A machine learning tool for re-planning and adaptive RT: A multicenter cohort investigation.

PURPOSE: To predict patients who would benefit from adaptive radiotherapy (ART) and re-planning intervention based on machine learning from anatomical and dosimetric variations in a retrospective dataset. MATERIALS AND METHODS: 90 patients (pts) treated for head-neck cancer (H&N) formed a multicenter data-set. 41 H&N pts (45.6%) were considered for learning; 49 pts (54.4%) were used to test the tool. A homemade machine-learning classifier was developed to analyze volume and dose variations of parotid glands (PG). Using deformable image registration (DIR) and GPU, patients' conditions were analyzed automatically. Support Vector Machines (SVM) was used for time-series evaluation. "Inadequate" class identified patients that might benefit from replanning. Double-blind evaluation by two radiation oncologists (ROs) was carried out to validate day/week selected for re-planning by the classifier. RESULTS: The cohort was affected by PG mean reduction of 23.7±8.8%. During the first 3weeks, 86.7% cases show PG deformation aligned with predefined tolerance, thus not requiring re-planning. From 4th week, an increased number of pts would potentially benefit from re-planning: a mean of 58% of cases, with an inter-center variability of 8.3%, showed "inadequate" conditions. 11% of cases showed "bias" due to DIR and script failure; 6% showed "warning" output due to potential positioning issues. Comparing re-planning suggested by tool with recommended by ROs, the 4th week seems the most favorable time in 70% cases. CONCLUSIONS: SVM and decision-making tool was applied to overcome ART challenges. Pts would benefit from ART and ideal time for re-planning intervention was identified in this retrospective analysis.

[Psychiatric aspects in workers subject to mobbing]. / Aspetti psichiatrici del lavoratore oggetto di mobbing.

BACKGROUND: Mobbing in the language of ethologists means a particular behaviour of a group of animals consisting of several members forming an alliance against a single animal, in order to eliminate this animal away from the group. This term has been adopted in current usage to mean a kind of relationship at the workplace that, by aggressive and underhand means, aims at influencing or expelling the person. The term "bossing" is used to indicate a negative action, under the meaning described above, made by one or more senior persons, or possibly by the employer. In the Italian Parliament, under the current legislature, several bills are pending regarding this problem. Besides the aspects of topical interest in the problem, there are first and foremost the different kinds of reaction-adaptation to mobbing, according to the type of individual internal working models in action, that can be anxious/avoiding, anxious/resistant or disorganised. OBJECTIVES: The purpose of our study was a clinical evaluation of the different ways of adaptation-reaction to a mobbing-type relationship at the workplace, and of the type of internal working models found among the examined patients. METHODS: A clinical interview was carried out with 40 patients who, over a period of 12 months of observation, came to request a clinical assessment, for medical-legal reasons, of their psycho-pathological state and ways to react to adverse situations at the workplace, such as a mobbing or bossing. RESULTS: Besides the psychological and relational effects of mobbing, the reactions of the examined subjects to mobbing are also described, considering also the different cognitive self-organization possibilities, according to the individual internal working model, regarding patterns of attachment in adult age. The most frequent internal working model seems to be the one related to resistant attachment, followed by the avoidance and lastly--rarely--the disorganized model. Furthermore we observed among these subjects a certain deficit in meta-cognitive capacity of self reflection and decentralization. CONCLUSIONS: Cognitive therapy is proposed as the most effective of therapeutic approaches, associated with symptomatic psycho-pharmacological therapy as needed. Initial clinical results on cognitive therapy of these patients are reported. The individual type of internal working model seems to be the critical element in mobbing reaction and, besides specific intervention plans regarding relationship in the workplace, individual psychotherapy appears to be the best instrument of treatment and prevention of the psychopathologic effects caused by mobbing.

Effects of estrogens and androgens on erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase activities during the menstrual cycle.

