Higher Necrosis Rates Research Articles

Malignancy progression and treatment efficacy estimation of osteosarcoma patients based on in vitro cell culture model and analysis

BackgroundOsteosarcoma (OS) usually happens in patients under 20 years old and is notorious for its low survivorship and limb loss. Personalized medicine is a viable approach to increase the efficiency of chemotherapy which is the main prognostic factor for survivorship after surgical treatment. MethodsIn this five-year prospective observational study, we collected primary cells of osteosarcoma from 15 patients, and examined the correlation between clinical characters of patients and cell properties characterized using various in vitro assays. The properties including genes expression, pro-angiogenic capability and anti-cancer drug response are characterized respectively by using RT-PCR, tube formation assay, osteogenesis assay and drug testing on 3D tumor spheroid model. ResultThe results suggest that OS patients with higher MMP9 expression levels have higher probability to develop skip metastasis (p = 0.041). The 3D tumor spheroid test based on the median lethal dose from 2D culture provides some prognostic value. Patients do not response well to methotrexate (MTX) show higher percentage of high pathology grade (p = 0.009) and lung metastasis (p = 0.044). Also, patients respond well to ifosfamide (IFO) have higher probability to achieve high tumor necrosis rate (p = 0.007). ConclusionThe association between cell properties and clinical characters of patients provided by our data can act as potential prognostic factors to help physicians to develop effective personalized chemotherapy for osteosarcoma treatments.

The Epidemiology and Clinical Features of Deinagkistrodon acutus Envenomation: A Retrospective Study from a Medical Center in Hangzhou, Southeast China.

Deinagkistrodon acutus envenomation is one of the most common types of venomous snakebite in China and causes a series of envenomating effects on its victims. However, more specific information on the characteristics of D. acutus envenomation is rare in the English literature. Therefore, we aimed to give a detailed description of the epidemiological and clinical features of patients with D. acutus envenomation. Patients who were admitted with D. acutus envenomation between January 2018 and December 2021 were enrolled in this retrospective study. The data on demographics, clinical manifestations, laboratory features, management, and outcomes were collected. A total of 158 cases of D. acutus envenomation were enrolled. Men (n = 121; 76.6%) and rural populations (n = 133; 84.2%) were the high-risk groups, and most incidents (n = 141; 89.2%) happened between May and September. The specific effect was tissue necrosis at bite site, which occurred in 72 patients (45.6%). Other envenomation effects include extensive limb swelling, blistering, wound bleeding, and coagulopathy. In the envenomed patients, 155 (98.1%) received antivenom, 47 (29.7%) needed operations, 20 (12.7%) required intensive care, and one died. Deinagkistrodon acutus envenomation is a common snakebites emergency in Hangzhou area. A high rate of tissue necrosis at bite site and venom-induced consumption coagulopathy are the characteristics of D. acutus envenomation. Although the mortality rate is low, some patients still require intensive care.

Risk Factors for Skin Flap and Nipple-Areolar Necrosis in Patients Undergoing Nipple-Sparing Mastectomy With Deep Inferior Epigastric Perforator Flap Reconstruction.

Nipple-sparing mastectomy (NSM) with deep inferior epigastric perforator (DIEP) flap reconstruction is a surgical option for select patients with or at risk of breast cancer. However, post-operative skin flap and nipple-areolar complex (NAC) necrosis remain common complications. This study aimed to identify factors associated with necrosis in patients undergoing NSM with DIEP reconstruction. A retrospective cohort study was performed from 2015 to 2023. 74 variables were analyzed in patients undergoing NSM with DIEP. Patients were stratified into 3 groups based on post-operative skin/NAC necrosis: none, partial thickness, and full thickness. Comparative and descriptive statistics were performed via t-tests, ANOVA, and chi-squared tests. 34 women with 31 breast cancers met inclusion. 44% experienced necrosis: 15% partial thickness and 29% full thickness. The majority were white (85.3%) with mean age of 50 years (SD = 9.11). In patients with immediate DIEP reconstruction, hypoperfused areas identified by SPY angiography increased risk of necrosis (P = .012). Approximately 50% of both partial thickness and full thickness necrosis patients had concerns on SPY angiography. Former smokers in the full thickness necrosis group had more pack years than those without necrosis (9 vs .65 pack years, P = .035). In patients receiving NSM with DIEP flap reconstruction, those with hypoperfusion on SPY angiography and longer smoking history had higher necrosis rates. This supports the continued used of SPY angiography and the role of pre-operative counseling in former smokers with increased pack years on their risk of necrosis and the role of preventative measures in the perioperative setting.

Reassessing acquired neonatal intestinal diseases using unsupervised machine learning.

