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Unrepairable comminuted fractures of the radial head Mason type III or type IV have poor outcomes when treated by open reduction and internal fixation. Radial head resection has been proposed as good option for surgical treatment, while in the last decades, the development of technology and design in radial head prosthesis has increased efficacy in prosthetic replacement. The present review was conducted to determine the best surgical treatment for comminuted radial head when ORIF is not possible. Better outcomes are reported for radial head arthroplasty in terms of elbow stability, range of motion, pain, and fewer complications compared to radial head excision. Nevertheless, radial head resection still can be considered an option of treatment in isolated radial head fractures with no associated ligament injuries lesion of ligaments or in case of older patients with low demanding function.

The authors describe a case-oriented seminar on managed care designed to teach psychiatric residents and medical students the principles of cost containment and delivery of quality care. The participants engage in role-play (reviewer, provider, appeal arbitrator) to elucidate the process. The response of the participants indicates that this seminar is a useful teaching model. Salient points regarding the content and process of the seminar are discussed in some detail.

In this paper, we review the published evidence about the long-term efficacy of the available human papillomavirus (HPV) vaccines and their safety profile. Two prophylactic HPV vaccines – bivalent (bHPV) and quadrivalent (qHPV) – are now available, and vaccination programs are being widely implemented, primarily targeting adolescent girls. Efficacy has been widely demonstrated for both vaccines. Since the risk of HPV exposure potentially persists throughout a woman’s sexual life, vaccine duration of protection is critical to overall effectiveness. Interpreting the results of long-term efficacy studies for the two HPV vaccines can be puzzling, due to the heterogeneity of studies, different methods used in the assessment of immunogenicity, histopathological and virological end points, and statistical power issues. Moreover, an immunologic correlate of protection has not yet been established, and it is unknown whether higher antibody levels will really result in a longer duration of protection. Disease prevention remains the most important measure of long-term duration of vaccine efficacy. To date, the longest follow-up of an HPV vaccine has been 9.4 years for the bHPV vaccine. Long-term follow-up for qHPV vaccine goes up to 8 years. The vaccine continues to be immunogenic and well tolerated up to 9 years following vaccination. All randomized controlled clinical trials of the bHPV and the qHPV vaccines provide evidence of an excellent safety profile. The most common complaint reported is pain in the injection site, which is self-limiting and spontaneously resolved. The incidence of systemic adverse events (AEs), serious AEs, and discontinuations due to a serious AE reported in clinical studies are similar between the two vaccines and their control groups. In particular, no increased risk of autoimmune disease has been shown among HPV-vaccinated subjects in long-term observation studies. As these are crucial topics in HPV vaccination, it is important to establish systems for continued monitoring of vaccine immunogenicity, efficacy, and safety over time.

Gamma-hydroxybutyric acid is an allegedly benign illicit substance that is gaining increasing recognition and attention among substance abusers and athletes. Alongside foreign-made brands, the compound is also easily available, at low cost because of the facility with which it can be produced in one's kitchen. Named by some “Nature's Quaalude” or sold as a health product, it is often used with a false sense of security as it may cause serious and disabling complications, as illustrated by this clinical vignette.

Objective : The authors describe demographic data, the distribution of diagnoses, and comorbid psychoactive substance use in a large sample of patients involuntarily admitted to a psychiatric hospital from multiple crisis centers and explore the relative roles these variables may play in service utilization and admission rates. Method : Data on demographic characteristics and comorbid psychoactive substance use in 2,200 consecutive involuntary hospital admissions of 1,755 psychiatric patients were gathered. Pertinent demographic and comorbidity data at first admission for the 1,755 patients, 314 of whom were admitted more than once, were analyzed ; then the data for the 1,441 single-admission patients and the data at first admission for the 314 patients who had multiple admissions were compared. Finally, the diagnostic distribution and comorbid psychoactive substance use in all 2,200 admissions were investigated, with attention to a subgroup of 88 high-risk patients (those with three or more admissions) who represented a total of 307 admissions. Results : Specific demographic characteristics were represented in the patient group at a high level of statistical significance. The diagnosis of schizophrenia was significantly overrepresented. Schizophrenia and psychosis not elsewhere classified clustered in the subgroup with a high risk of readmission. Conclusions: The results suggest a specific profile for the patient with heightened risk of hospital admission : a young, unmarried, African American male who has schizophrenia without comorbid substance abuse. An effect size data analysis identified marital status and a diagnosis of schizophrenia as the variables associated with the greatest likelihood of admission. Unexpectedly, the impact of comorbid psychoactive substance use was relatively modest and showed a uniform distribution among diagnostic groups.

