Internal medicine inpatients' prevalence of misdiagnosed severe osteoporosis.

Vertebral fractures (VF) related to osteoporosis (i.e., severe OP) increase the risk of disability and mortality, but they are often neglected. We observed a severe OP misdiagnosis in 28.9% of inpatients with previous spinal imaging positive for VFs. Diagnosing severe OP is crucial to reduce the health care costs of inpatients. INTRODUCTION: Vertebral fractures (VFs) related to osteoporosis (OP) increase the risk of additional fractures and death. In inpatients, VFs are often neglected with consequent delay in OP treatments, prolongation of hospitalization, and reduction of life expectancy. The aim of this study was to evaluate the prevalence of a misdiagnosed severe OP (i.e., with VF) in general medicine inpatients. METHODS: We evaluated inpatients of a Medicine Unit between January 2019 and December 2019 without severe OP diagnosis, who had spinal imaging. For each patient, we collected demographic data, previous or current OP treatment, and presence/number of VFs. Descriptive data were presented by medians (interquartile range [IQR]) for continuous data or as numbers (percentages) for categorical data. Differences between subgroups were analyzed with chi-square or Kruskal-Wallis tests as appropriate. p-values <0.05 were considered statistically significant. RESULTS: 793 subjects were admitted to inpatient's clinic: 235 (135 females and 100 males with a median age of 76.0 [64.0-83.0] years) were enrolled. One or more vertebral fractures were present in 28.9% (68/235) subjects; 47% (32/68) had two or more vertebral fractures. The majority of patients (55/68) with VFs had not previously received a severe OP diagnosis. CONCLUSIONS: Severe OP was misdiagnosed in at least 8.6% of inpatients. The prevalence dramatically increases (about 29%) in subjects with previous spinal imaging showing one or more VFs. More attention should be given to this co-morbidity, which is known to be an additional risk factor for disability and mortality.

Filgotinib as rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and progressive disability when inflammation cannot be sufficiently controlled. Despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs), up to 30% of RA patients do not reach or fail to maintain a good response over time. The recent introduction of Janus kinase inhibitors (JAKis) has widened the rheumatologist's armamentarium. Filgotinib, a selective JAK1 inhibitor, has been approved by the European Medicines Agency (EMA) for treatment of RA. Phase II and III studies highlighted filgotinib safety and efficacy in RA patients naive to DMARDs or with inadequate response to csDMARDs and bDMARDs. Filgotinib is administered orally at 200 mg every day. For patients older than 75 years or with moderate to severe renal impairment, a dose of filgotinib 100 mg every day is recommended.

[Polyarthritis flare in patient with ankylosing spondylitis treated with infliximab]. / Poliartrite febbrile in paziente affetto da spondilite anchilosante in trattamento con infliximab.

Over the last ten years, the treatment of seronegative spondyloarthropathies has changed dramatically with the introduction of the anti-tumor necrosis factor alpha (TNFα) agents. Nevertheless, there is a growing number of studies describing several adverse reactions in patients treated with biological agents. In the present report we describe the case of a 22-year-old male patient with ankylosing spondylitis who developed a "paradoxic" adverse reaction, while receiving infliximab.

[The ultrasound assessment of the psoriatic arthritis: from joint to skin]. / L'ecografia nella valutazione della artrite psoriasica: dalla articolazione alla cute.

There is a growing number of papers investigating the diagnostic potential of ultrasonography in the assessment of patients with psoriatic arthritis and supporting its higher sensitivity over clinical examination in the diagnosis of synovitis, enthesitis and tenosynovitis. Less attention has been paid on both skin and nail, frequently involved in this condition. The aim of this paper is to show the potential of ultrasound in a multi-target assessment (joints, tendons, entesis, skin and nails) in patients with psoriatic arthritis, using the last generation ultrasound equipment.

Expression of Id helix-loop-helix proteins in colorectal adenocarcinoma correlates with p53 expression and mitotic index.

Id helix-loop-helix (HLH) proteins function as regulators of cell growth and differentiation and when overexpressed can induce malignant transformation. In a series of 34 cases of primary human colorectal adenocarcinoma, immunoreactivity for Id1, Id2, and Id3 was found to be significantly elevated in tumor compared with normal mucosa (P = 0.001 for Id1 and Id2; P = 0.002 for Id3). No elevation of Id expression was observed in 17 cases of adenoma. Expression of Id1 and to a lesser extent of Id2 was correlated with mitotic index (P = 0.005 for Id1; P = 0.042 for Id2) in human adenocarcinomas, and expression of all three Id proteins was correlated with p53 immunoreactivity (a marker of mutational 'inactivation' of p53 function; P = 0.002 for Id1; P = 0.006 for Id2; P = 0.016 for Id3). In normal intestinal mucosa of p53-null mice and in spontaneous tumors arising in Min+/- mice, expression of all three Id proteins was also found to be up-regulated. Antisense oligonucleotide blockade of Id protein expression inhibited the proliferation of human adenocarcinoma cells. Enforced, ectopic expression of the E47 basic HLH (bHLH) protein in human adenocarcinoma cell lines efficiently sequestered endogenous Id proteins as Id-bHLH heterodimers, as shown by coimmunoprecipitation and subcellular colocalization studies. This led to growth arrest of the cells. Enforced overexpression of a mutant E47 protein, deficient in transactivation and DNA binding function, also partially inhibited cell growth. Taken together, these data imply that deregulated expression of Id proteins in colorectal adenocarcinoma arises at least in part as a consequence of loss of p53 function and contributes to the uncontrolled proliferation of tumor cells in colorectal cancer.

Nitroxides and malignant human tissues: electron spin resonance in colorectal neoplastic and healthy tissues.

Healthy and neoplastic colorectal human tissues of as many as 12 patients have been studied, immediately after surgery, by electron spin resonance (ESR) of stable nitroxides at physiological temperature. Cells were maintained in a living state using the McCoy's 5A culture medium. The very low concentration changes of hydrophilic and lipophilic nitroxides allowed us to establish that the response to the oxidative stress induced by the occurrence of nitroxides in healthy and tumor cells was very weak, thus suggesting these compounds are good candidates for contrast enhancement agents in magnetic resonance imaging of colorectal tumor. The analysis of the computed ESR line shape of lipophilic nitroxides in both healthy and malignant cells of the same patient agreed for an unmodified physical status of the membranes where they were mainly localized. The results reported here proved that the comparison between ESR results must be made in tissues from the same patient and that the physical status of the membranes depended more on the patient history than on changes in the colorectal cell membrane fluidity induced by the neoplastic process.

Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study.

PURPOSE: According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy. PATIENTS AND METHODS: Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery +/- radiotherapy. RESULTS: The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P: =.028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P: =.037) and third tertiles (58% v 78%, respectively; P: =.024). CONCLUSION: The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.

The effects of irradiation at different times of the day on rat intestinal goblet cells.

Quantitative changes in jejunal goblet cells were studied in control and whole body irradiated rats using PAS-Alcian blue staining of crypt sections. A circadian dependence was observed when control animals were killed at different times during the light/dark cycle. Irradiation with 3 Gy produced a 2-3-fold increase within 36 h in goblet cells relative to controls, followed by a reduction to very low levels. There was a return to pre-treatment levels later than was observed for the columnar cells. The present results on the pattern of response of goblet cells and those of brush border enzyme activity are consistent with the hypothesis that ionizing radiation can influence differentiation. In fact during the first hours after irradiation an early induction of differentiation is evident while during the early repopulation phase columnar cells prevailed relative to the goblet cells. Only at later times were normal differentiation patterns seen. Groups of animals exposed to the same dose of radiation at different times of the day showed similar general patterns of behaviour even if the group irradiated at midnight showed a more marked and longer lasting injury.

3H-thymidine labelling index (TLI) as a marker of tumour growth heterogeneity: evaluation in human solid carcinomas.

