Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Plitidepsin as a successful rescue treatment for prolonged viral SARS-CoV-2 replication in a patient with previous anti-CD20 monoclonal antibody-mediated B cell depletion and chronic lymphocytic leukemia.

BACKGROUND: There is an urgent need for highly efficacious antiviral therapies in immunosuppressed hosts who develop coronavirus disease (COVID-19), with special concern for those affected by hematological malignancies. CASE PRESENTATION: Here, we report the case of a 75-year-old male with chronic lymphocytic leukemia who was deficient in CD19+CD20+ B-lymphocyte populations due to previous treatment with anti-CD20 monoclonal antibodies. The patient presented with severe COVID-19 pneumonia due to prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and was treated with two courses of the antiviral plitidepsin on a compassionate use basis. The patient subsequently achieved an undetectable viral load, and his pneumonia resolved. CONCLUSIONS: Treatment with plitidepsin was well-tolerated without any further hematological or cardiovascular toxicities. This case further supports plitidepsin as a potential antiviral drug in SARS-CoV-2 patients affected by immune deficiencies and hematological malignancies.

Designing optimal human-modified landscapes for forest biodiversity conservation.

Agriculture and development transform forest ecosystems to human-modified landscapes. Decades of research in ecology have generated myriad concepts for the appropriate management of these landscapes. Yet, these concepts are often contradictory and apply at different spatial scales, making the design of biodiversity-friendly landscapes challenging. Here, we combine concepts with empirical support to design optimal landscape scenarios for forest-dwelling species. The supported concepts indicate that appropriately sized landscapes should contain ≥ 40% forest cover, although higher percentages are likely needed in the tropics. Forest cover should be configured with c. 10% in a very large forest patch, and the remaining 30% in many evenly dispersed smaller patches and semi-natural treed elements (e.g. vegetation corridors). Importantly, the patches should be embedded in a high-quality matrix. The proposed landscape scenarios represent an optimal compromise between delivery of goods and services to humans and preserving most forest wildlife, and can therefore guide forest preservation and restoration strategies.

SEOM clinical guideline for the management of immune-related adverse events in patients treated with immune checkpoint inhibitors (2019).

The use of immune checkpoint inhibitors has emerged as an effective treatment option for patients with several tumor types. By increasing the activity of the immune system, they can induce inflammatory side effects, which are often termed immune-related adverse events. These are pathophysiologically unique toxicities, compared with those from other anticancer therapies. In addition, the spectrum of the target organs is very broad. Immune-inflammatory adverse events can be life threatening. Prompt diagnosis and pharmacological intervention are instrumental to avoid progression to severe manifestations. Consequently, clinicians require new skills to successfully diagnose and manage these events. These SEOM guidelines have been developed with the consensus of ten medical oncologists. Relevant studies published in peer-review journals were used for the guideline elaboration. The Infectious Diseases Society of America grading system was used to assign levels of evidence and grades of recommendation.

A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors.

Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier: NCT01316263.

Safety of regadenoson in patients with severe chronic obstructive pulmonary disease / Seguridad de regadenosón en pacientes con enfermedad pulmonar obstructiva crónica severa

Objective. To assess the safety of regadenoson, a selective agonist of A2A adenosine receptors, combined with low-level exercise in subjects with severe chronic obstructive pulmonary disease (COPD), referred for myocardial perfusion imaging (MPI). Methods. We studied prospectively 12 male patients with severe COPD. Stress was 4min of low-level exercise with bolus injection of regadenoson (0.4mg) at 1.5min, followed by 99mTc-MPI agent injection. Demographics, medical history, lung medications, adverse events, oxygen saturation (SatO2), MPI findings for coronary artery disease (CAD), and changes in systolic blood pressure (SBP), and heart rate (HR) were registered. Results. The observed adverse event profile of regadenoson was similar to that of patients with mild-moderate COPD. There was no clinical exacerbation of COPD. Adverse events were self-limiting: dyspnea (33.3%), fatigue (25.0%), chest pain, headache (16.7%, respectively), and gastrointestinal discomfort, dry mouth, flushing, feeling hot and dizziness (8.3%, respectively). 25.0% of patients did not report any symptoms. We observed significant increases in SBP and HR from baseline (142.6mmHg±22.3 vs 152.5mmHg±18.5, and 80 b.p.m.±18 vs 105 b.p.m.±22, respectively; p<0.05). Conclusions. Regadenoson combined with low-level exercise is safe and well tolerated in stable patients with severe COPD undergoing MPI (AU)

Objetivo. Evaluar la seguridad de regadenosón, un agonista selectivo de los receptores adenosínicos A2A, combinado con ejercicio de baja intensidad, en sujetos con enfermedad pulmonar obstructiva crónica (EPOC) severa, en estudios de perfusión miocárdica. Métodos. Se estudiaron de forma prospectiva 12 pacientes con EPOC severa (todos ellos varones). El estrés consistió en la realización de un ejercicio de baja intensidad durante 4min junto con la administración de un bolo de regadenosón (0,4mg) a los 1,5min, seguido de la inyección del radiofármaco tecneciado de perfusión miocárdica. Se registraron los datos demográficos, el historial médico, la medicación para patología respiratoria, los efectos adversos, la saturación de oxígeno (SatO2), los hallazgos de enfermedad coronaria en el estudio de perfusión miocárdica y los cambios en la presión arterial sistólica (PAS) y la frecuencia cardiaca (FC). Resultados. El perfil de efectos adversos de regadenosón fue similar al de pacientes con EPOC leve-moderada. No se produjeron exacerbaciones clínicas de la EPOC. Los efectos adversos experimentados, todos autolimitados, fueron disnea (33,3%), cansancio (25%), dolor torácico, cefalea (16,7%, respectivamente), molestias gastrointestinales, boca seca, rubefacción, calor y mareos (8,3%, respectivamente). El 25% de los pacientes no informaron síntomas. Se observaron aumentos significativos desde los valores basales de la PAS y la FC (142,6mmHg±22,3 vs 152,5mmHg±18,5 y 80l.p.m.±18 vs 105l.p.m.±22, respectivamente; p<0,05). Conclusiones. Regadenosón combinado con ejercicio de baja intensidad es seguro y bien tolerado en pacientes con EPOC severa estable sometidos a estudios de perfusión miocárdica (AU)

Safety of regadenoson in patients with severe chronic obstructive pulmonary disease.