The authors describe a sample of 815 acutely ill schizophrenia patients hospitalized under a petition for involuntary inpatient treatment and illustrate how this group of patients can be considered as more representative of involuntary commitment status than more traditional "involuntary" patients drawn from State hospitals' wards. Available demographics of the general population from which the sample was drawn are also presented for comparison. The authors then report the gender distribution of several variables--age, marital status, psychoactive substance use, comorbidity, length of stay, and frequency of readmissions--among the study sample and discuss the relevance of these findings.

We examined the levels of activity of methyl-p-hydroxyphenyl-lactate esterase (MeHPLA-ase) and cytosolic Type-II-estrogen-binding sites (Type-II EBS) in 61 and 71 cases, respectively, of primary ovarian cancer. MeHPLA-ase activity and Type-II EBS were seen to by asymmetrically distributed, in that levels were skewed towards the lower values. A statistically significant direct correlation was found between MeHPLA-ase activity and Type-II EBS. MeHPLA-ase activity and Type-II EBS were inversely correlated with ER and PR levels and showed a trend towards inverse correlation with the percentage of cells in S-phase of the cell cycle. MeHPLA-ase activity and Type-II EBS did not correlate with clinico-pathological parameters. The median MeHPLA-ase activity tended to be higher in responders than in unresponsive patients, but statistical significance was not reached. Higher Type-II-EBS levels were found in cases showing complete and partial response to chemotherapy than in cases which did not respond. A statistically significant relationship was found between high MeHPLA-ase activity and longer overall survival. © 1995 Wiley-Liss, Inc.

The bisdioxopiperazine ICRF 187 is a potent intracellular chelating agent which effectively diminishes Adriamycin cardiotoxicity without compromising its antitumor activity. Our study aimed at verifying whether ICRF 187 can modulate the cytotoxic action of cisplatin (CDDP) on ovarian cancer cells. We used the A2780 ovarian cancer cell line and a subline resistant to CDDP (A2780-CDDP) obtained in our laboratory by continuous exposure of the parenatal cells to progressively increasing CDDP doses. In both cell lines ICRF 187 (0.1-0.5 microgram/ml) used in combination with CDDP (0.01-1 microgram/ml) produced a dose-dependent reduction of CDDP IC50 (the concentration inhibiting 50% of cell growth). Moreover, when ICRF 187 was used in combination with CDDP, analysis of the data by the isobole method showed that the combination of the two drugs produced a synergistic antiproliferative activity in both cell lines, with a CDDP potentiation up to fivefold. Our in vitro data show that ICRF 187 can synergize with CDDP. Prospective clinical trials are now needed to verify whether the addition of ICRF 187 to CDDP-containing regimens will result in an improved clinical response in ovarian cancer.

Frequency and results of urine toxicology screens in a state-guided system of emergency rooms in a large city were compared with frequency and results of the same tests in the same population at a university-run intensive treatment psychiatric unit. Differences both in prevalence and in results were noted, with the emergency rooms testing significantly less patients than the intensive treatment unit and documenting a significantly lower rate of active substance abuse comorbidity to psychiatric disorders. Possible explanations for these differences are discussed, including clinical, attitudinal, and cost containment factors. These findings have a definite impact on treatment decision making, diagnostic precision, and validity of epidemiologic reports.

