Donor KIR genotype based outcome prediction after allogeneic stem cell transplantation: no land in sight.

Optimizing natural killer (NK) cell alloreactivity could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). The donor's Killer-cell Immunoglobulin-like Receptor (KIR) genotype may provide important information in this regard. In the past decade, different models have been proposed aiming at maximizing NK cell activation by activating KIR-ligand interactions or minimizing inhibitory KIR-ligand interactions. Alternative classifications intended predicting outcome after alloHCT by donor KIR-haplotypes. In the present study, we aimed at validating proposed models and exploring more classification approaches. To this end, we analyzed samples stored at the Collaborative Biobank from HLA-compatible unrelated stem cell donors who had donated for patients with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS) and whose outcome data had been reported to EBMT or CIBMTR. The donor KIR genotype was determined by high resolution amplicon-based next generation sequencing. We analyzed data from 5,017 transplants. The median patient age at alloHCT was 56 years. Patients were transplanted for AML between 2013 and 2018. Donor-recipient pairs were matched for HLA-A, -B, -C, -DRB1, and -DQB1 (79%) or had single HLA mismatches. Myeloablative conditioning was given to 56% of patients. Fifty-two percent of patients received anti-thymocyte-globulin-based graft-versus-host disease prophylaxis, 32% calcineurin-inhibitor-based prophylaxis, and 7% post-transplant cyclophosphamide-based prophylaxis. We tested several previously reported classifications in multivariable regression analyses but could not confirm outcome associations. Exploratory analyses in 1,939 patients (39%) who were transplanted from donors with homozygous centromeric (cen) or telomeric (tel) A or B motifs, showed that the donor cen B/B-tel A/A diplotype was associated with a trend to better event-free survival (HR 0.84, p=.08) and reduced risk of non-relapse mortality (NRM) (HR 0.65, p=.01). When we further dissected the contribution of B subtypes, we found that only the cen B01/B01-telA/A diplotype was associated with a reduced risk of relapse (HR 0.40, p=.04) while all subtype combinations contributed to a reduced risk of NRM. This exploratory finding has to be validated in an independent data set. In summary, the existing body of evidence is not (yet) consistent enough to recommend use of donor KIR genotype information for donor selection in routine clinical practice.

Lung Cancer Screening: Low-Dose Thoracic Computed Tomography Performed in a High-Risk Portuguese Population.

INTRODUCTION: The Urgeiriça mines were once the main uranium producer in Portugal. The aim of this study was to estimate the benefit of low-dose chest computed tomography (LDCT) for lung cancer screening in former miners that were considered as being at high-risk. METHODS: A subgroup of former miners of the Uranium National Company exposed to uranium and with a smoking load greater than 20 pack-years, agreed to perform a LDCT. The Fleischner Society Guidelines were used to classify the nodules and establish follow-up. RESULTS: Initially, 265 former employees of the Uranium National Company were included. The mean time of employment was 15 (0 - 45) years. The non-smokers represented 50.9% and 30.2% were ever smokers; the remaining chose not to respond. One diagnosis of lung cancer was initially made. In the second phase, a subgroup of 66 former miner underwent a LDCT, 37 of whom presented pulmonary nodules. Most computed tomography (CT) scans revealed one single nodule (n = 13) and the mean size was 5 (1 - 16) mm. A suspicious 16 mm spiculated nodule was evaluated with PET/CT, and percutaneous and surgical biopsies, ultimately revealing a benign lesion. CONCLUSION: The data highlights the importance of lung cancer screening in high-risk populations. This was, to the best of our knowledge, the first study performed in Portugal and can act as a bridge towards a wider implementation in the country.

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry.

Introduction: COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Methods: This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. Results: The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. Discussion: Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.

Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. RESULTS: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/µL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. CONCLUSION: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.

Internet of Things and Enhanced Living Environments: Measuring and Mapping Air Quality Using Cyber-physical Systems and Mobile Computing Technologies.