OBJECTIVE: To assess the safety of regadenoson, a selective agonist of A2A adenosine receptors, combined with low-level exercise in subjects with severe chronic obstructive pulmonary disease (COPD), referred for myocardial perfusion imaging (MPI). METHODS: We studied prospectively 12 male patients with severe COPD. Stress was 4min of low-level exercise with bolus injection of regadenoson (0.4mg) at 1.5min, followed by (99m)Tc-MPI agent injection. Demographics, medical history, lung medications, adverse events, oxygen saturation (SatO2), MPI findings for coronary artery disease (CAD), and changes in systolic blood pressure (SBP), and heart rate (HR) were registered. RESULTS: The observed adverse event profile of regadenoson was similar to that of patients with mild-moderate COPD. There was no clinical exacerbation of COPD. Adverse events were self-limiting: dyspnea (33.3%), fatigue (25.0%), chest pain, headache (16.7%, respectively), and gastrointestinal discomfort, dry mouth, flushing, feeling hot and dizziness (8.3%, respectively). 25.0% of patients did not report any symptoms. We observed significant increases in SBP and HR from baseline (142.6mmHg±22.3 vs 152.5mmHg±18.5, and 80 b.p.m.±18 vs 105 b.p.m.±22, respectively; p<0.05). CONCLUSIONS: Regadenoson combined with low-level exercise is safe and well tolerated in stable patients with severe COPD undergoing MPI.

Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience.

OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.

Calciphylaxis, a cause of 99mTc-diphosphonate soft-tissue uptake / Calcifilaxis, una causa de captación de 99mTc-difosfonatos en partes blandas

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Guidelines for biomarker testing in metastatic melanoma: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), makes diagnostic and treatment recommendations for the management of patients with advanced or metastatic melanoma based on the current scientific evidence on biomarker use. This document thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the data available so far, this expert group recommends routinely testing patients with metastatic melanoma for BRAF mutation status, as the result affects the subsequent therapeutic management of these patients. The analysis of genetic alterations in KIT may be reasonable in patients with primary tumours in acral or mucosal sites or on chronically sun-exposed skin, in an advanced condition, but not in patients with other types of melanomas. This panel believes that testing for other genetic alterations, such as NRAS mutation status in patients not carrying BRAF mutations, GNAQ/GNA11 mutational analysis or genetic alterations in PTEN, is not currently indicated as routine clinical practice, because the results do not influence treatment planning in these patients at the present time. Other important issues addressed in this document are the organisational requirements and quality controls needed for proper testing of these biomarkers, and the legal implications to be borne in mind.

Utilidad de la SPECT-TAC en la identificación de fístulas en una peritoneogammagrafía / Utility of SPECT-CT in the identification of fistulas in a peritoneal scintigraphy

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Advances in cutaneous melanoma

After several decades of slow progress in the field of melanoma, significant advances have been reported in recent years. These include a better understanding of the molecular biology of the tumour, a new staging classification system, insights into the patterns of relapse in early stage, and new drugs for the treatment of advanced disease. Ipilimumab and vemurafenib have just been approved and provide a survival benefit in stage IV. Both compounds are under evaluation in the adjuvant setting, where interferon remains the only drug with proven efficacy. Further investigation is required to treat patients with primary or secondary resistance to new drugs (AU)

First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

BACKGROUND: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. CONCLUSION: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.

Preload dependence of gated cardiac SPECT-derived ventricular volumes in hemodialysis patients.

BACKGROUND: In hemodialysis (HD) patients, the intravascular volume expansion of the pre-HD state leads to a high preload. We aim to examine its effect on myocardial perfusion gated SPECT (MPGS)-derived left ventricular (LV) volumes. METHODS: The study comprised 50 end-stage renal disease (ESRD) patients on HD with normal 2-day stress/rest MPGS performed for kidney transplantation risk assessment. Patients (pts) comprised 23 men/27 women, with mean age of 59.4 ± 7.1 years. The time elapsed from the last HD session in hours was calculated on both days, and patients were classified according to whether it was higher (group A: 19 pts), lower (group B: 27 pts), or equal (group C: 4 pts) on the stress vs the rest day. End-diastolic, end-systolic volumes (EDV, ESV), and left ventricular ejection fraction (LVEF) were determined using QGS™ software. Transient ischemic dilation (TID) ratios were derived from the nongated images using QPS™ software. RESULTS: Volumes were significantly higher at stress in group A, at rest in group B, and similar in group C. TID ratios were significantly higher in group A vs groups B and C. CONCLUSIONS: MPGS-derived ventricular volumes are preload dependent. The high preload of the pre-HD state may mimic ischemic TID if occurring on the stress day and create confusion if coinciding with the rest day.

A phase II trial of first-line sorafenib in patients with metastatic renal cell carcinoma unwilling to receive or with early intolerance to immunotherapy: SOGUG Study 06-01

AIMS: Our aim was to evaluate first-line treatment of metastatic renal cell carcinoma (mRCC) with sorafenib in patients unwilling to receive immunotherapy or with early in