It has been demonstrated that the flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone; Q) inhibits the growth of several cancer cell lines. There is evidence suggesting that the antiproliferative activity of this substance is mediated by the so-called type II estrogen-binding site (type II EBS). We looked for the presence of type II EBS and the effect of Q on the proliferation of an Adriamycin-resistant estrogen-receptor-negative human breast-cancer cell line (MCF-7 ADRr). By whole-cell assay using estradiol labelled with 6,7-tritium [( 3H]-E2) as a tracer, we demonstrated that MCF-7 ADRr cells contain type II EBSs. Competition analysis revealed that diethylstilbestrol (DES) and Q competed with similar potency for [3H]-Es binding to type II EBSs. The antiestrogen tamoxifen (TAM) competed for type II EBSs, albeit to a lesser extent than either DES or Q. Growth experiments demonstrated that Q and DES exerted a dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 microM, whereas TAM was less effective. Q could also inhibit colony formation in a clonogenic assay. Our results indicate that multidrug-resistant estrogen-receptor-negative MCF-7 cells express type II EBSs and are sensitive to the inhibitory effect of Q. This substance could be the parent compound of a novel class of anticancer agents.

Several programs that have had varying success in providing rapid intervention in the treatment of acutely mentally ill patients have been dcscribed in the last decade (1-3). Such programs often constitute a muchneeded bridge to ongoing psychiatric treatment and services in the public sector for chronic mentally ill patients. This paper describes a short-term intensive psychiatric treatment unit at a general hospital in Philadelphia and provides data on the number of admissions and their disposition in the first 35 months ofthc program’s operation. The unit was a joint effort of the city’s Office ofMental Health and the department of psychiatry at Jefferson Medical College.

Radioreceptorial assessment of EGFR expression was prospectively performed on 60 primary human endometrial tumors. Of these, 26 were EGFR-positive while 13 expressed high EGFR levels. High EGFR levels correlated well with poor histopathological grading. No correlation with histopathological type, stage, myometrial invasion, lymph-node involvement or steroid hormone receptor status was observed. Disease-free survival rate was significantly shorter in the cases with high than in the cases with low EGFR levels. These results suggest a potential role of EGFR expression assessment in prognostic characterization of endometrial cancer patients.

The study investigated whether chronic mentally ill patients whose psychiatric relapse was complicated by active substance abuse recovered from relapse at a different rate than similar patients with no comorbid substance abuse.A total of 401 patients involuntarily hospitalized on a short-term psychiatric treatment unit received a urine toxicology screen on admission; the severity of their psychiatric symptoms was rated on the fifth day of hospitalization using the Brief Psychiatric Rating Scale (BPRS). Differences in scores between patients who had positive screens and those who had negative screens were evaluated for various diagnostic groups.Patients who had a positive screen and a primary discharge diagnosis of psychoactive substance abuse had a BPRS total score indicating less psychopathology than similarly diagnosed patients with negative screens. Patients who had positive screens and a diagnosis of personality disorder had some BPRS subscale scores indicating greater psychopathology than their counterparts with negative screens. No other significant differences in recovery rates between the two groups were found, although comparisons indicated trends toward faster recovery in some areas of functioning by schizophrenic patients with positive screens and affective disorder patients with negative screens.Results suggest that use of a urine toxicology screen and the BPRS early in treatment may aid in assessing the acute course of several psychiatric disorders and the effect of comorbidity.

A total of 247 chronic mentally ill patients committed for emergency involuntary hospitalization in a public intensive treatment unit were grouped on the basis of positive or negative urine toxicology screens for psychoactive substances at admission. Patients whose screens were positive for substance abuse were more likely to live alone or to be homeless, to be committed for making threats, and to have a diagnosis of organic mental disorder or substance abuse disorder. Patients who screened negative were more likely to live in a supervised setting, to be committed for actions such as assaults and suicidal behavior, and to have a diagnosis of schizophrenia or other psychotic disorder.

