Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas.

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future.

Outcomes in patients with burns to the perineum, buttocks and genitalia: A retrospective cohort study.

BACKGROUND: Burns that involve the perineum, buttocks and genitals (PBG) have been associated with more challenging therapeutic needs and worse clinical outcomes. We aimed to investigate whether PBG burns are an independent predictor for mortality, morbidity and complications in a large, heterogenous patient collective and in comparison to patients without PBG burns. PATIENTS AND METHODS: Patients admitted to a level one burn center between August 2014 and July 2022 were included and stratified based on the presence of PBG burns on admission (PBG & control group = CTR). Demographic baseline data, burn aetiology, inhalation trauma (IHT), full-thickness burns (FT), number of operations (NOR), mortality, length of ICU stay (LOS-ICU), length of in-hospital stay (LOHS) and bacteraemia were assessed to compare key clinical characteristics and outcomes between the groups. Multivariate regression analyses and a 1:1 propensity score matching were conducted for key clinical outcomes. RESULTS: A total of 1024 patients were included in the analysis (PBG: n = 227; CTR: n = 797). PBG burns were older (median (IQR) 54 (34-72) vs. 44, (30-61) years, p < 0.0001), more frequently female (35% vs. 23%, p = 0.002) presented with larger total body surface area (TBSA) burns overall (27 (32-39) vs. 10 (13-15) %, p < 0.0001) and sustained FT burns more frequently (69% vs. 26% p < 0.0001). Scald burns were more frequently the cause of PBG burns (45% vs. 15%, p < 0.0001), PBG patients needed twice as many surgical procedures (Mean (SD) 2 (2.84) vs. 1 (1.6), p < 0.0001) as CTR. In multivariate analyses, a significant correlation was identified between length of ICU stay and presence of PBG burns. Following strict cohort matching to account for sex, age, cause of burn, TBSA %, presence of FT burn, inhalation trauma and bacteraemia, PBG burns were an independent predictor for mortality (p = 0.0003). CONCLUSION: PBG burns are at risk for prolonged intensive care, hospitalization and complications during treatment. Furthermore, the presence of PBG burns appears to be a risk factor for mortality, irrespective of patient age, TBSA affected and other relevant covariates.

Multiparametric magnetic resonance imaging for radiation therapy response monitoring in soft tissue sarcomas: a histology and MRI co-registration algorithm.

Rationale: To establish a spatially exact co-registration procedure between in vivo multiparametric magnetic resonance imaging (mpMRI) and (immuno)histopathology of soft tissue sarcomas (STS) to identify imaging parameters that reflect radiation therapy response of STS. Methods: The mpMRI-Protocol included diffusion-weighted (DWI), intravoxel-incoherent motion (IVIM), and dynamic contrast-enhancing (DCE) imaging. The resection specimen was embedded in 6.5% agarose after initial fixation in formalin. To ensure identical alignment of histopathological sectioning and in vivo imaging, an ex vivo MRI scan of the specimen was rigidly co-registered with the in vivo mpMRI. The deviating angulation of the specimen to the in vivo location of the tumor was determined. The agarose block was trimmed accordingly. A second ex vivo MRI in a dedicated localizer with a 4 mm grid was performed, which was matched to a custom-built sectioning machine. Microtomy sections were stained with hematoxylin and eosin. Immunohistochemical staining was performed with anti-ALDH1A1 antibodies as a radioresistance and anti-MIB1 antibodies as a proliferation marker. Fusion of the digitized microtomy sections with the in vivo mpMRI was accomplished through nonrigid co-registration to the in vivo mpMRI. Co-registration accuracy was qualitatively assessed by visual assessment and quantitatively evaluated by computing target registration errors (TRE). Results: The study sample comprised nine tumor sections from three STS patients. Visual assessment after nonrigid co-registration showed a strong morphological correlation of the histopathological specimens with ex vivo MRI and in vivo mpMRI after neoadjuvant radiation therapy. Quantitative assessment of the co-registration procedure using TRE analysis of different pairs of pathology and MRI sections revealed highly accurate structural alignment, with a total median TRE of 2.25 mm (histology - ex vivo MRI), 2.22 mm (histology - in vivo mpMRI), and 2.02 mm (ex vivo MRI - in vivo mpMRI). There was no significant difference between TREs of the different pairs of sections or caudal, middle, and cranial tumor parts, respectively. Conclusion: Our initial results show a promising approach to obtaining accurate co-registration between histopathology and in vivo MRI for STS. In a larger cohort of patients, the method established here will enable the prospective identification and validation of in vivo imaging biomarkers for radiation therapy response prediction and monitoring in STS patients via precise molecular and cellular correlation.

