RESUMO
The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.
Assuntos
Evolução Molecular , Imunoterapia , Neoplasias Pulmonares , Platina , Carcinoma de Pequenas Células do Pulmão , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Células Clonais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Genes myc/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Platina/farmacologia , Platina/uso terapêutico , Recidiva , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapiaRESUMO
Cranial imaging (CI) is a widely used diagnostic procedure, especially in acute myeloid leukemia (AML) patients with suspected bleeding or infection. However, common clinical decision rules to guide CI do not apply to AML patients and the diagnostic yield and outcomes of CI for AML patients are largely unknown. We retrospectively evaluated all CI from newly diagnosed non-promyelocytic AML patients receiving intensive induction or consolidation chemotherapy between 2007 and 2019 for imaging indications, diagnostic yield, and consequences. A total of 110 of 462 patients (24%) received CI for 152 imagings in distinct clinical situations. Forty-four patients (40%) had at least one new and acute pathological finding. Main indication was focal neurologic deficit, craniocerebral trauma, and suspected cerebral hypertension. The most common new finding was intracranial hemorrhage (13% of all imagings), followed by sinusitis (9%). CI led to therapy change in 21 patients. There were no clear associations between indications, laboratory values, and a positive imaging. Positive imaging was associated with adverse overall survival. Our study suggests that the overall rate of ordered CI was appropriate and that CI should generally be performed at a low threshold. A systematized approach to CI may further increase diagnostic yield but is complicated by variable clinical presentation.
Assuntos
Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Leucemia Mieloide Aguda/diagnóstico por imagem , Leucemia Mieloide Aguda/tratamento farmacológico , Quimioterapia de Indução , Quimioterapia de Consolidação , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
OBJECTIVES AND METHODS: Venous thromboembolic (VTE) events are emerging as frequent complications in acute myeloid leukemia (AML); however, there is insufficient data regarding epidemiology, risk factors, and impact on outcomes. The optimal approach to balance risks of thrombosis and hemorrhage remains unclear. This retrospective single-center study in AML patients undergoing induction chemotherapy between 2007 and 2018 assessed incidence, risk factors, features, and outcomes of early-onset VTE. RESULTS: 423 patients (median age 59 years) were enrolled. VTE was diagnosed in 31 patients (7.3%) within 3 months of admission. The median time to VTE was 3 days. Non-central venous catheter (CVC)-related VTE occurred in 19 patients (61%). Main risk factor for VTE was leukocytosis at admission, independent of platelet counts/INR. Four patients (13%) exhibited VTE recurrence. No deaths directly related to VTE or major bleeding events associated with platelet-adjusted anticoagulation in patients with VTE were recorded. There was no clear impact of VTE on 1-year overall survival; however, non-CVC-related VTE may be associated with adverse outcomes. CONCLUSIONS: Early-onset VTE is a common complication in newly diagnosed AML patients admitted for induction chemotherapy. Leukocytosis is an independent VTE risk factor. The potentially adverse impact of non-CVC-related VTE merits further study.
Assuntos
Leucemia Mieloide Aguda , Tromboembolia Venosa , Trombose Venosa , Humanos , Pessoa de Meia-Idade , Tromboembolia Venosa/epidemiologia , Estudos Retrospectivos , Quimioterapia de Indução , Leucocitose , Trombose Venosa/etiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Hemorragia/tratamento farmacológico , Fatores de Risco , Anticoagulantes/efeitos adversosRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC) versus chemotherapy in clinical trials. In Germany, ICIs have been used clinically since 2015 for patients with advanced/metastatic NSCLC without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) aberrations. As part of I-O Optimise, a multinational research program utilizing real-world data on thoracic malignancies, we describe real-world treatment patterns and survival following reimbursement of ICIs for advanced NSCLC in Germany. METHODS: This retrospective cohort study included patients with locally advanced/metastatic NSCLC without known EGFR/ALK aberrations who received a first line of therapy at Frankfurt University Hospital between January 2012 and December 2018, with follow-up to December 2019 or death, whichever occurred first. Using electronic medical records, treatment patterns and survival outcomes were described by histology (squamous cell [SQ]; non-squamous cell [NSQ]/other) and time period (pre- and post-ICI