To discover novel prognostic biomarkers in ovarian serous carcinomas.
A meta-analysis of all single genes probes in the TCGA and HAS ovarian cohorts was performed to identify possible biomarkers ...using Cox regression as a continuous variable for overall survival. Genes were ranked by p-value using Stouffer's method and selected for statistical significance with a false discovery rate (FDR) <.05 using the Benjamini-Hochberg method.
Twelve genes with high mRNA expression were prognostic of poor outcome with an FDR <.05 (AXL, APC, RAB11FIP5, C19orf2, CYBRD1, PINK1, LRRN3, AQP1, DES, XRCC4, BCHE, and ASAP3). Twenty genes with low mRNA expression were prognostic of poor outcome with an FDR <.05 (LRIG1, SLC33A1, NUCB2, POLD3, ESR2, GOLPH3, XBP1, PAXIP1, CYB561, POLA2, CDH1, GMNN, SLC37A4, FAM174B, AGR2, SDR39U1, MAGT1, GJB1, SDF2L1, and C9orf82).
A meta-analysis of all single genes identified thirty-two candidate biomarkers for their possible role in ovarian serous carcinoma. These genes can provide insight into the drivers or regulators of ovarian cancer and should be evaluated in future studies. Genes with high expression indicating poor outcome are possible therapeutic targets with known antagonists or inhibitors. Additionally, the genes could be combined into a prognostic multi-gene signature and tested in future ovarian cohorts.
Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 ...study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy.
In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972.
Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5–25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2–45·2). The most common grade 3–4 adverse events (irrespective of causality) were haematological abnormalities—namely, anaemia (in nine 9% patients), leucopenia (30 29%), neutropenia (48 46%), and thrombocytopenia (seven 7%). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five 5% patients for each). No treatment-related deaths were reported.
Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial.
Pharma Mar.
El presente artículo tiene como objetivo analizar la experiencia de aprendizaje implementada en una plataforma de experiencias de aprendizaje en los procesos de capacitación continua de personas ...incorporadas al Colegio de Profesionales de Orientación, desde el enfoque de aprendizaje activo. Se utilizó una metodología sociocrítica y un diseño de investigación-acción participativa en un grupo de 13 personas colegiadas. Además, se llevó a cabo un diseño tecnopedagógico a través de sus etapas de diagnóstico, diseño, implementación y evaluación de la experiencia; el cual se desarrolla por medio de un curso incorporado a la oferta del Programa de Desarrollo Profesional, que fortalece el tema en atención socioemocional en entornos educativos. Los resultados muestran que, por medio de la plataforma Perusall®, se alcanza a integrar características del enfoque de aprendizaje activo. Entre las conclusiones, destacan la necesidad de elaborar propuestas centradas en los ambientes personalizados de aprendizaje; se encuentra que la plataforma de experiencias de aprendizaje (LXP) es una herramienta innovadora en el ámbito pedagógico e integradora de tecnologías recientes, así como que el diseño de conocimiento técnico pedagógico del contenido (TPACK) favorece una planificación estratégica y ágil en la elaboración de propuestas didácticas. Así mismo, se identifican características deseables para futuros procesos de capacitación a partir del enfoque propuesto, como mayores espacios sociocolaborativos, vinculación teórico-práctica con ambientes laborales y profundización del pensamiento crítico.
Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this ...study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma.
In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0–2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing.
Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% 95% CI 7–26) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% 95% CI 16–39) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four 6%) and weight loss (two 3%). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths.
Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941).
Epizyme.
Surgery is the primary therapy for localized chondrosarcoma; for locally advanced and/or metastatic disease, no known effective systemic therapy exists. Mutations in the isocitrate dehydrogenase 1/2 ...(IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a selective inhibitor of mutant IDH1 approved in the United States for specific cases of acute myeloid leukemia. We report outcomes of patients with advanced chondrosarcoma in an ongoing study exploring ivosidenib treatment.
This phase I multicenter open-label dose-escalation and expansion study of ivosidenib monotherapy enrolled patients with mutant
advanced solid tumors, including chondrosarcoma. Ivosidenib was administered orally (100 mg twice daily to 1,200 mg once daily) in continuous 28-day cycles. Responses were assessed every other cycle using RECIST (version 1.1).
