Background: Reconstruction with vascularized fibula grafts (VFG) after intercalary resection of sarcoma may offer longevity by providing early graft-host union and fracture healing. The ability of the fibula to hypertrophy under mechanical stress, as well as vascularized bone in the area, may also be advantageous, given that soft tissues may be compromised because of resection, chemotherapy, or radiation therapy. VFG with a massive allograft combines the primary mechanical stability of the graft with the biological potential of the vascularized fibula; however, complications and the durability of this combined reconstruction are not well described. Questions/purposes: (1) What was the proportion of complications after reconstruction with VFG, with or without allografts? (2) What was the functional result after surgical treatment as assessed by the Musculoskeletal Tumor Society (MSTS) score? (3) What was the survivorship of these grafts free from revision and graft removal? Methods: Between 1988 and 2021, 219 patients were treated at our institution for a primary malignant or aggressive benign bone tumor of the tibia with en bloc resection. Of those, 54% (119 of 219) had proximal tibial tumors with epiphyseal involvement and were treated with either intra-articular resection and reconstruction with an osteoarticular allograft, allograft-prosthesis composite (APC), or modular prosthesis according to age, diagnosis, and preoperative or postoperative radiotherapy. Nine percent (20) of patients had distal tibial tumors that were treated with intra-articular resection and reconstruction with ankle arthrodesis using allogenic or autologous grafts, and 0.5% (1 patient) underwent total tibial resection for extensive tumoral involvement of the tibia and reconstruction with an APC. Thirty-six percent (79) of patients had a metadiaphyseal bone tumor of the tibia and were treated with intercalary joint-sparing resection. We routinely use reconstruction with VFG after intercalary tibial resection for primary malignant or aggressive benign bone tumors in patients with long life expectancy and high functional demands and in whom at least 1 cm of residual bone stock of the proximal or distal epiphysis can be preserved. By contrast, we routinely use intercalary massive allograft reconstruction in short resections or in patients with metastatic disease who do not have long life expectancy. We avoid VFG in patients with tibial bone metastasis, patients older than 70 years, or primary bone tumors in patients who may undergo postoperative radiotherapy; in these patients, we use alternative reconstructive methods such as intercalary prostheses, plate and cement, or intramedullary nailing with cement augmentation. According to the above-mentioned indications, 6% (5 of 79) of patients underwent massive allograft reconstruction because they were young and had intercalary resections shorter than 7 cm or had metastatic disease at diagnosis without long life expectancy, whereas 94% (74) of patients underwent VFG reconstruction. The median age at operation was 16 years (range 5 to 68 years). The diagnosis was high-grade osteosarcoma in 22 patients, Ewing sarcoma in 19, adamantinoma in 16, low-grade osteosarcoma in five, fibrosarcoma in three, malignant fibrous histiocytoma and Grade 2 chondrosarcoma in two, and malignant myoepitelioma, angiosarcoma of bone, malignant peripheral nerve sheath tumor of bone, squamous cell carcinoma secondary to chronic osteomyelitis, and desmoplastic fibroma in one patient each. Median follow-up was 12.3 years (range 2 to 35 years). The median tibial resection length was 15 cm (range 7 to 27 cm), and the median fibular resection length was 18 cm (range 10 to 29 cm). VFG was used with a massive allograft in 55 patients, alone in 12 patients, and combined with allogenic cortical bone struts in seven patients. We used VFG combined with a massive allograft in patients undergoing juxta-articular, joint-sparing resections that left less than 3 cm of residual epiphyseal bone, for intra-epiphyseal resections, or for long intercalary resections wherein the allograft can provide better mechanical stability. In these clinical situations, the combination of a VFG and massive allograft allows more stable fixation and better tendinous reattachment of the patellar tendon. VFG was used with cortical bone struts in distal tibia intercalary resections where the narrow diameter of the allograft did not allow concentric assembling with the fibula. Finally, VFG alone was often used after mid- or distal tibia intercalary resection in patients with critical soft tissue conditions because of previous surgery, in whom the combination with massive allograft would result in a bulkier reconstruction. We ascertained complications and MSTS scores by chart review, and survivorship free from revision and graft removal was calculated using the Kaplan-Meier estimator. In our study, however, the occurrence of death as a competing event was observed in a relatively low proportion of patients, and only occurred after the primary event of interest had already occurred. Considering the nature of our data, we did not consider death after the primary event of interest as a competing event. Results: In all, 49% (36 of 74) of patients experienced complications and underwent operative treatment. There were 45 complications in 36 patients. There was one instance of footdrop secondary to common peroneal nerve palsy, four wound problems, one acute vein thrombosis of the VFG pedicle and one necrosis of the skin island, two episodes of implant-related pain, 10 nonunions, six fractures, six deep infections, nine local recurrences, one Achilles tendon retraction, one varus deformity of the proximal tibia with postoperative tibial apophysis detachment, one knee osteoarthritis, and one hypometria. The median MSTS score was 30 (range 23 to 30); the MSTS score was assessed only in patients in whom the VFG was retained at the final...

Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb ([MALVA] in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25). Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported. At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (<median) compared to 5.1 months for patients with baseline NER greater than the median (≥median) (P = .0005). Median OS was significantly longer for patients with baseline NER <median compared with patients with baseline NER ≥median (not reached vs. 11.7 months, respectively; P = .0016). Significantly better PFS and OS were confirmed for NER after 3 cycles of avelumab <median compared with NER ≥median at the same timepoint. NER <median may be predictive of PFS in aUC patients treated with avelumab, and prognostic for OS regardless of treatment. Prospective studies are warranted to validate NER as a readily available and reproducible laboratory-biomarker for efficacy outcomes of avelumab in aUC.

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

Background: Soft tissue sarcomas (STSs) are rare, highly malignant mesenchymal tumours, comprising approximately 1% of all adult cancers and about 15% of paediatric solid tumours. STSs exhibit considerable genomic complexity with diverse subtypes, posing significant clinical challenges. Objectives: This study aims to characterise the molecular signature of primary STS through liquid biopsies and the untargeted metabolomic profiling of 75 patients, providing deep insights into cellular processes and potential therapeutic targets. Methods: This study analysed serum samples using nuclear magnetic resonance (NMR) spectroscopy for metabolomic profiling. Multivariate data analysis and machine learning classifiers were employed to identify biomarkers. Results: A panel of eleven significant deregulated metabolites were discovered in serum samples of patients with STS, with potential implications for cancer diagnosis and treatment. Conclusions: Choline decrease emerged as a marker for cancer progression, highlighting the potential of targeting its metabolism for therapeutic approaches in STS. The NMR analysis protocol proved effective for determining circulating biomarkers from liquid biopsies, making it suitable for rare disease research.

(1) Background: We aim to address the following questions. What was the complication rate of vascularized fibula graft (VFG) combined with massive allograft in patients treated with joint-sparing resection around the knee for a high-grade osteosarcoma? What was the long-term survivorship of VFG free from revision and graft removal? What were the functional results as assessed by the Musculoskeletal Tumor Society (MSTS) score? (2) Methods: 39 patients treated in our unit for osteosarcoma around the knee with intercalary resection and reconstruction with VFG combined with massive allograft were included; 26 patients underwent intercalary tibial resection, while 13 underwent intercalary femoral resection. (3) Results: Mean Follow-Up was 205 months (28 to 424). Complications that required surgery were assessed in requiring surgical revision in 19 patients (49%) after a mean of 31 months (0 to 107), while VFG removal was necessary in three patients (8%). The revision-free survival of the reconstructions was 59% at 5 years and 50% at 10 to 30 years. The overall survival of the reconstructions was 95% at 5 to 15 years and 89% at 20 to 30 years. The mean MSTS score was 29.3 (23 to 30). (4) Conclusions: VFG represents an effective reconstructive option after joint-sparing intercalary resection around the knee for osteosarcoma.