Acquired neonatal intestinal diseases have an array of overlapping presentations and are often labeled under the dichotomous classification of necrotizing enterocolitis (which is poorly defined) or spontaneous intestinal perforation, hindering more precise diagnosis and research. The objective of this study was to take a fresh look at neonatal intestinal disease classification using unsupervised machine learning. Patients admitted to the University of Florida Shands Neonatal Intensive Care Unit January 2013-September 2019 diagnosed with an intestinal injury, or had imaging findings of portal venous gas, pneumatosis, abdominal free air, or had an abdominal drain placed or exploratory laparotomy during admission were included. Congenital gastroschisis, omphalocele, intestinal atresia, malrotation were excluded. Data was collected via retrospective chart review with subsequent hierarchal, unsupervised clustering analysis. Five clusters of intestinal injury were identified: Cluster 1 deemed the "Low Mortality" cluster, Cluster 2 deemed the "Mature with Inflammation" cluster, Cluster 3 deemed the "Immature with High Mortality" cluster, Cluster 4 deemed the "Late Injury at Full Feeds" cluster, and Cluster 5 deemed the "Late Injury with High Rate of Intestinal Necrosis" cluster. Unsupervised machine learning can be used to cluster acquired neonatal intestinal injuries. Future study with larger multicenter datasets is needed to further refine and classify types of intestinal diseases. Unsupervised machine learning can be used to cluster types of acquired neonatal intestinal injury. Five major clusters of acquired neonatal intestinal injury are described, each with unique features. The clusters herein described deserve future, multicenter study to determine more specific early biomarkers and tailored therapeutic interventions to improve outcomes of often devastating neonatal acquired intestinal injuries.

Outcomes following total ankle total talus replacement: A systematic review

BackgroundProsthetic substitution of the talus presents a significant challenge to the foot and ankle surgeon. The shear and compressive forces on the talus and its tenuous blood supply lead to high rates of avascular necrosis and eventual talar collapse. The purpose of this systematic review is to evaluate whether total ankle total talus replacement (TATTR) leads to improved clinical and radiographic outcomes with appropriate safety metrics in patients with a history of avascular necrosis or significant trauma. MethodsWe searched the concepts of talus, prosthesis, and arthroplasty in MEDLINE (PubMed), Embase (Elsevier), CINAHL Complete (EBSCOhost), and Scopus (Elsevier) from the database's inception through March 9, 2023. Inclusion Criteria were 1) previous trauma to the talus, 2) post-traumatic arthritis to the tibiotalar joint, 3) avascular necrosis of talus, 4) multiple failed prior interventions, 5) degenerative osteoarthritis to the tibiotalar joint, and 6) inflammatory arthropathy to tibiotalar joint. Patients less than 18 years of age and manuscripts in non-English languages were excluded. ResultsOf the 7625 references, 16 studies met the inclusion criteria, yielding data from 136 patients (139 ankles). The studies varied in design, with case reports and retrospective case series being predominant. The overall weighted average modified Coleman Methodology Score (mCMS) was 70.4 out of 100, indicating moderate flaws in study design that may be subject to various forms of bias and possible confounders. Demographics showed a diverse range of etiologies, with alumina ceramic being the primary prosthesis material. Functional scores demonstrated improvements in dorsiflexion and plantarflexion, although patient-reported outcome measures (PROs) were inconsistently reported. Complications included fractures, heterotopic ossification, prolonged wound healing, and infections. Revision details were sparsely reported. ConclusionTATTR is a promising treatment modality for improving short-term functional outcomes for patients with avascular necrosis or trauma-related issues. However, this systematic review underscores the need for standardized reporting, longer-term follow-ups, and further research to establish the procedure’s efficacy and safety, particularly in comparison to other treatment modalities. Level of EvidenceIII, Systematic Review of Level IV Studies

Clinical observation of Gofried positive buttress reduction in the treatment of young femoral neck fracture: A systematic review and meta-analysis.

Femoral neck fractures in young adults(<65 years), have always been a difficult problem, characterized by high rates of nonunion and avascular necrosis (AVN). The clinical efficacy of anatomical reduction and non-anatomical reduction methods needs to be supported by clinical data. Therefore, we conduct a meta-analysis on the clinical efficacy of different reduction methods to better guide clinical practice. Relevant studies published using internal fixation to treat femoral neck fracture in several databases were searched. The outcomes sought included Harris score and the rate of AVN, nonunion and femoral neck shortening (<5 mm). Included studies were assessed for methodological bias and estimates of effect were calculated. Potential reasons for heterogeneity were explored. The clinical results showed that compared with the anatomical reduction and positive buttress, there is no significant difference in the rate of AVN (OR = 0.87, 95%CI: 0.55-1.37, P = .55), nonunion (OR = 0.54, 95%CI: 0.21-1.41, P = .21), femoral neck shortening (<5 mm) (OR = 1.03,95%CI: 0.57-1.86, P = .92), the Harris score (MD = -0.28, 95%CI: -1.36-0.80, P = .61) and the excellent and good rate of Harris score (OR = 1.73, 95%CI: 0.84-3.56, P = .61). However, compared with negative buttress, the rate of AVN (OR = 0.62, 95%CI: 0.38-1.01, P = .05), nonunion (OR = 0.34, 95%CI: 0.12-1.00, P = .05) and femoral neck shortening (<5 mm) (OR = 0.27, 95%CI: 0.16-0.45, P < .00001) were significantly lower, and the Harris score (MD = 6.53, 95%CI: 2.55 ~ 10.51, P = .001) was significantly better in positive buttress. In the case of difficult to achieve anatomical reduction, for young patients (< 65 years) with femoral neck fracture, reduction with positive buttress can be an excellent alternative and negative buttress should be avoided as much as possible.

