Non-oncological Indications Research Articles

HPB SO77 - Effects of Patient and Operative Variables on Isolation of Primary Human Hepatocytes

Abstract Background Isolation of human primary hepatocytes from tissue samples derived from therapeutic hepatectomy offers an important resource for a range of pharmacological and toxicology based experimental platforms, whilst simultaneously providing an opportunity to reduce the use of animal models. This study analysed the impact of a range of patient and operative derived variables on the yield and viability of isolated human primary hepatocytes. Method Excess hepatic tissue from resected liver parenchyma was sampled from consented patients undergoing major and minor hepatectomy for a range of oncological and non-oncological indications. Tissue dissociation and hepatocyte isolation was performed using a two-step collagenase perfusion procedure. Hepatocyte viability was calculated using the Trypan blue exclusion test while hepatocyte yield was calculated by the number of cells isolated divided by the tissue mass isolated from. Patient and operative variables were collected retrospectively from 25 patients in a prospectively maintained database. Results Samples from normal liver parenchyma achieved high hepatocyte viability and yields in all patients. Improved hepatoctye viability was associated with female sex, with a 2.9% increase in viability in samples from women (P<0.05). Patient age, BMI, operative indication, neo-adjuvant chemotherapy, as well as prolonged intra-operative Pringle time and blood loss did not significantly affect hepatocyte yield or viability, allowing use of primary human hepatocytes from a wide range of patients in a plethora of translational research experiments. Conclusion High levels of hepatocyte viability and yield are achievable across a broad range of patients, even in instances patients with high burdens of disease, prolonged Pringle time or higher levels of intra-operative blood loss. Tissue samples from consenting patients undergoing therapeutic liver resection provide an invaluable resource for various translational experimental platforms, including primary human hepatocytes. To date, more than 400 patients have donated tissue used in a range of basic science techniques, significantly reducing reliance on animal models.

Diagnostic performance of simultaneous PET-MR versus PET-CT in oncology with an overview on clinical utility and referral pattern of PET-MR: a single institutional study.

PET-Magnetic Resonance (PET-MR) imaging is an upcoming investigative modality with a few installations in Asia and only three in India. PET-Computed Tomography (PET-CT) is an established diagnostic cornerstone for oncological indications but with limited resolution for small lesions due to low soft-tissue contrast and additional radiation exposure. Our primary objective was to evaluate the diagnostic performance of simultaneous PET-MR and PET-CT in lesion detection in oncological practice. Secondly to assess the referral pattern and study the clinical utility of PET-MR in a university hospital practice. A total of 100 consecutive biopsy-proven cancer patients (breast or lung malignancy with suspected metastases) underwent 18 F Fluorodeoxyglucose (FDG) PET-MR and PET-CT for staging as a single injection, double examination protocol. Morphological lesion detection on correlative imaging/histopathology was used as the gold standard. Analysing the referral pattern, a total of 9366 patients underwent simultaneous PET-MR imaging for various indications in the past 5 years since installation. 18 F FDG PET-MR detected 100% of primary tumours in breast/lung carcinoma patients while PET-CT was positive in 96%. Overall accuracy of nodal metastases detection for PET-MR and PET-CT was 96 and 88%, while for distant metastases the accuracy was 100 and 93%, respectively. FDG PET-MR proved more sensitive and specific than PET-CT for regional nodal ( P = 0.011 and P < 0.001) and distant metastases detection ( P = 0.017 and P < 0.001, respectively). Analysing the general referral pattern for PET-MR, the majority were oncology referrals when compared to nononcological indications (66.5, 33.5%). About 66.24% were FDG based, followed by 68 Ga Prostate-Specific Membrane Antigen (PSMA) and dodecane tetraacetic acid (DOTA). The general utility of PET-MR was found incremental in better delineation of small lesions especially in head, neck, liver, brain and gynaecological malignancies. In our past 5 years of PET-MR practice, we found that simultaneous PET-MR is a highly recommended ideal imaging technique for oncological and nononcological indications. It has excellent diagnostic performance with high sensitivity, specificity and accuracy when compared to PET-CT in primary tumour, nodal and distant metastases (TNM) staging in specific subgroup of breast and lung malignancy patients.