approval). RESULTS: Among eligible patients who started first-line treatment, 136 (pre-ICI) and 126 (post-ICI) had NSQ/other histology, and 32 (pre-ICI) and 38 (post-ICI) had SQ histology. Use of an ICI in the NSQ/other cohort increased from 5.9% (all second- or third-line) in the pre-ICI period to 57.1% (22.2% in first-line, including 13.5% as monotherapy and 8.7% combined with chemotherapy) in the post-ICI period. This was paralleled by a significant (P < 0.0001) prolongation of median (95% CI) OS from 9.4 (7.1-11.1) to 14.8 (12.7-20.5) months between the pre-ICI and post-ICI periods. A similar increase in the uptake of ICI was observed for the SQ cohort (from 3.1% pre-ICI [fourth-line] to 52.6% post-ICI [28.9% as first-line, including 15.8% as monotherapy and 13.2% combined with chemotherapy]); however, analysis of survival outcomes was limited by small group sizes. CONCLUSION: These real-world data complement clinical trial evidence on the effectiveness of ICIs in patients with advanced NSCLC and NSQ/other histology in Germany.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Receptores ErbB , HospitaisRESUMO
Background: Multi-morbidity poses a substantial challenge for health care in an aging population. Recent studies did not provide evidence for general side effects of anti-cancer therapy regarding the growth rate of coincident abdominal aortic aneurysms, although it was suggested that specific therapeutic substances might accelerate growth. Aneurysm pathology, however, differs with respect to localization. Hence, we present the first ever analysis on the association of cancer and cancer therapy with growth alteration of aneurysms of the ascending aorta (AscAA). Patients and methods: A retrospective single-center identification of AscAA+cancer patients was performed in the institutional picture archiving and communication system (PACS). Included were all patients with ≥2 CT angiograms over ≥6 months and additional malignancy. Clinical data and aneurysm diameters were retrieved and analyzed for an association of cancer (stratified by tumor entity) or cancer therapy (stratified by several classes of chemotherapeutic agents and radiation therapy) with annual growth rate, respectively. Statistics included t-test, Wilcoxon test, and a linear regression model accounting for initial AscAA diameter and type of treatment. Results: From 2003 to 2021, 151 patients (median age 70 years; 85% male) with AscAA and coincident 163 malignancies were identified. Prostate (37%) and hematologic cancer (17%) were most frequent. One-hundred-eleven patients (74%) received chemotherapy and 75 patients (50%) had radiation. After exclusion of six patients with an initial AscAA diameter >55 mm, the average annual AscAA growth rate was 0.18±0.64 mm/year, with only 12 patients experiencing a growth rate >1mm/year. Neither tumor entity nor radiation or chemotherapy - alone or in combination - were significantly associated with an alteration of the annual AscAA growth rate. Likewise, a subanalysis for singular chemotherapeutic agents did not reveal a specific association with AscAA growth alteration. Conclusions: Growth rates of AscAA are low in this cohort with coincident malignancy. Cancer and/or chemotherapy or radiation are not associated with an alteration of the annual growth rate. Additional control examinations seem unnecessary.
Assuntos
Aneurisma da Aorta Abdominal , Neoplasias , Humanos , Masculino , Idoso , Feminino , Estudos Retrospectivos , Aorta Torácica , Aorta/diagnóstico por imagem , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/terapiaRESUMO
The optimal follow-up care for relapse detection in acute myeloid leukemia (AML) patients in first remission after consolidation therapy with intensive chemotherapy is not established. In this retrospective study, we evaluate the diagnostic value of an intensive relapse surveillance strategy by regular bone marrow aspirations (BMA) in these patients. We identified 86 patients with newly diagnosed non-promyelocytic AML who had reached complete remission (CR) after intensive induction and consolidation chemotherapy between 2007 and 2019. Annual relapse rates were 40%, 17%, and 2% in years 1-3, respectively. Patients in CR were surveilled by BMA scheduled every 3 months for 2 years, followed by BMA every 6 months. This surveillance regimen detected 29 of 55 relapses (53%), 11 of which were molecular relapses (20%). The remaining 26 of 55 relapses (47%) were diagnosed by non-surveillance BMA prompted by specific suspicion of relapse. Most patients showed concurrent morphological abnormalities in peripheral blood (PB) at time of relapse. Seven percent of all morphological relapses occurred without simultaneous PB abnormalities and would have been delayed without surveillance BMA. Intensified monthly PB assessment paired with BMA every 3 months during the first 2 years may be a highly sensitive relapse surveillance strategy.