The effects of physiological changes in estrogens and androgens on the erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase enzyme activities during the menstrual cycle were investigated in healthy eumenorrheic women. Blood samples were taken on alternate days from twelve normally cyclic women (age range: 20 to 27 years; mean age: 24.1 years) from the first day of one menstrual cycle until the first day of the subsequent one. Plasma was analyzed for FSH, LH, estradiol, progesterone, testosterone, free testosterone and androstenedione concentrations. Erythrocyte superoxide dismutase, catalase and glutathione peroxidase activities were evaluated on the same days and cycle length was standardized on the basis of the preovulatory estradiol peak. Significant cyclic phase-related changes were observed in glutathione peroxidase (P<0.05), with higher glutathione peroxidase activity levels from the late follicular to the early luteal phase compared with those found in the early follicular phase (P<0.001 and P<0.002 respectively). A significant positive correlation was observed between mean estradiol and glutathione peroxidase cycle-related variations (r=0.80, P<0.001), whereas no significant cycle phase-dependent changes were seen in superoxide dismutase and catalase. No effect of progesterone and androgens on the erythrocyte antioxidant enzyme system was documented. The findings indicate that physiological ovarian estradiol production during the menstrual cycle may have an important role in regulating erythrocyte glutathione peroxidase activity.

Apoptotic and antiproliferative effects of gemcitabine and gemcitabine plus Ara-C on blast cells from patients with blast crisis chronic myeloproliferative disorders.

BACKGROUND: Blast phase of chronic myeloid leukemia (CML) as well as the rare acute transformation of other chronic myeloproliferative disorders constitute forms of leukemia that are particularly refractory, even to aggressive chemotherapy. Many attempts have thus been made to identify new drugs that could be active in these diseases. We wanted to evaluate whether gemcitabine (dFdC), a pyrimidine analogue widely employed in lung cancer chemotherapy, was able to block in vitro proliferation of bcr/abl-positive and bcr/abl-negative blast cells in primary culture. We already showed that gemcitabine is active in inhibiting proliferation and inducing apoptosis of HL60 cells. METHODS: We studied the influence of dFdC on the proliferative potential of blasts by means of tritiated thymidine uptake, colony formation in semisolid medium and cell cycle parameters at flow cytometry. The efficacy of dFdC in inducing apoptosis was evaluated by flow cytometry (A0 peak) and by DNA agarose gel electrophoresis. RESULTS: We demonstrated that dFdC already inhibits tritiated thymidine uptake at doses of 10 microM after 72 hours of culture, and that this effect is dose dependent. The addition of Ara-C 5 microM in the culture medium of dFdC provoked a synergistic inhibitory effect. Consistent results were obtained when cell cycle distribution was studied. In fact, cell incubation in the presence of dFdC resulted in a significant decrease of cells in S phase, although with a certain heterogeneity among cases. The antileukemic activity of dFdC appeared to be specific since it was mediated through apoptosis. We could demonstrate the appearance of the pre-G1 apoptotic peak at cytofluorimetric analysis, and the characteristic DNA fragmentation pattern at agarose electrophoresis in all 10 cases after treatment with different doses of dFdC. Induction of apoptosis was maximal for the highest doses of dFdC (100 mM) and for the combination of dFdC and Ara-C. INTERPRETATION AND CONCLUSIONS: Following incubation with Gemcitabine leukemic blasts from chronic myeloproliferative disorders are induced to accumulate intracytoplasmatic and nuclear Ara-C and undergo apoptosis. These observations suggest that gemcitabine could be considered a candidate drug, capable of being used in polychemotherapy of refractory acute phase chronic myeloproliferative disorders.

[Combination of beta-interferon and laser-CO2 therapy in female HPV genitalis]. / Associazione del beta-interferone alla terapia con laser-CO2 nell'HPV genitalis femminile.