Total Femur Replacement as a Salvage Procedure for Failed Distal Femur Megaprosthesis: A Case Report and Literature Reviews

Abstract Total femoral replacement (TFR) is not a common surgery and most indications are for oncological pathologies. However, there are few instances where non-oncological indications might necessitate TFR; this may be a salvage surgery for failed previous hip and/or knee surgeries with consequent significant femur bone loss. We present a 59-year-old obese woman with right thigh pain and difficulty with walking of 5 years duration. She had undergone bilateral total knee replacement 10 years earlier on account of severe knee osteoarthritis. She had a fall 3 years prior to presentation and sustained a periprosthetic fracture around the right knee which was managed with a fixed angle blade plate and screws. This was complicated by implant breakage and non-union. She subsequently had implant removal and a right distal femur replacement (DFR) surgery 2 years prior to presentation. A year after the DFR surgery, she began to experience “start-up” pain, instability around the knee and difficulty with walking without support. A clinical and radiologic diagnosis of aseptic loosening of the distal femur megaprosthesis was made and she was offered a revision DFR surgery which also failed due to poor cementing technique, bone loss at the proximal femur, and severe osteoporosis. Patient ended up with a right total femur replacement to salvage the limb. She had improved Lower Extremity Functional Score of 27 after 12-month follow-up. TFR is a viable salvage procedure for severely compromised femur and/or significant bone loss from multiple non-oncological surgeries of the femur.

TOTAL FEMORAL ARTHROPLASTY FOR NON-ONCOLOGICAL INDICATIONS

There is a paucity of data available for the use of Total Femoral Arthroplasty (TFA) for joint reconstruction in the non-oncological setting. The aim of this study was to evaluate TFA outcomes with minimum 5-year follow-up.This was a retrospective database study of TFAs performed at a UK tertiary referral revision arthroplasty unit. Inclusion criteria were patients undergoing TFA for non-oncological indications. We report demographics, indications for TFA, implant survivorship, clinical outcomes, and indications for re-operation.A total of 39 TFAs were performed in 38 patients between 2015–2018 (median age 68 years, IQR 17, range 46–86), with 5.3 years’ (IQR 1.2, 4.1–18.8) follow-up; 3 patients had died. The most common indication (30/39, 77%) for TFA was periprosthetic joint infection (PJI) or fracture-related infection (FRI); and 23/39 (59%) had a prior periprosthetic fracture (PPF). TFA was performed with dual-mobility or constrained cups in 31/39 (79%) patients. Within the cohort, 12 TFAs (31%) required subsequent revision surgery: infection (7 TFAs, 18%) and instability (5 TFAs, 13%) were the most common indications. 90% of patients were ambulatory post-TFA; 2 patients required disarticulation due to recurrent PJI. While 31/39 (79%) were infection free at last follow-up, the remainder required long-term suppressive antibiotics.This is the largest series of TFA for non-oncological indications. Though TFA has inherent risks of instability and infection, most patients are ambulant after surgery. Patients should be counselled on the risk of life-long antibiotics, or disarticulation when TFA fails.

ENDOPROSTHETIC REPLACEMENT FOR NON-ONCOLOGICAL CONDITIONS (EPRO) STUDY: A UK MULTICENTRE STUDY INTO CLINICAL OUTCOMES OF PROXIMAL FEMORAL REPLACEMENT

