Real-life use of ropeg-interferon α2b in polycythemia vera: patient selection and clinical outcomes.

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy.

Binding of an antimicrobial peptide to bacterial cells: Interaction with different species, strains and cellular components.

Antimicrobial peptides (AMPs) selectively kill bacteria by disrupting their cell membranes, and are promising compounds to fight drug-resistant microbes. Biophysical studies on model membranes have characterized AMP/membrane interactions and the mechanism of bilayer perturbation, showing that accumulation of cationic peptide molecules in the external leaflet leads to the formation of pores ("carpet" mechanism). However, similar quantitative studies on real cells are extremely limited. Here, we investigated the interaction of the dansylated PMAP23 peptide (DNS-PMAP23) with a Gram-positive bacterium, showing that 107 bound peptide molecules per cell are needed to kill it. This result is consistent with our previous finding for Gram-negative strains, where a similar high threshold for killing was determined, demonstrating the general relevance of the carpet model for real bacteria. However, in the case of the Gram-positive strain, this number of molecules even exceeds the total surface available on the bacterial membrane. The high affinity of DNS-PMAP23 for the anionic teichoic acids of the Gram-positive cell wall, but not for the lipopolysaccharides of Gram-negative bacteria, provides a rationale for this finding. To better define the role of anionic lipids in peptide/cell association, we studied DNS-PMAP23 interaction with E. coli mutant strains lacking phosphatidylglycerol and/or cardiolipin. Surprisingly, these strains showed a peptide affinity similar to that of the wild type. This finding was rationalized by observing that these bacteria have an increased content of other anionic lipids, thus maintaining the total membrane charge essentially constant. Finally, studies of DNS-PMAP23 association to dead bacteria showed an affinity an order of magnitude higher compared to that of live cells, suggesting strong peptide binding to intracellular components that become accessible after membrane perturbation. This effect could play a role in population resistance to AMP action, since dead bacteria could protect the surviving cells by sequestering significant amounts of peptide molecules. Overall, our data indicate that quantitative studies of peptide association to bacteria can lead to a better understanding of the mechanism of action of AMPs.

The impact of comorbidity and PSA doubling time on the risk of death in men experiencing PSA failure following radiation therapy with or with androgen deprivation therapy for unfavorable-risk prostate cancer.

BACKGROUND: The optimal management of men with PSA failure following initial prostate cancer (PC) therapy stratified by comorbidity is unknown. We investigated the impact that PSA doubling time (DT) and comorbidity had on the risk of all-cause mortality (ACM), prostate cancer-specific mortality (PCSM) and other-cause mortality (OCM) following PSA failure. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were randomized to receive radiation therapy alone or in combination with 6 months of androgen deprivation therapy (ADT); 108 men experienced PSA failure and formed the study cohort. Cox and Fine-Gray regression analysis was used to determine whether PSA DT was associated with the risk of ACM and PCSM/OCM, respectively, stratified by comorbidity status using a validated metric. RESULTS: After a median follow-up of 13.71 years following PSA failure, 81 of the 108 men (75%) died. Longer PSA DT was associated with a decreased risk of PCSM in men with no/minimal (adjusted hazard ratio (AHR) 0.33, 95% confidence interval (CI) 0.17-0.65, P=0.001) and moderate/severe comorbidity (AHR 0.014, 95% CI 0.002-0.129, P=0.0002). However, because of the different contributions of the risk of OCM to risk of ACM within comorbidity subgroups, increasing PSA DT was only associated with a decreased risk of ACM in men with no/minimal (AHR 0.69, 95% CI 0.50-0.96, P=0.03) but not moderate/severe comorbidity (AHR 0.95, 95% CI 0.51-1.78, P=0.87). CONCLUSIONS: Both the extent of comorbidity and the PSA DT should be taken into consideration when deciding on appropriate management and/or clinical trial eligibility at the time of PSA failure.

Duration of the anti-androgen in men undergoing 6 months of an LHRH agonist and radiation therapy for unfavorable-risk prostate cancer and the risk of death.

