Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party.

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9-19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory.

Buso H ，Adam E ，Arkwright PD ，Bhattad S ，Hamidieh AA ，Behfar M ，Belot A ，Benezech S ，Chan AY ，Crow YJ ，Dvorak CC ，Flinn AM ，Kapoor U ，Lankester A ，Kobayashi M ，Matsumura R ，Mottaghipisheh H ，Okada S ，Ouachee M ，Parvaneh N ，Ramprakash S ，Satwani P ，Sharafian S ，Triaille C ，Wynn RF ，Movahedi N ，Ziaee V ，Williams E ，Slatter M ，Gennery AR ... -  《-》

Autologous hematopoietic stem cell transplantation following high dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas.

Peinemann F ，Smith LA ，Bartel C 《Cochrane Database of Systematic Reviews》

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.

Kiene S ，Albrecht M ，Theurich S ，Scheid C ，Skoetz N ，Holtick U ... -  《Cochrane Database of Systematic Reviews》

Defining the optimum strategy for identifying adults and children with coeliac disease: systematic review and economic modelling.

Elwenspoek MM ，Thom H ，Sheppard AL ，Keeney E ，O'Donnell R ，Jackson J ，Roadevin C ，Dawson S ，Lane D ，Stubbs J ，Everitt H ，Watson JC ，Hay AD ，Gillett P ，Robins G ，Jones HE ，Mallett S ，Whiting PF ... -  《-》

Comparison of Two Modern Survival Prediction Tools, SORG-MLA and METSSS, in Patients With Symptomatic Long-bone Metastases Who Underwent Local Treatment With Surgery Followed by Radiotherapy and With Radiotherapy Alone.

