CS. We investigate the role of gender, disease etiology, duration, and degree of hypercortisolism as well as the impact of glucocorticoid receptor (GR) polymorphisms on the development of bone complications in CS. METHODS: Fifty-two patients with active CS (38 Cushing's disease and 14 with cortisol-secreting adrenal adenoma) were genotyped for GR polymorphisms (BclI, N363S, ER22/23EK, and A3669G). In all patients, clinical, hormonal, and biochemical markers of bone turnover, densitometric parameters [lumbar spine and left femur bone mineral density (BMD), T-score, Z-score] as well as the prevalence of bone demineralization and both vertebral and peripheral fractures were assessed. RESULTS: No differences were found in bone complications according to gender, disease etiology, and genetic variants distribution. Fractured patients compared to non-fractured ones showed increased levels of urinary free cortisol (UFC) and a more compromised densitometric profile. UFC levels correlated with the occurrence of vertebral fractures (r = 0.43, p = 0.009) while midnight serum cortisol correlated with L1-L4 BMD values (r = -0.35, p = 0.04). Disease duration correlated with the presence of peripheral fractures (r = 0.36, p = 0.04). CONCLUSIONS: While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism.

Inferring biological mechanisms from spatial analysis: prediction of a local inhibitor in the ovary.

Female mammals are born with a lifetime's supply of oocytes individually enveloped in flattened epithelial cells to form primordial follicles. It is not clear how sufficient primordial follicles are maintained to sustain the reproductive lifespan, while providing an adequate supply of mature oocytes for ovulation. Locally produced growth factors are thought to be critical regulators of early follicle growth, but knowledge of their identity and source remains incomplete. Here, we have used a simple approach of spatial analysis of structures in histological tissue sections to identify likely sources of such regulatory molecules, narrowing the field for future screening for candidate growth factors or antagonists. We have quantified the relative spatial positions of primordial (resting) follicles and growing follicles in mice on days 4, 8, and 12 after birth, and calculated interfollicular distances. Follicles were significantly less likely to have started growing if they had 1 or more primordial follicles close by (within 10 mum), predicting that primordial follicles inhibit each other. This approach allows us to hypothesize that primordial follicles produce a diffusible inhibitor that prevents neighboring primordial follicles from growing. Such an approach has wide applicability within many branches of developmental and cell biology for studying spatial signaling within tissues and cells.

Review of Relative effectiveness assessments (REAs) of pharmaceuticals at the European network for health technology assessment (EUnetHTA): A first step towards a consolidated European perspective on comparative effectiveness & safety?

OBJECTIVES: REAs from Joint Action (JA1-3) were reviewed and compared versus Health Technology Assessments (HTA) in France, Germany, UK, Italy. METHODS: EUnetHTA REAs published until end of 2019 were identified. Leveraging information derived from the HTA bodies' website key process (population; timing; national HTA bodies involved) and content characteristics (evidence base; comparative therapy, endpoints, subgroups) were determined and compared against national appraisals. RESULTS: All twelve pharmaceutical EUnetHTA assessment finalized until end of 2019 were included with Ustekinumab being the most recent (October 2019) and Pazopanib the first assessment (September 2012). In all but three assessments EUnetHTA's assessment did not cover the full EMA indication. Since JA3 time intervals between EMA approval and EUnetHTA assessment were < 80 days. Number of (co-)authoring HTA bodies ranged between 2 (in 6 REAs) and > 10 (Pazopanib). EUnetHTA did consider non - RCT evidence in 7 procedures; take a rather inclusive approach regarding appropriate comparative treatments; approach endpoints less restrictively than e.g. the German IQWiG/GBA; not apply a predetermined set of subgroups analyses. In seven REAs, national appraisal showed inhomogeneities across the 4 countries. National appraisals for Sotagliflozin and Ustekinumab were not yet available. CONCLUSIONS: A joint European HTA assessment has the potential to address the challenge of heterogeneity across the various national European HTA bodies and to determine joint European clinical development data standards that are aligned with regulatory requirements.

Reader variability in reporting breast imaging according to BI-RADS assessment categories (the Florence experience).