Zegocractin to Reduce the Severity of Asparaginase Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: Results of the Phase 1 Portion of the Crspa Study

INTRODUCTION Asparaginase-associated pancreatitis (AAP) is one of the most severe and dreaded complications during therapy of childhood acute lymphoblastic leukemia (ALL). It is characterized by intense abdominal pain, nausea/ vomiting, and systemic inflammatory response syndrome. AAP can result in chronic complications such as insulin dependence, exocrine pancreatic insufficiency, and chronic pain. These symptoms are more common when pancreatic necrosis or pancreatic pseudocysts develop immediately after AAP. Treatment for AAP has historically been limited to supportive care. However, a novel calcium release activated calcium channel blocker, zegocractin (formerly CM4620), currently in clinical trials in adults with pancreatitis, may reduce the severity of AAP. We thus developed the phase 1/2 CRSPA study to identify the recommended phase 2 dose (RP2D) of zegocractin in children and young adults with AAP during ALL treatment. METHODS To investigate the characteristics of AAP in the absence of zegocractin, we retrospectively evaluated patients treated on the Total Therapy XVI study (T16) who developed pancreatitis within 30 days of receiving asparaginase (AAP). In the CRSPA trial, patients with ALL experiencing AAP were offered trial enrollment and provided informed consent/ assent. Participants underwent initial CT either prior to or on day 1 of CRSPA therapy. Zegocractin was administered as a 4-hour infusion on days 1-4 starting at dose level 1 (30mg/m 2 on day 1 and 42mg/m 2 on days 2-4), with dose limiting toxicities (DLT) defined as any CTCAE grade 3-5 toxicity not attributable to either pancreatitis or ALL therapy. Planned dose escalation was guided by a Keyboard design. The primary efficacy endpoint of the study focused on the occurrence of pancreatic necrosis or pseudocyst on CT after day 28. RESULTS Among 598 patients treated on T16, 51 (8.5%) developed AAP. The mean age at AAP onset was 10.3 (range 2.2-21.4) years; 34 were male and 17 were female. 9 received low-risk therapy while the remainder were on standard- or high-risk therapy. Adequate follow-up imaging was available for 39 patients. Of these, 22 (56% of those with imaging, 43% of all AAP patients) had peri-pancreatic fluid collections (PPFC; N=18) and/or pancreatic necrosis (N=14). Mean hospitalization was 12.1 days (range 2-70), mean ICU time in the 11 (21.6%) patients requiring ICU care was 5.1 days (1-9), and mean duration of total parenteral nutrition (TPN) in the 27 (52.9%) patients needing it was 37.7 days (3-153). Among the 9 patients (median age 8.8, range 3.1-17.6 years) treated in the first cohort of the Keyboard design phase 1 portion of CRSPA, 1 had a DLT (infusion reaction during dose 1) characterized by ill feeling and shortness of breath. The infusion was stopped and diphenhydramine was administered with symptomatic improvement. However, the symptoms recurred and worsened as the patient's AAP symptoms worsened. The event was retrospectively felt to be related to AAP rather than study medication, but it remained as a DLT. None of the other 8 patients treated at dose level 1 experienced a DLT. Pharmacokinetic analysis indicated that drug exposure at dose level 1 was at least as high as that seen in adults treated at the adult RP2D (i.e. 2 mg/kg on days 1-2 and 1.6 mg/kg on days 3-4). Because dose level 1 was well tolerated, we amended the protocol and evaluated whether there was a preliminary efficacy signal prior to dose escalation. Among the 8 patients who received all 4 doses and were evaluable for efficacy, 1 had a small PPFC and none had significant pancreatic necrosis on follow-up imaging; mean hospitalization was 6.3 days (range 5-8), 1 patient needed ICU care (3 days), and none required TPN. To further assess preliminary efficacy, CTs from the T16 cohort were matched on sex and age with CRSPA patients at a 2:1 ratio and were evaluated by a blinded radiologist. The mean CT severity index was 5.4 in the historical controls vs. 2.4 in the CRSPA patients evaluable for efficacy. CONCLUSION Patients with AAP receiving supportive care in the historical T16 cohort experienced a high rate of pancreatic necrosis and pseudocyst. The CRSPA study established dose level 1 as the RP2D of zegocractin for children with ALL experiencing AAP. The phase 1 portion of the study has provided promising data on zegocractin efficacy. Moving forward, the ongoing phase 2 portion of the study will further assess and validate the efficacy of zegocractin in treating AAP.

