Daratumumab in multiple myeloma: experience of the multiple myeloma GIMEMA Lazio group.

Daratumumab (DARA) is a human IgG-K monoclonal antibody (MoAb) targeting CD38 that is approved alone or in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone for relapsed or refractory MM (RRMM) in patients previously exposed or double refractory to proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). However, there are limited data on its clinical activity and tolerability in real-world patients. Therefore, in the present study, we aim to determine the efficacy and toxicity profile of daratumumab in a real-life setting. In this study, we report the experience of the multiple myeloma GIMEMA Lazio Group in 62 relapsed/refractory MM patients treated with daratumumab as monotherapy who had previously received at least two treatment lines including a PI and an IMiDs or had been double refractory. Patients received DARA 16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression or unacceptable toxicity. The overall response rate to daratumumab was 46%. Median progression-free survival (PFS) and overall survival reached 2.7 and 22.4 months, respectively. DARA was generally well tolerated; however, 2 patients interrupted their therapy due to adverse events. Present real-life experience confirms that DARA monotherapy is an effective strategy for heavily pre-treated and refractory patients with multiple myeloma, with a favorable safety profile.

High-Precision Probe of the Fully Sequential Decay Width of the Hoyle State in

The decay path of the Hoyle state in ^{12}C (E_{x}=7.654 MeV) has been studied with the ^{14}N(d,α_{2})^{12}C(7.654) reaction induced at 10.5 MeV. High resolution invariant mass spectroscopy techniques have allowed us to unambiguously disentangle direct and sequential decays of the state passing through the ground state of ^{8}Be. Thanks to the almost total absence of background and the attained resolution, a fully sequential decay contribution to the width of the state has been observed. The direct decay width is negligible, with an upper limit of 0.043% (95% C.L.). The precision of this result is about a factor 5 higher than previous studies. This has significant implications on nuclear structure, as it provides constraints to 3α cluster model calculations, where higher precision limits are needed.

RadioLab project: knowledge of radon gas in Italy.

RadioLab is an Italian project, addressed to school-age people, and designed for the dissemination of scientific culture on the theme of environmental radioactivity, with particular regards to the importance of knowledge of radon gas exposure. The project is a nationwide initiative promoted by the National Institute of Nuclear Physics- INFN. First tool used by the project, and of immediate impact to assess the public awareness on radon, is the administration of the survey "do you know the radon gas?". In the survey, together with the knowledge of radon and of its sources, information on personal, cultural and territorial details regarding the interviewees are also taken. Reasonably, the survey invests not only young people, but also their relatives, school workers and, gradually, the public. The survey is administrated during exhibitions or outreach events devoted to schools, but also open to the public. The survey is in dual form: printed and online. The online mode clearly leads RadioLab project even outside the school environment. Based on the results of the survey, several statistical analyses have been performed and many conclusions are drawn about the knowledge of the population on the radon risk. The RadioLab benefit and the requirement to carry on the project goals, spreading awareness of environmental radioactivity from radon, emerge. The dataset involves all twenty Italian regions and consists of 28,612 entries covering the 5-year period 2018-2022.

Geotechnical and environmental radioactivity investigations at Al Sadis Min Uktober city, Cairo municipality (Egypt), for the high-speed railway construction.