230 women affected by HPV genital infection diagnosed by macroscopic examination, colposcopy and Pap test, were divided into two groups, of 95 and 135 people respectively, homogeneous for lesion localization and extension. The first group was treated with laser CO2 and the second group was treated with laser CO2 and intramuscular beta-interferon. We evaluated the side effects, the clinical results and the incidence of recurrences after 1, 6 and 12 months after the complete destruction of the lesions. At the first control, in both groups, we found no persistence of the lesions. At the second control after 6 months recurrences were present in 19 patients of the first group and in 7 patients of the second group. 51 recurrences were present after 12 months in the first group and 14 in the second group. The difference, evaluated with the chi 2 test, was found to be statistically significant (p < 0.01 after 6 months and p < 0.001 after 12 months).

Reversal of heparin anticoagulation by recombinant platelet factor 4 and protamine sulfate in baboons during cardiopulmonary bypass.

The ability of recombinant platelet factor 4 and protamine to neutralize heparin after cardiopulmonary bypass was compared in anesthestized baboons. Clotting titration curves of heparinized baboon blood demonstrate an anticoagulant effect of protamine that is not seen with recombinant platelet factor 4. Neither drug caused meaningful changes in central pressures or cardiac output within 30 minutes after injection. After 30 minutes of cardiopulmonary bypass, recombinant platelet factor 4 normalized thrombin times and activated partial thromboplastin times within minutes of injection, but protamine did not. Neither drug altered bleeding times. Recombinant platelet factor 4 caused a species-specific leukopenia in baboons and significantly increased activated complement protein 3 (C3a) more than protamine. However, the increase in plasma C3a was small and neither drug caused a significant increase in plasma neutrophil elastase-alpha 1 proteinase inhibitor complex. We conclude that recombinant platelet factor 4 is effective and safe in baboons, does not have an anticoagulant effect with excess concentration, and reverses in vivo heparin more rapidly than protamine. The data support progression to a clinical trial.

Iloprost and echistatin protect platelets during simulated extracorporeal circulation.

Temporary, reversible inhibition of platelets during cardiopulmonary bypass is an attractive strategy to protect platelets and normalize postoperative bleeding times. Iloprost, an analogue of prostacyclin, and the disintegrins reversibly inhibit platelets by different mechanisms. We tested the hypothesis that reduced doses of iloprost and either echistatin, a natural disintegrin, or RO43-5054, a peptidomimetic, in combination provide better platelet protection than any drug alone during simulated extracorporeal circulation. Thirty-five recirculation studies using fresh, heparinized human blood in an extracorporeal perfusion circuit that contained a 0.45-m2 spiral coil membrane oxygenator were performed. Iloprost, but neither echistatin nor RO43-5054, increased platelet cyclic adenosine monophosphate. Combinations of iloprost and either fibrinogen receptor antagonist at reduced doses submaximally increased platelet cyclic adenosine monophosphate. Platelet adhesion and release of beta-thromboglobulin antigen was completely inhibited by combinations of the two classes of drugs, but only partially inhibited by each drug alone. Combinations of drugs also completely inhibited platelet aggregation to adenosine diphosphate; these platelets retained full sensitivity to adenosine diphosphate after 90 minutes of recirculation when drugs were removed by gel filtration. We conclude that combinations of iloprost and a fibrinogen receptor antagonist at doses that are unlikely to produce clinical side effects completely inhibit platelet activation and preserve platelet function during in vitro extracorporeal circulation.

Leiomyoma of the ovary. Case report.

The leiomyoma of the ovary is a very rare form of ovarian neoplasia, while its uterine localization is very common and diffused. It occurs prevalently in post-menopausal women usually causing abdominal swelling and pain. Such a case occurred in our observation and we report it here.

Tissue factor is expressed on monocytes during simulated extracorporeal circulation.

