Ethical considerations for the age of non-governmental space exploration.

Mounting ambitions and capabilities for public and private, non-government sector crewed space exploration bring with them an increasingly diverse set of space travelers, raising new and nontrivial ethical, legal, and medical policy and practice concerns which are still relatively underexplored. In this piece, we lay out several pressing issues related to ethical considerations for selecting space travelers and conducting human subject research on them, especially in the context of non-governmental and commercial/private space operations.

Aging and putative frailty biomarkers are altered by spaceflight.

Human space exploration poses inherent risks to astronauts' health, leading to molecular changes that can significantly impact their well-being. These alterations encompass genomic instability, mitochondrial dysfunction, increased inflammation, homeostatic dysregulation, and various epigenomic changes. Remarkably, these changes bear similarities to those observed during the aging process on Earth. However, our understanding of the connection between these molecular shifts and disease development in space remains limited. Frailty syndrome, a clinical syndrome associated with biological aging, has not been comprehensively investigated during spaceflight. To bridge this knowledge gap, we leveraged murine data obtained from NASA's GeneLab, along with astronaut data gathered from the JAXA and Inspiration4 missions. Our objective was to assess the presence of biological markers and pathways related to frailty, aging, and sarcopenia within the spaceflight context. Through our analysis, we identified notable changes in gene expression patterns that may be indicative of the development of a frailty-like condition during space missions. These findings suggest that the parallels between spaceflight and the aging process may extend to encompass frailty as well. Consequently, further investigations exploring the utility of a frailty index in monitoring astronaut health appear to be warranted.

Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review.

Outer space is an extremely hostile environment for human life, with ionizing radiation from galactic cosmic rays and microgravity posing the most significant hazards to the health of astronauts. Spaceflight has also been shown to have an impact on established cancer hallmarks, possibly increasing carcinogenic risk. Terrestrially, women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore, historically, they have been permitted to spend significantly less time in space than men. In the present review, we focus on the effects of microgravity and radiation on the female reproductive system, particularly gynecological cancer. The aim is to provide a summary of the research that has been carried out related to the risk of gynecological cancer, highlighting what further studies are needed to pave the way for safer exploration class missions, as well as postflight screening and management of women astronauts following long-duration spaceflight.

Safety and Efficacy of Subcutaneous Rituximab in Previously Untreated Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Results from an Italian Phase IIIb Study.

Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505.

Restoring global offset and lower limb length with a 3 offset option double-tapered stem.

BACKGROUND: A proper restoration of hip biomechanics is fundamental to achieve satisfactory outcomes after total hip arthroplasty (THA). A global hip offset (GO) postoperatively reduction of more than 5 mm was known to impair hip functionality after THA. This study aimed to verify the restoration of the GO radiographic parameter after primary THA by the use of a cementless femoral stem available in three different offset options without length changing. METHODS: From a consecutive series of 201 patients (201 hips) underwent primary cementless THA in our center with a minimum 3-year follow up, 80 patients (80 hips) were available for complete radiographic evaluation for GO and limb length (LL) and clinical evaluation with Harris hip score (HHS). All patients received the same femoral stem with three different offset options (option A with - 5 mm offset, option B and option C with + 5 mm offset, constant for each sizes) without changing stem length. RESULTS: Mean GO significantly increased by + 3 mm (P < 0.05) and mean LL significantly decreased by + 5 mm (P < 0.05) after surgery, meaning that postoperatively the limb length of the operated side increased by + 5 mm. HHS significantly improved from 56.3 points preoperatively to 95.8 postoperatively (P < 0.001). Offset option A was used in 1 hip (1%), B in 59 hips (74%) and C in 20 hips (25%). CONCLUSIONS: The femur is lateralized with a mean of + 5 mm after surgery than, the native anatomy, whatever type of stem was used. Thus, the use of this 3-offset options femoral stem is effective in restoring the native biomechanical hip parameters as GO, even if 2 offset options were considered sufficient to restore GO.

The value of a standardized and reproducible surgical technique in treatment of Vancouver B2 periprosthetic fractures: our experience.