This paper presents a real-time air quality monitoring system based on Internet of Things. Air quality is particularly relevant for enhanced living environments and well-being. The Environmental Protection Agency and the World Health Organization have acknowledged the material impact of air quality on public health and defined standards and policies to regulate and improve air quality. However, there is a significant need for cost-effective methods to monitor and control air quality which provide modularity, scalability, portability, easy installation and configuration features, and mobile computing technologies integration. The proposed method allows the measuring and mapping of air quality levels considering the spatial-temporal information. This system incorporates a cyber-physical system for data collection and mobile computing software for data consulting. Moreover, this method provides a cost-effective and efficient solution for air quality supervision and can be installed in vehicles to monitor air quality while travelling. The results obtained confirm the implementation of the system and present a relevant contribution to enhanced living environments in smart cities. This supervision solution provides real-time identification of unhealthy behaviours and supports the planning of possible interventions to increase air quality.

How Allogeneic Hematopoietic Stem Cell Transplantation has Evolved Over Time: 30-Years' Experience at a Single Institution.

INTRODUCTION: Allogeneic stem cell transplantation is an established procedure for a variety of diseases of the hematopoietic system. Our transplant program started in 1987 and since then advances have been made in the care of patients undergoing transplantation. We conducted a study to evaluate whether the changes implemented over time have improved the outcomes of transplantation. MATERIAL AND METHODS: We analyzed changes in patients, cell source, transplantation and outcome among 682 consecutive patients receiving their first transplant between 1987 and 2016. We compared overall survival, progression-free survival, the incidence of nonrelapse mortality and relapse in 10-year cohorts over the three decades of the study. RESULTS: The median age of transplanted patients, the use of peripheral blood and unrelated donors all increased very significantly. There was an increase in the number of high-risk patients when comparing the first decade with the two subsequent ones. The 3-year non-relapse mortality decreased significantly from 29% to 20% (p = 0.045), while the overall survival, progression free survival and cumulative incidence of relapse remained stable. DISCUSSION: Allogeneic hematopoietic stem cell transplantation has evolved considerably since its introduction in clinical practice. In the present study, we evaluated how these changes affected our practice along 30 years of activity and compared the results with those published in the literature. CONCLUSION: Despite increasing age, higher risk patients and the increasing use of unrelated donors our results show a continuous significantly reduced non-relapse mortality, with stable overall survival, progression free survival and relapse rate.

Introdução: A transplantação alogénica de células hematopoiéticas é utilizada regularmente no tratamento de uma grande variedade de doenças hematológicas. O nosso programa de transplantação teve início em 1987 e desde então têm sido numerosos os avanços nesta área. Este estudo foi conduzido para avaliar se as alterações introduzidas ao longo de 30 anos melhoraram os resultados obtidos. Material e Métodos: Analisámos os resultados numa população de 682 doentes submetidos consecutivamente a um primeiro transplante alogénico entre 1987 e 2016. Para tal, os doentes foram divididos em intervalos de 10 anos e comparámos a sobrevida global, a sobrevida livre de progressão, a mortalidade não associada a recaída e as recaídas em cada década do estudo. Resultados: A mediana de idades dos doentes transplantados, a utilização de células progenitoras provenientes do sangue periférico e a transplantação com dadores não familiares aumentaram muito significativamente ao longo do estudo. Verificou-se, comparativamente com a primeira década, um aumento do número de doentes de alto risco nas duas décadas subsequentes. A mortalidade não relacionada com recidiva, avaliada aos três anos pós-transplante, diminuiu significativamente de 29% para 20% (p = 0,045), mantendo-se estáveis a sobrevida global e a sobrevida livre de progressão, assim como a incidência cumulativa de recaídas. Discussão: A transplantação alogénica hematopoiética tem evoluído consideravelmente desde a sua introdução na prática clínica. No presente trabalho são avaliados os reflexos dessa evolução ao longo de 30 anos sendo analisados os resultados obtidos e comparados com os referidos na literatura. Conclusão: Apesar das características mais desfavoráveis verificadas ao longo das três décadas (doentes mais idosos, doenças de risco mais elevado, aumento do número de dadores não familiares) foi possível reduzir significativamente a mortalidade associada ao procedimento, mantendo-se estáveis a sobrevida global e livre de progressão, assim como a incidência de recaídas.

