BACKGROUND: Radiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness and lymphoedema. The use of radiation dose and volume thresholds, called dose constraints, may potentially reduce the development of toxicities in STSE. The aim of this study is to determine predictors of radiotherapy-related side effects for STSE.
METHODS: Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) is a multicentre observational study comprising two cohorts (PredicT A and B). PredicT A, a retrospective analysis of the UK VorteX (NCT00423618) and IMRiS clinical trials (NCT02520128), is aimed at deriving a statistical model for development of dose-volume constraints. This model will use receiving operator characteristics and multivariate analysis to predict radiotherapy side effects and patient-reported outcomes. PredicT B, a prospective cohort study of 150 patients with STSE, is aimed at testing the validity of those dose-volume constraints. PredicT B is open and planned to complete recruitment by September 2024.
BACKGROUND: PredicT B has received ethical approval from North West - Liverpool Central Research Ethics Committee (20/NW/0267). Participants gave informed consent to participate in the study before taking part. We will disseminate our findings via publications, presentations, national and international conference meetings and engage with local charities.
BACKGROUND: NCT05978024.

OBJECTIVE: Prognostic factors have been well described for osteosarcoma, but analyses evaluating the further course of long-term survivors are lacking. We used the large database of the Cooperative Osteosarcoma Study Group (COSS) to perform such an analysis.
METHODS: The COSS database 1980-04/2019 was searched for 5-year survivors of primary high-grade central osteosarcoma of the extremities or trunk. Identified patients were analyzed for their further survival outcomes, assessing potentially prognostic and predictive factors already evident at initial disease presentation and treatment as well as their disease course during the first 5 years of follow-up.
RESULTS: Two thousand and nine former eligible patients were identified (median age at initial diagnosis 15.1 (2.5-63.0) years; male vs. female 1149 (57.2%) vs. 860 (42.8%); extremities vs. trunk 1927 (95.9%) vs. 82 (4.1%); extremity primaries <1/3 vs. ≥1/3 of the involved bone 997 (67.8%) vs. 474 (32.2%) (456 unknown); localized vs. primary metastatic 1881 (93.6%) vs. 128 (6.4%); osteosarcoma as a secondary malignancy 41/2009 (2.0%)). Therapy starting by chemotherapy versus primary surgery 1860 (92.6%) versus 149 (7.4%); definitive tumor surgery by limb salvage versus ablative 1347 (67.0%) versus 659 (1 no surgery, 2 unknown); tumor response to preoperative chemotherapy documented for 1765 (94.9%) patients receiving neoadjuvant chemotherapy, good (<10% viable tumor) versus poor 1130 (64.0%) versus 635 (36.0%), local radiotherapy documented for 19 (0.9%) tumors. Recurrence during preceding 5 years no versus yes 1681 (83.7%) versus 328 (16.3%). Median follow-up starting 5 years after initial diagnosis 6.1 (0.002-32.2) years; 1815 survivors and 194 deaths. Overall survival after another 5/10/15/20 years 91.7%/88.9%/85.8%/83.4% for all patients; 97.5%/95.2%/92.4%/89.9% if in remission years 1-5 versus 62.7%/57.3%/53.0%/51.2% if recurrence year 1-5 (p < 0.001). Significant predictors of survival for all patients age at diagnosis (p = 0.038), tumor site (p = 0.030), having experienced the osteosarcoma as secondary malignancy (p < 0.001), tumor response to preoperative chemotherapy (p = 0.002). Multivariate Cox regression testing possible for 1759 (87.6%) patients with complete dataset: Having had a recurrence in years 1-5 (p < 0.001), older age at diagnosis (p = 0.009), and osteosarcoma as secondary malignancy (p = 0.013) retained significance.
CONCLUSIONS: Highly important predictors of death such as the extent of tumor response to chemotherapy no longer remain valid after 5-year survival. The individual history of malignancies and their outcomes seems to gain pivotal importance.
CONCLUSIONS: This benchmark analysis clearly defined risk factors for the further course of 5-year survivors from osteosarcoma. It argues for large disease-oriented databases as well as for very long follow-up periods. Novel findings will most likely require innovative statistical models to analyze such cohorts.

The cellular and genetic networks that contribute to the development of the zeugopod (radius and ulna of the forearm, tibia and fibula of the leg) are not well understood, although these bones are susceptible to loss in congenital human syndromes and to the action of teratogens such as thalidomide. Using a new fate-mapping approach with the Chameleon transgenic chicken line, we show that there is a small contribution of SHH-expressing cells to the posterior ulna, posterior carpals and digit 3. We establish that although the majority of the ulna develops in response to paracrine SHH signalling in both the chicken and mouse, there are differences in the contribution of SHH-expressing cells between mouse and chicken as well as between the chicken ulna and fibula. This is evidence that, although zeugopod bones are clearly homologous according to the fossil record, the gene regulatory networks that contribute to their development and evolution are not fixed.

Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.

The axolotl (Ambystoma mexicanum) is renowned for its remarkable regenerative capabilities, which are not diminished by the transition from a neotenic to a metamorphic state. This study explored the microbiome dynamics in axolotl limb regeneration by examining the microbial communities present in neotenic and metamorphic axolotls at two critical stages of limb regeneration: pre-amputation and during blastema formation. Utilizing 16S rRNA amplicon sequencing, we investigated the variations in microbiome profiles associated with different developmental and regenerative states. Our findings reveal a distinct separation in the microbiome profiles of neotenic and metamorphic samples, with a clear demarcation in microbial composition at both the phylum and genus levels. In neotenic 0DPA samples, Proteobacteria and Firmicutes were the most abundant, whereas in neotenic 7DPA samples, Proteobacteria and Bacteroidetes dominated. Conversely, metamorphic samples displayed a higher abundance of Firmicutes and Bacteroidetes at 0DPA and Proteobacteria and Firmicutes at 7DPA. Alpha and beta diversity analyses, along with dendrogram construction, demonstrated significant variations within and between the sample groups, suggesting a strong influence of both developmental stage and regenerative state on the microbiome. Notably, Flavobacterium and Undibacterium emerged as distinctive microbial entities in neotenic 7DPA samples, highlighting potential key players in the microbial ecology of regeneration. These findings suggest that the axolotl\'s microbiome is dynamically responsive to blastema formation, and they underscore the potential influence of microbial communities on the regeneration process. This study lays the groundwork for future research into the mechanisms by which the microbiome may modulate regenerative capacity.

BACKGROUND: Oncologic surgical resection is the standard of care for extremity and truncal soft tissue sarcoma (STS), often accompanied by the addition of pre- or postoperative radiation therapy (RT). Preoperative RT may decrease the risk of joint stiffness and fibrosis at the cost of higher rates of wound complications. Hypofractionated, preoperative RT has been shown to provide acceptable outcomes in prospective trials. Proton beam therapy (PBT) provides the means to decrease dose to surrounding organs at risk, such as the skin, bone, soft tissues, and adjacent joint(s), and has not yet been studied in patients with extremity and truncal sarcoma.
METHODS: Our study titled \"PROspective phase II trial of preoperative hypofractionated protoN therapy for extremity and Truncal soft tissue sarcOma (PRONTO)\" is a non-randomized, prospective phase II trial evaluating the safety and efficacy of preoperative, hypofractionated PBT for patients with STS of the extremity and trunk planned for surgical resection. Adult patients with Eastern Cooperative Group Performance Status ≤ 2 with resectable extremity and truncal STS will be included, with the aim to accrue 40 patients. Treatment will consist of 30 Gy radiobiological equivalent of PBT in 5 fractions delivered every other day, followed by surgical resection 2-12 weeks later. The primary outcome is rate of major wound complications as defined according to the National Cancer Institute of Canada Sarcoma2 (NCIC-SR2) Multicenter Trial. Secondary objectives include rate of late grade ≥ 2 toxicity, local recurrence-free survival and distant metastasis-free survival at 1- and 2-years, functional outcomes, quality of life, and pathologic response.
CONCLUSIONS: PRONTO represents the first trial evaluating the use of hypofractionated PBT for STS. We aim to prove the safety and efficacy of this approach and to compare our results to historical outcomes established by previous trials. Given the low number of proton centers and limited availability, the short course of PBT may provide the opportunity to treat patients who would otherwise be limited when treating with daily RT over several weeks. We hope that this trial will lead to increased referral patterns, offer benefits towards patient convenience and clinic workflow efficiency, and provide evidence supporting the use of PBT in this setting.
BACKGROUND: NCT05917301 (registered 23/6/2023).