PURPOSE: To retrospectively review results and complications of our standardized surgical technique addressed exclusively to Vancouver B2 fractures. METHODS: From January 2006 to July 2016, we treated 235 consecutive patients, 47 males and 188 females, mean age at surgery of 71 ± 10 years, with periprosthetic B2 fractures. Exclusion criteria were other kind of periprosthetic fractures and other femoral fractures. The patients were assessed clinically and radiographically following our standard protocol at the last available follow-up. The mean follow-up time was 6.4 years. Radiographic evaluation was performed according to Beals and Tower's criteria and clinical evaluation was performed using the Harris Hip Score and clinical exam. RESULTS: From the starter cohort of 235, 207 patients (88.1%) were fully evaluated, while 28 were lost to follow-up. According to Beal and Tower's criteria, we found excellent results in 72 patients (34.8%), good results in 133 patients (64.3%), and poor results in 2 patients (0.9%). Mean HHS was 75 ± 9 points, with a statistically significant correlation between good functional results and better radiographic assessment (p = 0.001). The use of support plate (p = 0.008) and the acetabular revision (p = 0.002) showed a statistically significant distribution with worse radiographic results. Late complications detected were ten dislocations. CONCLUSION: Our experience suggests that using a standardized and reproducible surgical technique, as our technique proposed, can surely reduce surgical time, the complication rate, and the mortality rate. During acetabular evaluation, the choice of performing a cup revision must be weighed on overall patient's assessment.

Tibial Tubercle Osteotomy in Total Knee Arthroplasty: Midterm Results Experience of a Monocentric Study.

Purpose Difficult primary total knee arthroplasty (TKA) and revision TKA may be high demanding, especially during joint exposure. Aim of this article is to evaluate the clinical and radiological outcomes of a series of patients, who underwent TKA and revision TKA, where tibial tubercle osteotomy (TTO) was performed. Methods We retrospectively reviewed a cohort of 79 consecutives TKAs where TTO was performed. Patients were assessed clinically and radiographically at their last follow-up (mean, 7.4 ± 3.7 years). Clinical evaluation included the Knee Society Score (KSS), the pain visual analogue scale (VAS), and range of motion. Radiological assessment included the evaluation of radiolucent lines, osteolysis, cortical bone hypertrophy, time of bone healing of the TTO fragment, and the hardware complication. Results KSS raised from 40.7 ± 3.1 to 75 ± 4.3 ( p < 0.0001). Knee flexion increased from 78.7 ± 9.9° to 95.0 ± 9.5° ( p < 0.0001), and VAS improved from 7.9 ± 0.9 to 3.8 ± 1 ( p < 0.0001). No signs of loosening or evolutive radiolucency lines were found. Osteolytic areas around the stem were detected. No significant association was found between the implant design and the outcomes, while aseptic loosening showed significantly better results. Complications were: 4 painful hardware, 3 late periprosthetic infections, 1 extension lag of 5°, and 3 flexion lag. Conclusion Our experience suggests the use of TTO to improve the surgical approach in difficult primary TKA or revision TKA. A precise surgical technique leads to good results with low risk of complications. Level of Evidence Level IV, therapeutic case series.

Tibial tubercle osteotomy (TTO) in total knee arthroplasty, is it worth it? A review of the literature.

INTRODUCTION: Tibial tubercle osteotomy (TTO) is a well-established extensile approach to improve joint visualization and implant removal. Despite this, TTO is a challenging technique with a long learning curve and potential pitfalls. Complications are not infrequent, even if performing the correct surgical steps. Aim of this paper is to review the current literature about TTO, its safeness and reliability, and finally the complications rate. MATERIALS AND METHODS: We performed a systematic review of the available English literature, considering the outcomes and the complications of TTO. The combinations of keyword were "tibial tubercle osteotomy", "total knee arthroplasty", "total knee revision", "outcomes", "complication" and "surgical approach". RESULTS: From the starting 322 papers available, 26 manuscripts were finally included. Most of the papers show significant improvements in clinical outcomes, both in primary and in revision procedures. Radiographic fragment healing is close to 100%. Related complications can range from 3.8-20%. CONCLUSION: TTO may be necessary to correct pathological tuberosity position or patella tracking. However, TTO is a challenging technique to improve the surgical approach during total knee arthroplasty. A strict surgical technique can lead to better results and to minimize complications. However, it is not clear if the improved outcome can outweigh the longer surgery and the higher risk of pitfalls.