Objective: The authors examined the (under) utilization of the psychiatric consultation service for patients aged sixty to seventy-five who were hospitalized for medical reasons, and explored whether one could retrospectively document and identify a greater need for psychological support than the one reflected in the number of actual consultations requested. Three questions were addressed: 1) the psychiatric consultation rate; 2) the frequency of unrecognized medical, psychiatric, and psychosocial complicating factors; and 3) whether the distribution of these factors differed by gender. Method: Records of 203 consecutively-admitted elderly patients hospitalized on medical wards were reviewed by two experienced general hospital psychiatrists for any indication of medical, psychiatric, and psychosocial risk factors. The frequency of actual psychiatric consultations was also recorded. Results: Three or more risk factors were noted in the records of 36 percent of all patients. Consultation was sought for only 3 percent. Gender differences in type and distribution of risk factors were identified. Conclusions: Indicators and profiles that define probable need for psychiatric consultation were identified and briefly discussed. More well-designed, prospective studies testing these indicators and profiles are needed.

Intracerebroventricular injections of gamma-aminobutyric acid (GABA) and of the GABA-transaminase inhibitor, ethanolamine-O-sulphate (EOS), decreased the food intake of freely-fed (GABA and EOS) and food-deprived rats (EOS). The effect, still evident 24 h after treatment, was not decreased by the GABA receptor-blocker bicuculline. In contrast, intracerebroventricular injections of the GABA receptor-agonist, muscimol, caused an increase in food intake of freely-fed rats that was antagonized by bicuculline. The eating of animals receiving only bicuculline was stimulated in free-feeding and depressed in food-deprived conditions. These opposite results suggest that muscimol binds preferentially to some GABA receptors, probably those within the satiety-controlling areas (i.e. ventromedial hypothalamus), and that bicuculline influences mainly those postsynaptic neurons where GABAergic inputs prevail. These observations and the data from EOS- and GABA-treated rats provide evidence for involvement of GABA neurons in the regulation of feeding behaviour. The balance of the different effects produced in each of these areas by this modulation appears to be a decrease in feeding behaviour.

The distribution of calcitonin (CT) binding sites in serial sections of the rat brain and spinal cord has been examined by an ‘in vitro’ autoradiographic technique using a radioisotope-sensitive sheet film and [125I]salmon CT. Autoradiograms of the diencephalic region had the highest grain density throughout the entire hypothalamus, with the exception of the nuclei ventromedialis, posterior and mammillaris, which were not labeled at all. In the brainstem, large amounts of grains were found in the ventrolateral division of the periaqueductal gray, in the locus coeruleus, in the nucleus tractus spinalis nervi trigemini and in the raphe obscurus, pallidus and magnus, while a widespread and lower grain density was observed in the reticular formation. In the spinal cord the labeling was discretely localized in laminae IV, V and VI of the dorsal horn. The observed distribution of CT binding sites is closely related to the neuroendocrine and analgesic effects of exogenous CT and reinforces the concept of a possible neuromodulatory role proposed for the peptide at brain level.

alpha 1- and beta-adrenoceptors were studied ex vivo in the brains of rats receiving repeated daily treatment with the standard antidepressant imipramine or the atypical antidepressant S-adenosyl-L-methionine (SAM), which has minimal effects on monoamine reuptake or turnover. Consistent with past studies, a decrease in the density of beta receptors at three weeks and an increase in the affinity of alpha 1 receptors for the agonist phenylephrine at one week of treatment was observed with imipramine. By comparison, an increase in the density of beta receptors and a decrease in the affinity of alpha 1 receptors for phenylephrine was observed at one week of treatment with SAM. These changes were no longer apparent at three weeks of treatment. The results suggest that treatment with SAM does lead to changes in adrenergic neurotransmission, but that down regulation of beta receptors or increased agonist affinity of alpha 1 receptors may not be necessary for the production of antidepressant effects.