Widespread skin nodules as a manifestation of breakthrough invasive aspergillosis in a bone marrow transplant patient.

Invasive aspergillosis (IA) is a life-threatening complication of bone marrow transplantation manifesting most often as a respiratory tract infection with potential hematogenous dissemination to any organ. The authors report an unusual case of IA manifesting as widespread subcutaneous nodules, with intact overlying skin, complicating pulmonary infection in a transplanted patient who received mold-active antifungal prophylaxis. The present case emphasizes the relevance of cellular immunity, in particular T lymphocytes, in the control of invasive fungal disease and highlights the potential role of positron emission tomography scan in assessing its dissemination.

[High dose chemotherapy with autologous stem-cell support in germ cell tumors: The Instituto Português de Oncologia de Lisboa Francisco Gentil Series]. / Quimioterapia de alta dose com suporte hematopoiético autólogo em tumores de células germinativas Experiência do Instituto Português de Oncologia de Lisboa Francisco Gentil.

BACKGROUND: High dose chemotherapy with autologous stem cell transplantation (HDCT-ASCT) has been administered to patients with high-risk germ cell tumours (GCT). The role of this treatment for GCT still remains unclear, including the identification of subgroups more likely to benefit from such strategy. METHODS: A retrospective review was conducted of all male patients with gonadal and extra gonadal GCT treated with HDCT-ASCT between 1996 and 2008 at the Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). RESULTS: Twenty patients were treated with HDCT-ASCT, 17 with primary testicular tumours, two mediastinal and one retroperitoneal GCT. According to the International Germ Cell Cancer Consensus Group (IGCCCG) classification, at diagnosis three patients had good risk, four intermediate, eight poor but for the patients left the risk group could not be ascertained. In eight patients HDCT-ASCT was used upfront, after induction with first-line conventional chemotherapy, and in the remaining 12 for relapsed GCT. One patient had platinum-resistant and another platinum-refractory disease. Only two patients had Beyer score > 2. All but one patient were treated with ICE (Ifosfamide, Carboplatin, Etoposide). Six patients underwent a second HDCT-ASCT course. The 5-year overall survival and progression free survival were respectively 53% and 44%; both patients with mediastinal GCT are long term survivors. CONCLUSION: Randomized studies to date have failed to indicate a survival advantage for HDCT-ASCT in GCT. This series is small and heterogeneous which prevents us from drawing conclusions regarding the benefit of this treatment for GCT. However, we could confirm the lack of benefit of HDCT-ASCT for platinum-resistant GCT and to question the absolute contraindication to this therapeutic modality in mediastinal GCT. HDCT-ASCT should therefore be performed exclusively in experienced centers and, preferably, in the setting of clinical trials.

[High-dose chemotherapy and stem-cell in patients with breast cancer]. / Quimioterapia intensiva comsuporte hematopoiético autólogoem doentes com carcinoma da mama.

BACKGROUND: The treatment of breast cancer patients with high-dose chemotherapy and stem-cell support is still highly controversial. The elucidation of its clinical benefit awaits the maturation of on-going clinical trials. METHODS: Patients with chemotherapy-sensitive metastatic or locally advanced disease and patients with stage II/III disease and at least four positive axillary lymph nodes in the initial surgical specimen were eligible for transplantation. RESULTS: Fifty-five women underwent transplantation between 1994 and 2000. For the 19 women with metastatic disease, the median time to progression was seven month and survival 28 months. Only two patients are progression-free, at 48 and 77 months, both with supraclavicular and/or cervical lymph node-only disease. For the 36 women with stage II/III disease, the median time to progression and survival were both 65 months -19 are alive, 18 disease-free. Among the subgroup of 23 patients with 10 or more positive axillary nodes, the five-year event-free survival was 57%. CONCLUSION: The clinical benefit of stem-cell transplantation for metastatic breast cancer is limited since the time to progression and survival after transplantation is similar to those reported in patients with newly diagnosed metastases and treated with conventional-dose chemotherapy. However, in patients with high-risk stage II/III disease the time to progression is longer than that reported for similar patients treated with conventional systemic treatment. These results are similar to previous reports in the literature.