High rate of avascular necrosis but excellent patient-reported outcomes after open reduction and internal fixation (ORIF) of proximal humerus fracture dislocations: should ORIF be considered as primary treatment?

Proximal humerus fracture dislocations, excluding 2-part greater tuberosity fracture dislocations, are rare injuries. Outcomes after open reduction and internal fixation (ORIF) of these injuries have not been well described in the literature. The purpose of this study was to report the radiographic and functional outcomes of patients who underwent ORIF of a proximal humerus fracture dislocation. All skeletally mature patients who underwent ORIF of a proximal humerus fracture dislocation between 2011 and 2020 were identified. Patients with isolated greater tuberosity fracture dislocations were excluded. The primary outcome was American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score at a minimum of 2 years. Secondary outcomes were the development of avascular necrosis (AVN) and reoperation rate. Twenty-six patients met the inclusion criteria. The mean age was 45 years (standard deviation 16), and 77% were men. Median time to reduction and surgery was 1 day (interquartile range [IQR] 1-5). There were 2 (8%) Neer 2-part fractures, 7 (27%) 3-part, and 17 (65%) 4-part fractures. Fifty-four percent (54%) involved the anatomic neck and 31% included a head-split component. Thirty-nine percent (39%) were anterior dislocations. The rate of AVN was 19%. The reoperation rate was 15%. Reoperations included removal of hardware (2), subscapularis repair (1), and manipulation under anesthesia (1). No patients went on to arthroplasty. ASES scores were available for 22 patients (84%) including 4 of 5 patients with AVN. The median ASES score at a mean of 6.0 years postoperatively was 98.3 (IQR 86.7-100, range 63.3-100) and was not different in those with or without AVN (median 98.3 vs. 92.0, P=.175). Only the presence of medial comminution and nonanatomic head shaft alignment on postoperative radiographs were associated with increased risk of AVN. Radiographic rates of AVN (19%) and reoperation (15%) were high in this series of patients undergoing ORIF of proximal humerus fracture dislocations. Despite this, none of the patients required arthroplasty, and patient-reported outcome scores at an average of 6 years postinjury were excellent, with a median ASES score of 98.5. ORIF should be considered as primary method of treatment in proximal humerus fracture dislocations not only in young patients but also middle-aged patients.

Treatment perspective after failed open reduction of congenital hip dislocation. A systematic review.

Failure of open reduction of developmental hip dislocation is a serious complication and revision surgery appear to be technically demanding with high complication rates. Little attention has been given in literature to patients in whom open reduction of developmental hip dislocation has failed. We present a systematic review about current perspectives and timing when to perform surgical revision after failed open reduction of developmental hip dislocation in children. Following the recommendations of the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) statements we performed a comprehensive search of the PubMed and Google Scholar bibliographic database in order to select all studies published between 1980 and 2022. Studies were screened for the reasons for failure of open reduction, timing when revision surgery was performed, and for the surgical techniques used for revision. A total of 10 articles including 252 patients and 268 hips has been recorded. The most common causes of re-dislocation after open reduction are inadequate exposure and failure to release the obstructing soft tissues inside and around the hip. In 90% of the cases the anterolateral approach was performed for revision surgery. Avascular necrosis occurred in 5%-67% of cases and was the most encountered complication. Redislocation of developmental hip dislocation after an open reduction has poor long-term outcomes mainly due to a high rate of avascular necrosis of the femoral head. It is mandatory to obtain a stable reduction at the second surgery combining soft tissue release, capsulorrhaphy, pelvic and femoral osteotomies.

Breast reconstruction for locally advanced breast cancer previously submitted to mastectomy and an ipsilateral thoracoabdominal dermofat (ITADE) flap.

Thoracoabdominal (TA) flaps are a good option for primary closure of small and medium defects after mastectomy for locally advanced breast tumours. Although they have a higher rate of necrosis than myocutaneous flaps, they can be easily performed by breast surgeons. Few studies on this procedure have been reported, and we have been unable to identify any prior publications reporting breast reconstruction with TA flaps.

Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery.