BACKGROUND: Whether adding a first-generation anti-androgen (AA) to a luteinizing hormone-releasing hormone agonist in the radiotherapeutic management of unfavorable-risk prostate cancer (PC) reduces the risk of all-cause and PC-specific mortality (ACM and PCSM) among men within differing comorbidity subgroups is unknown. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were enrolled in a randomized trial comparing radiation with or without 6 months of androgen-deprivation therapy (ADT). Partial AA use (median: 4.2 months) occurred in 29 of the 102 men randomized to ADT. Cox, and Fine and Gray's regressions were used to evaluate the impact of full versus partial AA use on PCSM and ACM-risk within comorbidity subgroups. RESULTS: After a median follow-up of 16.62 years, 156 men died. In men with moderate to severe comorbidity increasing death was observed as treatment transitioned from no to partial to full ADT (P=0.02) with an increased ACM-risk with full versus partial AA use (adjusted hazard ratio (AHR), 2.25 (95% confidence interval (CI), 0.94-5.41); P=0.07); whereas only 1 and no PC deaths occurred in men receiving a partial versus full AA course, respectively. Among men with no or minimal comorbidity there was no decrease in ACM (AHR, 0.97 (95% CI, 0.49-1.91); P=0.92) or PCSM-risk (AHR 0.39 (95% CI 0.07-52.18); P=0.28) in comparing full versus partial AA use. CONCLUSION: Increasing AA use by 2 months does not appear to impact survival in men with localized unfavorable-risk PC and no or minimal comorbidity, but may shorten survival in men with moderate to severe comorbidity, raising concern regarding in whom and for how long the AA should be prescribed.

Coronary artery disease, cerebral non-fatal ischemic stroke in retinal vein occlusion: an 8-yr follow-up.

Forty-five consecutive subjects (26M, 19F; mean age 54 ± 14 yrs) with a diagnosed retinal vein occlusion (RVO), were followed-up for 8 yrs. As many as 145 sex-age- and blood pressure-matched individuals (78M, 67F; mean age 54.4 ± 13.5 yrs), that did not experience any vascular event, served as controls. At the time of the RVO, controls and subjects did not differ as to hypercholesterolemia, hypertrigliceridemia, diabetes mellitus, smoking habits, inherited/acquired thrombophilia. At the follow-up completion, they differed as to statin consumption (p = 0.016). During the 8-yrs follow-up, in the control population, 11 out of 145 (7.6%) subjects had experienced a major vascular event (8 coronary artery disease; 3 cerebral non-fatal ischemic stroke). In contrast, of the 45 subjects with a history of RVO, as many as 10 (22.2%) had experienced a major vascular event: 4 coronary artery disease; 4 cerebral non-fatal ischemic stroke; 2 cardiovascular + cerebrovascular event (p = 0.012). A prolonged antiplatelet treatment, prior to the major vascular event, was found in 5/45 cases (11.1%) vs 23/145 (15.9%) controls (p = 0.63). In contrast, a long-lasting administration of anti-hypertensive drugs, to achieve a control of blood pressure, was found in 83.4% of controls and only in 46.7% of cases (p < 0.0001). In conclusion, in a 8-yr follow-up, coronary artery disease and/or non-fatal ischemic stroke were more common in subjects with a history of RVO than in a large setting of subjects comparable for cardiovascular risk factors. These data also argue for RVO as a vascular disease in which aggressive anti-hypertensive therapy to prevent stroke and/or myocardial infarction is needed.

Optimal duration of SLIT.

A review of SLIT studies reveals that both cumulative dose and maintenance schedules have widely varied between the published clinical trials. Pre-co-seasonal treatment for pollen allergy seems to be better than coseasonal treatment. There is a number of studies evaluating different durations of SLIT, but the heterogeneity of the study design, allergen extracts and outcome measures make it difficult to produce a meta-analysis on SLIT efficacy according to duration. Overall,duration of both the build-up phase and the maintenance treatment does not seem to influence the effectiveness of SLIT. This suggests that the quality of the extract is more important in determining the clinical response to SLIT than duration of therapy. Further studies are warranted to establish optimal duration of SLIT treatment.

[Intolerance to food additives: an update]. / L'intolleranza ad additivi alimentari: un update.