Certain forms of extracorporeal circulation exemplified by cardiopulmonary bypass require continuous high-dose anticoagulation to prevent thromboembolic complications. We hypothesized that monocytes may be stimulated to express tissue factor (TF) during prolonged simulated extracorporeal circulation. TF was identified both by flow cytometry by using three TF-specific monoclonal antibodies and functional assay of procoagulant activity (PCA). TF significantly increased between 2 and 6 hours of simulated extracorporeal circulation by both analyses. Relative fluorescence on monocytes increased from a control value of 100 to 313 +/- 79 on cells from the simulated extracorporeal circuit (p < 0.05). PCA increased from 21 +/- 8 to 775 +/- 326 pg TF/10(6) monocytes (p < 0.05) and was blocked 99.6% by preincubation of cells with a mixture of monoclonal antibodies to TF. By 6 hours, the number of leukocytes in the circuit was decreased by 43%. The cells were recovered from the oxygenator membrane by washing with EDTA. Compared with initial values, by 6 hours, both TF antigen at 378 +/- 90 (p < 0.05) and PCA at 1,357 +/- 280 pg TF/10(6) monocytes (p < 0.01) were highest in the recovered cells. Cells incubated for 6 hours and not subjected to simulated extracorporeal circulation did not increase TF. Examination of monocytes for the adhesive receptor CD11b/18 (Mac-1) paralleled TF expression, providing an additional putative receptor for the coagulant proteins, factor X and fibrinogen or fibrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Upregulation of Mac-1 surface expression on neutrophils during simulated extracorporeal circulation.

The leukocyte integrin Mac-1 (alpha m beta 2, CD11b/18 CR3, MO1), in addition to binding iC3b, has been shown to be the receptor for the coagulation proteins fibrinogen, factor X, and high molecular weight kininogen. Mac-1 is known to be upregulated by agonists that stimulate neutrophils or monocytes. Previous studies from this laboratory have documented neutrophil activation during cardiopulmonary bypass. We therefore used an experimental model for cardiopulmonary bypass, a simulated extracorporeal circulation, to study the surface expression of Mac-1 on peripheral blood leukocytes by immunofluorescence flow cytometry. The number of Mac-1 receptors in polymorphonuclear leukocytes had increased 2.2 times and 2.9 times baseline by 2 hours at 37 degrees C and 28 degrees C, respectively (p < 0.001). Neutrophil elastase-alpha 1-proteinase inhibitor complexes (a measure of neutrophil degranulation) increased more than sixfold from 41 micrograms/L to 256 micrograms/L after 2 hours at 28 degrees C. The number of Mac-1 receptors expressed on polymorphonuclear leukocytes correlated with polymorphonuclear leukocyte elastase complexes (r = 0.93). Mac-1--bearing lymphocytes did not display any change in receptor number in the simulated extracorporeal circulation. By 2 hours, monocytes at 37 degrees C showed only insignificant increase; at 28 degrees C they displayed a 1.6 times increase (p < 0.05). By maintaining a temperature-matched standing control samples, we could prove that, unlike the Mac-1 in polymorphonuclear leukocytes, this increase in monocyte Mac-1 is not from bypass but is rather an effect of temperature. These data suggest that a receptor for procoagulant proteins on circulating polymorphonuclear leukocytes (Mac-1) is upregulated during simulated extracorporeal circulation.

The effects of hypothermia and injury severity on blood loss during trauma laparotomy.

To assess the relationships between core temperature (T) and other factors relating to operating room (OR) blood loss and mortality following abdominal injury, the records of 122 patients undergoing laparotomy for trauma at Detroit Receiving Hospital over a 1-year period (1989) were reviewed. Most injuries were penetrating (86%) and the mortality rate was 8.2%. Overall, 57 of 122 (47%) had hypothermia (T < or = 35 degrees C) upon arrival in the OR. There was a significant correlation between admission blood pressure and lowest intraoperative temperature (r = 0.60; p < 0.001). Multiple regression analysis revealed that the patient's lowest temperature (p < 0.001) and Trauma Score (TS); p < 0.0015), but not Abdominal Injury Severity Score (AISS) (p = 0.25) correlated with OR blood loss. The 28 patients with high TS (15 or 16) and AISS > or = 9 had significantly less blood loss when the OR temperature was maintained above 35 degrees C versus 33 degrees-35 degrees C (540 +/- 580 mL vs. 1820 +/- 1160 mL; p < 0.003). This suggests that hypothermia may exacerbate OR blood loss independent of degree of physiologic or anatomic injury. Thus hypothermia is common in patients undergoing a laparotomy for trauma. Trauma scores and the presence of shock preoperatively correlate with the development of intraoperative hypothermia. Hypothermic patients with similar injury severity have greater blood loss. Prevention and rapid correction of hypothermia during resuscitation and surgery appear to be extremely important in reducing blood loss in this patient population.

