Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants.

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia-spectrum disorders, but evidence-based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long-acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head-to-head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta-analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, "high" confidence in the results was found for (in descending order of effect magnitude) amisulpride-oral (OS), olanzapine-OS, aripiprazole-LAI, olanzapine-LAI, aripiprazole-OS, paliperidone-OS, and ziprasidone-OS. "Moderate" confidence in the results was found for paliperidone-LAI 1-monthly, iloperidone-OS, fluphenazine-OS, brexpiprazole-OS, paliperidone-LAI 1-monthly, asenapine-OS, haloperidol-OS, quetiapine-OS, cariprazine-OS, and lurasidone-OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing "moderate" confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia-spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best-performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low- and middle-income countries and constrained-resource settings, where few medications may be selected. Results from this network meta-analysis can inform clinical guidelines and national and international drug regulation policies

Role of Close Endocervical Margin in Treatment Failure After Cervical Excision for Cervical Intraepithelial Neoplasia: A Retrospective Study

Context.-A significant negative trend in length of cone excision has been observed in recent years, leading to a higher percentage of positive endocervical excision margin and close (<1 mm) negative endocervical margin cases.Objective.-To evaluate the rate of disease persistence and recurrence after cervical excision for cervical intraepithelial neoplasia in relation to a close (<1 mm), negative, or positive endocervical margin.Design.-We retrospectively analyzed a cohort of patients with cervical intraepithelial neoplasia having a carbon dioxide laser cervical excision performed by the same operator. We evaluated the rate of positive follow-up in relation to the status of endocervical margin.Results.-We found a higher percentage of positivity at follow-up and recurrence rate between 13 and 24 months in patients with positive margin than for patients with negative or close endocervical margin (P = .005 and P = .006, respectively), with no difference between negative and close margin (7.0% versus 8.3%, P = .89, and 1.2% versus 0%, P = .83, respectively).Conclusions.-Women with close and negative endocervical margin presented similar risk of positivity at long-term follow-up, disease persistence, and recurrence between 13 and 24 months, so the histopathologic report of a free endocervical margin less than 1 mm should not categorize the patient as being at increased risk of treatment failure. Therefore, the only information that the pathologist should report is the state of the margin (positive or negative), regardless of the negative endocervical margin length

Histopathological findings in hysterectomy for cervical stenosis in postmenopausal women: A retrospective case series

Objective: To analyze the histopathological findings in postmenopausal women who underwent hysterectomy for postsurgical cervical stenosis, evaluating the incidental findings of preinvasive or invasive uterine and cervical disease. Methods: Retrospective case series of postmenopausal women who underwent hysterectomy for postsurgical cervical stenosis at Gynecological Oncology Unit of Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico Aviano-National Cancer Institute from January 2014 to January 2021. Results: During the study period, 36 women underwent hysterectomy for postsurgical cervical stenosis at our institution. Cervical stenosis occurred 10.2 ± 5.6 years from the onset of menopause. In particular, 26 (72.2%) patients underwent a single loop electrosurgical excision procedure or carbon dioxide (CO2)-laser conization before the onset of stenosis. The remaining 10 (27.8%) women had multiple surgical excision before the onset of stenosis. At the final histopathological analysis, 17 (47.2%) patients had a preinvasive or invasive gynecological disease. In particular, 9 cases of cervical disease (including 1 case of endocervical squamous cell carcinoma pT1a) and 6 cases of endometrial hyperplasia emerged. Also, 2 cases of tubo-ovarian diseases were found. Conclusions: Postsurgical cervical stenosis is a challenging clinical condition, especially in women treated for cervical intraepithelial neoplasia or microinvasive cervical cancer. As shown, cervical stenosis can prevent an adequate gynecological follow-up and a prompt diagnosis of malignancies. Therefore, postmenopausal women with cervical stenosis should be carefully counseled, and hysterectomy could be a reasonable option, especially in those cases in which a conservative approach is not feasible, failed, or is not accepted by the patient

Effect of age and cone dimensions on cervical regeneration: An Italian multicentric prospective observational study