The inter- and intraobserver agreement (K statistic) in reporting according to BI-RADS assessment categories was tested on 12 dedicated breast radiologists, with little prior working knowledge of BI-RADS, reading a set of 50 lesions (29 malignant, 21 benign). Intraobserver agreement (four categories: R2, R3, R4, R5) was fair (0.21-0.40), moderate (0.41-0.60), substantial (0.61-0.80) or almost perfect (>0.80) for one, two, five or four radiologists, or (six categories: R2, R3, R4a, R4b, R4c, R5) fair, moderate, substantial or almost perfect for three, three, three or three radiologists, respectively. Interobserver agreement (four categories) was fair, moderate or substantial for three, six, or three radiologists, or (six categories) slight, fair or moderate for one, six, or five radiologists. Major disagreement occurred for intermediate categories (R3=0.12, R4=0.25, R4a=0.08, R4b=0.07, R4c=0.10). We found insufficient intra- and interobserver consistency of breast radiologists in reporting BI-RADS assessment categories. Although training may improve these results, simpler alternative reporting methods (systems), focused on clinical decision-making, should be explored.

Factors influencing the observed half-lives of specific synthetic capacities in Saccharomyces cerevisiae.

We have identified a variety of factors affecting the stability of allophanate hydrolase-specific and gross cellular protein synthetic capacities. These synthetic capacities have been extrapolated by many laboratories to represent functional messenger RNAs. Synthetic capacity turnover rates that we measured were greater in diploid organisms than in haploid strains and were proportional to the temperature of the culture medium. The stability of allophanate hydrolase-specific synthetic capacity was not influenced by alterations in the nitrogen source provided in the culture medium, but was increased up to 15-fold by the total inhibition of protein synthesis. Cultures in which protein synthesis was inhibited as little as 20% exhibited hydrolase-specific synthetic capacities more than 2-fold greater than those observed in the absence of inhibition.

Categorizing breast mammographic density: intra- and interobserver reproducibility of BI-RADS density categories.

The inter- and intraobserver agreement (kappa-statistic) in reporting according to Breast Imaging Reporting and Data System (BI-RADS((R))) breast density categories was tested in 12 dedicated breast radiologists reading a digitized set of 100 two-view mammograms. Average intraobserver agreement was substantial (kappa=0.71, range 0.32-0.88) on a four-grade scale (D1/D2/D3/D4) and almost perfect (kappa=0.81, range 0.62-1.00) on a two-grade scale (D1-2/D3-4). Average interobserver agreement was moderate (kappa=0.54, range 0.02-0.77) on a four-grade scale and substantial (kappa=0.71, range 0.31-0.88) on a two-grade scale. Major disagreement was found for intermediate categories (D2=0.25, D3=0.28). Categorization of breast density according to BI-RADS is feasible and consistency is good within readers and reasonable between readers. Interobserver inconsistency does occur, and checking the adoption of proper criteria through a proficiency test and appropriate training might be useful. As inconsistency is probably due to erroneous perception of classification criteria, standard sets of reference images should be made available for training.

The role of an acute pasireotide suppression test in predicting response to treatment in patients with Cushing's disease: findings from a pilot study.

Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing's disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1-9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 µg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 µg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 ± 24.3 and 48.1 ± 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term.

Revascularization of the circumflex coronary artery in the atrioventricular groove.

Complete myocardial revascularization entails the grafting of all vessels of adequate size demonstrating occlusive arteriosclerotic vascular disease. Revascularization of the circumflex coronary artery in the atrioventricular groove has been a major surgical challenge because of the difficulty of exposing it. We discuss here our operative technique in 12 consecutive patients requiring revascularization of that segment of the circumflex coronary artery. Eleven grafts studied in the postoperative period were found to be patent, and the clinical course of the remaining patient and direct observations, including enzyme studies and periodic stress testing, have not shown any evidence of graft failure.

Vascular grafts in microvascular surgery. An experimental study.