Methods for detecting early signs of AIDS dementia complex in asymptomatic HIV-1-infected subjects.

OBJECTIVES: To determine the optimal diagnostic procedures for identifying early signs of AIDS dementia complex (ADC) in asymptomatic HIV-1-infected individuals, in order to prevent further cognitive function impairment by early treatment. DESIGN: Study patients had been referred electively and consecutively to hospital; all had been referred for the first time and gave informed consent. Inclusion criteria were (1) lack of history and/or symptoms of psychosis and neurological disorders; (2) lack of active viral, protozoan or fungal pathology; (3) abstinence from heroin and/or cocaine for at least 6 months before baseline evaluation. SETTINGS: Subjects were seen at the L. Spallanzani Hospital for Infectious Diseases, Rome, Italy between March 1989 and March 1991. PARTICIPANTS: Eighty-two asymptomatic HIV-1-infected subjects: 41 drug users, 27 homosexuals and 14 heterosexuals. MAIN OUTCOME MEASURES: All subjects were evaluated using Wechsler-Bellevue I, Benton C form and Bender tests. Thirty-nine subjects underwent single-photon emission computed tomography (SPECT) and 12 magnetic resonance imaging (MRI). The immunological status of each subject was determined. RESULTS: On psychometric testing, 23 out of the 82 (28%) asymptomatic subjects had a mental decay percentage (MD%) > or = 20%. Cerebral perfusion abnormalities were detected in 31 out of 39 (79.48%) subjects who underwent SPECT; MRI abnormalities were observed in seven out of 12 (58%) subjects. Twelve out of 23 subjects with MD% > or = 20, 15 out of 29 subjects with SPECT abnormalities and four out of seven patients with MRI abnormalities had total CD4+ lymphocyte counts > or = 500 x 10(6)/l. CONCLUSIONS: The high incidence of abnormal SPECT and of MD% > or = 20 in asymptomatic HIV-1-infected patients, and the lack of correlation between immunological status and degree of mental decay, SPECT and MRI abnormalities raise many questions about subclinical HIV-1 neurological disease.

Simultaneous ovarian and intrauterine pregnancy: case report.

The simultaneous presence of an ovarian and a normal intrauterine pregnancy is a very rare condition. We report such a case seen as an ovarian cyst during gestation. It was immediately and successfully treated, thus allowing for the normal physiologic continuation of the gestation.

Multianalytic study on cervical HPV lesions.

Nowadays new sophisticated techniques of molecular biology based on the principles of hybridization between nucleic acids, allow a correct diagnosis of genital HPV infection. In the present paper, beside traditional diagnostic methods, we used In Situ Hybridization (ISH) and Polymerase Chain Reaction (PCR) to detect the presence of HPV types 6, 11, 16, 18, 31 and 33. We tested ten patients affected by cervical lesions of high histological atypias associated with HPV, who underwent surgical conization. Types 6 and 11, at low risk of evolution, are less frequent than 31 and 33, at medium grade of evolution, and than 16 and 18 which are at high risk of evolution.

Evaluation of tumor-associated trypsin inhibitor (TATI) in women with benign and malignant gynecological disease.

Tumor-associated trypsin inhibitor (TATI) was assayed in healthy subjects and in women with benign and malignant gynecological diseases. Significantly lower levels were found in boys than in healthy adult subjects. No variations in level were evident over the course of a 24 h period. At a cut-off level of 20 micrograms/l elevated concentrations were found in 42%, 11.4% and 19% of women with ovarian, endometrial and cervical neoplasia, respectively. In patients with ovarian tumors TATI level were elevated both in mucinous and serous tumors. TATI does not seem to be useful for diagnosis of uterine tumors, but could have a specific place in the study and management of ovarian tumors, in which serum concentrations can reach levels 100-200 micrograms/l. In the other gynecological diseases maximum levels of 30-40 micrograms/l were observed.