Assuntos
Medula Óssea , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva , Indução de Remissão , Estudos RetrospectivosRESUMO
OBJECTIVES AND METHODS: Intracranial hemorrhage (ICH) in acute myeloid leukemia (AML) patients is a major concern due to the increased risk of mortality. Few studies have examined ICH specifically in newly diagnosed AML patients receiving intensive induction chemotherapy (IC) and prophylactic platelet transfusions during thrombocytopenia <10/nL. This retrospective cohort study included 423 newly diagnosed AML patients without acute promyelocytic leukemia who underwent IC between 2007 and 2019. We assessed risk factors, clinical features, and outcomes of ICH. RESULTS: 17 of 423 patients (4%) suffered ICH during hospital stay, and 4 patients (24%) died directly because of ICH despite routine prophylactic platelet transfusions. Patients with ICH had a negatively impacted overall survival (median OS, 20.1 vs. 104.8 months) and were more likely not to continue with curative treatment. Main risk factors were female gender, severe thrombocytopenia, and decreased fibrinogen. Patients with subsequent ICH also had laboratory signs of liver dysfunction. CONCLUSIONS: Intracranial hemorrhage remains a potentially deadly complication with notable incidence despite prophylactic platelet substitution, suggesting that additional prophylactic interventions may be required to further reduce the frequency of ICH in high-risk patients. Unrecognized genetic factors may simultaneously predispose to AML and platelet dysfunction with ICH.
Assuntos
Hemorragias Intracranianas/diagnóstico , Hemorragias Intracranianas/etiologia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imuno-Histoquímica , Quimioterapia de Indução/métodos , Hemorragias Intracranianas/mortalidade , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI.
Assuntos
Injúria Renal Aguda/etiologia , Quimioterapia de Indução/efeitos adversos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Treatment-related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.
Assuntos
Quimioterapia de Indução/efeitos adversos , Leucemia Mieloide Aguda/terapia , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
PURPOSE: To investigate the work situation of lung cancer survivors and to identify the factors associated with their returning to work. METHODS: Descriptive analysis and logistic regression were used to evaluate study population characteristics and independent factors of subsequently returning to work. To analyze time to return to work, Cox regression was used. RESULTS: The study sample included 232 lung cancer survivors of working age from 717 enrolled participants in the multi-center cross-sectional LARIS (Quality of Life and Psychosocial Rehabilitation in Lung Cancer Survivors) study. About 67% of the survivors were not employed during the survey. More than 51% of the survivors who were employed before their illness did not return to their work. The survivors who had returned to their careers were younger, associated with higher household income, lower fatigue score, and stable relationship and vocational training. Patients who received social service counseling showed a higher chance of regaining their career. CONCLUSIONS: Lung cancer survivors were found to be associated with a high risk of unemployment and very low professional reintegration after interruption due to illness. More comprehensive studies are needed to support lung cancer survivors and targeting of patients in need of special attention in rehabilitation that would benefit from the findings in the present study.
Assuntos
Sobreviventes de Câncer/psicologia , Neoplasias Pulmonares/psicologia , Retorno ao Trabalho/tendências , Adulto , Estudos Transversais , Feminino , Alemanha , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Sobreviventes/psicologiaRESUMO
INTRODUCTION: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. METHODS: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. RESULTS: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. CONCLUSION: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adesão à Medicação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/psicologia , Feminino , Humanos , Neoplasias Pulmonares/psicologia , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.