Objectives To evaluate cervical regeneration at 6 months following excisional treatment for high-grade cervical intraepithelial neoplasia (CIN), and to investigate the effect of cone dimensions, age of patients and technique of excision on the efficacy of the regeneration process. Design Prospective observational multicentric study. Setting Three tertiary care and research centres. Participants Among the 197 eligible women of childbearing age, older than 25 years of age, undergoing for the first time a loop electrosurgical excision procedure or carbon dioxide laser cervical excision for a high-grade CIN at the colposcopy-directed cervical punch biopsy, and with a final diagnosis of high-grade CIN, 165 completed the 6-month follow-up and were included in the analysis. Primary outcome measures The cervical length and volume regeneration (%) after 6 months from procedure were determined by three-dimensional ultrasound, and the correlation of regeneration with cone dimensions, age and excision technique was evaluated. Results The mean\ub1SD cervical length regeneration at 6 months was 89.5%\ub16.3% and the mean\ub1SD cervical volume regeneration was 86.3%\ub113.2%. At the multivariate analysis, a significant and independent inverse correlation between excised cone length and cervical regeneration emerged (r=-0.39, P&lt;0.001). A significantly negative trend in length regeneration at 6 months from procedure with an increasing class of cone length was found (P&lt;0.001). No significant association was found in relation with patient age at the time of procedure or with the technique of excision. Conclusions Cervical length regeneration at 6 months from excisional treatments is negatively affected by an increasing cone length but not from the age of the patient or the technique of excision. While still achieving equal clinical efficacy, it is crucial to contain cone dimensions, in order to favour a greater length regeneration, reducing the cervical harm and the potential future obstetric complications

Extramammary Paget’s Disease of the Vulva and Concomitant Premalignant/Malignant Vulvar Lesions: A Potential Challenge in Diagnosis and Treatment

The aim of the present study was to evaluate the incidence of concomitant vulvar cancers or premalignant lesions in women surgically treated for extramammary Paget’s disease of the vulva (EMPDV) through a multicenter case series. The medical records of all women diagnosed with and treated for EMPDV from January 2010 to December 2020 were retrospectively analyzed. Women with EMPDV and synchronous vulvar cancer, vulvar intraepithelial neoplasia (VIN) and/or lichen sclerosus (LS) at the histology report were included in the study. A total of 69 women eligible for the present study were considered. Concomitant vulvar lesions occurred in 22 cases (31.9%). A total of 11 cases of synchronous VIN (50%) and 14 cases (63.6%) of concomitant LS were observed. One patient (4.5%) had synchronous vulvar SCC (FIGO stage 1B). Women with EMPDV and concomitant premalignant/malignant vulvar lesions had a significantly higher rate of invasive EMPDV and wider lesions with an extravulvar involvement. The specific meaning of the association between EMPDV, VIN, SCC and LS remains unclear. The potential overlapping features between different vulvar lesions highlight the importance of dedicated gynecologists and pathologists in referral centers

Epidemiological and Clinical Characterization of Superinfections in Critically Ill Coronavirus Disease 2019 Patients

To describe the epidemiology of superinfections (occurring > 48 hr after hospital admission) and their impact on the ICU and 28-day mortality in patients with coronavirus disease 2019 with acute respiratory distress syndrome, requiring mechanical ventilation

Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections

Objectives: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options.Methods: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death.Results: Seventeen patients treated for &gt;72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3-10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression.Conclusions: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF

IGFBP-6 Alters Mesenchymal Stromal Cell Phenotype Driving Dasatinib Resistance in Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative characterized by Philadelphia chromosome/translocation t(9;22) and proliferating granulocytes. Despite the clinical success of tyrosine kinase inhibitors (TKi) agents in the treatment of CML, most patients have minimal residual disease contained in the bone marrow microenvironment, within which stromal cells assume a pro-inflammatory phenotype that determines their transformation in cancer-associated fibroblasts (CAF) which, in turn can play a fundamental role in resistance to therapy. Insulin-like Growth Factor Binding Protein-6 (IGFBP-6) is expressed during tumor development, and is involved in immune-escape and inflammation as well, providing a potential additional target for CML therapy. Here, we aimed at investigating the role of IGFBP-6/SHH/TLR4 axis in TKi response. We used a CML cell line, LAMA84-s, and healthy bone marrow stromal cells, HS-5, in mono- or co-culture. The two cell lines were treated with Dasatinib and/or IGFBP-6, and the expression of inflammatory markers was tested by qRT-PCR; furthermore, expression of IGFBP-6, TLR4 and Gli1 were evaluated by Western blot analysis and immumocytochemistry. The results showed that both co-culture and Dasatinib exposure induce inflammation in stromal and cancer cells so that they modulate the expression of TLR4, and these effects were more marked following IGFBP-6 pre-treatment suggesting that this molecule may confer resistance through the inflammatory processes. This phenomenon was coupled with sonic hedgehog (SHH) signaling. Indeed, our data also demonstrate that HS-5 treatment with PMO (an inducer of SHH) induces significant modulation of TLR4 and overexpression of IGFPB-6 suggesting that the two pathways are interconnected with each other and with the TLR-4 pathway. Finally, we demonstrated that pretreatment with IGFBP-6 and/or PMO restored LAMA-84 cell viability after treatment with Dasatinib, suggesting that both IGFBP-6 and SHH are involved in the resistance mechanisms induced by the modulation of TLR-4, thus indicating that the two pathways may be considered as potential therapeutic targets