Comparison of dosimetry with magnetic resonance and computed tomography imaging delineation of surgical bed volume in breast cancer irradiation.

Background: Postoperative radiotherapy after conservative surgery for patients with breast cancer usually includes focal over-irradiation (boost) to the surgical bed (SB). Irradiation planning using computed tomography (CT) is difficult in many cases because of insufficient intrinsic soft tissue contrast. To ensure appropriate radiation to the tumor, large boost volumes are delineated, resulting in a higher dose to the normal tissue. Magnetic resonance imaging (MRI) provides superior soft tissue contrast than CT and can better differentiate between normal tissue and the SB. However, for SB delineation CT images alone remain the pathway followed in patients undergoing breast irradiation. This study aimed to evaluate the potential advantages in boost dosimetry by using MRI and CT as pre-treatment imaging. Methods: Eighteen boost volumes were drawn on CT and MRI and elastically co-registered using commercial image registration software. The radiotherapy treatment plan was optimized using the CT volumes as the baseline. The dose distributions of the target volumes on CT and MRI were compared using dose-volume histogram cutoff points. Results: The radiation volumes to the SB varied considerably between CT and MRI (conformity index between 0.24 and 0.67). The differences between the MRI and CT boost doses in terms of the volume receiving 98% of the prescribed dose (V98%) varied between 10% and 30%. Smaller differences in the V98% were observed when the boost volumes were delineated using MRI. Conclusion: Using MRI to delineate the volume of the SB may increase the accuracy of boost dosimetry.

A Literature Systematic Review with Meta-Analysis of Symptoms Prevalence in Covid-19: the Relevance of Olfactory Symptoms in Infection Not Requiring Hospitalization.

PURPOSE OF REVIEW: To investigate the association between the olfactory dysfunction and the more typical symptoms (fever, cough, dyspnoea) within the Sars-CoV-2 infection (COVID-19) in hospitalized and non-hospitalized patients. RECENT FINDINGS: PubMed, Scopus and Web of Science databases were reviewed from May 5, 2020, to June 1, 2020. Inclusion criteria included English, French, German, Spanish or Italian language studies containing original data related to COVID19, anosmia, fever, cough, and dyspnoea, in both hospital and non-hospital settings. Two investigators independently reviewed all manuscripts and performed quality assessment and quantitative meta-analysis using validated tools. A third author arbitrated full-text disagreements. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), 11 of 135 studies fulfilled eligibility. Anosmia was estimated less prevalent than fever and cough (respectively rate difference = - 0.316, 95% CI: - 0.574 to - 0.058, Z = - 2.404, p < 0.016, k = 11 and rate difference = - 0.249, 95% CI: - 0.402 to - 0.096, Z = - 3.185, p < 0.001, k = 11); the analysis between anosmia and dyspnoea was not significant (rate difference = - 0.008, 95% CI: - 0.166 to 0.150, Z = - 0.099, p < 0.921, k = 8). The typical symptoms were significantly more frequent than anosmia in hospitalized more critical patients than in non-hospitalized ones (respectively [Q(1) = 50.638 p < 0.000, Q(1) = 52.520 p < 0.000, Q(1) = 100.734 p < 0.000). SUMMARY: Patient with new onset olfactory dysfunction should be investigated for COVID-19. Anosmia is more frequent in non-hospitalized COVID-19 patients than in hospitalized ones.

Clinical impact of the new SIAPEC-IAP classification on the indeterminate category of thyroid nodules.

BACKGROUND: The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. MATERIALS AND METHODS: This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. RESULTS: 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. CONCLUSIONS: This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.

Characterization of a novel HLA-C allele, HLA-C*04:288, in an Italian patient.

The novel HLA-C*04:288 differs from HLA-C*04:01:01:06 by a single nucleotide substitution in exon 2.

Identification of the new HLA-DPB1 allele, DPB1*647:01, in an Italian patient with leukemia.