Twenty-one patients (escalation, n = 12; expansion, n = 9) with advanced chondrosarcoma received ivosidenib (women, n = 8; median age, 55 years; range, 30-88 years; 11 had received prior systemic therapy). Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. Twelve patients experienced grade ≥ 3 AEs; only one event was judged treatment related (hypophosphatemia, n = 1). Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals. Median progression-free survival (PFS) was 5.6 months (95% CI, 1.9 to 7.4 months); the PFS rate at 6 months was 39.5%. Eleven (52%) of 21 patients experienced stable disease.
In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control. Future studies of ivosidenib monotherapy or rational combination approaches should be considered in patients with advanced mutant
chondrosarcoma.
Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, ...CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.
The prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II ...study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB conjugated to the microtubule inhibitor, monomethyl auristatin E.
Patients aged ≥12 years and <50 years with relapsed or refractory OS were eligible. GV 1.9 mg/kg/dose was administered on day 1 of each 21 day cycle. Pharmacokinetics were mandatory in patients aged <15 years. gpNMB expression was measured by immunohistochemistry. The primary end-point was disease control at 4 months and Response Evaluation Criteria in Solid Tumours response. A 2-stage design was used to determine efficacy.
Twenty-two patients were enrolled, and all were evaluable for response. Antibody–drug conjugate levels were detectable in patients, although small numbers limit comparison to adult data. The toxicities observed were similar to the previous studies with GV. The most common grade III adverse event was rash. One death from end organ failure occurred possibly related to GV. Of the 22 patients, one patient had a partial response, and two had stable disease. There was no correlation between gpNMB expression and response to GV.
GV was well tolerated in this population. Although there was some antitumour activity, the extent of disease control in stage I did not meet the level required to proceed to stage II.
NCT02487979.
•GV was well tolerated with no unexpected toxicities in AYAs with recurrent OS.•AOST1521 rapidly enrolled AYAs (median age 20 years) with recurrent OS.•Although disease control was not met, some AYAs had responses, and there may be a role for GV in OS.
Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, ...particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors.
This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days.
In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response.
ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted.
Dasatinib may be an active agent in assorted indolent sarcomas. The impact of endpoint selection, well‐defined cohorts, and responses (Choi criteria vs Response Evaluation Criteria in Solid Tumors) ...are discussed. See also pages 90‐7.
Coronavirus disease 2019 (COVID-19) has resulted in an increase in known risk factors for mental health problems. Mexico adopted lockdown and physical distancing as a containment strategy with ...potential consequences on day to day life, such as social isolation, loss of income and loneliness that can have important consequences in terms of mental health.
We aimed to examine the effect of the initial phases of the COVID-19 pandemic on psychological distress, well-being and perceived physical health among Mexican-base respondents and to examine whether coping strategies would play a potential intermediating role in relation to these variables. Under the Existential Positive Psychology perspective, an emphasis was made on meaning-centered coping.
A cross-sectional study was conducted between April 30 and June 16th 2020 among 604 Mexicans-base respondents of which 471 were women and 132 men. Data was collected by using online questionnaires. Psychological distress was measured using the Depression, Anxiety, and Stress Scale (DASS-21). The Brief COPE Inventory was used to assess problem-focused and emotion-focused coping strategies. We also used the Meaning-Centered Coping Scale (MCCS). PERMA-Profiler was used to assess well-being, perceived physical health, and loneliness. Profiler and Descriptive analyses and bivariate linear regression were performed to examine the association of variables.
45.9% of the participants reported moderate to extremely severe psychological distress. Our results demonstrate that problem-focused and emotion-focused coping were positively related to psychological distress, whereas meaning-centered coping was negatively associated with distress. Furthermore, psychological distress played a potential negative role in the perceived physical health, while meaning-centered coping and well-being buffered the negative influence of psychological distress on perceived physical health (completely standardized indirect effect = -0.01, SE: 0.012, 95% CI -0.065; -0.017.
Meaning-centered coping was found to suppress the negative influence of psychological distress on sensation of decreased physical health corroborating the critical role of meaning in life in promoting well-being. Future studies can further examine the value of the critical role of meaning in life in promoting well-being as a protective factor against severe distress during traumatic events. Findings of this study can be used to orient policies and interventions aimed to alleviate suffering in the midst of the COVID-19 pandemic.
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