Ten-Year Results of Primary and Revision Condylar-Constrained Total Knee Arthroplasty in Patients with Severe Coronal Plane Instability.

OBJECTIVE: To retrospectively review the results at minimum ten years after surgery of a consecutive series of total knee arthroplasties (TKAs) performed using a constrained condylar implant in patients with severe coronal plane instability. MATERIALS AND METHODS: The series comprised of 44 patients (45 knees) who received primary (19 knees) or revision (26 knees) TKA with a constrained condylar implant between 2001 and 2003 at a single institution. RESULTS: There were no revisions or any other surgery related complications at a mean implantation time of 11.0 years. In 38 patients (15 knees in the primary group and 24 knees in the revision group) who were available for clinico-radiographic follow-up at a minimum of ten years, there was no sign of radiographic loosening. Two patients showed cortical hypertrophy at the extension stem tip but none complained of pain around the stem tip. According to the TLKSS score grading, 73% of the patients in the primary group had results categorized as good or excellent, while 54% of the patients in the revision group had fair results. Four patients (one (7%) in the primary group and three (13%) in the revision group) had poor results. The median WOMAC Index was 80.2% (interquartile range: 74.0% - 81.2%) and 74.0% (interquartile range: 72.1% - 75.8%) in the primary and in the revision groups, respectively (p=0.010). CONCLUSION: This study showed satisfactory clinical outcomes with no re-operations at minimum ten years after implantation in patients who had undergone primary or revision TKA with a condylar constrained implant.

High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial.

PURPOSE: Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine. PATIENTS AND METHODS: The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival. RESULTS: At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine. CONCLUSION: HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.

Hip arthroplasty in a patient with congenital pubic diastasis and bladder exstrophy.

We report a total hip arthroplasty performed for arthritis and osteonecrosis in a patient with congenital pubic diastasis and bladder exstrophy. A satisfactory outcome was achieved after appropriate consideration of the technical and biomechanical issues involved.

Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab.

In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59(-)). The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients.

A large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory (n = 16), or relapsed (n = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible.

M4 acute myeloid leukemia: the role of eosinophilia and cytogenetics in treatment response and survival. The GIMEMA experience.

BACKGROUND: Myelomonocytic acute myeloid leukemia (M4-AML) is frequently associated with the cytogenetic marker inv(16) and/or the presence of eosinophilia. The aim of this study was to analyze the incidence and prognostic role of these factors in a large series of patients. DESIGN AND METHODS: Adult patients with acute myeloid leukemia consecutively enrolled in the GIMEMA trials AML10 and LAM99p were retrospectively analyzed. RESULTS: Among 1686 patients, 400 cases of M4-AML were identified; of these, 78% had neither eosinophilia nor inv(16), 6% had eosinophilia only, 8% had inv(16) only and 8% had both. Univariate analysis showed that both eosinophilia and inv(16) were correlated with a higher probability of complete remission, lower resistance to chemotherapy and increased overall survival. Multivariate analysis showed that the simultaneous presence of the two factors significantly increased the probabilities of both complete remission and overall survival. The presence of only one of the two factors also increased the probabilities of complete remission and overall survival, but not to a statistically significant extent. The relapse-free survival of the responding patients was not influenced by the two factors. CONCLUSIONS: In a large series of patients with M4-AML we confirmed the favorable role of inv(16), but the weight of this factor among the whole M4 population was of limited relevance. Eosinophilia, which affects a small proportion of cases, also emerged as a favorable prognostic factor. Based on the results of this large case population, overall and relapse-free survival rates of patients with M4-AML are not significantly better than those of patients with non-M4 AML, while the concomitant presence of both inv(16) and eosinophilia was associated with a significantly improved prognosis.