Non-invasive monitoring of neoadjuvant radiation therapy response in soft tissue sarcomas by multiparametric MRI and quantification of circulating tumor DNA-A study protocol.

BACKGROUND: Wide resection remains the cornerstone of localized soft-tissue sarcomas (STS) treatment. Neoadjuvant radiation therapy (NRT) may decrease the risk of local recurrences; however, its effectiveness for different histological STS subtypes has not been systematically investigated. The proposed prospective study evaluates the NRT response in STS using liquid biopsies and the correlation of multiparametric magnetic resonance imaging (mpMRI) with histopathology and immunohistochemistry. METHODS: Patients with localized high-grade STS, who qualify for NRT, are included in this study. LIQUID BIOPSIES: Quantification of circulating tumor DNA (ctDNA) in patient blood samples is performed by targeted next-generation sequencing. Soft-tissue sarcoma subtype-specific panel sequencing in combination with patient-specific exome sequencing allows the detection of individual structural variants and point mutations. Circulating free DNA is isolated from peritherapeutically collected patient plasma samples and ctDNA quantified therein. Identification of breakpoints is carried out using FACTERA. Bioinformatic analysis is performed using samtools, picard, fgbio, and the MIRACUM Pipeline. MPMRI: Combination of conventional MRI sequences with diffusion-weighted imaging, intravoxel-incoherent motion, and dynamic contrast enhancement. Multiparametric MRI is performed before, during, and after NRT. We aim to correlate mpMRI data with the resected specimen's macroscopical, histological, and immunohistochemical findings. RESULTS: Preliminary data support the notion that quantification of ctDNA in combination with tumor mass characterization through co-registration of mpMRI and histopathology can predict NRT response of STS. CLINICAL RELEVANCE: The methods presented in this prospective study are necessary to assess therapy response in heterogeneous tumors and lay the foundation of future patient- and tumor-specific therapy concepts. These methods can be applied to various tumor entities. Thus, the participation and support of a wider group of oncologic surgeons are needed to validate these findings on a larger patient cohort.

Risk factors in distal interphalangeal joint arthrodesis in the hand: a retrospective study of 173 cases.

In this retrospective study we aimed to analyse the risk factors for complications after different methods of distal interphalangeal arthrodesis in the hand. Forty-four per cent were treated with K-wire/cerclage fixation, 46% with X-fuse® implants (Stryker GmbH, Selzach, Switzerland) and 10% with headless compression screws (HBS®-screw, KLS Martin Group, Tuttlingen, Germany). The median follow-up was 16 weeks (range 6-224). The overall complication incidence was 44% (minor complications 29% and major 15%). The logistic regression showed that osteoarthritis, revisional arthrodesis and smoking had a negative impact on the total complication incidence. A Cox-regression analysis showed that HBS®-screw arthrodesis was associated with a significantly lower incidence of major complications compared with K-wire/cerclage and X-Fuse®-arthrodesis. Revisional arthrodesis was five times more frequently connected with major complications than primary surgery. Smokers were three times more likely to experience major complications than non-smokers. We conclude that arthrodesis of the distal interphalangeal joint often leads to complications. Risk factors must be kept in mind.Level of evidence: III.

Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas.