Transarterial radioembolization (TARE) has recently been recognized as a bridging/downstaging therapy to surgery for early hepatocellular carcinomas (HCCs) with high rates of complete pathological necrosis (CPN) on liver explants. In patients with portal vein tumoral thrombus (PVTT), multifocal or large tumors, TARE has mainly a palliative role and surgery remains controversial in this poor-prognosis population. Personalized dosimetry recently proved to outperform standard dosimetry used in prior negative Y90 randomized-controlled trials. In this retrospective study, we evaluated safety, radiological and pathological response and outcomes in HCC patients with PVTT, multifocal or large tumors, who underwent surgery after downstaging using TARE with Y90-loaded glass microspheres with personalized dosimetry. Between December 2015 and October 2021, 18 unresectable patients (14/18 with PVTT) had surgery (16 resections, 2 liver transplantations) 6.2 months (range, 2-14.6 months) after a single Y90 treatment. No 90-day mortality was reported. Objective modified response criteria in solid tumors (mRECIST) response were noted in all but one patient. Complete and extensive (50-99%) necrosis was observed in 36% and 45% of tumors, respectively. The post-treatment tumor-absorbed dose significantly differed depending on the extent of pathological necrosis (P=0.045). Median overall survival and progression-free survival (PFS) were respectively of 61.8 months [95% CI: 31.4 months-not reached (NR)] and 49.3 months (95% CI: 14 months-NR). PFS was longer in patients with complete imaging response [median NR (none recurred or died) vs. 21.5 months (95% CI: 10.1 months-NR), P<0.001] and in those with complete pathological response [median NR vs. 22.5 months (95% CI: 10.1 months-NR), P<0.001]. Y90 TARE using personalized dosimetry can provide high rates of imaging and pathological response in patients with PVTT, large or multifocal HCC. Subsequent surgery is safe and leads to outcomes far exceeding expectations in an otherwise poor prognosis population with no chance for cure. Clinical trial number: NCT05045573.

Comparative Study of DIEP and PAP Flaps in Breast Reconstruction: Reconstructive Outcomes and Fat Necrosis.

This study compared the reconstructive outcomes and fat necrosis of the profunda artery perforator (PAP) flap with those of the deep inferior epigastric perforator (DIEP) flap. Data on all DIEP and PAP flap breast reconstructions performed between 2018 and 2021 at Asan Medical Center were compared. The overall reconstructive outcomes and presence of fat necrosis were analyzed through ultrasound evaluation performed by a board-certified radiologist. The PAP (n = 43) and DIEP flaps (n = 99) were used to reconstruct 31 and 99 breasts, respectively. The average age of the patients in the PAP flap group (39.1 ± 7.3 years) was lower than in the DIEP flap group (47.4 ± 7.7 years), and the body mass index (BMI) of patients undergoing PAP flap reconstruction (22.7 ± 2.8 kg/m2) was lower than those undergoing DIEP flap reconstruction (24.3 ± 3.4 kg/m2). There was no total loss of both flaps. Donor site morbidity was higher in the PAP flap group (11.1%) compared with the DIEP flap (1.0%). The rate of fat necrosis was higher in the PAP flaps (40.7%) than in the DIEP flaps (17.8%) during ultrasound. In our study, we found that PAP flap reconstruction tended to be performed in patients who were younger with lower BMIs compared with the DIEP flap. Successful reconstructive outcomes were observed in both the PAP and DIEP flaps; however, a higher rate of necrosis was observed in the PAP flap compared with the DIEP flap.

PS-C37-6: IDENTIFICATION OF ALDOSTERONE-DRIVER SOMATIC MUTATIONS IN CELL-FREE DNA FROM ADRENAL VEIN SAMPLES OF PRIMARY ALDOSTERONISM PATIENTS

Objective: Cell-free DNA fragments (cf-DNA) of tumour cells are often found in the blood downstream to the tumour due to the high apoptosis or necrosis rate of the cells. Primary aldosteronism (PA), a curable cause of secondary hypertension, are commonly due to an autonomous aldosterone-producing adenoma that harbours a somatic mutation in an aldosterone-driver gene. We thus aimed to see if genotyping of cf-DNA for mutations in aldosterone-driver genes could be used as a biomarker for APA. Design and Methods: Genotyping of cf-DNA from the adrenal vein samples (AVS) of PA patients was performed using the Agena MassARRAY platform and validated by Sanger sequencing. In this study, six samples of cf-DNA from the left and right adrenals of three PA patients were interrogated. Results: Of the three PA patients, two had left adrenalectomy and one had right adrenalectomy. CTNNB1 S45 mutation was detected by the Agena MassArray platform in the cf-DNA of both right adrenal and left adrenal vein samples of all patients (Patient 1, Patient 2 and Patient 3). In Patient 1, Sanger sequencing confirmed a CTNNB1 S45del mutation in both cf-DNA of right adrenal and left adrenal vein samples. In Patient 3, who was found to have left adrenal hyperplasia, the cf-DNA of the right adrenal and left adrenal vein samples was also detected to have a KCNJ5 G151R mutation by the Agena MassArray platform which was confirmed by Sanger sequencing. Interestingly, only the cf-DNA of the left adrenal was found to have a CACNA1D S672L mutation in Patient 3. Conclusion: These results suggest that genotyping cf-DNA from AVS samples are able to detect aldosterone-driver mutations present in the APA. However, as AVS is an invasive procedure, it would be best if genotyping of cf-DNA from periphery blood can be performed. Therefore, further work is needed to ensure this strategy can be non-invasive as then it can be used as a screening method before AVS.

The Outcome of Discontinuing Tyrosine Kinase Inhibitors in Advanced Sarcoma Following a Favorable Tumor Response to Antiangiogenics Therapy.