The growth hormone (GH)-releasing effect of thyrotropin-releasing hormone (TRH) was investigated in rats in which central nervous system (CNS)-anterior pituitary (AP) connections had been experimentally interrupted. Sprague-Dawley (SD) female and male rats, underwent bilateral electrolytic lesions in the median eminence (ME) or the ventromedial nuclei (VMN) or were sham-operated (sham-op). Fifteen days after surgery, 0.9% NAACl or TRH was injected iv into sham-op rats or those with lesions in the CNS, anesthetized with urethane, and blood was drawn at 5 and 10 min posttreatment. In the rats with ME lesions, TRH at all the doses used (0.1, 0.4 and 0.8 microng/100 g BW) induced a marked, although not dose-related GH rise, which was not present in sham-op rats after TRH, or after NaCl administration to either rats with ME lesions or sham-op rats. In SD male rats lesioned in the VMN, TRH at doses of 0.4 and 0.8 microng/100 g BW induced significant GH rises, while the lowest TRH dose (0.1 microng/100 g BW) was ineffective; again, TRH was ineffective at all doses used in sham-op rats. Concomitant evaluation of the prolactin (PRL)-releasing effect of TRH (0.1-0.8 microng/100 g BW), showed a striking elevation of plasma PRL in both female and male sham-op controls, but no PRL rise in the rats with ME lesions. The results reveal that in the rat with surgical separation of the anterior pituitary from the CNS, a direct GH-releasing effect of TRH can be obtained, whereas its PRL-releasing effect is no longer observed, and suggest that, by analogy, the GH-releasing effect of TRH present in some disease states of the human may be due to an impairment of CNS-AP connections.

After degeneration of serotoninergic neurons induced by either transection of the ascending neuronal pathways originating from the nucleus raphe dorsalis or intraventricular 5,6-dihydroxytryptamine administration, the number of binding sites for [3H] d -Ala2, Met5-enkephalinamide was significantly reduced. This decrease in binding sites does not seem to be related to the opiate receptors present on dopaminergic terminals, nor is it due to a simple decrease in serotoninergic neuronal tone, since after p-chlorophenylalanine (100 mg/kg × 4 days) the number of striatal binding sites for the opiate ligand was not diminished. On the other hand, shortly after mechanical interruption of the raphe-striatal serotoninergic fibers, at a time when the metabolic processes are still functioning in the lesioned neurons, morphine still increased the striatal content of 5-hydroxyindoleacetic acid. These results suggest the presence of opiate receptors on striatal serotoninergic terminals, where they may modulate the presynaptic activity of these neurons.

The administration of salmon Calcitonin (sCT) intravenously (2.5 or 10 μg/kg) or into the lateral cerebral ventricles (2.5 or 25 ng/rat, i.c.v.) of unanaestized male rats induced clearcut decreases in plasma prolactin(PRL) levels. The i.c.v. injection of one of these doses of sCT (25 ng/rat) into rats with median eminence lesions was completely ineffective, while it induced a dramatic decrease in plasma PRL levels of sham-operated rats. Morphine- and heat stress-stimulated PRL levels were also abolished by sCT injection (250 ng/rat i.c.v.). The sCT-induced decrease in PRL levels was completely overcome by haloperidol, a dopamine-receptor blocker. We conclude that sCT may affect PRL secretion via an hypothalamic system, probably involving dopaminergic neurons. The present results indicate that CT, like many others peptides, may affect PRL secretion, directly or indirectly, even though further research is necessary to determine whether this effect has pharmacological or physiological importance.

