Reclassification of Appendiceal Mucinous Neoplasms and Associated Pseudomyxoma Peritonei According to the Peritoneal Surface Oncology Group International Consensus: Clinicopathological Reflections of a Two-Center Cohort Study.

BACKGROUND: International consensus on classifications of appendiceal mucinous neoplasms (AMNs) and associated pseudomyxoma peritonei (PMP) have been carefully made but clinicopathological associations supporting decision making remain scarce. OBJECTIVE: This study aimed to assess interdependence between AMNs and PMP and provide directions for clinical management. METHODS: This two-center retrospective cohort study reviewed patients with PMP treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between 2005 and 2021. The primary objective was to reassess histopathologic grade of AMNs and PMP according to the Peritoneal Surface Oncology Group International classification and to establish its interdependence. Secondary outcomes were recurrence rate, PMP grade progression, ovarian involvement, and overall survival (OS). RESULTS: Of 105 patients included, 78 (74.3%) had low-grade AMNs as the primary tumor, 8 (7.6%) had high-grade AMNs, 7 (6.7%) had mucinous adenocarcinoma (MAC), 1 (0.9%) had MAC with signet ring cells (SRC), and 11 (10.5%) had unidentified tumors. Overall, 11 patients (10.5%) had no PMP, 21 (20.0%) had acellular mucin, 56 (53.3%) had low-grade PMP, 12 (11.4%) had high-grade PMP, and 5 (4.8%) had PMP-SRC. In 11 cases (13.3%), AMNs and matching PMP grade differed. Over a 16-year follow-up, recurrence occurred in 31.8%, with three cases showing histopathologically changed PMP. Ovarian involvement was observed in 43/65 females (66.2%). Median OS was 13.8 years, and 5-year OS rates were 100%, 74.4%, 44.4%, and 20% for acellular mucin, low-grade PMP, high-grade PMP and PMP-SRC, respectively (p < 0.001). CONCLUSIONS: AMN histology does not always reflects its associated PMP grade, while PMP grade strongly influences survival. Ovarian involvement and recurrent PMP showing unchanged histopathological features are common.

Exploring the incidence of dysplasia or adenocarcinoma in early onset Barrett's esophagus.

BACKGROUND: Currently data on the risk of progression to and lifetime risk of cancer are not available for patients with young onset Barrett's esophagus (BE). Our aim was to obtain epidemiologic data on the incidence of dysplasia or adenocarcinoma in young onset BE in the Netherlands by collecting data on all histologically confirmed cases over a prolonged period of 25 years between January 1, 1991 and December 31, 2015. METHODS: Data were obtained from the Dutch National Pathology Registry. Patients were included if there was a suspicion of BE visualized in the esophagus during the endoscopic examination in combination with a concordant histologic diagnosis of intestinal metaplasia. RESULTS: 231 patients with early onset BE were identified (median age 26 years [range 0-29 years]), with 17 progressing to dysplasia (6 prevalent and 11 incident). For the patients with incident dysplasia, the median surveillance time between the diagnosis of early onset BE and diagnosis of dysplasia was 5 years (range 0-16 years). The incidence rate of dysplasia was 7.3 per 1000 person-years. There were three patients who developed adenocarcinoma (1 prevalent and 2 incident), who were diagnosed at ages 28, 35, and 36 years. The incidence rate of adenocarcinoma was 1.3 per 1000 person-years. CONCLUSIONS: In this 25-year period, 231 patients were diagnosed with early onset BE in the Netherlands, with 17 patients progressing to dysplasia and three developing adenocarcinoma. This corresponded to incidence rates of 7.3 per 1000 person-years for dysplasia and 1.3 per 1000 person-years for adenocarcinoma.

Tamsulosin use in benign prostatic hyperplasia and risks of Parkinson's disease, Alzheimer's disease and mortality: An observational cohort study of elderly Medicare enrollees.