Contrary to common believing, the prevalence of the intolerance to food additives in the general population is rather low. Nowadays many doubts persist with regard both to the pathogenetic mechanisms and to the clinical and diagnostic aspects in this field. Symptoms due to, or exacerbated from, food additives usually involve non-IgE-mediate mechanisms (pseudo-allergic reactions, PAR) and are usually less severe of those induced by food allergy. The most frequent clinical feature of the intolerance to food additives still remains the urticaria-angioedema syndrome, although these substances are really involved only in a minority of patients. Other possible clinical features include anaphylaxis, atopic eczema, behaviour disturbances, asthma and non-allergic rhinitis. The diagnostic approach consists in diary cards, reporting symptoms and food habits, elimination diet and double blinded placebo-controlled oral challenge with suspected additives. However, such procedure still remains poorly standardized and numerous uncertainties persist with regard to optimal conditions for performing and interpret the challenge results. The therapeutic approach consists in the exclusion of foods and products containing the additive involved, and, in patients not compliant to the diet, in treatment with symptomatic drugs.

Prevalence of atopic symptoms among blood donor carriers of mannose-binding lectin variant alleles.

Mannose-binding lectin (MBL) is a C-type soluble collectin involved in the innate immune response. Carriers of MBL gene variant alleles (MBLva) have decreased plasma concentrations of MBL and increased susceptibility to bacterial and viral infections. The aim of the present study is to test the hypothesis that carriers of MBLva could have a different frequency of atopic symptoms as compared to wild-type carriers. A total of 385 consecutively enrolled Caucasian blood donors were studied. Blood specimens underwent genomic analysis and genotyping for MBLva by polymerase chain reaction (PCR). MBLva carrier status was associated with a reduced frequency of allergic rhinitis (OR 0.41 [95% CI 0.2 to 0.8], chi2 = 6.98, p =.008). No relationship was found between MBLva carrier status and asthma or atopic skin symptoms. MBLva might be one of the host-related genetic factors involved in atopic disorders, namely allergic rhinitis.

Macrophage receptors implicated in the "adaptive" form of innate immunity.

The adaptive component of innate immunity occurs during the course of infection when antigen presenting cells alter expression of soluble or surface associated pattern recognition receptors. This results in increased recognition of a broad spectrum of pathogens, enhancement of effector functions and altered regulation of the inflammatory response.

Clinical non-instrumental evaluation of dysphagia.

Clinical non-instrumental evaluation plays an important role in the assessment of the dysphagic patient. This evaluation, called "bedside examination", aims to establish whether dysphagia is present, evaluating severity, determining the alterations which cause it, planning rehabilitation, testing outcome of treatment. The assessment takes into consideration anamnesis regarding the swallowing problem, evaluation of the anatomy and functionality, of sensitivity and the reflexes, of the swallowing apparatus. Finally, the oral feeding test is performed, which evaluates the oral and pharyngeal phases of swallowing. The examination performed in the neurologic patient is different from that performed in the patient submitted to ENT or maxillo-facial surgery.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer.

PURPOSE: To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS: The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION: A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

A practical method to achieve prostate gland immobilization and target verification for daily treatment.

PURPOSE: A practical method to achieve prostate immobilization and daily target localization for external beam radiation treatment is described. METHODS AND MATERIALS: Ten patients who underwent prostate brachytherapy using permanent radioactive source placement were selected for study. To quantify prostate motion both with and without the presence of a specially designed inflatable intrarectal balloon, the computerized tomography-based coordinates of all intraprostatic radioactive sources were compared over 3 consecutive measurements at 1-min intervals. RESULTS: The placement and inflation of the intrarectal balloon were well tolerated by all patients. The mean (range) displacement of the prostate gland when the intrarectal balloon was present vs. absent was 1.3 (0-2.2) mm vs. 1.8 (0-9.1) mm (p = 0.03) at 2 min respectively. The maximum displacement in any direction (anterior-posterior, superior-inferior, or right-left) when the intrarectal balloon was inflated vs. absent was reduced to < or =1 mm from 4 mm. CONCLUSIONS: Both prostate gland immobilization and target verification are possible using a specially designed inflatable intrarectal balloon. Using this device, the posterior margin necessary on the lateral fields to ensure dosimetric coverage of the entire prostate gland could be safely reduced to 5 mm and treatment could be set up and verified using a lateral portal image.

Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer.

CONTEXT: Combined treatment using radiation therapy (RT) and androgen suppression therapy (AST) is used to treat men with clinically localized adenocarcinoma of the prostate, but outcome using this combined therapy compared with RT alone is not known. OBJECTIVE: To determine the relative efficacy of RT plus AST vs RT alone among men with clinically localized prostate cancer. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 1586 men with prostate cancer who were treated between January 1989 and August 1999 using 3-dimensional conformal RT with (n = 276) or without (n = 1310) 6 months of AST. MAIN OUTCOME MEASURE: Relative risk (RR) of prostate-specific antigen (PSA) failure (defined according to the American Society for Therapeutic Radiology and Oncology consensus statement), by treatment and high-, intermediate-, or low-risk group based on serum PSA level, biopsy Gleason score, and 1992 American Joint Commission on Cancer clinical tumor category. RESULTS: Estimates of 5-year PSA outcome after RT with or without AST were not statistically different among low-risk patients (P =.09), whereas intermediate- and high-risk patients treated with RT plus AST had significantly better outcomes than those treated with RT alone (P<.001 and =.009, respectively). The RR of PSA failure in low-risk patients treated with RT plus AST was 0.5 (95% confidence interval [CI], 0.3-1.1) compared with patients treated with RT alone. The RRs of PSA failure in intermediate-risk and high-risk patients treated with RT plus AST compared with RT alone were 0.2 (95% CI, 0. 1-0.3) and 0.4 (95% CI, 0.2-0.8), respectively. CONCLUSIONS: Our data suggest a significant benefit in 5-year PSA outcomes for men with clinically localized prostate cancer in intermediate- and high-risk groups treated with RT plus AST vs those treated with RT alone. Results from prospective randomized trials currently under way are needed to validate these findings. JAMA. 2000;284:1280-1283

Tamsulosin palliates radiation-induced urethritis in patients with prostate cancer: results of a pilot study.

PURPOSE: A pilot study was performed to determine the effectiveness of Flomax (tamsulosin HCl) in the management of acute radiation urethritis in prostate cancer patients undergoing conformal external beam radiation therapy (RT). Potential predictors of response to Flomax were evaluated. METHODS AND MATERIALS: From January 1998 to April 1998, 26 consecutive patients who developed symptoms of radiation urethritis while undergoing RT for prostate cancer were treated with Flomax, a superselective alpha1A-adrenergic antagonist. A genitourinary review of systems served as the instrument used to assess baseline urinary function and treatment response. RESULTS: The initial response rate to Flomax was 62% (16/26) at the 0.4 mg level and 60% (6/10) at the 0.8 mg level. Half of the 16 patients who initially responded to 0.4 mg subsequently progressed. Three-fourths of those patients who progressed, however, achieved a durable response with the 0.8 mg dose. Therefore urinary symptoms were ultimately controlled in 77% (20/26) of the patients. After correcting for the testing of multiple hypotheses (n = 5), the presence of benign prostatic hyperplasia (BPH) approached statistical significance for predicting the initial response to the 0.4 mg dose of Flomax (78% vs. 25%, p = 0.03). CONCLUSION: Flomax appears to be effective in relieving the symptoms of radiation urethritis. A Phase II trial is justified and in progress.

[Effect of hormone replacement therapy on postmenopausal ocular function]. / Effetti della terapia ormonale sostitutiva sulla funzionalità oculare in postmenopausa.

OBJECTIVE: Determination of the effects of hormonal replacement therapy (HRT) on various ocular parameters and symptoms in postmenopausal women. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, University "Federico II" of Naples. PATIENTS: 14 healthy women treated orally with equine conjugated estrogen in continuous (0,625 mg/daily) and acetate-medroxyprogesteron (10 mg/daily) from 17th to 28th day for three months. MEASURES: Ocular symptomatology, intraocular pressure (IOP), lacrimal secretion, reflected and basal and corneal thickness. RESULTS: After 3 months of HRT the IOP was reduced of 10.8% (p < 0.005), the lacrimal secretion, reflected and basal, increased of 19% and 48%, respectively and the corneal thickness increased of 16.6%. CONCLUSION: The HRT has a positive effect on ocular physiology.