This large UK multicentre study evaluates clinical outcomes and identifies factors associated with local complication following PFR for non-oncological conditions.132 patients across four UK centres underwent PFR from 01/08/2004-28/03/2023 with median follow-up of 1.9 (Q10.5-Q34.2) years. 75 (56.8%) patients were female and the mean age was 74.0 (SD 11.7) years. 103 (78%) patients had Charleston Comorbidity Index ≥3. ASA class was III or IV in 66.6%. Indications were infected revision (39, 29.5%), periprosthetic fracture (36, 27.3%), acute trauma (30, 22.7%), aseptic revision (17, 12.9%), failed trauma (nine, 6.8%) and complex primary arthroplasty (one, 0.8%). The primary outcome was the local complication rate. Secondary outcomes were systemic complications, reoperation and mortality rates. Comparisons were made with t-tests and Chi2 tests to investigate patient and surgical factors associated with local complication. Statistical significance was p&lt;0.05.There were 37(28.0%) local complications. These were 18 (13.6%) dislocations, eight (6.1%) prosthetic joint infections, four (3.0%) haematomas, three (2.3%) superficial infections, one (0.8%) wound dehiscence, one (0.8%) sciatic nerve palsy and one (0.8%) femoral perforation. Dislocation mostly occurred in conventional articulations (12, 9.1%) followed by dual-mobility cups (three, 2.3%), constrained cups (two, 1.5%) and hemiarthroplasty (one, 0.8%). Median time to local complication was 30 (Q14-Q3 133) days. Seven (5.3%) patients developed a systemic complication. Thirty-three (25.0%) patients underwent reoperation. Thirty-day and one-year mortality rates were 3.8% and 12.1%, respectively. Longer surgical waiting times (7.9 \[SD 16.9) versus 2.6 \[SD 4.4\] days, p&lt;0.001) and longer operating times (212.5 \[SD 71.8\] versus 189.4 \[SD 59.3\] mins, p=0.0450) were associated with local complication.Due to its high complication rate, PFR should be a salvage option when performed for non-oncological indications. Conventional articulations should be avoided. PFR should be delivered in a timely manner and ideally as dual-consultant cases to reduce operating time.

Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy?

B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.

The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress.

Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.

Total femoral arthroplasty for non-oncological indications.

Total femoral arthroplasty (TFA) is a rare procedure used in cases of significant femoral bone loss, commonly from cancer, infection, and trauma. Low patient numbers have resulted in limited published work on long-term outcomes, and even less regarding TFA undertaken for non-oncological indications. The aim of this study was to evaluate the long-term clinical outcomes of all TFAs in our unit. Data were collected retrospectively from a large tertiary referral revision arthroplasty unit's database. Inclusion criteria included all patients who underwent TFA in our unit. Preoperative demographics, operative factors, and short- and long-term outcomes were collected for analysis. Outcome was defined using the Musculoskeletal Infection Society (MSIS) outcome reporting tool. Overall, 38 TFAs were identified. The mean age was 73 years (42 to 80). All patients underwent TFA for non-oncological indications, most commonly as a consequence of infection (53%) and periprosthetic fracture (26%). The mean follow-up time was ten years (0 to 26); 63% of TFAs were considered a success based upon the MSIS outcome reporting tool. The mean time between TFA and death was 8.5 years (0.2 to 19.2), with two patients dying within one year of surgery. Within the cohort, 66% suffered at least one complication, dislocation being most common (37%); 55% of the total cohort required at least one subsequent operation. In total, 70% of TFAs undertaken for infection were considered infection-free at time of final follow-up. The percentage of mobile patients improved from 52% to 65% between pre- and postoperation, with all patients being able to at least transfer from bed to chair at time of final review. This study is the largest in the UK assessing the use of TFA in patients with bone loss secondary to non-oncological conditions. It demonstrates that TFA has a significant complication profile, however it is favourable in terms of mortality and rehabilitation when compared to amputation and disarticulation.