(1) Background: The use of antiangiogenic TKIs (AA-TKIs) has recently emerged as a major paradigm shift in the treatment of advanced sarcoma. However, the feasibility of drug holidays for patients demonstrating a very favorable response remains unknown. (2) Methods: We aim to explore the outcomes of patients with advanced sarcoma who discontinued AA-TKIs after a (near-) complete remission or were long-term responders. Patients with advanced disease were included if they had bilateral or multiple lung metastases, extrapulmonary recurrence, a short disease-free interval, etc., at the initiation of AA-TKIs. (3) Results: A total of 22 patients with AA-TKI discontinuation were analyzed, with a median follow-up of 22.3 months post-discontinuation. Prior to discontinuation, there were four drug-induced complete remissions (CRs), twelve surgical CRs, and six long-term responders. Disease progression was observed in 17/22 (77.3%) patients, with a median of 4.2 months. However, since the majority were still sensitive to the original AA-TKIs and amenable to a second surgical remission, 7 out of these 17 patients achieved a second CR after disease progression and were thus considered as relapse-free post-discontinuation (pd-RFS). Therefore, the pd-RFS and post-discontinuation overall survival (pd-OS) in the last follow-up were 12/22 (54.5%) and 16/22 (72.7%), respectively. Remarkably, surgical CR and drug tapering off (versus abrupt stopping) were associated with a greater pd-RFS and pd-OS (p < 0.05). Furthermore, higher necrosis rates (p = 0.040) and lower neutrophil-to-lymphocyte ratios (NLR) (p = 0.060) before discontinuation tend to have a better pd-RFS. (4) Conclusions: Our results suggest that AA-TKI discontinuation with a taper-off strategy might be safe and feasible in highly selected patients with advanced sarcoma. Surgical CR, NLR, and tumor necrosis rates before discontinuation were potential biomarkers for AA-TKI withdrawal.

Tumor Microenvironment and Microvascular Density in Human Glioblastoma

Glioblastoma (GBM) is a very aggressive form of cancer affecting the central nervous system. Although it occurs almost exclusively in the brain, glioblastoma can also appear in the brainstem, cerebellum, and spinal cord. It is characterized by high rates of proliferation, invasion, and necrosis. Moreover, GBM is a highly vascularized tumor and presents resistance to therapy. Recent data indicate that GBM cells are surrounded by a microenvironment (TME) which includes a complex network constituted of cellular/extracellular components and vessels able to influence both tumor growth and angiogenesis. In this retrospective study, we evaluated 30 bioptic specimens of adult patients diagnosed with IDH1 wild type GBM taken at the time of the first diagnosis. Each section has been divided into two experimental zones: the tumor side and the healthy surrounding tissue. We performed a series of immunohistochemical stainings with the purpose of evaluating the presence of total and M2 macrophages, CD4+-, CD8+-lymphocytes, and CD34+ microvessels. In addition, we have also evaluated the percentage of cells expressing bcl6 and p53 to determine any possible correlations with TME. Our data showed a significant increase in the total and M2 type macrophages, of CD4+ and CD8+ lymphocytes, and of CD34+ microvessels in the tumoral area respective to the healthy zone. We also confirmed our previous data showing the higher number of p53 and BCL6+ cells in the tumor area with a positive correlation between BCL6 and CD34+ microvessels. In conclusion, the data that came from this work support the important role played by microenvironment components in GBM progression. These results could contribute to the generation of new specific therapies useful in preventing GBM progression.

Abstract C016: New treatment modality for pancreatic cancer-Vascular Targeted Photodynamic therapy with WST11 (Padeliporfin) combined with endovascular light delivery