Informal caregivers play a significant role in providing care for older, often vulnerable, patients, and supporting them as they live with chronic diseases. Due to the rising prevalence of older vascular patients and their use of healthcare, the role of their informal caregivers will become more important. However, little is known about the experiences of informal caregivers of patients with critical limb-threatening ischemia and the impact of informal care on different aspects of these caregivers\' lives. In addition, literature does not describe the burden this role brings with it, or lack thereof. Therefore a qualitative study using a phenomenological approach, specifically interpretive phenomenological analysis, was used to gain insight into the experiences of the primary informal caregivers of patients with chronic limb-threatening ischemia. Data were collected via semi-structured interviews and focus groups discussions. Fifteen primary informal caregivers of patients with critical limb-threatening ischemia under the care of the vascular surgeon at a tertiary teaching hospital in the Netherlands were included. Data analysis yielded three themes: the perceived identity of this group of caregivers; the varying intensity of informal care; and the collaboration between informal carers, their care recipients and the professional care provider within the vascular surgery department. In contrast to carers of other chronic diseases, the shifting intensity of care that informal caregivers of critical limb-threatening ischemia patients experience seems to prevent long-term overload. Adapting to that fluctuating situation requires flexibility from healthcare providers within the vascular surgery department. In addition, professionals need to involve informal caregivers in the patient\'s decision-making process and recognize their role in that process.

In triatomines, vectors of Chagas disease, active dispersal takes place by walking and flying. Flight has received more attention than walking although the last is the dispersal modality used by nymphs due to their lack of wings and also used by adults, which would facilitate the colonization and reinfestation of houses after vector control actions. The present work studied the morphometrical variation of Triatoma infestans legs, the main vector of Chagas disease the Southern Cone of South America. We described morphometric traits and the natural variation of each leg segment. Different linear, size and shape variables of each component of the three right legs of fifth instar nymphs of T. infestans were analyzed using morphometric tools. We analyzed differentiation, variation and correlation for each segment across the fore-, mid and hind legs using different statistical approaches such as general linear model, canonical variates analysis, test of equality of coefficient of variation and partial least square analysis. We also analyzed variation and correlation between segments within each leg with partial least square and morphometric disparity analyses. Our results showed that the segments differed between legs, as general trends, the dimensions (length, width and/or size) were greater in the hind legs, smaller in the forelegs and intermediate in the mid ones. The femur and tibia (length and/or width) showed differences in morphometric variation between legs and the femur and tibia showed the highest levels of correlation between legs. On the other hand, in the fore- and mid legs, the femur (length or width) showed similar variation with tibia and tarsus lengths, but in the hind legs, the femur showed similar variation with all segments and not with the tibia length, and there were strong correlations between linear measurement within each leg. Our results suggest that the femur and tibia could play a determining role in the coordination between the legs that determines the walking pattern. Considering that these segments would also be linked to the specific function that each leg has, this study suggests a preponderant role of the femur and tibia in the walking locomotion of T. infestans.

OBJECTIVE: ILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM).
METHODS: In this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs).
RESULTS: A total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms.
CONCLUSIONS: For patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial.

BACKGROUND: Control of massive hemorrhage (MH) is a life-saving intervention. The use of tourniquets has been studied in prehospital and battlefield settings but not in aquatic environments.
OBJECTIVE: The aim of this research is to assess the control of MH in an aquatic environment by analyzing the usability of two tourniquet models with different adjustment mechanisms: windlass rod versus ratchet.
METHODS: A pilot simulation study was conducted using a randomized crossover design to assess the control of MH resulting from an upper extremity arterial perforation in an aquatic setting. A sample of 24 trained lifeguards performed two randomized tests: one using a windlass-based Combat Application Tourniquet 7 Gen (T-CAT) and the other using a ratchet-based OMNA Marine Tourniquet (T-OMNA) specifically designed for aquatic use on a training arm for hemorrhage control. The tests were conducted after swimming an approximate distance of 100 meters and the tourniquets were applied while in the water. The following parameters were recorded: time of rescue (rescue phases and tourniquet application), perceived fatigue, and technical actions related to tourniquet skills.
RESULTS: With the T-OMNA, 46% of the lifeguards successfully stopped the MH compared to 21% with the T-CAT (P = .015). The approach swim time was 135 seconds with the T-OMNA and 131 seconds with the T-CAT (P = .42). The total time (swim time plus tourniquet placement) was 174 seconds with the T-OMNA and 177 seconds with the T-CAT (P = .55). The adjustment time (from securing the Velcro to completing the manipulation of the windlass or ratchet) for the T-OMNA was faster than with the T-CAT (six seconds versus 19 seconds; P < .001; effect size [ES] = 0.83). The perceived fatigue was high, with a score of seven out of ten in both tests (P = .46).
CONCLUSIONS: Lifeguards in this study demonstrated the ability to use both tourniquets during aquatic rescues under conditions of fatigue. The tourniquet with the ratcheting-fixation system controlled hemorrhage in less time than the windlass rod-based tourniquet, although achieving complete bleeding control had a low success rate.