PURPOSE: To study the effects of benign prostatic hyperplasia treatments, namely: alpha-adrenergic receptor blockers, 5-alpha-reductase inhibitors and phosphodiesterase-5 inhibitors on the risk of Parkinson's disease, Alzheimer's disease and mortality. MATERIALS AND METHODS: All male Medicare enrollees aged 65 or above who were diagnosed with benign prostatic hyperplasia and received one of the study drugs between 2007-2020 were followed-up for the three outcomes. We used Cox regression analysis to assess the relative risk of each of the outcomes for each study drug compared to the most prescribed drug, tamsulosin, while controlling for demographic, socioeconomic and comorbidity factors. RESULTS AND CONCLUSIONS: The study analyzed 1.1 million patients for a mean follow-up period of 3.1 years from being prescribed one of the study drugs. For all outcomes, patients on tamsulosin were used as the reference for comparison. For mortality, alfuzosin was associated with 27% risk reduction (HR 0.73, 95%CI 0.68-0.78), and doxazosin with 6% risk reduction (HR 0.94, 95%CI 0.91-0.97). For Parkinson's disease, terazosin was associated with 26% risk reduction (HR 0.74, 95%CI 0.66-0.83), and doxazosin with 21% risk reduction (HR 0.79, 95%CI 0.72-0.88). For Alzheimer's disease, terazosin was associated with 27% risk reduction (HR 0.73, 95%CI 0.65-0.82), and doxazosin with 16% risk reduction (HR 0.84, 95%CI 0.76-0.92). Tadalafil was associated with risk reduction (27-40%) in all 3 outcomes. More research is needed to elucidate the underlying mechanisms of these observations. Given the availability of safer alternatives for treating benign prostatic hyperplasia, caution should be exercised when using tamsulosin in elderly patients, especially those with an increased risk of developing neurodegenerative diseases.

G-Net: Implementing an enhanced brain tumor segmentation framework using semantic segmentation design.

A fundamental computer vision task called semantic segmentation has significant uses in the understanding of medical pictures, including the segmentation of tumors in the brain. The G-Shaped Net architecture appears in this context as an innovative and promising design that combines components from many models to attain improved accuracy and efficiency. In order to improve efficiency, the G-Shaped Net architecture synergistically incorporates four fundamental components: the Self-Attention, Squeeze Excitation, Fusion, and Spatial Pyramid Pooling block structures. These factors work together to improve the precision and effectiveness of brain tumor segmentation. Self-Attention, a crucial component of G-Shaped architecture, gives the model the ability to concentrate on the image's most informative areas, enabling accurate localization of tumor boundaries. By adjusting channel-wise feature maps, Squeeze Excitation completes this by improving the model's capacity to capture fine-grained information in the medical pictures. Since the G-Shaped model's Spatial Pyramid Pooling component provides multi-scale contextual information, the model is capable of handling tumors of various sizes and complexity levels. Additionally, the Fusion block architectures combine characteristics from many sources, enabling a thorough comprehension of the image and improving the segmentation outcomes. The G-Shaped Net architecture is an asset for medical imaging and diagnostics and represents a substantial development in semantic segmentation, which is needed more and more for accurate brain tumor segmentation.

Enhancing brain tumor segmentation in MRI images using the IC-net algorithm framework.

Brain tumors, often referred to as intracranial tumors, are abnormal tissue masses that arise from rapidly multiplying cells. During medical imaging, it is essential to separate brain tumors from healthy tissue. The goal of this paper is to improve the accuracy of separating tumorous regions from healthy tissues in medical imaging, specifically for brain tumors in MRI images which is difficult in the field of medical image analysis. In our research work, we propose IC-Net (Inverted-C), a novel semantic segmentation architecture that combines elements from various models to provide effective and precise results. The architecture includes Multi-Attention (MA) blocks, Feature Concatenation Networks (FCN), Attention-blocks which performs crucial tasks in improving brain tumor segmentation. MA-block aggregates multi-attention features to adapt to different tumor sizes and shapes. Attention-block is focusing on key regions, resulting in more effective segmentation in complex images. FCN-block captures diverse features, making the model more robust to various characteristics of brain tumor images. Our proposed architecture is used to accelerate the training process and also to address the challenges posed by the diverse nature of brain tumor images, ultimately leads to potentially improved segmentation performance. IC-Net significantly outperforms the typical U-Net architecture and other contemporary effective segmentation techniques. On the BraTS 2020 dataset, our IC-Net design obtained notable outcomes in Accuracy, Loss, Specificity, Sensitivity as 99.65, 0.0159, 99.44, 99.86 and DSC (core, whole, and enhancing tumors as 0.998717, 0.888930, 0.866183) respectively.