The present study aims to evaluate the possibility of constructing a new high-speed railway (HSR) at Al Sadis Min Uktober city, Cairo (Egypt): geotechnical and environmental radiological hazards are estimated from several collected soil and water samples. A variety of laboratory geotechnical tests such as grain size, free swelling test, liquid and plastic limits, chemical analysis and uniaxial compression strength are applied to sixty-one drill holes. A geotechnical examination of the coarse-grained soil at the foundation level classified it as poorly graded soil. The results of the investigation of fine-grained soil at the foundation level shown that the liquid limit ranges from 22% to 55%, the plastic limit ranges from 12% to 28%, the plasticity index varies from 11% to 33%, free swelling varies from 51% to 71%. Mechanically, the uniaxial compressive strength values on rock samples range from 6.96 MPa to 142.39 MPa. The radioactive study is performed to detect the 226Ra, 232Th, and 40 K activity concentrations of the soil samples: their mean values are 34 ± 10 Bq·kg-1, 14 ± 5 Bq·kg-1 and 552 ± 20 Bq·kg-1, respectively. The values of radiological hazard indexes are not exceeded the permissible limits: e.g. the mean value of absorbed dose rate is 47 ± 6 nGy h-1; the annual gonadal dose equivalent is 0.3 ± 0.04 mSv·y-1; the lifetime cancer risk is 02 ± 0.2·10-3. Thus, the soil in the studied railway area is safe to use in building materials and infrastructure applications: the radiological hazards and the geotechnical studies confirmed the studied area is suitable to construct a new community having a HSR. According to the SWOT-PEST and environmental impact analyses, the construction of the HSR meets the criteria of the Kyoto Protocol, the EU Climate and Energy policy, and other international treaties.

Radon surveys and effectiveness of remedial actions in spas on the Ischia island (Italy).

The possible damaging effects on human health of inhaled radon and its decay products are of interest to workers and the public. In particular, radon in thermal environments often occurs in high concentrations. Therefore, investigations and remedial actions are important to reduce activity concentration values and associated risk. This work concerns the analysis of two surveys of radon gas activity concentration carried out in 2006/2007 and 2019/2020 at twenty thermal spas on the island of Ischia (Italy). Annual measurements were carried out in workplaces located in the basement and ground floor using passive CR-39 detectors. In the spas involved in both surveys, the effectiveness of the remedial actions, implemented by the owners, was assessed obtaining an average percentage reduction of 74%. Considerations were made about the annual effective dose, and the location of the spas taking into account the geological setting of the volcanic nature of the island.

Ground-state proton decay of 69Br and implications for the 68Se astrophysical rapid proton-capture process waiting point.

We report on the first direct measurement of the proton separation energy for the proton-unbound nucleus (69)Br. Bypassing the (68)Se waiting point in the rp process is directly related to the 2p-capture rate through (69)Br, which depends exponentially on the proton separation energy. We find a proton separation energy for (69)Br of Sp((69)Br )= -785(-40)(+34) keV; this is less bound compared to previous predictions which have relied on uncertain theoretical calculations. The influence of the extracted proton separation energy on the rp process occurring in type I x-ray bursts is examined within the context of a one-zone burst model.

Effects of kaolin on Ophelimus maskelli (Hymenoptera: Eulophidae) in laboratory and nursery experiments.

Although recent research has demonstrated that clays provide satisfactory control of some agricultural insect pests, the effect of clays on gall wasps that damage forest trees has not been previously reported. The aim of the current study is to evaluate the effectiveness of the clay kaolin in the laboratory and in the field in reducing the damage caused by the eulophid Ophelimus maskelli (Ashmead) on seedlings of eucalyptus (Eucalyptus L'Hér.) species. In the laboratory, kaolin + wetting agent significantly reduced the percentage of infested leaves and the number of galls per leaf. In the nursery, gall number per leaf was not correlated with leaf area with kaolin + wetting agent but was related to leaf area for all other treatments (wetting agent alone, imidacloprid, and untreated control). In the nursery, gall number per leaf was lower with kaolin + wetting agent and with imidacloprid than with the other two treatments. Overall, kaolin effectively reduced eulophid infestations, and its effect was more persistent than that of imidacloprid. Although application of kaolin might not be feasible on large forested areas, kaolin could represent a valuable control method in nurseries, where the repeated application with more toxic chemicals can result in high concentrations of residual pesticides in the soil.

LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells.

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

Safety of recreational scuba diving in type 1 diabetic patients: the Deep Monitoring programme.