MP34-19 PERIOPERATIVE AND LONG-TERM INFECTIOUS COMPLICATIONS AFTER RADICAL CYSTECTOMY: A PROSPECTIVE OBSERVATIONAL STUDY

You have accessJournal of UrologyCME1 Apr 2023MP34-19 PERIOPERATIVE AND LONG-TERM INFECTIOUS COMPLICATIONS AFTER RADICAL CYSTECTOMY: A PROSPECTIVE OBSERVATIONAL STUDY Benedikt Ebner, Judith Hirsch, Yannic Volz, Lennert Eismann, Benazir Abrarova, Robert Bischoff, Nikolaos Pyrgidis, Julian Hermans, Christian Stief, and Gerald Bastian Schulz Benedikt EbnerBenedikt Ebner More articles by this author , Judith HirschJudith Hirsch More articles by this author , Yannic VolzYannic Volz More articles by this author , Lennert EismannLennert Eismann More articles by this author , Benazir AbrarovaBenazir Abrarova More articles by this author , Robert BischoffRobert Bischoff More articles by this author , Nikolaos PyrgidisNikolaos Pyrgidis More articles by this author , Julian HermansJulian Hermans More articles by this author , Christian StiefChristian Stief More articles by this author , and Gerald Bastian SchulzGerald Bastian Schulz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003268.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical cystectomy (RC) is associated with a high risk of infectious complications. This risk does not only apply for the perioperative phase, but also for the long-term. Despite significant morbidity, these complications are inadequately investigated. This is the first prospective study that systematically assesses infectious complications after RC. METHODS: Patients undergoing RC because of oncological and non-oncological indications are prospectively enrolled in this ongoing observational study. Perioperative parameters are assessed at standardized time points and include infectious laboratory parameters (leukocytes, CRP, IL-6, Procalcitonin) as well as microbiological analyses (wound drainage, urine samples). Follow-up examinations are performed 3, 6, and 12 months after surgery and include questionnaires, blood tests, and urosonography. An Ethical Committee approval has been obtained and the study has been registered on ClinicalTrials.gov (NCT05153694). RESULTS: We performed an interim analysis of 50 patients. The median age was 69 years (84% male, 16% female). 40.0% received an ileal conduit (IC) and 60.0% a neobladder (NB). 50.0% of patients presented with a urinary tract infection preoperatively, but only 25.0% reported dysuria. The hospital antibiotic (AB) prophylaxis standard of cefuroxime (5 d) and metronidazole (3 d) was extended in 97.6% of patients. Microbiological analysis of the wound drainage on the 1st postoperative day (POD) showed bacterial growth in 18.2%. The urine culture on the 8th POD was positive in 65.9%. 40.0% had at least one episode of fever (≥38°C) during the inpatient stay. The incidence of fever between IC and NB was not significantly different (OR 0.88; p=0.24). Also, there was no significant association between the level of IL-6 on the 1 st POD or the results of the microbiological analyses (wound drainage and urine samples) and the occurrence of fever (p=0.82; p=0.83; p=0.93, respectively). 50.0% reported the intake of at least one AB drug and 31.4% reported an emergency consultation due to RC-associated fever in the first 3 months after surgery, respectively. There was no significant difference between IC and NB for these follow-up results (p=0.17; p=0.55, respectively). CONCLUSIONS: This is the first systematic and comprehensive prospective study assessing infectious complications after RC. Importantly, our preliminary results indicate that these complications are severely underestimated both during the inpatient stay, but also in the long-term. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e467 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Benedikt Ebner More articles by this author Judith Hirsch More articles by this author Yannic Volz More articles by this author Lennert Eismann More articles by this author Benazir Abrarova More articles by this author Robert Bischoff More articles by this author Nikolaos Pyrgidis More articles by this author Julian Hermans More articles by this author Christian Stief More articles by this author Gerald Bastian Schulz More articles by this author Expand All Advertisement PDF downloadLoading ...

Incidental finding of [99mTc]Tc-MIBI uptake in a post-radiotherapy breast without recurrence of cancer.

The oncophilic nature of [99mTc]Tc-MIBI makes this radiopharmaceutical useful in cancer diagnostics, with particular emphasis on breast cancer. Increased uptake of [99mTc]Tc-MIBI in tests performed for non-oncological indications always raises the suspicion of its neoplasmatic character and requires further clinical diagnostics, which is especially justified in patients with a previous history of cancer. However, the presented case illustrates that focally increased uptake of [99mTc]Tc-MIBI is not always associated with the presence of cancer cells and may result from post-therapeutic changes.