First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Revalidating the prognostic relevance of the Abbreviated Burn Severity Index (ABSI): A twenty-year experience examining the performance of the ABSI score in consideration of progression and advantages of burn treatments from a single center in Vienna.

BACKGROUND: The Abbreviated Burn Severity Index (ABSI) is a five-variable scale to help evaluate burn severity upon initial assessment. As other studies have been conducted with comparatively small patient populations, the purpose of this study is to revalidate the prognostic relevance of the ABSI in our selected population (N = 1193) 4 decades after its introduction, considering the progress in the treatment of severe burn injuries over the past decades. In addition, we evaluate whether comorbidities influence the survival probability of severely burned patients. METHODS: This retrospective study presents data from the Center for Severely Burned Patients of the General Hospital in Vienna. We included 1193 patients for over 20 years. Regression models were used to describe the prognostic accuracy of the ABSI. RESULTS: The ABSI can still be used as a prognostic factor for the probability of survival of severely burned patients. The odds of passing increases by a factor of 2.059 for each unit increase in the ABSI with an area under the curve value of 0.909. Over time, the likelihood of survival increased. The existence of chronic kidney disease negatively impacts the survival probability of severely burned patients. CONCLUSION: The ABSI can still be used to provide accurate information about the chances of survival of severely burned patients; however, further exploration of the impact of chronic kidney disease on the survival probability and adding variables to the ABSI scale should be considered. The probability of survival has increased over the last 20 years.

Use of menopausal hormone therapy beyond age 65 years and its effects on women's health outcomes by types, routes, and doses.

OBJECTIVES: The study aims to assess the use of menopausal hormone therapy beyond age 65 years and its health implications by types of estrogen/progestogen, routes of administration, and dose strengths. METHODS: Using prescription drug and encounter records of 10 million senior Medicare women from 2007-2020 and Cox regression analyses adjusted for time-varying characteristics of the women, we examined the effects of different preparations of menopausal hormone therapy on all-cause mortality, five cancers, six cardiovascular diseases, and dementia. RESULTS: Compared with never use or discontinuation of menopausal hormone therapy after age 65 years, the use of estrogen monotherapy beyond age 65 years was associated with significant risk reductions in mortality (19% or adjusted hazards ratio, 0.81; 95% CI, 0.79-0.82), breast cancer (16%), lung cancer (13%), colorectal cancer (12%), congestive heart failure (CHF) (5%), venous thromboembolism (3%), atrial fibrillation (4%), acute myocardial infarction (11%), and dementia (2%). For the use of estrogen and progestogen combo-therapy, both E+ progestin and E+ progesterone were associated with increased risk of breast cancer by 10%-19%, but such risk can be mitigated using low dose of transdermal or vaginal E+ progestin. Moreover, E+ progestin exhibited significant risk reductions in endometrial cancer (45% or adjusted hazards ratio, 0.55; 95% CI, 0.50-0.60), ovarian cancer (21%), ischemic heart disease (5%), CHF (5%), and venous thromboembolism (5%), whereas E+ progesterone exhibited risk reduction only in CHF (4%). CONCLUSIONS: Among senior Medicare women, the implications of menopausal hormone therapy use beyond age 65 years vary by types, routes, and strengths. In general, risk reductions appear to be greater with low rather than medium or high doses, vaginal or transdermal rather than oral preparations, and with E2 rather than conjugated estrogen.

Contralateral Thoracotomy With Extracorporeal Circulation for Reoperative Resection of a Kommerell Diverticulum.

Reoperative vascular ring surgery is uncommon. Standard redo ipsilateral thoracotomy may present technical challenges and risks. We describe a patient with right aortic arch, aberrant left subclavian artery, and a Kommerell diverticulum in whom previous vascular ring division via left thoracotomy did not relieve dysphagia. Three years after the unsuccessful operation, left subclavian-carotid transposition via supraclavicular incision followed by resection of the Kommerell diverticulum via right thoracotomy with extracorporeal circulation relieved symptoms. Contralateral thoracotomy with extracorporeal circulation provides a safe, alternative approach to redo ipsilateral thoracotomy for resection of a symptomatic Kommerell diverticulum. We review the literature on the incidence, surgical indications, and operative approaches to manage symptoms from a Kommerell diverticulum.

Skin Bank Establishment in Treatment of Severe Burn Injuries: Overview and Experience with Skin Allografts at the Vienna Burn Center.