Assuntos
Carbapenêmicos/administração & dosagem , Clostridioides difficile , Glicopeptídeos/administração & dosagem , Quimioterapia de Indução , Tempo de Internação , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Enterocolite Pseudomembranosa/tratamento farmacológico , Enterocolite Pseudomembranosa/epidemiologia , Feminino , Humanos , Incidência , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: Red blood cell (RBC) transfusions are needed by almost every acute myeloid leukaemia (AML) patient undergoing induction chemotherapy and constitute a cornerstone in supportive measures for cancer patients in general. Randomized controlled trials have shown non-inferiority or even superiority of restrictive transfusion guidelines over liberal transfusion guidelines in specific clinical situations outside of medical oncology. In this study, we analysed whether more restrictive RBC transfusion reduces blood use without affecting hard outcomes. MATERIALS AND METHODS: A total of 352 AML patients diagnosed between 2007 and 2018 and undergoing intensive induction chemotherapy were included in this retrospective analysis. In the less restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 8 g/dl (2007-2014). In the restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 7 g/dl (2016-2018). Liberal transfusion triggers were never endorsed. RESULTS: A total of 268 (76·1%) and 84 (23·9%) AML patients fell into the less restrictive and restrictive transfusion groups, respectively. The less restrictive transfusion group had 1 g/dl higher mean haemoglobin levels, received their first RBC transfusions earlier and needed 1·5 more units of RBC during the hospital stay of induction chemotherapy. Febrile episodes, C-reactive protein levels, admission to the intensive care unit, length of hospital stay as well as response and survival rates did not differ between the two cohorts. CONCLUSION: From our retrospective analysis, we conclude that a more restrictive transfusion trigger does not affect important outcomes of AML patients. The opportunity to test possible effects of the more severe anaemia in the restrictive transfusion group on quality of life was missed.
Assuntos
Transfusão de Eritrócitos/métodos , Leucemia Mieloide Aguda/terapia , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/normas , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de SobrevidaRESUMO
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severely reduced activity of the von-Willebrand factor-cleaving protease ADAMTS13, mainly caused by anti-ADAMTS-13 antibodies. Although several test systems for ADAMTS13 measurement exist, long turn-around times hamper the usability in daily practice. We performed a method comparison study for two commercially available ADAMTS13 assays and evaluated the agreement between the fully-automated rapid turn-over HemosIL AcuStar ADAMTS13 Activity assay and the manually performed TECHNOZYM ADAMTS-13 Activity assay. Twenty-four paired test samples derived from 10 consecutively recruited patients (n = 8, acquired TTP; n = 1, atypical hemolytic uremic syndrome; n = 1, control), of which nine test samples were collected in case of clinically apparent TTP and 13 samples were collected from TTP patients in clinical remission were included. Overall correlation between the TECHNOZYM and AcuStar assay was good with a Pearson R of 0.93 (p < 0.001). Agreement between the assays assessed with the Passing-Bablok analysis showed high agreement with an Intercept of - 2.56 (95% confidence interval [CI], - 5.07 to - 0.86) and Slope of 1.04 (95% CI 0.84-1.17). The absolute mean bias was 2.54% (standard difference [SD], 6.38%; 95% CI to 10.0-15.05%). Intra-method reliability was high with an absolute mean bias of - 0.13% (SD 3.21%; 95% CI to 6.42-6.16%). The observer agreement for categorial thresholds (> or < 10% ADAMTS3 activity) was kappa = 0.82 (95% CI 0.59-1.0). Conclusively, overall agreement between the testing methods was sufficient and we support previously published data suggesting the AcuStar assay being a valuable and accurate tool for ADAMTS13 activity testing and TTP diagnostics.
Assuntos
Proteína ADAMTS13/sangue , Ensaios Enzimáticos/métodos , Púrpura Trombocitopênica Trombótica/enzimologia , Proteína ADAMTS13/metabolismo , Humanos , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
PURPOSE: Little is known about the use of psychosocial services in lung cancer survivors and patients who have survived the diagnosis for at least one year. We investigated the frequency of use, stratified by radiation therapy received, its associated factors, and the reasons for non-use of those services. METHODS: We performed a multicenter (nâ¯= 6 hospitals) cross-sectional study using data from medical records, patient reported questionnaires, and computer-assisted telephone interviews. Odds ratios (OR) for factors potentially associated with the use of any type of psychosocial services were calculated using multivariable logistic regression. RESULTS: We included 604 lung cancer patients/survivors. Of them, 60% (69% of those who had received radiotherapy) had used some kind of psychological and/or social service in the past (47% psychological, 42% social); 39% had used inpatient care, 24% outpatient care (cancer counselling center, general counselling center, psychological counselling by family doctor, psychotherapy, patient support group, pastoral work). Of those who visited a rehabilitation clinic, 66% received psychosocial care there. Factors associated with using psychosocial services in general were female gender (OR 1.96, 95% CI 1.32-2.93), poor emotional functioning (per unit decrease: OR 0.99, 95% CI 0.98-0.996), and younger age (per year decrease: OR 0.95, 95% CI 0.93-0.97). CONCLUSIONS/IMPLICATIONS: The high proportion of psychosocial care users among lung cancer survivors in Germany indicates that patients are interested in using it and that an unmet need exists. The creation of a broad spectrum of easily accessible services with high quality is important to enable and facilitate use.