BACKGROUND: Synovial sarcoma (SS) is a malignant soft tissue tumor of mesenchymal origin that frequently occurs in young adults. Translocation of the SYT gene on chromosome 18 to the SSX genes on chromosome X leads to the formation of oncogenic fusion genes, which lead to initiation and proliferation of tumor cells. The detection and quantification of circulating tumor DNA (ctDNA) can serve as a non-invasive method for diagnostics of local or distant tumor recurrence, which could improve survival rates due to early detection. METHODS: We developed a subtype-specific targeted next-generation sequencing (NGS) approach specifically targeting SS t(X;18)(p11;q11), which fuses SS18 (SYT) in chromosome 18 to SSX1 or SSX2 in chromosome x, and recurrent point mutations. In addition, patient-specific panels were designed from tumor exome sequencing. Both approaches were used to quantify ctDNA in patients' plasma. RESULTS: The subtype-specific assay allowed detection of somatic mutations from 25/25 tumors with a mean of 1.68 targetable mutations. The minimal limit of detection was determined at a variant allele frequency of 0.05%. Analysis of 29 plasma samples from 15 tumor patients identified breakpoint ctDNA in 6 patients (sensitivity: 40%, specificity 100%). The addition of more mutations further increased assay sensitivity. Quantification of ctDNA in plasma samples (n = 11) from one patient collected over 3 years, with a patient-specific panel based on tumor exome sequencing, correlated with the clinical course, response to treatment and tumor volume. CONCLUSIONS: Targeted NGS allows for highly sensitive tumor profiling and non-invasive detection of ctDNA in SS patients, enabling non-invasive monitoring of tumor dynamics.

Augmentation of Hiatal Repair with the Ligamentum Teres Hepatis for Intrathoracic Gastric Migration After Bariatric Surgery.

PURPOSE: The augmentation of hiatoplasty (HP) with the ligamentum teres hepatis (LTA) is a new concept for intrathoracic migration of a gastric sleeve or pouch (ITGM). We retrospectively analyzed all cases of hiatal hernia repair in a single center between 2015 and 2019. METHODS: A total of 171 patients underwent 307 hiatal hernia repairs after sleeve gastrectomy (SG) (n = 79), Roux-en-Y gastric bypass (RYGB) (n = 129), and one anastomosis gastric bypass (OAGB) (n = 99). Each hiatal hernia repair was defined as a "case" and assigned to the LTA group or the non-LTA group. The primary outcome was the recurrence of ITGM as detected by endoscopy or CT. RESULTS: The basic characteristics in the LTA group (78 cases) and the non-LTA group (229 cases) were comparable with the exception of the rate of revisional HP (72% vs. 21%), the rate of prior conversion to RYGB (33% vs. 17%), the initial BMI (45.9 ± 8.2 kg/m2 vs. 49.0 ± 8.8 kg/m2), and the follow-up (7 months (1-16) vs. 8 months (1-54)). The ITGM recurrence rate was 15% in the LTA group and 72% in non-LTA group (p < 0.001). Multivariate analysis showed that the length of ITGM and the type of surgical repair were independent risk factors. The addition of LTA to HP lowered the probability of ITGM recurrence by a factor of 0.35 (p = 0.015), but the conversion from SG or OAGB to RYGB did not reduce the risk. CONCLUSIONS: LTA reduces the risk of early ITGM recurrence. The long-term durability, however, needs to be further investigated.

The New Interest of Bariatric Surgeons in the Old Ligamentum Teres Hepatis.

The search for an operation that effectively prevents and treats intrathoracic gastric migration (ITGM) after bariatric surgery has revived a long-forgotten technique: ligamentum teres cardiopexy (LTC) by which a vascularized flap of the teres ligament is wrapped around the distal esophagus. The systematic search of publications in the English language revealed 4 studies (total number of patients 53) in the non-bariatric literature with an unsatisfactory resolution of GERD. There were 5 reports from the bariatric literature with small patient numbers (total 64) and a short follow-up (6-36 months). There were no objective signs of gastric remigration in 93% of investigated patients. Acknowledging the limitations of these preliminary reports, bariatric surgeons are encouraged to further investigate the potentials of LTC in their patients.