Many studies deal with the analysis of cell kinetic, cytogenetic, biochemical and molecular cell biology parameters to identify prognostic factors relating to tumour growth but all methods use only a small part of the total tumour mass. This study is devoted to the analysis of the heterogeneity of the growth of human solid tumours assaying proliferative activity by means of 3H-thymidine labelling index (TLI) in a fixed number of samples collected in different areas of the lesion (larynx and colon cancers), or in different lesions of the same subject (breast and bladder cancers). Each sample (at the macroscopic level) was divided into small fragments (at the microscopic level) and proliferative activity was determined. The analysis of variance for hierarchical designs demonstrated that in all cases a high component of the variance is attributable to the subjects and to the fragments whereas the variance attributable to the different areas is very low. The heterogeneity of proliferative activity displays a higher focal variability among the fragments (microscopic level) compared with that among areas (macroscopic level) within subjects, provided an adequate number of fragments and cells are counted. In multiple synchronous carcinoma of the bladder the wide variability of proliferation among the single lesions demonstrated that it is necessary to analyse all the tumours in a subject because each one is characterized by a different cell growth potential.

Biological properties associated with the enhanced lung-colonizing potential in a B16 murine melanoma line grown in a medium conditioned by syngeneic Corynebacterium parvum-elicited macrophages.

A previous study by our laboratory showed that the peritoneal murine Corynebacterium parnum-elicited macrophages released into their growth medium an activity which enhanced the ability of B16-F10 melanoma cells to form experimental metastases in the lung of syngeneic mice. In the present study, we used a clone of B16-F10 line (F10-M3 cells) to investigate whether the increase in lung-colonizing potential due to the pro-clonogenic activity released by C. parvum-elicited macrophages was associated with biological properties characteristic of a metastatic phenotype. We have found that the pulmonary retention, growth rate in lung parenchyma, invasiveness through Matrigel, adhesiveness to IL-1-activated endothelium and MHC class I expression were increased in F10-M3 cells stimulated by the macrophage pro-clonogenic activity. By using an in vitro experimental protocol, the enhancement of lung-colonizing potential in the stimulated melanoma cells turned out to be a transient phenomenon as was the increase of invasiveness through Matrigel and the higher expression of MHC class I antigens. In conclusion, the melanoma cells stimulated by the pro-clonogenic activity released by C. parvum-elicited macrophages showed changes in biological parameters which are relevant to metastatic diffusion. These changes appeared as a temporary phenomenon which sustains the view that the metastatic phenotype represents a transient biological character influenced by host factors.

Serum tissue polypeptide antigen (TPA): a marker of acute injury of salivary glands during radiation therapy.

The modifications of serum concentrations of TPA were monitored in patients undergoing curative radiation therapy. Patients with tumors localized in the head and neck were treated with one of four different schedules based on conventional fractionation or multiple daily fractionation where the dose per fraction and total daily dose varied. Serum TPA increased immediately on the first day of irradiation: the higher the dose, the greater the increase. These increases disappeared rapidly after the first few days of treatment. A more limited rise was observed in some cases when treatment was renewed after the first week-end split or after more prolonged interruptions. Results demonstrated that TPA is a valid biochemical marker of acute radiation injury to the salivary tissue.

Post-irradiation hyperamylasemia as a biological dosimeter.

Serum alpha-amylase was measured before and 24 h after either total body (31 patients) or localized irradiation including the salivary glands (40 patients) or the pancreatic area (22 patients). A significant increase in amylasemia was observed for doses to the parotid glands larger than 0.5 Gy. A sigmoid function of dose was fitted to the data and predicted a maximum amylasemia level for doses larger than 4 Gy and smaller than 10 Gy. The raw data from other published series were adequately described by the same model. However, the confidence limits of the parameters remained wide, because of a considerable interindividual variability. Post-irradiation hyperamylasemia appears to provide a good criterion for triage of accidentally irradiated patients: 24 h after a dose larger than 2 Gy to the parotid glands, 91% of the patients had an amylasemia level higher than 2.5-fold the upper normal value (sensitivity). Conversely, 96% had their serum amylasemia lower than 2.5-fold the upper normal value when dose was smaller than 2 Gy (specificity). However, a retrospective estimation of the absorbed dose (dosimetry) is not likely to be very precise because of the large interindividual variability.

Brush border intestinal enzymes after multiple daily fractionation.