Assuntos
Sobreviventes de Câncer/psicologia , Neoplasias Pulmonares/psicologia , Sistemas de Apoio Psicossocial , Adulto , Fatores Etários , Idoso , Sobreviventes de Câncer/estatística & dados numéricos , Ajustamento Emocional , Feminino , Alemanha , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Equipe de Assistência ao Paciente , Fatores SexuaisRESUMO
The 2016 revised World Health Organization (WHO) classification of lymphoid neoplasms included the category of high-grade B cell lymphomas (HGBLs) with combined MYC and BCL2 and/or BCL6 rearrangements (double-hit, DH). However, the clinical features of B cell precursor leukemia (BCP-ALL) that harbor DH genetics remain widely unknown. We performed a retrospective analysis of the German Multicenter Study Group for Adult ALL registry and a literature search for de novo DH-BCP-ALLs. We identified 6 patients in the GMALL registry and 11 patients published in the literature between 1983 and June 2018. Patients of all ages (range, 15-86 years) are affected. There is a high incidence of meningeal disease and other extramedullary disease manifestations. Current treatment approaches are mainly ALL-based and are sufficient to induce first complete remissions, but progression-free survival is only 4.0 months (95% CI, 1.5-6.5 months) and all patients succumb to their disease, once relapsed, with a median survival of 5.0 months (95% CI, 3.1-6.9 months), despite intensive salvage and targeted therapy approaches. Of all patients, only two that attained an initial complete remission were alive at data cutoff. In all cases, the BCL2 gene was rearranged to be in proximity to the IGH locus, whereas MYC had various translocation partners juxtaposed. There was no significant survival difference between IG and non-IG translocation partners (HR, 1.03; 95% CI, 0.33-3.2; p = 0.89). In conclusion, de novo DH-BCP-ALL is an aggressive B cell malignancy with deleterious outcome. Physicians have to be aware of this rare disease subset due to the atypical clinical behavior and especially because latest classification systems do not cover this sub-entity.
Assuntos
Genes bcl-2 , Genes myc , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Proteínas Proto-Oncogênicas c-bcl-6/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Rearranjo Gênico do Linfócito B , Humanos , Infiltração Leucêmica , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Intervalo Livre de Progressão , Recidiva , Terapia de Salvação , Translocação Genética , Adulto JovemRESUMO
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
Assuntos
Aminopiridinas , Carcinoma Pulmonar de Células não Pequenas , Lactamas Macrocíclicas , Lactamas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Pirazóis , Humanos , Lactamas/efeitos adversos , Aminopiridinas/efeitos adversos , Aminopiridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Gerenciamento ClínicoRESUMO
OBJECTIVE: The concept of lines of therapy (LOT) in cancer treatment is often considered for decision making in tumor boards and clinical management, but lacks a common definition across medical specialties. The complexity and heterogeneity of malignancies and treatment modalities contribute to an inconsistent understanding of LOT among physicians. This study assesses the heterogeneity of understandings of the LOT concept, its major dimensions, and criteria from the perspective of physicians of different specialties with an oncological focus in Germany. Semi-structured expert interviews with nine physicians were conducted and evaluated using qualitative content analysis. RESULTS: Most interviewees agreed that there is no single definition for LOT and found it difficult to explicate their understanding. A majority of experts stated that they had already encountered misunderstandings with colleagues regarding LOT and that they had problems with deciphering LOT from the medical records of their patients. Disagreement emerged about the roles of the following within the LOT concept: maintenance therapy, treatment intention, different therapy modalities, changing pharmaceutical agents, and therapy breaks. Respondents predominantly considered the same criteria as decisive for the definition of LOT as for a change in LOT (e.g., the occurrence of a progression event or tumor recurrence).
Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Masculino , Feminino , Entrevistas como Assunto , Alemanha , Pessoa de Meia-Idade , Pesquisa Qualitativa , Adulto , Médicos/psicologiaRESUMO
PURPOSE: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. METHODS: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2). RESULTS: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). CONCLUSION: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.
RESUMO
BACKGROUND: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials. METHODS: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels. RESULTS: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival. CONCLUSION: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit.