Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Virtual reality in preoperative imaging in maxillofacial surgery: implementation of "the next level"?

Not only are current imaging techniques - cone-beam computed tomography (CT), CT, and magnetic resonance imaging (MRI) - becoming more precise in capturing data, but the illustration and interpretation of the acquired images is no longer limited to conventional display screens or projectors. The so-called "virtual reality" (VR) glasses have the potential to engage the viewer in a 3-dimensional space, and ultimately to enable evaluation of the reconstructed anatomical structures from a new perspective. For the first time in the field of oral and maxillofacial surgery (OMFS), a 3-dimensional imaging dataset (cone-beam CT, CT, and MRI) can be evaluated by using VR glasses. A medical student, an OMFS resident, and an OMFS consultant rated the preoperative usability of VR glasses to improve the operative understanding of three cases: a deeply impacted wisdom tooth, a fracture of the lower jaw, and an oncological resection. VR glasses seem to help to simplify operations and give the surgeon a good preoperative overview of the intraoperative findings, particularly in the evaluation of impacted teeth and hard tissue structures. In addition, VR glasses seem to be a promising innovation to help in the training of surgical residents and to teach students. However, the more experienced the surgeon, the smaller is the additional value of VR glasses. Preoperative examination using VR glasses can aid better understanding and planning of the surgical site in the future, and is an innovative piece of advanced technology for displaying CT, cone-beam CT, and MRI anatomical data.

Is there an ideal way to close the donor site of radial forearm free flaps?

Radial forearm free flaps (RFFF) are the "workhorse" of reconstructive head and neck surgery, but have considerable morbidity at the donor site. The aim of this study was to review current publications about the incidence and type of morbidity and the different techniques used for closure of the site. We screened the MEDLINE database to find relevant papers using the terms "RFFF head and neck" and "RFFF donor site". Abstracts were filtered, and the full texts studied carefully. We found 1056 publications during the period 1982-2017 of which 389 were studied in full, and 39 studies were finally included in the review. We found four main methods of closure of the donor site: full-thickness skin grafts (FTSG); split-thickness skin grafts (STSG); modified techniques for raising the flap and closure of the wound by local flaps; and others (such as allografts, expanders, and vacuum bandages). For STSG and FTSG the preparation of the donor site seems to be a relevant factor. Special attention should be paid to the coverage of the flexor tendons. FTSG give better aesthetic results than STSG. Closure by local flaps may achieve primary closure of the donor site without a third surgical site, but the techniques are limited by the amount of tissue required at the site of the defect. The most common side effects are disorders of wound healing such as exposed tendons. To avoid exposure of the tendons, flexor tendons should be covered with muscle bellies when STSG are used. It is still not clear whether many other reported side effects (such as impairment of sensitivity) are induced by raising the flap or closing the donor site. There is an argument for closure of individual donor sites independently, but there is no one method of closure for all donor sites, because each has its specific disadvantages and complications.

Preoperative assessment of the risk of postoperative death in patients with oral squamous cell carcinoma: a consideration beyond age, sex, and stage of cancer.

Despite improvements in the management of patients in critical care, about 3% patients who have an operation with curative intent for oral squamous cell carcinoma (SCC) do not survive their stay in hospital. Our aim was to assess the risk factors for postoperative death that were independent of the stage of the cancer, or the age and sex of the patients. We screened 4760 consecutive inpatients at a maxillofacial tertiary care centre from 2011 to 2016, and 34 of them had died within the first three months after operation. We matched them with a further 34 patients with the same TNM stage, age, and sex. General personal and clinical data and preoperative laboratory values were screened, and we applied a Charlson Comorbidity Score (for anaesthetic risk) for each group. Patients' mean (SD) age was 66 (12) years old. There was no significant difference in sex (p=1), age (p=0.718), or TNM classification. Those who died after operation had significantly more renal (p=0.027) and gastrointestinal (p=0.006) diseases, but cardiac diseases (p=0.468) and diabetes mellitus (p=1) were not significant risk factors in themselves. Patients who died postoperatively had significantly worse risk scores (p=0.001) overall. The most common causes of death were septic shock (n=10) and acute cardiac (n=9) or respiratory failure (n=7). Our findings suggested that general diseases were not intrinsically a contraindication for operation with curative intent. The Charlson Comorbidity Score helped to detect potentially fatal courses and could be useful in the preoperative assessment of patients whose general health is not good.

The safety of paediatric dentistry procedures under general anaesthesia. A five-year experience of a tertiary care center.

AIM: Frequently general anaesthesia (GA) is used to treat noncompliant children. Especially in children with morbid diseases general anaesthesia can be a challenging procedure for anaesthetists. The aim of this paper was to evaluate the risks and adverse reactions with a special focus on the impact of existing medication conditions and syndromes. MATERIALS AND METHODS: and methods Records of children up to 10 years of age, who were admitted for paediatric dentistry procedures under GA from January 2011 to December 2016 at the University Hospital of the University of Aachen (Germany), were reviewed. A special attention was paid to the intra- and perioperative critical adverse reactions and concomitant systemic conditions and their impact on treatment outcome. RESULTS: Two hundred and twenty patients were admitted for dental restorations. Critical adverse reactions occurred in 4% of the treated patients and they were statistically significantly (p=0.004) related to the ASA classification above II. The use of a laryngeal mask airway was significantly associated (p<0.001) with a shorter duration of surgery. Most common concomitant medical conditions were congenital heart disease, mental retardation and inherited syndromes. CONCLUSION: Although the administration of general anaesthesia in infants and children can be regarded as a safe procedure, clinically significant adverse reactions can occur, especially in patients with an existing medical condition.

Chronic myeloid leukaemia in Spain: Its presentation characteristics have changed. Spanish section of the EUTOS population-based registry. / Leucemia mieloide crónica en España: sus características de presentación han cambiado. Sección española del registro poblacional EUTOS.

OBJECTIVES: To provide more reliable data on the epidemiology of chronic myeloid leukaemia (CML) in Spain than are currently available. MATERIAL AND METHODS: The EUTOS population-based project of European LeukemiaNet is a population registry of new CML cases in patients 18 years of age or older from 22 European areas. The Spanish section included the autonomous communities of Madrid, Castilla-La Mancha and Aragon, from 1-2-2010 to 31-12-2012. RESULTS: A total of 250 cases were recorded in 35 months. The overall incidence was 1.08 cases/10(5) inhabitants-year, with a predominance of men (58%) and clear differences among the communities. The incidence standardised by age was similar (overall, 1.04; men, 1.31; women, 0.81). The median age was 54 years. The incidence increased with age, reaching a peak at>65 years, although 31.7% of cases appeared between the ages of 20 and 44 years. Four percent of cases were diagnosed in advanced stages (2.4% in accelerated phase, 1.6% in blast crisis), 56% were asymptomatic, 38% had splenomegaly, and the Sokal score was high in 11% (lower than what was previously reflected in the literature). CONCLUSIONS: The current incidence of CML in Spain is higher than previously reported and similar to that of the European studies. Unlike the classical descriptions, CML presented mostly in asymptomatic form, with no splenomegaly, less leucocytosis and in stages with better prognosis.

European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia.

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.

Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.

The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

The EUTOS prognostic score: review and validation in 1288 patients with CML treated frontline with imatinib.

The introduction of tyrosine kinase inhibitors (TKI) in the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) has revolutionized the outcome, but the prognosis of the disease is still based on prognostic systems that were developed in the era of conventional chemotherapy and interferon (IFN)-alfa. A new prognostic score including only two variables, spleen size and basophils, was developed for the prediction of complete cytogenetic response (CCyR) and progression-free survival (PFS). The score was based on a large series of patients who were enrolled in prospective multicenter studies of first-line imatinib treatment. The prognostic value of the EUTOS (European Treatment and Outcome Study for CML) score has now been tested in an independent, multicenter, multinational series of 1288 patients who were treated first-line with imatinib outside prospective studies. It was found that also in these patients, the EUTOS prognostic score was predictive for CCyR, PFS and overall survival (OS). In addition, the prognostic value of the score was reported to be significant in seven of the eight other independent studies of almost 2000 patients that were performed in Europe, the Americas and Asia. The EUTOS risk score is a valid tool for the prediction of the therapeutic effects of TKI, particularly imatinib.