Various compounds with different blocking potencies on histamine H2 -receptors were administered to rats both into the carotid (ia)and into the brain ventricles (icv) and their effects on PRL release were evaluated. The drugs were cimetidine, as reference compound, ranitidine, 5 to 7 times as potent, and oxmetidine, 8 to 10 times as potent. PRL was measured in blood samples collected at –15, 0 and +5, +10, +20 and +40min after treatment. Cimetidine (80mg/kg) and ranitidine (30mg /kg), when injected ia as a single bolus, induced prompt increases (P < 0.01) in PRL. On the contrary, oxmetidine (the most potent H2 antagonist), even at the high dose of 80 mg/kg ia,had no effect on PRL release. When the drugs were given icv (0.2 iμmol/rat or 0.8 μmol/rat), none of them caused any significant PRL release. These results suggest that tiistamine H2 -blocking potency is not correlated with PRL release. Furthermore, the PRL-releasing activity of the drugs seems not to be dueto anyaction on the central neural control ...

Summary Glucoprivation effects on blood glucose (BG) and insulin (I) secretion have been investigated in rats bearing electrolytic lesions in the hypothalamic glucoreceptor areas. Systemic administration of 2-deoxy-D-glucose (2-DG) to rats bilaterally lesioned 24–48 hr before in the ventromedial (VMH) or/and ventrolateral (LHA) hypothalamus induced a BG rise and inhibition of rise in plasma I levels not dissimilar from those elicited in sham-operated rats. The threshold dose for 2-DG effects (60 mg/kg) was the same for VMH-LHA lesioned rats and sham-operated controls. These results suggest the existence of peripheral glucoreceptors for the hyperglycemic and insulin inhibiting effects of 2-DG but do not exclude the presence in the brain of other glucosensitive areas besides the VMH and LHA.

Calcitonin (CT) injected into the brain ventricles (ICV) of conscious rabbits induced an analgesia not reversable by naloxone which could be repeatedly elicited (for 5 days), while tolerance to morphine developed. CT and morphine synergized in vivo when administered ICV in combination. CT did not alter electrically-induced contractions of guinea-pig myenteric plexus-longitudinal muscle and no displace of 3 H-dihydromorphine by CT was observed in brain opiate receptor preparations. We have concluded that the mechanism of centrally induced CT analgesia may be opiate-independent.

The effects of intracerebroventricular (icv;25ng/rat) or iv (10 micrograms/kg) salmon calcitonin (sCT) on PRL secretion were determined in lactating rats and compared to the effects in intact or ovariectomized-estrogen-treated female rats. The icv or iv injections of sCT 9 days after estrogen treatment did not significantly lower the PRL levels in intact rats. In ovariectomized-estrogen-primed animals, sCT (icv or iv) did not modify the afternoon surge of PRL secretion when injected during the surge, nor did it delay or attenuate the increasing secretory activity when administered (iv) before the afternoon surge had begun. On the contrary, 30 or 60 min after the icv or iv administration of sCT to lactating rats, suckling-induced PRL secretion was prevented. These results and our previous evidence that a greater dose of sCT is needed to decrease the less intense morphine- or stress-induced PRL secretion indicate differential hypoprolactinemic properties of sCT, which are particularly striking during lactation. While the mechanisms underlying these selective activities deserve further investigation, the proposed participation of PRL in the regulation of calcium metabolism during lactation suggests that the potent PRL inhibitory effect of CT in this condition should be regarded as one factor in the complex mechanism that prevents bone loss and protects the maternal skeleton.

The biochemical effects of 6-methyltetrahydropterin (6-MPH4), a synthetic analogue of tetrahydrobiopterin (BH4), the hydroxylase cofactor, were investigated on striatal dopaminergic neurons in the rat. Although a single parenteral dose of 6-MPH4 (18 or 54 mg/kg) did not significantly increase the content of dopamine (DA) or its acidic metabolites, L-didrohyphenylanine (L-DOPA) accumulation after decarboxylase inhibition was evident in rats receiving 54 mg/kg of 6-MPH4. On the other hand, 6-MPH4 (18 mg/kg) potentiated the reserpine-induced DA metabolism as demonstrated by increased HVA levels. In a behavioural test, 6-MPH4 partially prevented haloperidol-induced catalepsy. BH4 concentrations could thus be subsaturating with respect to tyrosine hydroxylase (TH), particularly when the enzyme activity is stimulated and the results suggest that cofactor supply may have pharmacological significance.