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Early detection and surgical removal of PDAC, when the cancer is localized with no clinical evidence for systemic spread, may be curative but tumor spread into the vicinity of major blood vessels, e.g. superior mesenteric artery (SMA), can be lethal and therefore avoid surgery. Here we show that Vascular Targeted Photodynamic therapy (VTP) with WST11 in combination with immune modulating chemotherapeutic agents allows PDAC tumors ablation while preserving large normal vessels and tissues in animal models. New endovascular illumination system recently developed by our group (1) provides the light needed for such ablation with no damage to the SMA and complete remodeling of the surrounding normal tissue. Methods: Two orthotopic models of pancreatic cancer (KPC-Luc-mcherry and non-labeled KPC tumors (NL-KPC)) in C57B mice were subjected to VTP, alongside intraperitoneal gemzar (GEM) or cyclophosphamide (CTX) treatment. multiplex immunohistochemistry (mIHC) and single analyses using 10X Genomics platform of tumor were performed for resolving the key factors in the therapeutic process. Results: Comparing the KPC-Luc-mcherry with the NL-KPC tumor, we found that non labeled KPC has the typical morphology of human PDAC, immunologically cold and is highly aggressive compared with KPC-Luc-mcherry. WST11-VTP results in high cure rate (~50%) of animals bearing small KPC-Luc-mcherry tumors, larger tumors required combinations with metronomic administration of GEM. High rate of complete necrosis (95-100%) was achieved also with the non-labled PDAC tumors but prolonged disease- free survival required combination with CTX. The mechanism of action for both tumor models involves co-generation of oxygen and NO radicals through local photoexcitation of WST11, followed by iNOS consumption and vascular break down. Infiltration of immune cells alarmed by HMGB1 and other DAMPs leads to annihilation of residual cancer cells and prolonged anticancer immunity. The administration of CTX amplifies and prolonged the VTP oxidative stress. Conclusion: WST11-VTP combination with immune modulating chemotherapeutic agents administrations, activated by endovascular illumination through the SMA, may provide solution to the unmet need of early stage diagnosed PDAC patients. (1) Franz E. Boas et al, “Downstaging Locally Advanced Pancreatic Cancer To Resectability: Perivascular Ablation Using An Intra-arterial Balloon Laser Catheter In Pigs”, Abstract Archives of the RSNA, RSNA 2021,SDR-IR-13- “Redefining radiology” 11/29-12/4, 2021 Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Dina Priese, Yaniv Cohen, Zachary Zacks, Gil Stelzer, David P. Kelsen, Hooman Yarmohammadi, Alice C. Wei, Stephen B. Solomon, Avidgor Scherz. New treatment modality for pancreatic cancer-Vascular Targeted Photodynamic therapy with WST11 (Padeliporfin) combined with endovascular light delivery [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C016.

Outcomes Following Total Talus Replacement: A Systematic Review

Category: Ankle; Hindfoot; Trauma Introduction/Purpose: Prosthetic substitution of the talus presents a unique challenge to the foot and ankle surgeon. The shear and compressive forces on the talus and its tenuous blood supply lead to high rates of avascular necrosis with possible talar collapse. The purpose of this systematic review is to evaluate whether total talus replacements (TTR) lead to improved clinical outcomes with appropriate safety metrics in patients with a history of avascular necrosis or significant trauma. Methods: Concepts of talus and arthroplasty were searched in MEDLINE (PubMed), Embase (Elsevier), CINAHL Complete (EBSCOhost), and Scopus (Elsevier) from the database's inception through November 4, 2021. Inclusion Criteria were 1) previous trauma to the talus, 2) post-traumatic or degenerative arthritis to the tibiotalar joint, 3) avascular necrosis of talus, 4) multiple failed prior interventions, 5) degenerative osteoarthritis to the tibiotalar joint, and 56) inflammatory arthropathy to tibiotalar joint. Manuscripts in non-English languages or those with concomitant total ankle arthroplasty or revision arthroplasty were excluded. All study designs were eligible according to the Journal of Bone and Joint Surgery criteria level I-IV. The modified Coleman Methodology Score was used to evaluate study quality and the Methodological Index for Non-Randomized Studies criteria was used to assess risk of bias. Results: Twenty-two studies of 191 patients (196 tali) at an average age of 50 (14-80) years were included (Figure 1a). Nineteen studies utilized third generation implants, two studies used first generation (n=9), and one study used second generation implants (n = 14) made of ceramic (n=82), cobalt chrome (n=49), or titanium (n=23) (Figure 1b). Radiographic and patient-reported outcomes are outlined in Figure 1c. The most common adverse outcome was osteosclerosis of the tibia (n=24), calcaneus (n=19), and navicular (n=5). Additionally, hindfoot varus (n=3), ankle discomfort (n = 3), decreased subtalar motion (n=7), periprosthetic fracture (n=1), calcaneal fracture (n=1), delayed wound healing (n=3), hindfoot valgus (n=1), prosthetic stem sunken into the talar neck (n=1), superficial peroneal nerve neuroma (n=1), loosening (n=2) were reported. Eight revisions were reported. Conclusion: TTR is an appealing option to maintain range of motion through the tibiotalar joint and allow for maintenance of more normal foot and ankle biomechanics. Given promising early- and mid-term outcomes, TTR is becoming more widely used in the setting of talar collapse. Still, high complication rates, especially adjacent joint osteoarthritis, may remain under-reported in the literature given inadequate long-term follow-up. Future research should aim to expand upon the indications of TTR, elucidate survivorship and complication rates, and directly compare TTR to existing forms of salvage options for advanced talar avascular necrosis.