AIM: To verify whether, with thorough practical and theoretical training, well-controlled, non-complicated diabetic patients can safely go diving underwater with no additional medical or metabolic risks. METHODS: Twelve diabetic patients participated in the study after undergoing training focused on their diabetic status. Two dives per day were scheduled during two five-day stays on the island of Ventotene (Italy). Capillary blood glucose (BG) was checked at 60, 30 and 10 minutes before diving, and corrective measures adopted if necessary, based on BG absolute levels and dynamics. A device for continuous subcutaneous glucose monitoring (CGM), expressly modified for the purpose, was worn during dives. RESULTS: Data were gathered from 90 dives; mean BG at 60, 30 and 10 minutes before diving was 205.8+/-69.6 mg/dL, 200.0+/-66.4 mg/dL and 200.5+/-61.0mg/dL, respectively. In 56 of the 90 dives, supplementary carbohydrates or insulin were necessary, but only one dive was interrupted on account of hypoglycaemic symptoms. Mean post-dive BG was 158.9+/-80.8 mg/dL. CGM recordings showed that glucose levels gradually decreased during the dives (nadir: -19.9%). CONCLUSION: Experienced, well-controlled, complication-free young diabetic patients can safely go scuba diving, provided that they apply a rigorous protocol based on serial pre-dive BG measurements. The specific variables of underwater diving do not appear to involve significant additional risks of hypoglycaemia.

Modeling Environmental Influences in the Psyllaephagus bliteus (Hymenoptera: Encyrtidae)-Glycaspis brimblecombei (Hemiptera: Aphalaridae) Parasitoid-Host System.

Glycaspis brimblecombei Moore (Hemiptera: Aphalaridae) is an invasive psyllid introduced into the Mediterranean area, where it affects several species of Eucalyptus. Psyllaephagus bliteus Riek (Hymenoptera: Encyrtidae) is a specialized parasitoid of this psyllid that was accidentally introduced into Italy in 2011. We developed a model of this host-parasitoid system that accounts for the influence of environmental conditions on the G. brimblecombei population dynamics and P. bliteus parasitism rates in the natural ecosystem. The Lotka-Volterra-based model predicts non-constant host growth and parasitoid mortality rates in association with variation in environmental conditions. The model was tested by analyzing sampling data collected in Naples in 2011 (before the parasitoid was present) and defining several environmental patterns, termed Temperature-Rain or T-R patterns, which correspond to the host growth rate. A mean value of the host growth rate was assigned to each T-R pattern, as well as a variation of the parasitoid mortality rate based on temperature thresholds. The proposed model was applied in simulation tests related to T-R patterns carried out with a data series sampled between June 2014 and July 2015 in five Italian sites located in Campania, Lazio, Sicily, and Sardinia regions. The simulation results showed that the proposed model provides an accurate approximation of population trends, although oscillation details may not be apparent. Results predict a 64% reduction in G. brimblecombei population density owing to P. bliteus parasitoid activity. Our results are discussed with respect to features of the host-parasitoid interaction that could be exploited in future biological control programs.

Relationship between somatomedin-C and growth hormone levels in acromegaly: basal and dynamic evaluation.

The relationship between basal and stimulated plasma GH and somatomedin-C (SmC) levels in acromegalic patients was evaluated. The basal plasma SmC levels of 66 patients were significantly correlated (P less than 0.01) with mean daily plasma GH levels, but not with the percent GH increase after GH-releasing hormone or TRH or the GH decrease after acute bromocriptine administration. Bromocriptine (7.5-15 mg/day) administration for 9.2 +/- 0.9 (+/- SD) months in 20 patients significantly (P less than 0.05) decreased GH levels. SmC decreased significantly [from 9.8 +/- 1.9 to 5.1 +/- 0.7 U/ml (mean +/- SE)] only in the 10 patients who had the more marked GH inhibition. The administration of a somatostatin analog, SMS 201-995 (100 micrograms twice daily), to 12 patients for 16 weeks significantly decreased plasma GH and SmC levels beginning on the second day of therapy; normal SmC levels were achieved in 5 of 12 patients. Pituitary adenomectomy resulted in normal GH and SmC levels in 10 of 12 and 8 of 12 patients, respectively. Our data indicate an overall dependency of plasma SmC levels on plasma GH levels in acromegaly, although similar GH levels may have differing somatomedin-stimulating activities. A derangement in the feedback mechanisms controlling GH secretion is indicated by the failure of elevated SmC levels to influence the GH responsiveness to releasing hormones. In evaluating pharmacological or surgical treatments of acromegaly, a single plasma SmC value can reliably replace several plasma GH determinations.