Depending on their extent, burn injuries require different treatment strategies. In cases of severe large-area trauma, the availability of vital skin for autografting is limited. Donor skin allografts are a well-established but rarely standardized option for temporary wound coverage. Ten patients were eligible for inclusion in this retrospective study. Overall, 202 donor skin grafts obtained from the in-house skin bank were applied in the Department of Plastic and Reconstructive and Aesthetic Surgery, Medical University of Vienna. Between 2017 and 2022, we analysed the results in patient treatment, the selection of skin donors, tissue procurement, tissue processing and storage of allografts, as well as the condition and morphology of the allografts before application. The average Abbreviated Burn Severity Index (ABSI) was 8.5 (range, 5-12), and the mean affected total body surface area (TBSA) was 46.1% (range, 20-80%). In total, allograft application was performed 14 times. In two cases, a total of eight allografts were removed due to local infection, accounting for 3.96% of skin grafts. Six patients survived the acute phase of treatment. Scanning electron microscope images and histology showed no signs of scaffold decomposition and intact tissue layers of the allografts. The skin banking program and the application of skin allografts at the Vienna Burn Center can be considered successful. In severe burn injuries, skin allografts provide time by serving as sufficient wound coverage after early necrosectomy. Having an in-house skin banking program at a dedicated burn centre is particularly advantageous since issues of availability and distribution can be minimized. Skin allografts provide a reliable treatment option in patients with extensive burn injuries.

GRU-SVM Based Threat Detection in Cognitive Radio Network.

Cognitive radio networks are vulnerable to numerous threats during spectrum sensing. Different approaches can be used to lessen these attacks as the malicious users degrade the performance of the network. The cutting-edge technologies of machine learning and deep learning step into cognitive radio networks (CRN) to detect network problems. Several studies have been conducted utilising various deep learning and machine learning methods. However, only a small number of analyses have used gated recurrent units (GRU), and that too in software defined networks, but these are seldom used in CRN. In this paper, we used GRU in CRN to train and test the dataset of spectrum sensing results. One of the deep learning models with less complexity and more effectiveness for small datasets is GRU, the lightest variant of the LSTM. The support vector machine (SVM) classifier is employed in this study's output layer to distinguish between authorised users and malicious users in cognitive radio network. The novelty of this paper is the application of combined models of GRU and SVM in cognitive radio networks. A high testing accuracy of 82.45%, training accuracy of 80.99% and detection probability of 1 is achieved at 65 epochs in this proposed work.

Lipopolysaccharide-binding protein expression is associated to the metastatic status of osteosarcoma patients.

Osteosarcoma (OS) is a rare malignant primary bone tumours characterized by a high genetic and cell composition heterogeneity. Unfortunately, despite the use of drug combinations and the recent development of immunotherapies, the overall survival has not improved in the last four decades. Due to the key role of the tumour microenvironment in the pathogenesis of OS, a better understanding of its microenvironment is mandatory to develop new therapeutic approaches. From retrospective biological cohorts of OS, we analysed by immunohistochemistry the presence of lipopolysaccharide (LPS)-binding protein (LBP) in diagnostic biopsies with local disease and compared their level of infiltration to patients suffering from metastatic status. LBP is considered as a marker of LPS exposure and can indirectly reflect the presence of Gram-negative microbiota. LBP were detected in the cytoplasm of OS cells as well as in tumour-associated macrophage. Tumour samples of patients with local disease were significantly enriched in LBP compared to tumour tissues of patients with metastatic status. Lung metastatic tissues showed similar level of LBP compared to paired primary tumours. Overall, this study strongly suggests the presence of Gram-negative bacteria in OS tissues and demonstrated their significant differential level according the metastatic status. This tumour-associated microbiome may help in the conceptualisation of new therapeutic approach to trigger efficient therapeutic responses against cancer.

Intensive care in an older population: Influence of age, comorbidities and sex in 304 plastic and reconstructive surgical patients older than 75 years.