A novel HLA-DPB1 allele, named HLA-DPB1*647:01, identified in a leukemia patient.

Characterization of a novel HLA-B*18 variant allele, HLA-B*18:122, by genome sequencing.

The HLA-B*18:122 allele showed four nucleotide differences from HLA-B*18:01:01:01.

Identification of a new HLA-A*24 allele, A*24:309, in an Italian bone marrow donor.

A novel class I human leukocyte antigen allele HLA-A*24:309 is described.

Characterization of a novel HLA-B allele (HLA-B*18:108) by intron-exon sequencing of the HLA-B locus.

HLA-B*18:108 has two nucleotide changes from B*18:01:01:02 at nt 430 where A → G and nt 431 where G → A.

A simple ultrasound score for the identification of candidates to fine needle aspiration of thyroid nodules.

BACKGROUND: Cytological examination of fine needle aspirates (FNA) is the standard procedure for discriminating potentially malignant thyroid nodules to be referred to surgery. In a fraction of cases, ultrasound (US) examination could provide information theoretically sufficient to avoid FNA, when typical US features suggesting malignancies are lacking. AIM: The aim of this study was to construct a simple US score predicting malignant nodules so as to reduce the number of unnecessary FNA. SUBJECTS AND METHODS: In a series of 1632 consecutive patients undergoing US-guided FNA (1812 nodules), echostructure, echogenicity, margins, halo, microcalcification, and vascularization were assessed. RESULTS: At multivariate analysis, the following parameters showed a strong predictive value for positive cytology (Thy 4 and Thy 5, suspicious and diagnostic for malignancy, respectively, according to the Thyroid British Association): solid echostructure, irregular margins and hypoechogenicity [adjusted odd ratio (OR) 5.13 (1.58-16.66), 3.03 (1.70-5.39), 2.05 (1.17-3.57), respectively]. A 10-point Thyroid Risk Ultrasound Score (TRUS) was constructed on the basis of the adjusted OR. A TRUS≥6 identified malignant nodules with sensitivity and specificity of 73% and 65%, respectively. Among the patients with follicular lesions (Thy 3) and final diagnosis of carcinoma, about 65% had a TRUS≥6.0. CONCLUSIONS: The sensitivity of TRUS, although higher than that of other scores, could still be insufficient for the identification of patients who could avoid FNA in routine clinical practice, whereas its predictive value for Thy 3 lesions deserves further investigations.

Spinal anesthesia plus ketamine-midazolam sedation for pediatric orthopedic surgery in a developing country.

INTRODUCTION: Spinal anesthesia produces a profound and uniformly distributed sensory block with rapid onset and muscle relaxation, and results in complete control of cardiovascular and stress responses. Ketamine is an anesthetic agent that is widely used for pediatric sedations in settings where safety and efficacy of the agents are mandatory because of limited healthcare resources. The authors report on their experience in a refugee hospital located in Bol-la (Saharawi, Algeria). METHODS: Spinal anesthesia was performed for orthopedic surgery procedures in children. Before the spinal puncture, the patients were sedated with intramuscular ketamine followed by intravenous ketamine and midazolam. Boluses of midazolam were also administered throughout the surgery to keep the patients sedated; spinal anesthesia was performed with levobupivacaine 0.25 mg/kg. RESULTS: There were no intraoperative adverse events; vital signs were within the normal pediatric ranges during the procedures and there was no need to switch to general anesthesia. In the postoperative period, no symptoms of dural puncture headache or postoperative delirium or nightmares were reported. CONCLUSION: Based on the authors' experience, the combination of spinal anesthesia and sedation with midazolam and ketamine was found to be a safe approach for children undergoing orthopedic surgery in a low resources setting.

Effectiveness and safety of cholinesterase inhibitors in elderly subjects with Alzheimer's disease: a "real world" study.

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerated.