Serum type III procollagen propeptide levels in acromegalic patients.

Serum type III procollagen propeptide (PIIIP) is a reliable index of tissue collagen synthesis. Since in acromegaly there is increased collagen production, we measured serum PIIIP in acromegalic patients before any treatment (basal), during medical treatment with the somatostatin analog SMS 201-995, and after pituitary adenomectomy. In all patients, serum GH and plasma somatomedin-C (SmC) levels were also measured. Basal serum PIIIP levels were significantly (P less than 0.01) higher in acromegalic patients (mean +/- SEM, 22.7 +/- 2.1 ng/ml) than in normal subjects (n = 30; 9.7 +/- 0.5 ng/ml), and they were significantly correlated with plasma SmC values (r = 0.31; P less than 0.05). A significant (P less than 0.01) reduction in PIIIP levels occurred in patients treated with SMS 201-995 or surgery (from 24.3 +/- 2.7 to 12.4 +/- 1 ng/ml) as well as in GH and SmC levels. The maximum percent decrease in serum PIIIP was significantly correlated with those in GH (r = 0.65; P less than 0.01) and SmC (r = 0.60; P less than 0.01). Serum PIIIP levels did not change in those patients in whom neither GH nor SmC were decreased by treatment. In conclusion, serum PIIIP levels are elevated in acromegalic patients, and they decline in parallel with GH and SmC during medical or surgical treatment. Serum PIIIP measurements may be useful in the evaluation of acromegalic patients to gain information on the biological activity of GH and in monitoring the course of the disease.

Bromocriptine does not alter growth hormone (GH) responsiveness to GH-releasing hormone in acromegaly.

GHRH (100 micrograms) and TRH (200 micrograms) were administered to 24 active acromegalic patients before and during chronic bromocriptine (Br) treatment (Br, 10-15 mg/day for 3-5 months) to evaluate the possible effects of the dopamine agonist on GH release induced by these releasing hormones. Mean daily plasma GH levels were reduced by Br treatment from 34 +/- 40 (SD) to 16 +/- 19 ng/ml (P less than 0.01). No significant changes were found when comparing the GH response to GHRH as mean area under the response curve (nanograms per min/ml above the basal) (pretreatment, 5453 +/- 7843; during Br, 7017 +/- 12763 ng/ml . min), and as mean individual peak GH values (pretreatment, 130 +/- 148; during Br, 126 +/- 187 ng/ml) before and during treatment. The percentage GH increase (pretreatment, 340 +/- 354; during Br, 617 +/- 539%) was however significantly higher during Br. Br treatment significantly reduced the GH response to TRH in terms of mean of individual peak levels (from 136 +/- 134 to 60 +/- 52 ng/ml; P less than 0.01) and area under the response curve (from 3142 +/- 3998 to 1331 +/- 1646 ng/min . ml; P less than 0.01). However, the percentage GH increase was not significantly different (pretreatment, 486 +/- 729; during Br, 1059 +/- 1862%). When the patients were divided into Br responders, i.e. mean daily GH reduction during Br of at least 50% below baseline, and nonresponders, the initial response to GHRH was significantly higher in the latter group, but was unaffected by Br treatment in either group. On the contrary, the response to TRH, statistically significant initially only in the Br responder group, was reduced by Br treatment. We suggest that cells sensitive to Br and TRH but not to GHRH (lactotroph-like) and cells sensitive to GHRH but not to Br (pure somatotrophs) may coexist in GH-secreting adenomas.

Homogeneity in the growth hormone-lowering effect of dopamine and somatostatin in acromegaly.