YÜKSEK YAĞLI DİYET / STREPTOZOTOSİN İLE İNDÜKLENEN DİYABETİK FARELERDE METFORMİNİN HEPATORENAL HASARA KARŞI KORUYUCU ETKİLERİ

AMAÇ: Sunulan bu çalışmada yüksek yağlı diyet ve streptozotosin ile deneysel tip 2 diyabet oluşturulan farelerde metformin tedavisinin karaciğer ve böbrek dokularında antioksidan etkisinin araştırılması amaçlandı.GEREÇ VE YÖNTEM: Yirmi bir adet yetişkin (11-12 haftalık 15-18 g) C57BL6 erkek fare rastgele üç gruba ayrıldı; Kontrol grubu (K), Diyabet grubu (D), ve Diyabet+Metformin tedavi grubu (D+MTF). D ve D+MTF grupları 4 hafta süreyle yağ oranı %60 olan yüksek yağlı diyetle beslendi. 4. Haftanın sonunda 30 mg/kg tek doz streptozotosin intraperitoneal uygulanarak tip 2 diyabet oluşturuldu. Metformin 300 mg/kg/gün dozunda gavaj ile verildi. Deney sonunda alınan karaciğer ve böbrek örneklerinde; glutatyon (GSH), katalaz (KAT) ve malondialdehit (MDA) düzeyleri spektrofotometrik yöntemle ölçüldü. Hemotoksilen ve Eozin ile boyanan doku kesitleri histomorfolojik olarak değerlendirildi.BULGULAR: Çalışma sonuçları diyabetik hayvanların karaciğer ve böbrek dokularında MDA düzeylerinin arttığını gösterdi. Metformin tedavisinin her iki dokuda da MDA düzeylerini azaltıp, GSH ve KAT düzeylerini artırdığı ancak bu artışın karaciğerde anlamlı düzeyde olmadığı (p&amp;gt;0,05), böbrekte ise anlamlı düzeyde olduğu bulundu (p&amp;lt;0,05). Ayrıca Histopatolojik değerlendirme sonuçlarında D+MTF grubunda nadir alanlarda vakuolizasyon, yer yer nekroz ve sinozoidal tıkanıklık görülürken, D grubu karaciğerlerinde yoğun vakuolizasyon, yüksek oranda sinozoidal tıkanıklık ve nekroz görüldü. Böbrek dokusunda K grubunda tübüler yapının normal yapıda olduğu; D grubunda, tübüllerin genişlediği ve yoğun kanama alanlarının olduğu; D+MTF grubunda ise nadir alanlarda tübül yapılarında vakuollerin olduğu görüldü.SONUÇ: Bu çalışmanın sonuçları, Diyabette dokularda oksidatif stresin oluştuğunu, metformin tedavisinin diyabette artan oksidatif stres üzerinde düzeltici etki göstererek dokularda hasar oluşmasını engellediğini göstermektedir.

Review on acute pancreatitis attributed to COVID-19 infection.

The coronavirus disease 2019 (COVID-19) is known to cause gastrointestinal symptoms. Recent studies have revealed COVID-19-attributed acute pancreatitis (AP). However, clinical characteristics of COVID-19-attributed AP remain unclear. We performed a narrative review to elucidate relation between COVID-19 and AP using the PubMed database. Some basic and pathological reports revealed expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, key proteins that aid in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the pancreas. The experimental and pathological evaluation suggested that SARS-CoV-2 infects human endocrine and exocrine pancreas cells, and thus, SARS-CoV-2 may have a direct involvement in pancreatic disorders. Additionally, systemic inflammation, especially in children, may cause AP. Levels of immune mediators associated with AP, including interleukin (IL)-1β, IL-10, interferon-γ, monocyte chemotactic protein 1, and tumor necrosis factor-α are higher in the plasma of patients with COVID-19, that suggests an indirect involvement of the pancreas. In real-world settings, some clinical features of AP complicate COVID-19, such as a high complication rate of pancreatic necrosis, severe AP, and high mortality. However, clinical features of COVID-19-attributed AP remain uncertain due to insufficient research on etiologies of AP. Therefore, high-quality clinical studies and case reports that specify methods for differential diagnoses of other etiologies of AP are needed.

The modern management of untreated large (>2 cm) brain metastases: a narrative review.

Our objective was to identify contemporary management options for large brain metastases reported in literature, specifically evaluating local control and risk of toxicity. Large brain metastases are typically defined as lesions >2 cm in diameter, and historically conferred poor outcomes due to the high rates of radiation necrosis and less local control in comparison to smaller brain metastases. A literature search examining modern management of large brain metastases was performed using ovid-MEDLINE. A total of 18 articles met criteria for review, evaluating single fraction radiosurgery [stereotactic radiosurgery (SRS)] and multi-fraction stereotactic radiation therapy (MFSRT) in both the definitive and post-operative cavity setting, as well as targeted therapies. Multi-fractionated radiosurgery represents a modern and attractive treatment approach in the definitive management of patients with large brain metastases, with equivalent local control and reduced rates of radionecrosis less than 13% in comparison to single fraction SRS. In cases where surgery is indicated, fractionated cavity radiation should be considered for large tumor bed volumes. More research is needed for the optimal dose and fractionation regimen for optimal tumor control with reduced risk of radiation toxicity, but common regimens include 3-5 fractions while meeting appropriate biologically effective dose (BED) goals. Future areas of interest include targeted therapies in the initial management of brain metastases as well as pre-operative radiation therapy to reduce risk of leptomeningeal disease (LMD).