[Risk of recurrence following partial thyroidectomy for benign lesions. Report of 58 patients 15-25 years after surgery]. / Il rischio di recidiva dopo tiroidectomia parziale per lesione benigna. Indagine condotta su 58 pazienti 15-25 anni dopo l'intervento.

BACKGROUND: Since the 1980's, thanks to the introduction of new techniques and methods for the study of thyroid function, new light has been shed on certain aspects of thyroid disease that constitute the basis for surgical therapy. Multinodular goiter is a disorder affecting the entire gland, even when alterations mostly or exclusively involve a single lobe. The functional deficit resulting from partial or subtotal resection has a hypertophic/hyperplastic effect on the remaining parenchyma. Partial resections often lead to postoperative hypothyroidism, usually of a subclinical nature, which implies difficult management by means of replacement therapy. METHODS: The authors report a series of 58 patients who underwent partial thyroidectomy to treat benign thyroid disease at the 2nd Surgical Department of the University of Florence during the period 1975-1985. RESULTS: Of these patients, operated on more than 15 years ago, 36.2% - the majority of whom (87.5%) have constantly been on substitutive therapy using L-thyroxin - currently shows no alteration of the remaining parenchyma. Conversely, in 60.3% of the patients there was evidence of nodular/pseudonodular alterations; in this group, only 40% of the patients were on substitutive therapy. There seems to be no doubt that, with few exceptions, disease involving an apparently circumscribed area of the thyroid in reality affects the entire parenchyma. CONCLUSIONS: Total thyroidectomy, therefore, represents the most appropriate treatment for multinodular goiter, even when the disease is limited to one lobe, thereby providing a cure for the disease and at the same time a state of euthyroidism easily achieved with the proper therapy.

Parathyroid glands: combination of (99m)Tc MIBI scintigraphy and US for demonstration of parathyroid glands and nodules.

PURPOSE: To determine the appropriate choice of imaging techniques for localization of nodular lesions of parathyroid glands. MATERIALS AND METHODS: First, computed tomographic (CT), magnetic resonance (MR), ultrasonographic (US), and technetium 99m methoxyisobutyl-isonitrile (MIBI) scintigraphic images in 49 patients with primary hyperparathyroidism were retrospectively evaluated. A single-blind, prospective study that included 16 patients with primary hyperparathyroidism was then conducted. MR, US, scintigraphic, and color Doppler US images of the neck were obtained and analyzed. RESULTS: In the retrospective study, CT, MR imaging, and US had low sensitivity (13%, 17%, and 27%, respectively) and specificity (39%, 65%, and 65%, respectively). Scintigraphy had 57% sensitivity and 85% specificity. In the prospective study, the use of latest-generation MR and US equipment and the participation of experienced operators led to improved sensitivity and specificity for these techniques. The combination of US and scintigraphy resulted in improved sensitivity (96%), specificity (83%), and positive and negative predictive values (88% and 94%, respectively), relative to the results obtained with either method alone. Doppler US was of little help in the setting of small glands. CONCLUSIONS: The combination of (99m)Tc MIBI scintigraphy and US performed by well-trained operators with up-to-date instruments appeared to be the best diagnostic tool for the preoperative diagnosis of parathyroid disease.

Nonsubstrate recognition site residues are involved in testosterone hydroxylation by cytochrome P450 CYP 2C11.

We have previously characterized an allelic variant of cytochrome P450 CYP 2C11 from the Gunn rat that differs at three positions (amino acids 4, 116, and 187) from the predominant allele from Wistar rats and that displays a dramatically reduced testosterone hydroxylation activity. To assess the relative contribution of these mutations to the decrease in the enzymatic activity we constructed single and double mutants and coexpressed them with reductase. Testosterone metabolism was determined with a baculovirus/insect cell expression system. None of the identified positions alone is critical for the activity since the reversion of one of these mutations is unable to restore fully the Wistar-type activity. The activity of CYP 2C11 containing either the Asn116Ser substitution or the Phe187Leu represents congruent with30% of the activity of the CYP 2C11 Wistar-type protein. In contrast, the activity of the Val4Ala mutated protein is only 10% that of the Wistar-type protein, close to that of the Gunn-type protein. This study reevaluates the contribution of amino acid 4 to the catalysis by cytochrome P450 2C11 and points out the role of extra SRS residues.