The modifications in brush border enzyme activity of the epithelial cell of the small intestine were studied after multiple daily fractionation (MDF) of 3 Gy X and 3 Gy X 2 X 2 (12 h split). Disaccharase and dipeptidase activities changed in the same way after irradiation. The results show that both total doses caused the three known phases of increase, decrease, and a return to normal. With MDF, activity at the end of irradiation was similar to or greater than that of controls and remained higher longer than a single dose of 8 Gy. However, the return to normal occurred sooner than after a single dose of 8 Gy. After 11 days, circadian oscillations of brush border enzyme activity appeared similar to those of controls in many segments of the intestine, reaching the highest activity during the night and the lowest in the afternoon.

Analysis of HPV16, 18, 31, and 35 DNA in pre-invasive and invasive lesions of the uterine cervix.

AIMS: To analyse the physical state of different human papillomavirus (HPV) DNAs in 55 intraepithelial and invasive HPV associated cervical neoplasms. METHODS: Restriction analysis, using a panel of five HPV type specific enzymes, was carried out for each sample; this was followed by Southern blot analysis. RESULTS: Six (25%) of 24 cervical intraepithelial neoplasms had integrated DNA of different HPV types. In contrast, integration was detected in 25 (81%) of 31 cervical carcinomas. Tumour samples revealed differences in the integration profile of HPV16 and the other HPV types. Six (26%) of 23 HPV16 associated cancers contained only episomal DNA. In contrast, all eight tumours containing HPV18, 31, or 35 revealed integrated DNA exclusively. CONCLUSIONS: The results suggest that in advanced cervical intraepithelial neoplasia lesions, a subset of lesions can be identified in which the viral genome is integrated and there is a greater risk of malignant progression. In addition, HPV16 DNA was not present in the integrated form in 26% of tumours, suggesting that integration and subsequent inactivation of the transcriptional regulator, E2, are not essential steps for the development of HPV16 associated carcinoma. In this respect, the behaviour of HPV16 associated tumours is different from HPV18, 31, and 35 associated tumours, where the viral genome is always present in the integrated form.

Marker determination for response monitoring: radiotherapy and disappearance curves.

This paper reports the results of studies on the possible role of biochemical markers in monitoring the effects of ionizing radiations and in the follow-up of cancer patients submitted to radiotherapy. Three different case series were analyzed: patients with head and neck cancer, prostate carcinoma and residual thyroid tumors or uptaking metastases (131-Iodine therapy). Serum TPA and amylase were serially determined in patients with head and neck or thyroid cancer to measure the radiation damage to the salivary glands. In the former group a statistically significant correlation between the increase of both molecules and the total dose administered after the first day of treatment (2, 3, 4 or 6 Gy) was observed. In patients treated for thyroid cancer the damage to the salivary glands was revealed by an increase in TPA and amylase serum levels, dependent on the dose of 131-Iodine administered. Moreover, an association was demonstrated between pretreatment values of TPA in patients with head and neck tumors and prognosis: patients with values below the cutoff have significantly higher survival rates than those with higher values. In patients with prostate carcinoma PSA was confirmed to have better diagnostic and prognostic value than PAP. Patients with metastases show an inversion or lack of negative trend in PSA levels observed in the disease-free patients. This precedes the clinical diagnosis of metastases by 1 to 15 months.

Polyamines in the small intestine of rats after whole-body irradiation.

The behaviour of polyamines (putrescine, spermidine and spermine) in the small intestine was studied in rats exposed to a single whole-body dose of 3 Gy administered at four different times of the day. Polyamine content decreased a few hours after irradiation but quickly returned to normal values. Putrescine levels reached the lowest values and returned to the control levels later than spermidine and spermine. A temporary increase in spermidine and spermine content was observed from 5 to 20 days. The postirradiation behaviour of the animals exposed at different times of the day showed no important differences. Polyamine modifications were studied in relation to [3H]thymidine uptake and other morphological and biochemical parameters. The results indicate that polyamine content can be used to monitor the damage and recovery phases of radiation injury in the small intestine.

Cell kinetics in rat small intestine after exposure to 3 Gy of gamma-rays at different times of the day.