We have studied the effect of maximally inhibiting doses of dopamine (DA) or somatostatin on GH levels in 39 acromegalic patients. The GH-lowering effects of the two drugs were highly variable in different patients. A significant correlation (r = 0.45; P < 0.01) was found between the percent changes obtained during the infusions of DA (500 microgram/min) and somatostatin (3.33 microgram/min). Pretreatment with L-sulpiride markedly blunted the inhibitory effect of DA but did not affect the response to somatostatin. We conclude that the GH-secreting cells of acromegalic patients contain separate receptors for DA and somatostatin. We hypothesize that the partial or total lack of responsiveness to DA or somatostatin may be due to the loss of receptors for these agents on the GH-secreting neoplastic cells.

Changes in growth hormone (GH) secretion induced by human pancreatic GH releasing hormone-44 in acromegaly: a comparison with thyrotropin-releasing hormone and bromocriptine.

We studied the effects of 100 micrograms human pancreatic GH releasing hormone-44 (GRH) in 35 acromegalic patients. Plasma GH levels significantly increased [basal, 30 +/- 10 (SE) ng/ml; peak, 82 +/- 21 ng/ml; P less than 0.01], but a wide intersubject variability of the responses was found (range, 20-1602%). No relationship was found between the percentage GH increase after GRH and basal values of GH, PRL, or somatomedin-C. All patients also underwent an acute test with bromocriptine (2.5 mg orally) and TRH (200 micrograms iv). When dividing the patients according to their GH responsiveness to bromocriptine (Br), an inverse correlation (r = -0.42, P less than 0.05) was found between percentage of GH changes after GRH and after Br; moreover Br responder patients had a lesser (P less than 0.001) GH increase after GRH (124 +/- 27%) than nonresponders (562 +/- 116%). No relationship was found between the GH response to TRH and GRH, and no differences were found between the percentage GH increase after TRH (513 +/- 117%) and after GRH (349 +/- 71%). We conclude that the tumoral somatotrophs are sensitive to their specific releasing hormone and we suggest that the presence in the adenoma of cells with surface membrane receptors similar to those on the lactotropes may explain the lower sensitivity to GRH of Br responders compared to nonresponders.

Chronic treatment of pathological hyperprolactinemia and acromegaly with the new ergot derivative terguride.

The long term effectiveness and tolerance of terguride, a new ergot derivative, as initial therapy were evaluated in 20 patients with pathological hyperprolactinemia (PHP; group A) and 7 patients with acromegaly. We also studied 10 patients with PHP whose treatment was changed from bromocriptine or lisuride to terguride (group B). Terguride, given for at least 6 months in divided doses ranging from 0.25-1.50 mg/day to group A patients, resulted in normal (11 patients) or markedly reduced plasma PRL levels. Gonadal function was restored in all but 2 patients in this group, and the tumors shrank in 3 of 5 patients with a macroprolactinoma and in 1 of 3 patients with a microprolactinoma. In group B patients, positive effects of the previous treatment on PRL levels, gonadal function, and tumor growth were maintained by terguride. Terguride suppressed plasma GH levels below 50% of baseline in 4 of the 7 acromegalic patients. Two of the 27 patients initially treated with terguride complained of mild nausea and postural hypotension only after the first dose (0.25 mg) of the drug. No patient in group B had any side-effects during terguride, with the exception of 1 patient who was also intolerant to bromocriptine. We conclude that terguride is an effective well tolerated dopaminergic agent in PHP.

Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine.

We studied the effects of acute and chronic sc administration of SMS 201-995 (SMS), a long-acting somatostatin analog, in acromegalic patients. The results were compared with those obtained in the same patients treated with oral bromocriptine (Brc). A single dose of 50 micrograms SMS administered to 28 patients induced a more rapid, greater, and more prolonged reduction in plasma GH levels than did 2.5 mg Brc. Chronic treatment [60-330 days; mean 208 +/- 23 (+/- SEM)] with SMS (100-300 micrograms/day) induced in 16 patients a significantly greater decrease in mean plasma GH and somatomedin-C levels than did 20 mg Brc. Combined treatment with the 2 agents had an additional effect. The clinical and metabolic parameters of acromegaly dramatically improved in all patients whose plasma GH and somatomedin-C levels decreased even if they were not normalized by SMS. Reduction in tumor size occurred in 3 of the 10 patients examined by computed tomography before and during SMS treatment. We conclude that SMS is more effective than Brc and that the 2 drugs may be complementary in the medical treatment of acromegaly.