Survival estimation for patients with symptomatic skeletal metastases ideally should be made before a type of local treatment has already been determined. Currently available survival prediction tools, however, were generated using data from patients treated either operatively or with local radiation alone, raising concerns about whether they would generalize well to all patients presenting for assessment. The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA), trained with institution-based data of surgically treated patients, and the Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy model (METSSS), trained with registry-based data of patients treated with radiotherapy alone, are two of the most recently developed survival prediction models, but they have not been tested on patients whose local treatment strategy is not yet decided. (1) Which of these two survival prediction models performed better in a mixed cohort made up both of patients who received local treatment with surgery followed by radiotherapy and who had radiation alone for symptomatic bone metastases? (2) Which model performed better among patients whose local treatment consisted of only palliative radiotherapy? (3) Are laboratory values used by SORG-MLA, which are not included in METSSS, independently associated with survival after controlling for predictions made by METSSS? Between 2010 and 2018, we provided local treatment for 2113 adult patients with skeletal metastases in the extremities at an urban tertiary referral academic medical center using one of two strategies: (1) surgery followed by postoperative radiotherapy or (2) palliative radiotherapy alone. Every patient's survivorship status was ascertained either by their medical records or the national death registry from the Taiwanese National Health Insurance Administration. After applying a priori designated exclusion criteria, 91% (1920) were analyzed here. Among them, 48% (920) of the patients were female, and the median (IQR) age was 62 years (53 to 70 years). Lung was the most common primary tumor site (41% [782]), and 59% (1128) of patients had other skeletal metastases in addition to the treated lesion(s). In general, the indications for surgery were the presence of a complete pathologic fracture or an impending pathologic fracture, defined as having a Mirels score of ≥ 9, in patients with an American Society of Anesthesiologists (ASA) classification of less than or equal to IV and who were considered fit for surgery. The indications for radiotherapy were relief of pain, local tumor control, prevention of skeletal-related events, and any combination of the above. In all, 84% (1610) of the patients received palliative radiotherapy alone as local treatment for the target lesion(s), and 16% (310) underwent surgery followed by postoperative radiotherapy. Neither METSSS nor SORG-MLA was used at the point of care to aid clinical decision-making during the treatment period. Survival was retrospectively estimated by these two models to test their potential for providing survival probabilities. We first compared SORG to METSSS in the entire population. Then, we repeated the comparison in patients who received local treatment with palliative radiation alone. We assessed model performance by area under the receiver operating characteristic curve (AUROC), calibration analysis, Brier score, and decision curve analysis (DCA). The AUROC measures discrimination, which is the ability to distinguish patients with the event of interest (such as death at a particular time point) from those without. AUROC typically ranges from 0.5 to 1.0, with 0.5 indicating random guessing and 1.0 a perfect prediction, and in general, an AUROC of ≥ 0.7 indicates adequate discrimination for clinical use. Calibration refers to the agreement between the predicted outcomes (in this case, survival probabilities) and the actual outcomes, with a perfect calibration curve having an intercept of 0 and a slope of 1. A positive intercept indicates that the actual survival is generally underestimated by the prediction model, and a negative intercept suggests the opposite (overestimation). When comparing models, an intercept closer to 0 typically indicates better calibration. Calibration can also be summarized as log(O:E), the logarithm scale of the ratio of observed (O) to expected (E) survivors. A log(O:E) > 0 signals an underestimation (the observed survival is greater than the predicted survival); and a log(O:E) < 0 indicates the opposite (the observed survival is lower than the predicted survival). A model with a log(O:E) closer to 0 is generally considered better calibrated. The Brier score is the mean squared difference between the model predictions and the observed outcomes, and it ranges from 0 (best prediction) to 1 (worst prediction). The Brier score captures both discrimination and calibration, and it is considered a measure of overall model performance. In Brier score analysis, the "null model" assigns a predicted probability equal to the prevalence of the outcome and represents a model that adds no new information. A prediction model should achieve a Brier score at least lower than the null-model Brier score to be considered as useful. The DCA was developed as a method to determine whether using a model to inform treatment decisions would do more good than harm. It plots the net benefit of making decisions based on the model's predictions across all possible risk thresholds (or cost-to-benefit ratios) in relation to the two default strategies of treating all or no patients. The care provider can decide on an acceptable risk threshold for the proposed treatment in an individual and assess the corresponding net benefit to determine whether consulting with the model is superior to adopting the default strategies. Finally, we examined whether laboratory data, which were not included in the METSSS model, would have been independently associated with survival after controlling for the METSSS model's predictions by using the multivariable logistic and Cox proportional hazards regression analyses. Between the two models, only SORG-MLA achieved adequate discrimination (an AUROC of > 0.7) in the entire cohort (of patients treated operatively or with radiation alone) and in the subgroup of patients treated with palliative radiotherapy alone. SORG-MLA outperformed METSSS by a wide margin on discrimination, calibration, and Brier score analyses in not only the entire cohort but also the subgroup of patients whose local treatment consisted of radiotherapy alone. In both the entire cohort and the subgroup, DCA demonstrated that SORG-MLA provided more net benefit compared with the two default strategies (of treating all or no patients) and compared with METSSS when risk thresholds ranged from 0.2 to 0.9 at both 90 days and 1 year, indicating that using SORG-MLA as a decision-making aid was beneficial when a patient's individualized risk threshold for opting for treatment was 0.2 to 0.9. Higher albumin, lower alkaline phosphatase, lower calcium, higher hemoglobin, lower international normalized ratio, higher lymphocytes, lower neutrophils, lower neutrophil-to-lymphocyte ratio, lower platelet-to-lymphocyte ratio, higher sodium, and lower white blood cells were independently associated with better 1-year and overall survival after adjusting for the predictions made by METSSS. Based on these discoveries, clinicians might choose to consult SORG-MLA instead of METSSS for survival estimation in patients with long-bone metastases presenting for evaluation of local treatment. Basing a treatment decision on the predictions of SORG-MLA could be beneficial when a patient's individualized risk threshold for opting to undergo a particular treatment strategy ranged from 0.2 to 0.9. Future studies might investigate relevant laboratory items when constructing or refining a survival estimation model because these data demonstrated prognostic value independent of the predictions of the METSSS model, and future studies might also seek to keep these models up to date using data from diverse, contemporary patients undergoing both modern operative and nonoperative treatments. Level III, diagnostic study.

Lee CC ，Chen CW ，Yen HK ，Lin YP ，Lai CY ，Wang JL ，Groot OQ ，Janssen SJ ，Schwab JH ，Hsu FM ，Lin WH ... -  《-》