Prevalence and management of anaemia in patients with non-myeloid cancer undergoing systemic therapy: a Spanish survey

BACKGROUND: The present study aimed to provide updated data on anaemia prevalence and management in cancer patients undergoing systemic therapy in Spain. METHODS: This was a multicenter, observational, cross-sectional study performed in 2008. Eligible patients were ≥18 years, with non-myeloid malignancies treated with systemic therapy [chemotherapy (CT), hormonal therapy or immunotherapy]. Anaemia was defined according to WHO as haemoglobin (Hb) < 12 g/dL. RESULTS: The study included 214 patients with a median age of 63 years (range 20-91), 58 % women, 73 % with solid tumours, and 79 % with advanced disease. CT was used in 91 % of patients (26 % with platinum compounds), hormonal therapy in 8.5 %, and immunotherapy in 8.5 %. In our study, 48.1 % of patients [95 % confidence interval (CI) 45.2-58.6] showed anaemia (31 % symptomatic): 42.0 % mild (10 ≤ Hb ≤ 11.9 g/dL), 5.6 % moderate (8 ≤ Hb ≤ 9.9 g/dL), and 0.5 % severe (Hb < 8 g/dL). A higher prevalence was observed in patients treated with CT (51 vs. 20 %, p = 0.01), platinum-based CT (70 vs. 47 %, p = 0.01) or palliative CT (61 vs. 39 %, p = 0.003). Anaemia was also more frequent in patients with more than three lines of CT (83 %) and in the fourth or subsequent CT cycle (58 %). Management in the previous 4 weeks in patients with anaemia was: 62 % did not receive treatment (92 % mild), 24 % received erythropoiesis-stimulating agents (ESAs), 14 % received iron and 8.7 % received transfusion. CONCLUSIONS: In Spanish hospitals, about half of patients with non-myeloid malignancies undergoing systemic therapy fulfilled anaemia criteria (87 % mild). Approximately two-third of patients with anaemia do not receive specific treatment and ESA use is below current guidelines (AU)

Prevalence and management of anaemia in patients with non-myeloid cancer undergoing systemic therapy: a Spanish survey.

BACKGROUND: The present study aimed to provide updated data on anaemia prevalence and management in cancer patients undergoing systemic therapy in Spain. METHODS: This was a multicenter, observational, cross-sectional study performed in 2008. Eligible patients were ≥18 years, with non-myeloid malignancies treated with systemic therapy [chemotherapy (CT), hormonal therapy or immunotherapy]. Anaemia was defined according to WHO as haemoglobin (Hb) < 12 g/dL. RESULTS: The study included 214 patients with a median age of 63 years (range 20-91), 58 % women, 73 % with solid tumours, and 79 % with advanced disease. CT was used in 91 % of patients (26 % with platinum compounds), hormonal therapy in 8.5 %, and immunotherapy in 8.5 %. In our study, 48.1 % of patients [95 % confidence interval (CI) 45.2-58.6] showed anaemia (31 % symptomatic): 42.0 % mild (10 ≤ Hb ≤ 11.9 g/dL), 5.6 % moderate (8 ≤ Hb ≤ 9.9 g/dL), and 0.5 % severe (Hb < 8 g/dL). A higher prevalence was observed in patients treated with CT (51 vs. 20 %, p = 0.01), platinum-based CT (70 vs. 47 %, p = 0.01) or palliative CT (61 vs. 39 %, p = 0.003). Anaemia was also more frequent in patients with more than three lines of CT (83 %) and in the fourth or subsequent CT cycle (58 %). Management in the previous 4 weeks in patients with anaemia was: 62 % did not receive treatment (92 % mild), 24 % received erythropoiesis-stimulating agents (ESAs), 14 % received iron and 8.7 % received transfusion. CONCLUSIONS: In Spanish hospitals, about half of patients with non-myeloid malignancies undergoing systemic therapy fulfilled anaemia criteria (87 % mild). Approximately two-third of patients with anaemia do not receive specific treatment and ESA use is below current guidelines.

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4-20 x 10(9)/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

Intracerebral Hodgkin's lymphoma in a patient with human immunodeficiency virus.

Central nervous system (CNS) involvement by Hodgkin Lymphoma (HL) is rarely reported. Retrospective and prospective cohort studies suggest an incidence of 0.2-0.5%, mostly in relapsed disease. In spite of a 3 to 18-fold increased risk of HL in patients with human immunodeficiency virus (HIV), only two cases have been reported so far. In this paper, we now report a third case of HIV patient with HL who progressed with isolated CNS infiltration after a standard chemotherapy induced clinical remission. In 1991, when the first case of intracerebral involvement in HIV+ HL was reported an increase of this type of cases would have been expected, but only one more case has been reported since then.