Summary End-to-side portacaval shunts were prepared in mature male rats and their uricemia was measured 7,14,21 and 30 days after the surgery. Due to hepatic uricase exclusion, a sustained increase in serum uric acid over preoperative levels was found between 7 and 21 days after operation. After that, uric acid levels slowly declined, probably as a consequence of the formation of adhesions between the portal circulation and the liver. The hyperuricemic portacaval-shunted rat is a suitable animal model for assaying exogenously administered uricase, and may help also in research studies in the area of hyperuricemic syndromes.

It has been repeatedly reported that calcitonin treatment in various diseases with high levels of bone resorption is associated with an antalgic effect, the mechanism of which is far from been clarified. The involvment of prostaglandins and thromboxane in hyperalgesia prompted us to consider the possibility that calcitonin induces its antalgic effect through on interference with prostaglandin and thromboxane synthesis. Guinea pig lung which, perfused with arachidonic acid releases in the perfusate a mixture of thromboxane and prostaglandins, each measurable on a separate smooth muscle tissue (rabbit aorta and rat stomach strip), was used as a test system. Calcitonin added to the perfusion fluid was shown to inhibit the synthesis both of prostaglandins and thromboxane. The concentration of calcitonin (salmon) which decreased the activity of arachidonic acid by 50% (KB) was 0.27 and 0.40 nmoles for prostaglandins and thromboxane respectively. In the experiments carried out using Ca ++ concentration in the perfusion fluid 50% higher than normal (0.28 g/l), calcitonin inhibition of prostaglandins and thromboxane was unchanged (KB = 0.23 and 0.36 nmoles respectively). The reported results by indicating that calcitonin has an influence on cyclooxygenase as indomethacin (used as reference standard) whose it is well known the activity at this level, support the interesting possibility that the antalgic effect consequent to the treatment with the hormone is due, at least in part, to a mechanism involving the prostaglandin synthetase system.

Objective: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia. Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes. Results: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test). Conclusions: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.

Background: Primary prevention through vaccination is a prophylactic approach aiming to reduce the risk of developing human papillomavirus (HPV)-related lesions. No mature and long-term data supported the adoption of vaccination in women undergoing conization. Methods: This is a retrospective multi-institutional study. Charts of consecutive patients undergoing conization between 2010 and 2014 were collected. All patients included had at least 5 years of follow-up. We compared outcomes of patients undergoing conization plus vaccination and conization alone. A propensity-score matching algorithm was applied in order to reduce allocation biases. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, charts of 1914 women were analyzed. The study group included 116 (6.1%) and 1798 (93.9%) women undergoing conization plus vaccination and conization alone, respectively. Five-year recurrence rate was 1.7% (n = 2) and 5.7% (n = 102) after conization plus vaccination and conization alone, respectively (p = 0.068). After the application of a propensity-score matching, we selected 100 patients undergoing conization plus vaccination and 200 patients undergoing conization alone. The crude number of recurrences was 2 (2%) and 11 (5.5%) for patients undergoing conization plus vaccination and conization alone, respectively (p = 0.231). Vaccination had no impact on persistent lesions (no negative examination between conization and new cervical dysplasia, p = 0.603), but reduced the risk of recurrent disease (patients who had at least one negative examination between conization and the diagnosis of recurrent cervical dysplasia, p = 0.031). Conclusions: Patients having vaccination experience a slightly lower risk of recurrence than women who had not, although not statistically significantly different. Further evidence is needed to assess the cost effectiveness of adopting vaccination in this setting.

