Women undergoing peripartum hysterectomy due to obstetric hemorrhage: A prospective population-based study.

INTRODUCTION: Peripartum hysterectomy is usually undertaken in cases of life-threatening obstetric hemorrhage to prevent the death of the mother. Near-miss events are still under-researched and inappropriate care continues to be a critical issue, even in countries with advanced obstetric surveillance systems. The aim of the present study was to estimate the prevalence, associated factors, management and intraoperative and postoperative complications of peripartum hysterectomy due to obstetric hemorrhage. MATERIAL AND METHODS: A prospective population-based study has been conducted in six Italian regions covering 49% of births in Italy. The study population comprised all women aged 11-59 years undergoing peripartum hysterectomy, from September 2014 to August 2016, due to obstetric hemorrhage within 7 days of delivery. In each maternity unit a trained reference person reported incident cases using electronic data collection forms. The background population comprised all women who delivered in the participating regions during the study period. RESULTS: The overall peripartum hysterectomy prevalence was 1.09 per 1000 maternities, with a large variability among regions, ranging from 0.52 to 1.60. Previous cesarean section (relative risk [RR] 4.97, 95% CI 4.13-5.96), assisted reproductive technology (RR 5.99, 95% CI 4.42-8.11) multiple pregnancy (RR 5.03, 95% CI 3.57-7.09) and maternal age ≥35 years (RR 2.69, 95% CI 2.25-3.21) were the main associated factors for hysterectomy. The most common causes of peripartum hysterectomy were uterine atony (45.1%) and abnormally invasive placentation (40.2%). Intensive care unit admission was reported in 49.9% of cases, 16.8% of women suffered severe morbidity and 5 women died. CONCLUSIONS: The rate of peripartum hysterectomy in Italy was three times higher compared with the UK, the Netherlands and the Nordic countries. The wide difference may be associated with women's characteristics, such as age at delivery and previous cesarean section, and with different management options leading to peripartum hysterectomy.

The way to move beyond the numbers: the lesson learnt from the Italian Obstetric Surveillance System.

OBJECTIVE: To describe the Italian Obstetric Surveillance System (ItOSS) investigating maternal death through incident case reporting and confidential enquiries. METHODS: All maternal deaths occurred in any public and private health facility in 8 Italian regions covering 73% of national births have been notified to the ItOSS. Every incident case is confidentially reviewed to assess quality of care and establish the cause and avoidability of the death. FINDINGS: A total of 106 maternal deaths among 1 455 545 live births have been notified to the surveillance system in 2013-17. Haemorrhage, sepsis and hypertensive disorders of pregnancy are the leading causes of direct maternal deaths due to obstetric causes. CONCLUSIONS: A maternal mortality surveillance system, including incidence reporting and confidential enquiries along with a retrospective analysis of administrative data sources, emerged as the best option for case ascertainment and for preventing avoidable maternal deaths.

2D versus 3D real time ultrasound with live xPlane imaging to visualize aortic and ductal arches: comparison between methods.