The Use of Megaprostheses in Severe Bone Loss due to Nononcological Indications: Three Case Reports and Literature Review

Reconstruction of severe bone loss and large skeletal defects using biologic materials with autograft or allograft and using tumor endoprostheses (megaprostheses) helped orthopedic surgeons as well as patients in the sparing of limbs. Several types of megaprostheses have been described in the literature for oncological indications with unpredictable outcomes and complication rates. We review single-centered experience of three nononcological cases to assess the safety of using megaprostheses in patients with severe bone loss without malignant disease. In addition, a literature review on the previous use of megaprostheses as treatment modality, their outcome, and complications was done until August 2022. All the participants were found to be good candidates for megaprostheses implants after their refusal of amputation. Their infections were eradicated before the implants, and also, the range of movement and improvements are satisfactory. In addition, according to the literature compared to the alternative of amputation, this operation has proven to be life-altering and revolutionary for many patients. We believe that megaprostheses might be a good limb salvage alternative in patients with significant bone loss and massive skeletal deformities, even in nononcological situations. Future studies should focus on ways to improve the material and design of the megaprostheses and study the long-term complications and survival rate of the implants.

Real-world patterns of opioid therapy initiation in Spain, 2012–2018: A population-based, retrospective cohort study with 957,080 patients and 1,509,488 initiations

Introduction: Europe has seen a steady increase in the use of prescription opioids, especially in non-cancer indications. Epidemiological data on the patterns of use of opioids is required to optimize prescription. We aim to describe the patterns of opioid therapy initiation for non-cancer pain and characteristics of patients treated in a region with five million inhabitants in the period 2012 to 2018. Methods: Population-based retrospective cohort study of all adult patients initiating opioid therapy for non-cancer pain in the region of Valencia. We described patient characteristics at baseline and the characteristics of baseline and subsequent treatment initiation. We used multinominal regression models to identify individual factors associated with initiation. Results: A total of 957,080 patients initiated 1,509,488 opioid treatments (957,080 baseline initiations, 552,408 subsequent initiations). For baseline initiations, 738,749 were with tramadol (77.19%), 157,098 with codeine (16.41%) 58,436 (6.11%) with long-acting opioids, 1,518 (0.16%) with short-acting opioids and 1,279 (0.13%) with ultrafast drugs. When compared to tramadol, patients initiating with short-acting, long-acting and ultrafast opioids were more likely to be older and had more comorbidities, whereas initiators with codeine were more prone to be healthier and younger. Treatments lasting less than 7 days accounted for 41.82% of initiations, and 11.89% lasted more than 30days. 19.55% of initiators with ultrafast fentanyl received more than 120 daily Morphine Milligram Equivalents (MME), and 16.12% of patients initiating with long-acting opioids were prescribed more than 90 daily MME (p < 0.001). Musculoskeletal indications accounted for 65.05% of opioid use. Overlap with benzodiazepines was observed in 24.73% of initiations, overlap with gabapentinoids was present in 11.04% of initiations with long-acting opioids and 28.39% of initiators with short-acting opioids used antipsychotics concomitantly. In subsequent initiations, 55.48% of treatments included three or more prescriptions (vs. 17.60% in baseline initiations) and risk of overlap was also increased. Conclusion: Opioids are initiated for a vast array of non-oncological indications, and, despite clinical guidelines, short-acting opioids are used marginally, and a significant number of patients is exposed to potentially high-risk patterns of initiation, such as treatments lasting more than 14 days, treatments surpassing 50 daily MMEs, initiating with long-acting opioids, or hazardous overlapping with other therapies.

Debridement, antibiotics, and implant retention in non-oncological femoral megaprosthesis infections: minimum 5\u2009year follow-up