Structure-function of cytochromes P450 and flavin-containing monooxygenases: implications for drug metabolism.

This article is a report on a symposium held at Experimental Biology '98 in San Francisco, California. Recent developments in site-directed mutagenesis, computer-modeling, and mechanistic analysis of cytochromes P450 and flavin-containing monooxygenases are described. A unifying theme is the elaboration of general approaches for understanding and predicting the function of individual forms of these enzymes. A related goal is the production of soluble forms of mammalian cytochromes P450 for X-ray crystallography.

Nutritional status modulates rat liver cytochrome P450 arachidonic acid metabolism.

Alterations in nutritional status affect hepatic cytochrome P450 levels. Since cytochromes P450 participate in the metabolism of arachidonic acid, we hypothesized that changes in liver P450 arachidonic acid metabolism occur during fasting and refeeding. Male Fisher 344 rats were either fed, fasted 48 hr (F48), fasted 48 hr and then refed 6 hr (F48/R6), or fasted 48 hr and then refed 24 hr (F48/R24). F48 rats had reduced body weight, increased plasma beta-hydroxybutyrate, and reduced plasma insulin compared with the other groups. Although there was no significant change in total liver P450 content, there was a significant 20%, 48%, and 24% reduction in total hepatic microsomal arachidonic acid metabolism in F48, F48/R6, and F48/R24 rats, respectively, compared with fed rats. Epoxygenase activity decreased by 28%, 51%, and 26% in F48, F48/R6, and F48/R24 rats, respectively. In contrast, omega-1 hydroxylase activity increased by 126% in F48 rats compared with fed rats. Immunoblotting revealed that levels of CYP2C11 protein were markedly reduced, whereas levels of CYP2E1 protein were markedly increased in the F48 and F48/R6 groups. In contrast, levels of CYP1A1, CYP1A2, CYP2B1, CYP2J3, CYP4A1, and CYP4A3 were unchanged with fasting/refeeding. Northern blots revealed that levels of CYP2C11 mRNAs were decreased, whereas CYP2E1 mRNAs were increased in F48 and F48/R6 rats. Recombinant CYP2C11 metabolized arachidonic acid primarily to epoxides with preference for the 14(S),15(R)-, 11(R), 12(S)-, and 8(S),9(R)- epoxyeicosatrienoic acid enantiomers. We conclude that (1) nutritional status affects hepatic microsomal arachidonic acid metabolism, (2) reduced epoxygenase activity in F48 and F48/R6 rats is accompanied by decreased levels of CYP2C11, (3) increased omega-1 hydroxylase activity is accompanied by augmented levels of CYP2E1, and (4) the effects of fasting on CYP2C11 and CYP2E1 expression occur at the pretranslational level.

The risk of non-Hodgkin's lymphoma after Hodgkin's disease, with special reference to splenic treatment.