The patency of microvascular grafts depends on the luminal diameter, which is determined by the amount of fibrin and platelets deposited on the intraluminal surface and the anastomotic site, and the extent of pseudointimal formation. An experimental microvascular model in rats has been developed in our laboratory using Indium-111-labeled platelets to measure the amount of deposition on grafts inserted into the infrarenal aorta. This study was designed to assess the patency rates in these grafts and the pathologic maturation as determined by light and electron microscopy. Our study suggests that substantial patency rates can be achieved in aspirin-treated rats, although there was little influence on the pathologic maturation. Indium-111 oxine-labeled platelets can be used to document platelet aggregation, and the technique can be a valuable adjunct in the study of microvascular grafts.

Analytic dependence of the pressure and energy of an atomic fluid under shear.

Nonequilibrium molecular dynamics simulations are reported at different strain rates (gamma;) for a shearing atomic fluid interacting via accurate two- and three-body potentials. We report that the hydrostatic pressure has a strain-rate dependence of gamma;(2), in contrast to the gamma;(3/2) dependence predicted by mode-coupling theory. Our results indicate that the pressure and energy of real fluids may display an analytic dependence on the strain rate. This is in contrast to previous work using either Lennard-Jones or Weeks-Chandler-Anderson potentials that had shown a gamma;(3/2) dependence of pressure and energy.

Energy and pressure of shearing fluids at different state points.

Nonequilibrium molecular dynamics simulations are reported at different strain rates (gamma) and thermodynamic state points for a shearing atomic fluid interacting via a Lennard-Jones potential. Our simulations are performed at the Lennard-Jones triple point, a point midway between the triple point and the critical point, and a high point closer to the critical temperature. We find that, for the mid-point and high point, the energy and hydrostatic pressures have strain-rate dependencies of gamma(2), in contrast to the gamma(3/2) dependencies predicted by mode coupling theory. This analytical dependence is consistent with a Taylor series expansion of these quantities as powers of the strain rate tensor. Only at the triple point does the pressure and energy display a nonanalytical dependence on gamma(3/2).

Swan-Ganz catheter induced pulmonary hemorrhage.

In over 3500 consecutive open heart procedures using Swan-Ganz catheterization at our institution, we have experienced three major pulmonary artery injuries secondary to this procedure. Pulmonary artery hemorrhage is a rare but frequently fatal complication and a mortality rate as high as fifty percent has been reported. In two of these cases, major retraction of the heart was needed for adequate exposure of the cardiac pathology. The Swan-Ganz catheter inadvertently was advanced into the wedge position for prolonged intervals of time, and periodic overdistention of the balloon occurred. The third case occurred in the cardiac catheterization laboratory. The need for aggressive surgical approach has been demonstrated. The authors have recommended steps to be taken when massive hemoptysis occurs and Swan-Ganz catheter perforation of the pulmonary artery is suspected. Re-evaluation of the "routine" use of the Swan-Ganz catheter may be necessary and overutilization may be a distinct possibility. When the use of this catheter is deemed appropriate, a more exact positioning of the distal portion of the catheter is mandatory if pulmonary artery perforation is to be avoided.

[Early diagnosis of prostatic carcinoma by random biopsies in 60 patients clinically negative but with PSA greater than 8.9 ng/ml]. / Diagnosi precoce del carcinoma prostatico tramite biopsie random in 60 pazienti clinicamente negativi per neoplasia ma con PSA superiore a 8.9 ng/ml.

60 patients, 64 years old on average, with no evidences of prostatic cancer, but with a PSA level greater than 8.9 ng/ml, have undergone six transrectal systematic sextant biopsies. All patients had no suspicious finding on digital rectal examination. Ultrasound transrectal examinations did not show hypoechoic areas suspected of a prostatic cancer. We used an automatic biopsy gun fitted with an 18 gauge biopsy needle. Three biopsies in each lobe, at the apex, in the midline zone and at the base of the prostate, in the parasaggital plane, was performed. No complications were found during following days. Of the 60 men, with a non suspicious prostate on rectal examination, 12 had prostatic cancer. They had, on average, a PSA level of 10.8 ng/ml. The PSAD level was, on average, of 0.18 and the Gleason score was, on average, of 3.8. The patients who underwent pelvic lymphadenectomy and radical prostatectomy did not have an infiltration of the glans capsule of seminal vesicles and no lymph node metastasis were found. In our study, the digital rectal and ultrasound examination alone would have missed the 23% of prostatic cancers. Therefore, according to the literature, the PSA makes us able to discover prostatic cancer more than the clinical and instrumental evaluation alone. Furthermore the ultrasound examination presents some diagnostic limits. Particularly it is very difficult to detect small cancer arising into the hypoechoic multinodular adenoma of the transition zone. In addition 10-20% of cancers, arising into the peripheral zone, are hysoechoic with the surrounding parenchyma. For that reason, when PSA value is greater then 8.9 ng/ml without clinical or ultrasound evidence of cancer, we recommend to perform six systematic sextant biopsies. At present, the real question is to determine whether this early diagnosis is useful for patients, because there is no certainty of the therapeutic benefit in terms of quantity and quality life.