PurposeMegaprostheses are increasingly utilised outside of the oncological setting, and remain at significant risk of periprosthetic joint infection (PJI). Debridement, antibiotic, and implant retention (DAIR) is an established treatment for PJI, however its use in non-oncological patients with femoral megaprostheses has not been widely reported. There are significant differences in patient physiology, treatment goals, and associated risks between these patient cohorts.MethodsWe identified 14 patients who underwent DAIR for a PJI of their femoral megaprostheses, between 2000 and 2014, whom had their index procedure secondary to non-oncological indications. Patients were managed as part of a multidisciplinary team, with our standardised surgical technique including exchange of all mobile parts, and subsequent antibiotic therapy for a minimum of 3 months. Patients were followed up for a minimum of 5 years.ResultsPatients included six proximal femoral replacements, five distal femoral replacements, and three total femoral replacements. No patients were lost to follow-up. There were six males and eight females, with a mean age of 67.2 years, and mean ASA of 2.3.Nine patients (64.3%) successfully cleared their infection following DAIR at a minimum of 5 year follow-up. Five patients (35.7%) required further revision surgery, with four patients cleared of infection. No patients who underwent DAIR alone suffered complications as a result of the procedure.ConclusionsThe use of DAIR in these complex patients can lead to successful outcomes, but the risk of further revision remains high. The success rate (64.3%) remains on par with other studies evaluating DAIR in megaprostheses and in primary arthroplasty. This study indicates judicious use of DAIR can be an appropriate part of the treatment algorithm.Level of evidenceII

Indocyanine green as a new trend in sentinel lymphatic node detection in oncogynecology.

In oncological surgery the importance of the sentinel node concept is increasing, as we are capable of reducing the surgical burden of patients and its associated morbidity and preserving adequate oncological safety at the same time. Recently, there has been development of lymph node mapping techniques, where the most promising method appears to be the immunofluorescent one using indocyanine green dye. This technique provides high sensitivity in sentinel node detection in comparison with other existing methods using a dye in combination with a radionuclide. The indocyanine green technique has several advantages, and at the same time, we can use this method in non-oncological indications in gynecological surgery.

Constraint in complex primary total knee arthroplasty: rotating hinge versus condylar constrained implants.

Condylar constrained knee arthroplasties (CCKAs) and rotating hinge knee arthroplasties (RHKAs) achieved good outcomes in complex primary total knee arthroplasties (TKAs); however, long-term comparative studies are few. Using an arthroplasty registry, we sought to assess and compare in CCKAs and RHKAs: (1) the intra-operative rates of complications, (2) the survival rates, (3) the reasons for revision, and (4) the adjusted hazard ratios for failure. 1432 constrained implants in primary TKAs performed for non-oncological indications were included: 703 RHKAs, 729 CCKAs. The two groups were comparable regarding age and gender. Kaplan-Meier curves were used to compare survival rates, multivariate analyses to assess the hazard ratios for failures. The mean follow-up was 4.1years (range 0-16.3) for CCKAs and 6.8years (0-18.1) for RHKAs. The intra/peri-operative complications were similar in both the cohorts, with similar rates of femoral and tibial fractures. 10-year implant survival rates were similar in both the cohorts (91.9%, CI 95% 89.2-93.9% in RHKAs; 93.4%, CI 95% 90.3-95.6% in CCKAs). Periprosthetic infection was the most common reason for revision in the two cohorts, followed by aseptic loosening. Breakage occurred in 3 RHKAs (0.4%). CCKAs and RHKAs had a similar distribution of revision causes. Males aged less than 60 had significantly more failures, regardless the constraint degree. Unstemmed CCKAs significantly failed more than RHKAs and stemmed CCKAs. Both modern CCKAs and RHKAs are viable long-term solutions in complex primary TKAs. More failures should be expected in males aged less than 60. IV, Therapeutic study.

POSC264 Negotiation Agreements with AIFA from January 2017 to May 2021 - Focus on Orphan Drugs

To analyze the agreements reached during P&R negotiation with AIFA by orphan drugs (ODs) designated by EMA, with P&R determination published in the Italian Official Journal (OJ) in the period January 2016-May 2021. ODs first P&R determinations published on OJ from January 2016 to May 2021 were collected and examined. The relevant data has been included in the database: ODs classification (A or H), negotiating conditions, presence of monitoring registers, financial and clinical/outcomes-based MEAs and Innovation Status recognition (IS). From 2016 to May 2021, 73 P&R determinations were published, and 59 ODs were reimbursed (class A or H), 22 (37%) for oncological indications, 37 (63%) for non-oncological indications; no agreement was reached for 14 (19%) ODs, which were classified in C. Regarding IS, 28 (48%) ODs obtained the status by CTS: 15 Full and 13 Conditional IS. Referring to therapeutic area, 13 (35%) non-oncological ODs and 14 (38%) oncological ODs obtained IS. 50 (85%) ODs obtained financial MEA, 2 (3%) ODs had a clinical MEA and 4 (7%) obtained both, financial and clinical MEAs. In addition, 40 (68%) presented a monitoring register. Concerning to therapeutic area, 32 (87%) non-oncological ODs had financial MEA, 2 (5%) clinical MEA and 1 (3%) both. On the other side, 18 (82%) oncological ODs had financial MEA and 3 (14%) had clinical and financial MEAs. During the period included in the study, the majority of ODs achieved reimbursement, most of them with one or more MEAs. In particular, there was a predominance of financial MEAs compared to clinical/outcomes-based MEAs. The analysis proved that therapeutic area didn’t impact on MEAs or IS assignment, in fact, two groups show similar percentages.