Qualitative and quantitative morphological changes in rat jejunum were studied after a whole-body exposure to 3 Gy of gamma rays. Four groups of animals were irradiated at different times of the day, namely midnight, 06.00, 12.00 and 18.00 hours. The number of epithelial cells, labelling and mitotic indices were evaluated in crypt sections and the spatial distribution of S-phase cells was determined. At 12 h after irradiation a marked reduction was observed in all parameters, but the proliferative activity was restored quickly and at 36 h after irradiation the values were significantly higher than the controls. The frequency distribution of labelled cells at different positions in the crypt was reduced at 12 h but a clear expansion of S phase cells to positions near to the crypt villus junction was observed during the recovery phase. The animals irradiated at different times of the day showed a similar general post-irradiation response in the number of cells along the side of the crypt, labelling and mitotic indices and in the distribution of S phase cells along the crypts. It is worth noting that the animals exposed at midnight had a distribution of S phase cells similar to controls at 72 h post-irradiation, i.e. earlier than the other groups.

Cell kinetics and biochemical parameters in breast cancer.

The study analyzes biochemical and cell kinetic parameters to characterize solid tumor growth in humans. The concentrations of polyamines, CEA, the thymidine labeling index (T.L.I.) and the mitotic index (M.I.) were determined on fragments of neoplastic tissue from 18 patients with breast carcinoma. Urinary polyamines were evaluated in the same patients. Two groups of patients were distinguished according to the median value of the with high T.L.I., M.I. and tissue polyamines were significantly higher than in the group with low T.L.I., whereas tissue CEA was lower, though in a not statistically significant way. Urinary polyamines showed no variations between groups. These preliminary results showed that T.L.I. levels were higher in patients who relapsed during a 4-year follow-up than in patients achieving complete remission and remaining disease free. Results concerning polyamine concentration showed that the tissue polyamine level in breast carcinoma indicated proliferative activity, but this does not seem to be valuable for current prognostic purposes.

Relationship between cytosol TPS, TPA and cell proliferation.

The serological tumor marker tissue polypeptide antigen (TPA) and the more recently identified tissue-specific polypeptide antigen (TPS) have been reported to be indicators of the proliferation rate of the tumor. In the present investigation we compared the cytosol level of the two markers with the proliferative activity of the tumor measured using the 3H-thymidine labelling index. The preliminary results presented here show that higher TLI is associated with lower cytosol levels of both TPA and TPS. TPA and TPS in the cytosol were significantly associated. These findings are in agreement with the previously demonstrated association between high TPA cytosol levels and better prognosis in breast cancer. Further studies are ongoing in order to: 1. confirm these findings in a larger patient series; 2. investigate any possible prognostic indication provided by TPS; 3. evaluate any possible biological meaning of the negative association between TPA/TPS and TLI in the cytosol of breast cancer.

Cell kinetics of melanocytes in common and dysplastic nevi and in primary and metastatic cutaneous melanoma.

The 3H-thymidine labelling (LI) and mitotic (MI) indexes were calculated in 29 cutaneous melanocytic lesions: 6 common nevi (CN), 11 dysplastic nevi, subclassified as nevi with architectural atypia (NAA = 4) and nevi with cyto-architectural atypia (NCAA = 7), 2 melanomas in situ (MIS), 4 invasive superficial spreading melanomas (IM) and 6 metastatic melanomas (MM). The LI mean values resulted to be: CN = 0.23%, NAA = 0.98%, NCAA = 1.79%, MIS = 5.75%, IM = 5.16%, MM = 3.80%. In CN, NAA, NCAA and MIS, these values were calculated at epidermal level; in IM and MM at dermal level. At dermal level, the LI mean values of CN, NAA and NCAA were: 0.20%, 0.20%, 0.23% respectively. The MI mean value was close to 0 in CN, NAA, NCAA, MIS; 0.18% in IM, 0.16% in MM. Confirming a low proliferative activity in CN and a high activity in melanomas (MIS, IM, MM), the results showed that dysplastic nevi (NAA, NCAA) had a proliferative activity intermediate between common nevi and melanomas. The lesions with melanocytic atypia (NCAA) resulted to have a higher proliferative activity than those without this histological feature (NAA).