[T1G3 transitional bladder neoplasms: what to do?]. / Neoplasia vescicale transizionale T1 G3: che fare?

The treatment of T1 G3 bladder cancer is still an issue surrounded by much conflict. TUR of the bladder tumor as single treatment is considered not valid to be successful. TUR associated with intravescical chemotherapy or, even better, local immunotherapy may be the treatment of first choice in monocentric cancer, while radical cystectomy is, at the moment, the treatment of first choice in pluricentric or Cis associated T1 G3 bladder cancer. Since 1980, 25 patients with transitional T1 G3 bladder cancer have been observed in our department. Thirteen patients had a pluricentric disease while the remaining 12 cases had a monocentric bladder cancer. 92% of the patients (12/13) with a monocentric lesion and treated with TUR and local chemotherapy (Doxorubicin or BCG) are disease free after an average follow up of 34 Months (range 12-60 months). While 100% patients with a pluricentric cancer and treated with cystectomy are disease free after an average follow-up of 37 months (range 12-122 months); the 4 remaining cases with a pluricentric bladder lesion who refused cystectomy experienced a relapse of the disease after a follow-up of 19 months (range 9-27 months) and, despite surgery, they died within 12 months.

[Complicated urachal cyst: a difficult differential diagnosis]. / Cisti dell'uraco complicata: una difficile diagnosi differenziale.

Embryologically, the allantois connects the urogenital sinus with the navel. Normally, the allantois is oblitered before the birth and is represented by a fibrous cord, called urachus, extending from the dome of the bladder to the navel. Urachal formation is directly related to bladder descent. Incomplete obliteration sometimes occurs. Disease rarely occurs in urachus, but adenocarcinoma is the most fearful and rare, and it represents the 0.01% of the whole adult carcinoma, the 0.17-0.34% of the whole bladder malignancy, and the 20-30% of the bladder adenocarcinoma. Yet urachus may be seat of other kinds of benign pathologies characterized by incomplete obliteration of its lumen. Only if the ends of the urachus seal off, a cyst of that body may form and may become quite large, presenting a low midline abdomen mass. Adenocarcinoma may occur in a urachal cyst, particularly at its vescical extremity. Cystis usually have an asymtomatic course. Occasionally these cystis can be discovered during sonographic examination. If the cyst becomes infected, signs of general and local sepsis will develop, sometimes involving the peritoneum. Sometimes, in these cases, it is difficult to diagnose the presence of an adenocarcinoma and, particularly, its cystic variant. By using the common diagnostic instrumental device, we cannot reach a certain diagnosis, essential to perform a correct medical or surgical treatment. The case reported concerns a twenty-five years old man, over and over again examined, complaining of ipo-mesogastric abdominal pain, mild fever, increment of flogosis index and transaminasis, microscopic hematuria and urinal discomfort. Sonographic suprapubic examination, performed during urological consultation, showed an urachal neoplasm. Cystoscopy and TC evaluation didn't permit a certain preoperative diagnosis. A surgical explorative operation was performed and the neoplasm, a part of a bladder dome, omental flap and a part of rectus muscles, were removed. In order to reconstruct the abdominal wall we used a large Polypropilene patch. The hystological report outlined a large urachal cyst, a flogosis and a purulent necrosis invading the surrounding tissue and the peritoneum. The patient was discharged after twenty-five days and he had a good functional performance. In the light of the reported case, the surgical treatment seems to be the best solution before the onset of complications that should expose patients to difficult and demolitive surgical operations and that should protract the hospitalization.