BACKGROUND: The diagnosis of congenital heart defects is challenging, especially for what concerns conotruncal anomalies. Indeed, although the screening techniques of fetal cardiac anomalies have greatly improved, the detection rate of conotruncal anomalies still remains low due to the fact that they are associated with a normal four-chamber view. Therefore, the study aimed to compare real-time three-dimensional echocardiography with live xPlane imaging with two-dimensional (2D) traditional imaging in visualizing ductal and aortic arches during routine echocardiography of the second trimester of gestation. METHODS: This was an observational prospective study including 114 women with uncomplicated, singleton pregnancies. All sonographic studies were performed by two different operators, of them 60 by a first level operator, while 54 by a second level operator. A subanalysis was run in order to evaluate the feasibility and the time needed for the two procedures according to fetal spine position and operator's experience. RESULTS: The measurements with 2D ultrasound were performed in all 114 echocardiographies, while live xPlane imaging was feasible in the 78% of the cases, and this was mainly due to fetal position. The time lapse needed to visualize aortic and ductal arches was significantly lower when using 2D ultrasound compared to live xPlane imaging (29.56 ± 28.5 s vs. 42.5 ± 38.1 s, P = 0.006 for aortic arch; 22.14 ± 17.8 s vs. 37.1 ± 33.8 s, P = 0.001 for ductal arch), also when performing a subanalysis according to operators' experience (P < 0.05 for all comparisons). Feasibility of live xPlane proved to be correlated with the position of the fetal spine and the operator's experience. DISCUSSION: To find a reproducible and standardized method to detect fetal heart defects may bring a great benefit for both patients and operators. In this scenario live xPlane imaging is a novel method to visualize ductal and aortic arches. We found that the position of the fetal spine may affect the feasibility of the method since, when the fetal back is anterior or transverse, the visualization of the correct view of three-vessels and trachea in order to set the reference line properly becomes more challenging. In addition, the fetal spine position influences the duration of the ultrasound examination. Regarding operator's skills and experience, in our study a first level operator was able to perform the complete 2D and xPlane examination in a lower number of cases compared to second level operators. In addition, the time required for the complete examination was higher for first level operators. This means that this technique is based on an adequate operators' expertise.

Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy.

PURPOSE: Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The present pilot study was carried out to assess whether C psittaci-eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas. PATIENTS AND METHODS: Nine patients with C psittaci-positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. RESULTS: All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response (> 50%) was observed in two patients, and minimal response (< 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. CONCLUSION: C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.

Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas.

We investigated the prevalence and prognostic role of CpG island methylation of the reduced folate carrier (RFC) gene promoter region in primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Genomic DNA from 40 PCNSL was used for methylation-specific polymerase chain reaction and bisulphite genomic sequencing of the RFC promoter region. Human immunodeficiency virus-negative systemic diffuse large B-cell lymphomas (DLBCL) were used as controls (n = 50). The impact on outcome of RFC promoter methylation was assessed in 37 PCNSL patients treated with high-dose methotrexate (HD-MTX)-based chemotherapy +/- radiotherapy. RFC promoter methylation occurred in 12 of 40 (30%) PCNSL and in four of 50 (8%) DLBCL (P = 0.01). Of 37 PCNSL treated with HD-MTX-based chemotherapy, methylation occurred in nine cases (24%, M-PCNSL), while 28 cases (76%, U-PCNSL) were negative. Three M-PCNSL (33%) and 15 U-PCNSL (54%) achieved complete remission (CR) after primary chemotherapy. Logistic regression confirmed the independent association between CR rate and International Extranodal Lymphoma Study Group score (P = 0.03), RFC promoter methylation (P = 0.07) and use of cytarabine (P = 0.08). The 3-year failure-free survival (FFS) and overall survival for M-PCNSL and U-PCNSL was 0% vs. 31 +/- 9% (P = 0.34) and 0% vs. 31 +/- 9% (P = 0.35) respectively. This is the first study to assess the methylation status of the RFC promoter in human tumour samples. RFC methylation is more common in PCNSL compared with systemic DLBCL, and is associated with a lower CR rate to HD-MTX-based chemotherapy. If confirmed in prospective trials on PCNSL treated with HD-MTX alone, these data may suggest the necessity for alternative strategies in M-PCNSL considering the increased risk of MTX resistance by tumour cells.

Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial.