AIM: An aging population will lead to an increasing demand for critical care resources. Hence, we evaluated the potential influence of age, comorbidities and sex in plastic and reconstructive patients ≥75 years that were admitted to the intensive care unit (ICU). METHODS: We included 304 patients who required intensive care between 2000 and 2019. Besides patient demographics, medical case characteristics were statistically evaluated. RESULTS: In this study, 184 patients were female (61%) (120 male), the median age was 81.8 years (25th and 75th percentiles: 77.4-87.2) with a range of 75.0-98.9 years. The median length of stay in the ICU was 12 days (25th and 75th percentiles: 3-28) with a range of 0-382 days. The reasons for admission were burn injury (n = 230, 76%), necrotizing fasciitis (n = 34, 11%), non-combustion-related traumas (n = 22, 7%) and postoperative observation after plastic surgery procedures (n = 18, 6%). In total, 108 patients (36%), who were significantly older (P = 0.005) and had a significantly shorter stay (P < 0.001) compared with the surviving cohort, died during their stay in the ICU. Our multivariable logistic regression model revealed that age (odds ratio: 1.05 [1.01, 1.09]; P = 0.017) and number of operations (odds ratio: 0.75 [0.60, 0.96]; P = 0.023) were significant predictors for death in the ICU. DISCUSSION: Age plays a critical role in determining fatal outcome of old patients requiring intensive care. In contrast, sex and number of comorbidities shows no significant influence. Geriatr Gerontol Int 2022; 22: 597-602.

Association of COVID-19 antigenicity with the development of antineutrophilic cytoplasmic antibody vasculitis.

Inflammatory processes, such as an infection or drug reaction, can cause antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Although quite rare, AAV may occur with SARS-coronavirus disease 2019 (COVID-19) antigenic exposure, either from infection or immunization. We present two cases of AAV: one that developed after COVID-19 infection presenting as diffuse alveolar haemorrhage and another that developed shortly after vaccination, presenting as granulomatous pulmonary nodules. Both patients improved with supportive care and immunosuppressive therapies. This adverse event appears to be a very rare complication of COVID-19 infection or vaccination. Early diagnosis of AAV is important because immunosuppressive therapy may improve patient outcomes.

Clinical Heterogeneity of the VEXAS Syndrome: A Case Series.

The objective of this study is to describe the clinical features and outcomes of patients with the newly defined vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Nine men with somatic mutations in the UBA1 gene were identified; the most frequent variant was p.Met41Thr (7 of 9, 78%). The median age at VEXAS diagnosis was 74 (67, 76.5) years, and patients had a median duration of symptoms for 4 years before diagnosis. Refractory constitutional symptoms (88%), ear and nose chondritis (55%), and inflammatory arthritis (55%) were common clinical features. Vasculitis was noted in 44%. All patients had significantly elevated inflammatory markers and macrocytic anemia. Thrombocytopenia was present in 66% at diagnosis of VEXAS. Eight patients had bone marrow biopsies performed. All bone marrows were hypercellular, and there was vacuolization of the erythroid (100%) or myeloid precursors (75%). Glucocorticoids attenuated symptoms at prednisone doses ≥20 mg per day, but no other immunosuppressive agent showed consistent long-term control of disease. One patient with coexisting plasma-cell myeloma received plasma-cell-directed therapy with improvement of the inflammatory response, which is a novel finding. In conclusion, VEXAS syndrome is a clinically heterogeneous, treatment-refractory inflammatory condition caused by somatic mutation of the UBA1 gene. Patients often present with overlapping rheumatologic manifestations and persistent hematologic abnormalities. As such, internists and subspecialists, including pathologists, should be aware of this condition to avert diagnostic delay, now that the etiology of this syndrome is known.

The intratumoral microbiome: Characterization methods and functional impact.

Live-pathogenic bacteria, which were identified inside tumors hundreds year ago, are key elements in modern cancer research. As they have a relatively accessible genome, they offer a multitude of metabolic engineering opportunities, useful in several clinical fields. Better understanding of the tumor microenvironment and its associated microbiome would help conceptualize new metabolically engineered species, triggering efficient therapeutic responses against cancer. Unfortunately, given the low microbial biomass nature of tumors, characterizing the tumor microbiome remains a challenge. Tumors have a high host versus bacterial DNA ratio, making it extremely complex to identify tumor-associated bacteria. Nevertheless, with the improvements in next-generation analytic tools, recent studies demonstrated the existence of intratumor bacteria inside defined tumors. It is now proven that each cancer subtype has a unique microbiome, characterized by bacterial communities with specific metabolic functions. This review provides a brief overview of the main approaches used to characterize the tumor microbiome, and of the recently proposed functions of intracellular bacteria identified in oncological entities. The therapeutic aspects of live-pathogenic microbes are also discussed, regarding the tumor microenvironment of each cancer type.

Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set.

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978.

First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II).

INTRODUCTION: Despite its increasing use, first-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX), hereinafter referred to as first-line bidirectional therapy, has never been prospectively investigated in patients with colorectal peritoneal metastases (CPM). As a first step to address this evidence gap, the present study aims to assess the safety, feasibility, antitumour activity, patient-reported outcomes, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM. METHODS AND ANALYSIS: In this single-arm, phase II study in two Dutch tertiary referral centres, 20 patients are enrolled. Key eligibility criteria are a good performance status, pathologically proven isolated unresectable CPM, no previous palliative systemic therapy for colorectal cancer, no (neo)adjuvant systemic therapy ≤6 months prior to enrolment and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Patients receive three cycles of bidirectional therapy. Each cycle consists of 6 weeks first-line palliative systemic therapy at the medical oncologists' decision (CAPOX-bevacizumab, FOLFOX-bevacizumab, FOLFIRI-bevacizumab or FOLFOXIRI-bevacizumab) followed by ePIPAC-OX (92 mg/m2) with an intraoperative bolus of intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Study treatment ends after the third ePIPAC-OX. The primary outcome is the number of patients with-and procedures leading to-grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0) up to 4 weeks after the last procedure. Key secondary outcomes include the number of bidirectional cycles in each patient, treatment-related characteristics, grade ≤2 adverse events, tumour response (histopathological, cytological, radiological, biochemical, macroscopic and ascites), patient-reported outcomes, systemic pharmacokinetics of oxaliplatin, costs, progression-free survival and overall survival. ETHICS AND DISSEMINATION: This study is approved by the Dutch competent authority, a medical ethics committee and the institutional review boards of both study centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NL8303.

Detection of tumor-derived cell-free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid.

Tumor-derived cell-free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases (CRC-LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC-PM). This study evaluated the presence of tumor-derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC-PM and in the plasma of 100 patients with isolated CRC-LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor-derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC-LM and 20% of CRC-PM patients and in peritoneal fluid in all CRC-PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC-PM plasma than in CRC-LM plasma (median MAF = 0.28 versus 18.9%, p < 0.0001; median MTc/ml = 21 versus 1,758, p < 0.0001). Within patients with CRC-PM, higher cfDNA levels were observed in peritoneal fluid than in plasma (median MAF = 16.4 versus 0.28%, p = 0.0019; median MTc/ml = 305 versus 21, p = 0.0034). These data imply that tumor-derived cfDNA in plasma is a poor biomarker to monitor CRC-PM. Instead, cfDNA detection in peritoneal fluid may offer an alternative to guide CRC-PM treatment decisions.

A modified microvascular "Tube-in-Tube" concept for penile construction in female-to-male transsexuals: Combined radial forearm free flap with anterolateral thigh flap.

INTRODUCTION: Phalloplasty is a complex surgical task and remains a significant challenge in plastic surgery. To date, there are various techniques; however, complication rates are still not satisfactory. Here, we present our surgical approach of a modified tube-in-tube concept combining a radial forearm free flap and an anterolateral thigh flap and assess its outcome in a series of female-to-male transsexuals. PATIENTS AND METHODS: In this report, 21 female-to-male transsexual patients were included. The first surgical step includes colpectomy and elongation of the fixed part of the urethra with a full-thickness skin graft. Subsequently, a radial forearm free flap was adapted to build the inner tube which represents the neourethra. For the last step, a free anterolateral thigh flap is utilized as the outer tube of the neophallus. All patients were evaluated regarding aesthetic and functional outcomes as well as postoperative complications and revision surgeries. RESULTS: Our results showed a 100% flap survival rate with a mean follow-up of 4.4 years (range, 2.7-6). Three radial forearm free flaps and one free anterolateral thigh flap presented with partial flap necrosis. Generally, complications occurred in 11 patients (52.4%). The most common complications were related to urethral reconstruction including fistula formation (n = 8) and stenosis (n = 5). All except one patient obtained the ability to void while standing. CONCLUSION: Despite the complexity, the initial results are very promising for a single-stage phalloplasty with complete functional creation of a neophallus. Further improvements have to be implemented for reduction of postoperative complications particularly regarding urethral reconstruction. LEVEL OF EVIDENCE: IV (Therapeutic).