Objective: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+). Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models. Results: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001). Conclusions: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child–Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800–1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50×103/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11–3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16–3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

The aim of this study was to investigate the prevalence of peritoneal human papillomavirus (HPV) infection in different clinical cervical cancer (CC) settings, and its association with potential clinical and/or histological factors. This is a single-center, prospective, observational study. Consecutive patients with newly diagnosed or recurrent/persistent CC, between March 2019 and April 2020, were included. A group of patients undergoing surgery for benign gynecological conditions was included as control group. All patients underwent HPV-DNA test in the cervix and in the peritoneal cavity simultaneously at time of surgery. Two-hundred seventy-two patients had cervical and peritoneal HPV test analyzed. Cervical and peritoneal HPV positivity (PHP) was found in 235 (88.0%) and 78 (28.7%) patients, respectively; the prevalence of PHP was 17.7% in early stage, 28.8% in locally advanced cervical cancer (LACC) and 46.6% in the metastatic/persistent/recurrent setting (P = .001). No control patient was found to have peritoneal HPV infection. Higher frequency of PHP was documented in patients with larger tumor size (P = .003), presence of cervical HPV 16/18 genotypes (P

Purpose: The purpose of this study was to assess the prognostic role and the perioperative outcomes of conization performed before radical hysterectomy in early-stage cervical carcinoma. Methods: This multicenter, retrospective observational cohort study included patients with FIGO 2009stage IB1 cervical carcinoma treated with radical hysterectomy between June 2004 and June 2019. Patients were divided into two groups according to conization before radical surgery. One-to-one case–control matching was used to adjust the baseline characteristics. Results: A total of 332 patients were included after propensity matching (166, 50% in each group). Twenty-four of 166 (14.4%) and 142 of 166 (85.6%) conization patients had negative and positive surgical margins on the conization specimen, respectively. No difference in intra- and postoperative complications was noted between the two groups (p=0.542 and p=0.180, respectively). Patients undergoing conization before radical hysterectomy received less adjuvant treatment (p20 mm and no conization before radical hysterectomy (p=0.011 and p=0.018, respectively). The only independent variable influencing OS was pathologic tumor diameter >20 mm (p=0.020). Conclusions: Conization before radical hysterectomy was associated with improved DFS and lower probability of receiving adjuvant treatment. No difference in perioperative complications and OS was evident. Tumor diameter >20 mm was found to be the only independent risk factor affecting OS in both groups.

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Background: The NGR-hTNF (asparagine–glycine–arginine–human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. Methods: Patients progressing after ⩾1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m−2 and doxorubicin 60 mg m−2 every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. Results: A total of 37 patients with platinum-free interval lower than 6 months (PFI

Background A prospective phase II study was conducted to evaluate the efficacy and toxicity of the combination docetaxel (Taxotere) (DTX) and oxaliplatin (OXA) in ovarian cancer patients recurring after a platinum-free interval (PFI) >12 months. Patients and methods DTX, 75 mg/m2, was administered by 60 min i.v. infusion, followed by OXA, 100 mg/m2, given by a 2 h i.v., on day 1 every 21 days. Results From October 2003 to June 2006, 43 ovarian cancer patients were enrolled. Median PFI was 26 months. All patients were available for response evaluation: 17 complete responses and 12 partial responses were registered, for an overall response rate of 67.4%. The median response duration was 10 months. Stable disease was documented in 11 patients (median duration = 5.5 months). The median time to progression and overall survival were 14 and 28 months. A total of 259 courses were administered. Grade 3–4 leukopenia was documented in 32.5% of the patients, while no case of severe anemia and thrombocytopenia was observed. Grade 3–4 neurotoxicity and grade 2 alopecia were observed in 9.3% and 34.9% of cases, respectively. Conclusion DTX/OXA combination is an active regimen with a favorable toxicity profile, for treatment of recurrent platinum-sensitive ovarian cancer patients.