Temozolomide is a well-tolerated alkylating agent, that is able to permeate the blood-brain barrier (BBB), and has additive cytotoxicity when given with radiotherapy (RT). A phase II trial assessing temozolomide 150 mg/m(2)/day, for 5 days every 28 days in primary central nervous system (CNS) lymphoma (PCNSL) patients with negative human immunodeficiency virus (HIV) serology, Eastern Cooperative Oncology Group (ECOG) performance status (PS)<4, previously treated with high-dose methotrexate-containing (HD-MTX) chemotherapy and/or RT was started. Twenty-three patients were enrolled. Median age was 60 years. Five complete remissions (median duration 6+ months; range 2-36 months), one partial response, four stable disease (median duration 7.2 months, range 2-16.5 months), and 13 progressions were observed. No major toxicities were observed, apart grade 3 vomiting in a single cycle. Main grade 1-2 toxicities were: 15% nausea, 6% vomiting, 9% fatigue and 9% neurological symptoms. This is the first prospective trial assessing single-agent activity in PCNSL at failure. Although some patients had a poor PS and had been heavily pre-treated, temozolomide yielded 26% objective responses and was well tolerated without any major toxicity.

Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas.

BACKGROUND: Ocular adnexal lymphomas may be antigen-driven disorders; however, the source of the putative antigen or antigens is still unknown. Hence, we assessed whether Chlamydiae infection is associated with the development of ocular adnexal lymphomas. METHODS: The presence of Chlamydia psittaci, trachomatis, and pneumoniae DNA was investigated by polymerase chain reaction in 40 ocular adnexal lymphoma samples, 20 nonneoplastic orbital biopsies, 26 reactive lymphadenopathy samples, and peripheral blood mononuclear cells (PBMCs) from 21 lymphoma patients and 38 healthy individuals. Seven patients with chlamydia-positive PBMCs were treated with the antibiotic doxycycline, and objective response was assessed in four patients with measurable lymphoma lesions. Differences in Chlamydiae DNA detection between the case patients and the control subjects were analyzed using the Fisher exact test. All statistical tests were two-sided. RESULTS: Thirty-two of the 40 (80%) ocular adnexal lymphoma samples carried C. psittaci DNA, whereas all lymphoma samples were negative for C. trachomatis and C. pneumoniae. In contrast, none of the 20 nonneoplastic orbital biopsies (0% versus 80%; P<.001) and only three of 26 (12%) reactive lymphadenopathy samples (12% versus 80%; P<.001) carried the C. psittaci DNA. Nine of 21 (43%) patients with chlamydia-positive lymphomas carried C. psittaci DNA in their PBMCs, whereas none (0%) of the healthy PBMC donors carried C. psittaci DNA in their PBMCs (43% versus 0%; P<.001). One month after doxycycline treatment, chlamydial DNA was no longer detectable in the PBMCs of all seven treated patients, and objective response was observed in two of the four evaluable patients. CONCLUSION: Patients with ocular adnexal lymphoma had a high prevalence of C. psittaci infection in both tumor tissue and PBMCs. Persistent C. psittaci infection may contribute to the development of these lymphomas, as was also supported by the clinical responses observed in this study with C. psittaci-eradicating antibiotic therapy.

Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type.

The clinical activity of rituximab has been evaluated in a phase 2 study in both untreated and relapsed mucosa-associated lymphoid tissue (MALT) lymphomas. Treatment consisted of 4 standard (375 mg/m2) weekly doses. Thirty-five patients were enrolled, and 34 completed the treatment program. The primary lymphoma location was stomach in 15 patients, and extragastric in 20. Eleven patients had previously been treated with chemotherapy. At study entry 12 patients had Ann Arbor stage IE, 3 had stage IIE, and 20 had stage IV disease. The overall response rate was 73% (95% confidence interval, 56%-87%), with 15 complete responses and 10 partial responses, and the response rate was significantly higher in the chemotherapy-naive patients, who had an 87% response rate compared with 45% of the previously treated patients (P =.03). The median response duration was 10.5 months. At a median follow-up of 15 months, 9 patients (26%) relapsed. The median time to treatment failure was 14.2 months in the whole series, but it was significantly longer (22 versus 12 months) in the chemotherapy-naive patients compared with those who had prior chemotherapy (P =.001). Most adverse events were of mild to moderate severity with no grade 4 toxicity. This study indicates that rituximab is safe with significant activity in MALT lymphomas.

