Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO)

Objective: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. Methods: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracycline-containing regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Results: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5–7.3) and 18.5 months (95%CI: 11.5–25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in = 2nd line (25.3 months) than in = 3rd (15.1 months) and with ECOG performance status = 1 at trabectedin start (19.8 months) than ECOG 2–3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radiochemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4–93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in = 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). Conclusions: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile

Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO)

Objective: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. Methods: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracyclinecontaining regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Results: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5–7.3) and 18.5 months (95%CI: 11.5–25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in ≤ 2nd line (25.3 months) than in ≥ 3rd (15.1 months) and with ECOG performance status ≤ 1 at trabectedin start (19.8 months) than ECOG 2–3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radiochemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4–93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in ≥ 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). Conclusions: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile

Evaluation of spacial resolution of a PET scanner through the simulation and experimental measurement of the Recovery coefficient

Purpose: In order to measure spatial resolution of a PET tomograph in clinical conditions, this study describes and validates a method based on the recovery coefficient, a factor required to compensate underestimation in measured radioactivity concentration for small structures. Methods: In a PET image, the recovery factors of radioactive spheres were measured and their comparison with simulated recovery coefficients yielded the tomographic spatial resolution. Following this methodology, resolution was determined in different surrounding media and several conditions for reconstruction, including clinical conditions for brain PET studies. All spatial resolution values were compared with those obtained using classical methods with point and line sources. Results: In each considered condition, spatial resolution of the PET image estimated using the recovery coefficient showed good agreement with classical methods measurements, validating the procedure. Conclusion: Measurement of the recovery coefficient provides an assessment of tomographic spatial resolution, particularly in clinical studies conditions

What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes

Secondary myelodysplastic syndrome after treatment for promyelocytic leukemia: clinical and genetic features of two cases

Acute promyelocytic leukemia (APL) represents a biologic and clinically well-defined subtype of acute nonlymphocytic leukemia with specific morphologic and karyotypic characteristics. Although secondary leukemia and myelodysplastic syndromes (MDS) are the most frequent secondary neoplasms following chemotherapy for acute leukemia, their development after complete remission in patients with APL is uncommon. We describe the clinical and genetic features of two APL patients who achieved CR after chemotherapy and all-trans retinoid acid treatment and subsequently developed a MDS. Therapy-related MDS karyotype changes such as abnormalities of chromosomes 5 and 7 were found in the cytogenetic analysis. Since TP53 alteration was detected in one case, possible implications of these findings in the onset of MDS are discussed

Secondary myelodysplastic syndrome after treatment for promyelocytic leukemia: clinical and genetic features of two cases

Acute promyelocytic leukemia (APL) represents a biologic and clinically well-defined subtype of acute nonlymphocytic leukemia with specific morphologic and karyotypic characteristics. Although secondary leukemia and myelodysplastic syndromes (MDS) are the most frequent secondary neoplasms following chemotherapy for acute leukemia, their development after complete remission in patients with APL is uncommon. We describe the clinical and genetic features of two APL patients who achieved CR after chemotherapy and all-trans retinoid acid treatment and subsequently developed a MDS. Therapy-related MDS karyotype changes such as abnormalities of chromosomes 5 and 7 were found in the cytogenetic analysis. Since TP53 alteration was detected in one case, possible implications of these findings in the onset of MDS are discussed

Efficacy and safety of trabectedin in metastatic uterine leiomyosarcoma: A retrospective multicenter study of the Spanish ovarian cancer research group (GEICO)

Objective: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. Methods: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracyclinecontaining regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Results: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5–7.3) and 18.5 months (95%CI: 11.5–25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in ≤ 2nd line (25.3 months) than in ≥ 3rd (15.1 months) and with ECOG performance status ≤ 1 at trabectedin start (19.8 months) than ECOG 2–3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radiochemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4–93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in ≥ 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). Conclusions: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile

Outcomes beyond the third month of anticoagulation in patients aged >75 years with a first episode of unprovoked venous thromboembolism

Background The ideal duration of anticoagulant therapy in elderly patients with unprovoked venous thromboembolism (VTE) has not been consistently evaluated. Methods We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the rate and severity of pulmonary embolism (PE) recurrences versus major bleeding beyond the third month of anticoagulation in patients >75 years with a first episode of unprovoked VTE. Results As of September 2017, 7,830 patients were recruited: 5,058 (65%) presented with PE and 2,772 with proximal deep vein thrombosis (DVT). During anticoagulant therapy beyond the third month (median, 113 days), 44 patients developed PE recurrences, 36 developed DVT recurrences, 101 had major bleeding, and 241 died (3 died of recurrent PE and 19 of bleeding). The rate of major bleeding was twofold higher than the rate of PE recurrences (2.05 [95% confidence interval, CI: 1.68–2.48] vs. 0.90 [95% CI: 0.66–1.19] events per 100 patient-years) and the rate of fatal bleeding exceeded the rate of fatal PE events (0.38 [95% CI: 0.24–0.58] vs. 0.06 [95% CI: 0.02–0.16] deaths per 100 patient-years). On multivariable analysis, patients who had bled during the first 3 months (hazard ratio [HR]: 4.32; 95% CI: 1.58–11.8) or with anemia at baseline (HR: 1.87; 95% CI: 1.24–2.81) were at increased risk for bleeding beyond the third month. Patients initially presenting with PE were at increased risk for PE recurrences (HR: 3.60; 95% CI: 1.28–10.1). Conclusion Prolonging anticoagulation beyond the third month was associated with more bleeds than PE recurrences. Prior bleeding, anemia, and initial VTE presentation may help decide when to stop therapy

Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa

HIV viral reservoirs are established very early during infection. Resident memory T cells (T) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4T display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4T expressing CD32. Cervical explant models show that CD4T preferentially support HIV infection and harbor more viral DNA and protein than non-T. Importantly, cervical tissue from ART-suppressed HIV women contain high levels of viral DNA and RNA, being the T fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4T as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider T phenotypes, which are widely distributed in tissues