Gonadotropin, prolactin and thyrotropin pituitary secretion after exogenous dehydroepiandrosterone-sulfate administration in normal women.

The effect of exogenous dehydroepiandrosterone-sulfate (DHAS) on luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL) and thyroid-stimulating hormone (TSH) pituitary secretion was studied in 8 normal women during the early follicular phase. The plasma levels of these hormones were evaluated after gonadotropin-releasing hormone (GnRH)/thyrotropin-releasing hormone (TRH) stimulation performed after placebo or after 30 mg DHAS i.v. administration. The half-life of DHAS was also calculated on two subjects; two main components of decay were detected with half-times of 0.73-1.08 and 23.1-28.8 h. The results show an adequate response of all hormones to GnRH or TRH tests which was not significantly modified, in the case of LH, FSH and PRL, when performed in the presence of high levels of DHAS. However, the TSH response to TRH was significantly less suppressed (p less than 0.05) (39%) after DHAS administration than during repeated TRH stimulation without DHAS (51%). The data support the hypothesis that DHAS does not affect LH, FSH and PRL secretion, while TSH seemed to be partially influenced.

[Implementation of a computerized pharmacological database for pediatric use]. / Realizzazione di un archivio farmacologico computerizzato ad uso pediatrico.

The authors present a pharmacological database to support teaching and care activity carried out in the Divisional Paediatric Ambulatory of the Catholic University of Rome. This database is included in a integrated system, ARPIA (Ambulatory and Research in Pediatric by Information Assistance), devoted to manage ambulatory paediatric data. ARPIA has been implemented by using a relational DBMS, very cheap and highly diffused on personal computers. The database specifies: active ingredient and code number related to it, clinical uses, doses, contra-indications and precautions, adverse effects, besides the possible wrapping available on the market. All this is showed on a single for that appears on the screen and allows a fast reading of the most important elements characterizing every drug. The search of the included drugs can be made on the basis of three different detailed lists: active ingredient, proprietary preparation and clinical use. It is, besides, possible to have a complete report about the drugs requested by the user. This system allows the user, without modifying the program, to interact with the included data modifying each element of the form. In the system there is also a fast consultation handbook containing for every active ingredient, the complete list of italian proprietary medicines. This system aims to give a better knowledge of the most commonly used drugs, not only limited to the paediatrician but also to the ambulatory health staff; an improvement of the therapy furthering, a more effective use of several pharmacological agents and first of all a training device not only to specialists but also to students.

Combination of flavone acetic acid (FAA) with adriamycin, cis-platinum and difluoromethylornithine (DFMO) in vitro against human colon cancer cells.

Unresectable solid tumors in the metastatic stage are quite resistant to current chemotherapy and radiation therapy regimens. Flavone acetic acid (FAA) is a novel antitumor agent which appears to work through a different mechanism than the conventional chemotherapeutic agents. In preclinical studies it has shown effectiveness against a variety of transplantable murine and human tumors and appears to be solid tumor selective. It also has non-overlapping toxicities as compared to conventional agents. We therefore investigated FAA in vitro against human colon cancer cells and explored whether its effectiveness could be enhanced in combination with other agents such as adriamycin (ADR), cis-platinum (CP) and difluoromethylornithine (DFMO)--an inhibitor of polyamine biosynthesis. Addition of FAA for 24 hours in liquid media produced dose dependent growth inhibition. Using soft agar colony assay, growth was inhibited by 58% by 3mM FAA and only 1.4% by 0.375mM FAA. The combination of FAA and cis-platinum produced synergism at the lower doses tested. The combination of FAA and adriamycin produced antagonism at all doses tested and the combination of FAA with DFMO did not produce results significantly different from DFMO alone. We conclude that enhancement of FAA activity can be achieved in combination with conventional antitumor agents, but may be drug and dose specific.