Prognostic value of bcl-6, CD10 and CD38 immunoreactivity in stage I-II gastric lymphomas: identification of a subset of CD10+ large B-cell lymphomas with a favorable outcome.

bcl-6, CD10 and CD38 are useful markers for identifying 2 molecularly and prognostically distinct profiles of diffuse large B-cell lymphomas (LCLs), defined as germinal-center B-like and activated B-like. We investigated the prognostic role of bcl-6, CD10 and CD38 immunoreactivity in 102 gastrectomized patients with primary gastric lymphomas (PGLs). There were 41 low-grade marginal zone lymphomas of MALT-type (LGML) and 61 diffuse large B-cell lymphomas with (DLCLMLs; n = 31) or without (DLCLs; n = 30) an LGML component. bcl-6, CD10 and CD38 were significantly more commonly expressed in DLCL or DLCML as compared with LGML (50% vs. 48% vs. 17%, p = 0.0002 for bcl-6; 27% vs. 26% vs. 0%, p = 0.0004 for CD10; 45% vs. 48% vs. 13%, p = 0.0005 for CD38, respectively). CD10 immunoreactivity was independently associated with a better survival in diffuse LCL patients (5-year overall survival: 88% +/- 8% vs. 66% +/- 7%; p = 0.04); bcl-6 or CD38 immunoreactivities did not disclose any prognostic implication. Age, presence of LGML component, lactic dehydrogenase serum levels and use of chemotherapy were additional independent prognostic factors. We conclude that CD10 immunoreactivity assessment could be a clear, easy-to-interpret and reliable prognostic factor in PGL. Accordingly, patients with CD10(+) gastric large B-cell lymphomas may be at reduced risk and eligible for clinical trials evaluating more conservative therapeutic options.

Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience.

PURPOSE: To identify survival predictors and to design a prognostic score useful for distinguishing risk groups in immunocompetent patients with primary CNS lymphomas (PCNSL). PATIENTS AND METHODS: The prognostic role of patient-, lymphoma-, and treatment-related variables was analyzed in a multicenter series of 378 PCNSL patients treated at 23 cancer centers from five different countries. RESULTS: Age more than 60 years, performance status (PS) more than 1, elevated lactate dehydrogenase (LDH) serum level, high CSF protein concentration, and involvement of deep regions of the brain (periventricular regions, basal ganglia, brainstem, and/or cerebellum) were significantly and independently associated with a worse survival. These five variables were used to design a prognostic score. Each variable was assigned a value of either 0, if favorable, or 1, if unfavorable. The values were then added together to arrive at a final score, which was tested in 105 assessable patients for which complete data of all five variables were available. The 2-year overall survival (OS) +/- SD was 80% +/- 8%, 48% +/- 7%, and 15% +/- 7% (P =.00001) for patients with zero to one, two to three, and four to five unfavorable features, respectively. The prognostic role of this score was confirmed by limiting analysis to assessable patients treated with high-dose methotrexate-based chemotherapy (2-year OS +/- SD: 85% +/- 8%, 57% +/- 8%, and 24% +/- 11%; P =.0004). CONCLUSION: Age, PS, LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survival. A prognostic score including these five parameters seems advisable in distinguishing different risk groups in PCNSL patients. The proposed score and its relevance in therapeutic decision deserve to be validated in further studies.

Current therapeutic approaches to primary CNS lymphoma.

The best therapeutic management in primary CNS lymphomas remains to be defined due to the small size and short follow-up of retrospective series, methodological pitfalls and limited number of prospective studies, and the paucity of randomized trials. This review focuses on the current therapeutic approaches, most commonly used drugs, role of intrathecal chemotherapy and indications for consolidation radiotherapy, providing recommendations for ordinary clinical practice. Some important therapeutic issues, such as the management of meningeal and intraocular lymphomas, as well as the relevance of salvage therapy as a playground for evaluation of new drugs, are also analyzed. Finally, the main open questions, as well as current and expected investigation trends are discussed.