Distal Femoral Replacement and Periprosthetic Joint Infection After Non-Oncological Reconstruction: A Retrospective Analysis.

Distal femoral replacement (DFR) is commonly used to manage massive bone loss around the knee arising from aseptic loosening, periprosthetic joint infection (PJI), and distal femoral fractures. A number of studies report the outcome of DFR with considerable variation in long-term survivorship. This study investigated the outcome of DFR for patients with aseptic failures, fractures, and PJI. A retrospective review of 182 patients who underwent DFR for non-oncological indications between 2002 and 2018 was conducted. Data collected included the following: indication, postoperative complications, reoperation, revision, and follow-up. Implant survivorship with Kaplan-Meier curves along with a log-rank test for different preoperative indications was performed. A Cox regression model was used to evaluate the risk of revision. The overall postoperative complication rate was very high at 36%. The most common complication was PJI (17%). The rate of reoperation for any cause was 29.7%, and the revision rate was 13.7%. The most common cause of re-revision was PJI (7.1%). Revision-free survivorship of the DFR implant was 91.6% at 1 year, 87.9% at 2 years, 82.5% at 5 years, and 73.4% at 10 years. Patients who had a prior-PJI had the lowest survivorship compared to patients undergoing DFR for management of periprosthetic fracture and mechanical loosening. Additionally, the prior-PJI group was at a fourfold increased risk of postoperative PJI compared to the aseptic group. DFR is a valuable reconstructive option for patients with massive bone loss around the knee. However, patients undergoing DFR are at high risk of complications, reoperations, and failure.

Repurposing of Clinically Approved Poly-(ADP-Ribose) Polymerase Inhibitors for the Therapy of Sepsis.

Sepsis' pathogenesis involves multiple mechanisms that lead to a dysregulation of the host's response. Significant efforts have been made in search of interventions that can reverse this situation and increase patient survival. Poly (ADP-polymerase) (PARP) is a constitutive nuclear and mitochondrial enzyme, which functions as a co-activator and co-repressor of gene transcription, thus regulating the production of inflammatory mediators. Several studies have already demonstrated an overactivation of PARP1 in various human pathophysiological conditions and that its inhibition has benefits in regulating intracellular processes. The PARP inhibitor olaparib, originally developed for cancer therapy, paved the way for the expansion of its clinical use for nononcological indications. In this review we discuss sepsis as one of the possible indications for the use of olaparib and other clinically approved PARP inhibitors as modulators of the inflammatory response and cellular dysfunction. The benefit of olaparib and other clinically approved PARP inhibitors has already been demonstrated in several experimental models of human diseases, such as neurodegeneration and neuroinflammation, acute hepatitis, skeletal muscle disorders, aging and acute ischemic stroke, protecting, for example, from the deterioration of the blood-brain barrier, restoring the cellular levels of NAD+, improving mitochondrial function and biogenesis and, among other effects, reducing oxidative stress and pro-inflammatory mediators, such as TNF-α, IL1-β, IL-6, and VCAM1. These data demonstrated that repositioning of clinically approved PARP inhibitors may be effective in protecting against hemodynamic dysfunction, metabolic dysfunction, and multiple organ failure in patients with sepsis. Age and gender affect the response to PARP inhibitors, the mechanisms underlying the lack of many protective effects in females and aged animals should be further investigated and be cautiously considered in designing clinical trials.