BACKGROUND AND OBJECTIVE: One of the consequences of the enormous improvement in survival rates of patients treated for Hodgkin's disease (HD) is the emergence in the long term of treatment-related complications, particularly secondary cancers. This study was undertaken to observe the occurrence of non-Hodgkin's lymphoma (NHL) in patients treated for HD and to identify the etiological role of various risk factors, especially spleen irradiation, in the pathogenesis of this illness. DESIGN AND METHODS: From 1972 to 1996, the Department of Radiation Oncology and the Hematology Section of "La Sapienza" University of Rome observed and analyzed the occurrence of NHL in 1,391 patients treated for HD. The average follow-up period was 84 months. For a more accurate calculation of the risk of the occurrence of NHL, the patients were first divided into 3 groups according to their initial treatment and also according to the total treatment they had received. Then, in order to establish the possible connection between NHL and splenic treatment the patients were also divided into 3 subgroups according to whether they had undergone splenectomy, splenic irradiation or neither of these. Two different methods of statistical analysis were used: (a) the cumulative risk (confidence interval) was evaluated in relation to treatment (initial and at the time of salvage) and (b) the Cox model was applied to identify the variables which play a role in the appearance of NHL. The cumulative risk of developing NHL was assessed using the Kaplan and Meier method. A multivariate analysis was performed using the Cox Proportional Hazard Model. RESULTS: A total of 20 cases of NHL were observed, appearing between 17 and 206 months after initial treatment. The cumulative risk was 0.8%, 1.8%, 2.6% and 3.5% at 5, 10, 15 and 20 years respectively. According to the multivariate analysis, significant risk factors were splenic irradiation and age (> 40 years). Splenic irradiation (vs no splenectomy/no splenic irradiation) showed a relative risk of 5.69, p = 0.0280, while age over 40 showed a relative risk of 3.05, p = 0.0152. INTERPRETATION AND CONCLUSIONS: From the results of this study, if appears that there is a possibility that splenic irradiation and age over 40 increase the risk of NHL in HD patients. Further studies are needed to investigate in greater depth the role of spleen irradiation in the occurrence of this illness.

Combined modality therapy in advanced Hodgkin's disease: a report on 218 patients with a median follow-up of eight years.

BACKGROUND AND OBJECTIVE: This study was designed to evaluate the efficacy and toxicity of monthly alternating ABVD/MOPP compared to ABVD/OPP regimens in patients with advanced stage Hodgkin's disease (HD), as well as in early stage patients with systemic symptoms and/or bulky disease. DESIGN AND METHODS: 218 patients with previously untreated HD entered this study: 106 patients in arm A (ABVD/MOPP) and 112 in arm B (ABVD/OPP). Patients received eight courses of one of the two regimens after stratification according to the stage. Patients in complete remission (CR) received 20 Gy to the involved field and 40 Gy to the spleen. The actuarial survival curves were performed according to Kaplan and Meier. RESULTS: No statistically significant differences were observed between the two arms in terms of CR rate and toxicity. However, analysis of total relapses revealed that patients treated with ABVD/OPP had a significantly higher likelihood of achieving a second CR compared to patients who entered the ABVD/MOPP arm. INTERPRETATION AND CONCLUSIONS: Both schemes of chemotherapy followed by radiotherapy produce high percentages of CR, low risk of relapse and an acceptable toxicity.

Radiation therapy and chemotherapy in the treatment of head and neck extranodal non-Hodgkin's lymphoma in early stage with a high grade of malignancy.

BACKGROUND: Optimal management of patients with localized head and neck extranodal lymphoma remains controversial, both because of the lack of randomized studies and because of the heterogenous grouping of most reported series. MATERIALS AND METHODS: Patients treated at our institution between 1974 and 1993 for extranodal head and neck lymphoma were retrospectively analyzed and classified. The therapy and outcome of 92 patients classified as having an intermediate (42) and high (50) level of malignancy according to the Working formulation and in stage I (39) or II (53) of the Ann Arbor Staging System were considered. Fifty-three patients (57.6%) received chemotherapy alone, and 39 (42.4%) combined radiochemotherapy. RESULTS: The different treatment schedules allowed these patients to achieve global actuarial 5-year overall, event-free, and relapse-free survival rates of 81.2%, 78.1% and 89.3%, respectively. The patients that received combined modality treatment reported actuarial 10-year event-free and relapse-free survival rates of 65.3% and 90.7%, respectively, with a suggestion of decreased treatment-related morbidity compared to patients treated with chemotherapy. CONCLUSIONS: Our results underscore the important treatment role of combined radiochemotherapy for early stage intermediate and high grade lymphomas.