Background: Allograft-prosthesis composite reconstruction after periacetabular resections allows for bony union and internal repair, restoring bone stock for further revisions; the allograft-prosthesis composite can be shaped according to the pelvic resection to reconstruct the complex bone anatomy. Recently, endoprosthetic reconstruction has become one of the most frequently used options to restore large periacetabular bone defects. However, a prosthetic reconstruction impairs pelvic bone stock preservation and often takes a long time to manufacture. Allograft reconstructions, on the other hand, allow for bony union and internal repair, and they restore bone stock for further revisions. In addition, allografts are usually readily available and can be shaped according to the pelvic resection, fully restoring the complex bone anatomy. Pelvic biological reconstructions may have still a role, and to our knowledge, there are few long-term results of allograft-prosthesis composite reconstruction of the pelvis after periacetabular resections for bone tumors. Questions/purposes: (1) What is the cumulative incidence percentage of patients who experienced complications after reconstruction with allograft-prosthesis composites after resection of periacetabular tumors? (2) What was the functional result after surgical treatment as assessed by the Musculoskeletal Tumor Society (MSTS) score at a minimum of 2 years? (3) What was the survivorship of these reconstructions free from revision and graft removal at 15 years? Methods: Between February 1994 and April 2023, a total of 174 patients were treated at the university hospital of Florence for primary and secondary malignant or aggressive benign bone tumors of the pelvis with en bloc resection. Of treated patients, 51 underwent periacetabular resection and allograft-prosthesis composite reconstruction. We included in the study only patients with at least 24 months of follow-up or those who had complications earlier; thus 96% (49 of 51) of the patients had the required minimum follow-up and were included. Among the included patients, 88% (43 of 49) were available for a minimum follow-up of 24 months, whereas 12% (6) had < 24 months of follow-up but had complications earlier; thus, they were included for the analysis of complication-free survivorship. Seventy-eight percent (38) of patients were treated with a pelvic allograft combined with an acetabular cage, 16% (8) of patients received only a cemented cup, and 6% (3) of patients received a stemmed cementless cup. The mean ± SD follow-up time was 100 ± 77 months. The mean ± SD age at the time of reconstruction was 47 ± 17 years; 37% (18 of 49) of patients were female and 63% (31) were male. According to the Enneking and Dunham classification of pelvic resections, 39% (19) of patients had a Type I-II resection, 24% (12) had a Type II, 22% (11) had a Type II-III, 8% (4) had a Type I-II-III, 4% (2) had a Type I-II-IV, and 2% (1) had a Type I-II-III-IV. All patients had primary or secondary malignant or benign aggressive bone tumors: high-grade central chondrosarcoma (39% [19 of 49]), Ewing sarcoma (14% [7]), high-grade osteosarcoma (10% [5]), metastasis from carcinoma (10% [5]), dedifferentiated chondrosarcoma (10% [5]), peripheral low-grade chondrosarcoma (2% [1]), giant cell tumor of bone (2% [1]), osteoblastoma (2% [1]), hemangioendothelioma of bone (2% [1]), undifferentiated pleomorphic sarcoma of bone (2% [1]), malignant peripheral nerve sheath tumor of bone (2% [1]), radiation-induced sarcoma (2% [1]), or solitary plasmacytoma (2% [1]). The cumulative incidence of major complications, defined as surgical revision of any component of the reconstruction for mechanical complications and/or infections either surgically treated or not, and removal of the allograft as endpoints indicating failure, respectively, were estimated according to the competing-risk method. Complications were assessed through the revision of clinical charts. Death before the primary event of interest was considered a competing event. Comparisons of cumulative incidence curves across patient subgroups were performed with the Gray test. Normality of variables was assessed using the Shapiro-Wilk test, and heteroscedasticity was assessed using the Levene test. Accordingly, postoperative functional outcomes were compared across groups using a Welch t-test. Group means were reported in each plot. The relationship between functional score and length of follow-up was determined using a Pearson correlation coefficient. Significance was set at p < 0.05. The functional results were assessed using the MSTS score. The MSTS score was evaluated in patients with at least 2 years of follow-up in whom the pelvic allograft was retained at last clinical follow-up. Functional outcomes were assessed through the review of our institutional database. Results: The cumulative incidence of major complications was 24% (95% confidence interval [CI] 13% to 37%) at 5 years and 33% (95% CI 20% to 46%) at 10 and 15 years. The mean ± SD MSTS score was 23 ± 5, assessed 10 ± 6 years after the procedure. The cumulative incidence of graft removal was 8% (95% CI 3% to 18%) at 5 and 10 years and 12% (95% CI 4% to 24%) at 15 years. Conclusion: Allograft-prosthesis composite may represent an effective reconstructive option after periacetabular resection for primary bone tumors even in the era of 3D-printed implants; it still could have a role in patients with long life expectancy who are treated for tumors that were not managed with chemotherapy or radiotherapy and in whom the iliac wing is fully or partially preserved. Larger studies comparing periacetabular allograft-prosthesis composite with other reconstructive options such as modular and custom-made endoprostheses, as well as recycled autograft-prosthesis composites, are warranted to assess the potential benefits of one technique over the other. Level of Evidence: Level...