Lisuride hydrogen maleate: evidence for a long lasting dopaminergic activity in humans.

In 12 acromegalics a single oral dose of 0.2 mg lisuride, an ergoline derivative, significantly reduced plasma PRL but not GH concentrations. Three-tenths milligram of the drug significantly reduced plasma levels of the two hormones. Four-tenths milligram of lisuride did not augment this inhibitory effect. Plasma PRL levels were suppressed in all patients, whereas GH levels were reduced by more than 50% of the base-line values in only seven patients who also responded to the administration of 2.5 mg bromocriptine (CB154). In the patients unresponsive to lisuride, CB154 also failed to change GH levels. The suppressive effect of lisuride started at 60 min (at 150 min for CB154) and plasma GH and PRL levels were still markedly suppressed at 300 min. Plasma GH and PRL concentrations were consistently reduced in two acromegalic patients during 2 weeks of chronic treatment with 0.3 mg lisuride four times a day. In six normal subjects, TRH-induced PRL release was significantly inhibited by pretreatment with 0.3 mg of the drug. The similarity in the effects of lisuride and CB154 suggests that the observed effects of lisuride on GH and PRL are attributable to the known dopaminergic activity of the drug. This conclusion is supported by the data showing that pimozide effectively counteracted the inhibitory action of lisuride on GH and PRL release. We suggest that lisuride may be of value in the medical treatment of acromegaly and hyperprolactinemic states.

Size reduction of macroprolactinomas by bromocriptine or lisuride treatment.

We have administered to 29 patients with macroprolactinoma the dopamine agonists bromocriptine and lisuride for 1-50 months (mean +/- SE, 12.7 +/- 1.8) in order to assess the effects of these drugs on tumor size. Fourteen patients were treated with bromocriptine (dose range, 7.5-20 mg/day), 12 patients were treated with lisuride (0.6-2 mg/day), and 3 patients were given both drugs. Computed tomography performed before and during treatment showed the occurrence of tumor shrinkage in 18 patients (62%), but in no case was a complete disappearance of the tumor observed. In 5 of these patients, it was even possible to document tumor shrinkage within the first month of treatment with low doses of the dopamine agonists, whereas in other patients, tumors shrank only after prolonged treatment with higher doses. Visual field and acuity improved or normalized in 8 of the 13 patients with visual defects; in some cases, the improvement was reported as early as 2 days after the treatment was started. Plasma PRL levels fell in all patients who showed a reduction in tumor size; in 2 other patients, PRL levels were only poorly suppressed, and tumor size remained unchanged. In the remaining patients, PRL levels were lowered without convincing evidence of tumor shrinkage. In considering the high percentage of patients showing tumor shrinkage under medical treatment, we propose a course with dopamine agonists as the first step in the management of patients with macroprolactinomas regardless of the presence of visual impairments.

Inhibitory effect of an ergoline derivative, methergoline, on growth hormone and prolactin levels in acromegalic patients.

Plasma levels of growth hormone (GH) and prolactin (PRL) were measured in twelve acromegalic patients after acute administration of an ergoline derivative (methergoline) which has been proposed as a specific serotoninergic blocking agent. The administration of methergoline (4 mg p.o.) was followed by a significant decrease in plasma GH and PRL concentrations. The administration to the same subjects of CB 154 (2.5 mg p.o.), a known stimulator of dopaminergic receptors, led to results almost superimposable to those obtained with methergoline although the suppressive effect of CB 154 on GH and PRL levels was more sustained. Also on the ground of results obtained in these patients with the use of cyproheptadine, phentolamine, or pimozide, we have concluded that methergoline inhibition of GH and PRL release is, in acromegalic patients, most probably due to a dopaminergic mechanism of action.