Effect of high-dose corticosteroid use on efficacy of immune checkpoint inhibitors in patients with renal cell carcinoma (RCC).

4583 Background: The use of High-Dose Corticosteroids (HDC) has been linked to poor outcomes in patients with lung cancer treated with immune checkpoint inhibitors (ICIs) (Ricciuti B, JCO, 2019). There is no data on the effect of HDC on renal cell carcinoma patients (RCC) treated with immunotherapy. We hypothesized that HDC use would be associated with worse outcomes in RCC patients receiving ICIs. Methods: This study evaluated a retrospective cohort of patients with RCC at Dana-Farber Cancer Institute in Boston, MA. Clinical information including demographics, IMDC risk score, RCC histology, steroid administration, ICI regimen, line of therapy, time to treatment failure (TTF) and overall survival (OS) were collected. Patients were divided into those receiving HDC (prednisone ≥10 mg or equivalent for ≥ 1 week, HDC group) or not receiving HDC (No-HDC group). HDC administration was evaluated in relation to TTF and OS in a univariate analysis (Log-rank test) and a multivariate analysis (Cox regression). Results: 190 patients with RCC receiving ICIs were included, with a median age of 59 years. HDC were administered to 56 patients and 134 patients received no (N= 116) or only low-dose (N=18) steroids. In the HDC group, 40 patients received steroids for immune-related adverse events, 8 for other cancer-related indications, and 8 for non-oncological indications. There was no difference in TTF between the HDC and No-HDC groups (12-mo TTF rate: 34.8 vs. 32.3%, respectively; log-rank p=0.65). Similarly, there was no difference in OS between the HDC and No-HDC groups (36-mo OS rate: 56.7 vs. 62.4%, respectively; log-rank p=0.97). After adjusting for IMDC risk group, RCC histology, ICI regimen type, and line of therapy, TTF and OS did not differ in the HDC group as compared to No-HDC group (HR=1.14 [95%CI: 0.80-1.62], p=0.44 and HR=1.17 [95%CI: 0.65-2.11], p=0.59, respectively). Conclusions: In this retrospective study of patients with RCC treated with ICIs, administration of high-dose corticosteroids was not associated with worse outcomes.[Table: see text]

Indications of amputation after limb-salvage surgery of patients with extremity-located bone and soft-tissue sarcomas: A retrospective clinical study.

This study aimed to investigate amputation-related factors after limb-salvage surgery (LSS) in patients with extremity-located bone and soft-tissue sarcomas and determine the relationship between these factors and patient survival. In this retrospective study at our institution, patients in whom LSS was first performed because of an extremity-located musculoskeletal sarcoma, and subsequently amputation was carried out for various indications were included. Patient and tumor characteristics, details of surgical procedures, indications of amputation, number of operations, presence of metastasis before amputation, and post-amputation patient survival rates were analyzed. A total of 25 patients (10 men, 15 women; mean age=41.96±21.88 years), in whom amputation was performed after LSS as initial resection of an extremity sarcoma or re-resection(s) of a local recurrence, were included in the study. The leading oncological indication for amputation was local recurrence that occurred in 18 (72%) patients. Non-oncological indications included prosthetic infection in 5 (20%), mechanical failure in 1 (4%), and skin necrosis in 1 (4%) patient. The patients underwent a median of 2 (range, 1-4) limb-salvage procedures before amputation. Distant organ metastasis was detected in 22 (88%) patients during follow-up; in 13 (52%) of these patients, metastasis was present before amputation. A total of 11 (44%) patients were alive at the time of study with no evidence of the disease (n=3) or with disease (n=8), and 14 (56%) patients died of disease. The mean overall and post-amputation survival were 47±20.519 (range, 11-204) months and 22±4.303 (range, 2-78) months, respectively. The median follow-up was 27 (range, 6-125) months. The most common causes of amputation after LSS were local recurrence and prosthetic infection. Patients who underwent amputation after LSS developed a high rate of distant organ metastasis during follow-up and had reduced survival. Level IV, Therapeutic Study.