Target Development towards First Production of High-Molar- Activity 44gSc and 47Sc by Mass Separation at CERN-MEDICIS.

The radionuclides 43Sc, 44g/mSc, and 47Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating natTi and natV target materials with protons. Maximizing the production yield of the therapeutic 47Sc in the highest cross section energy range of 24-70 MeV results in the co-production of long-lived, high-γ-ray-energy 46Sc and 48Sc contaminants if one does not use enriched target materials. Mass separation can be used to obtain high molar activity and isotopically pure Sc radionuclides from natural target materials; however, suitable operational conditions to obtain relevant activity released from irradiated natTi and natV have not yet been established at CERN-MEDICIS and ISOLDE. The objective of this work was to develop target units for the production, release, and purification of Sc radionuclides by mass separation as well as to investigate target materials for the mass separation that are compatible with high-yield Sc radionuclide production in the 9-70 MeV proton energy range. In this study, the in-target production yield obtained at MEDICIS with 1.4 GeV protons is compared with the production yield that can be reached with commercially available cyclotrons. The thick-target materials were irradiated at MEDICIS and comprised of metallic natTi, natV metallic foils, and natTiC pellets. The produced radionuclides were subsequently released, ionized, and extracted from various target and ion source units and mass separated. Mono-atomic Sc laser and molecule ionization with forced-electron-beam-induced arc-discharge ion sources were investigated. Sc radionuclide production in thick natTi and natV targets at MEDICIS is equivalent to low- to medium-energy cyclotron-irradiated targets at medically relevant yields, furthermore benefiting from the mass separation possibility. A two-step laser resonance ionization scheme was used to obtain mono-atomic Sc ion beams. Sc radionuclide release from irradiated target units most effectively could be promoted by volatile scandium fluoride formation. Thus, isotopically pure 44g/mSc, 46Sc, and 47Sc were obtained as mono-atomic and molecular ScF 2+ ion beams and collected for the first time at CERN-MEDICIS. Among all the investigated target materials, natTiC is the most suitable target material for Sc mass separation as molecular halide beams, due to high possible operating temperatures and sustained release.

Preoperative CA 19-9 Predicts Disease Progression in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: Patients with colorectal peritoneal metastases (CRPM) are increasingly treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Unfortunately, data identifying preoperative risk factors for poor oncologic outcomes after this procedure are limited. We aimed to determine the prognostic value of preoperative CEA, CA 125, and CA 19-9 on disease progression after CRS/HIPEC. METHODS: Patients with CRPM treated with curative intent CRS/HIPEC from 12 participating sites in the United States from 2000 to 2017 were identified. Progression-free survival (PFS), defined as disease progression or recurrence, was the primary outcome. RESULTS: In 279 patients who met inclusion criteria, the rate of disease progression was 63.8%, with a median PFS of 11 months (interquartile range [IQR] 5-20). Elevated CA 19-9 was associated with dismal PFS at 2 years (8.9% elevated vs. 30% not elevated, p < 0.01). In 113 patients who underwent upfront CRS/HIPEC, CA 19-9 emerged as the sole tumor marker independently predictive of worse PFS (hazard ratio [HR] 2.88, p = 0.048). In the subgroup of patients who had received neoadjuvant therapy (NAT), no variable was independently predictive of PFS. CA 19-9 levels over 37 U/ml were highly specific for accelerated disease progression after CRS/HIPEC. Lastly, there was no association between PFS and elevated CEA or CA 125. CONCLUSIONS: Elevated CA 19-9 is associated with decreased PFS in patients with CRPM. While traditionally CEA is the main tumor marker assessed in colon cancer, we found that CA 19-9 may better inform preoperative risk stratification for poor oncologic outcomes in patients with CRPM. However, prospective studies are required to confirm this association.

Continuous Wound Irrigation and Intraoperative Methadone Decreases Opioid Use and Shortens Length of Stay After CRS/HIPEC.

BACKGROUND: Epidural analgesia is resource and labor intense and may limit postoperative management options and delay discharge. This study compared postoperative outcomes after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) with epidural analgesia versus continuous wound infusion system (CWIS) with/without intraoperative methadone. METHODS: A single-institution, retrospective chart review was performed including all patients undergoing open CRS/HIPEC from 2018 to 2021. Patient demographics, surgical characteristics, length of stay, and in-hospital analgesic use were reviewed. In-hospital opioid exposure in morphine milligram equivalents (MME) was calculated. Multivariate analysis (MVA) for mean total and daily opioid exposure was conducted. RESULTS: A total of 157 patients were included. Fifty-three (34%) had epidural analgesia, 96 (61%) had CWIS, and 79 (50%) received methadone. Length of stay was significantly shorter with CWIS + methadone versus epidural (7 vs. 8 days, p < 0.01). MVA showed significantly lower mean total and daily opioid exposure with CWIS+methadone versus epidural (total: 252.8 ± 17.7 MME vs. 486.8 ± 86.6 MME; odds ratio [OR] 0.72, 95% confidence interval [CI] 0.52-0.98, p = 0.04; Daily: 32.8 ± 2.0 MME vs. 51.9 ± 5.7 MME, OR 0.72, 95% CI 0.52-0.99, p ≤ 0.05). The CWIS-only group (n = 17) had a significantly lower median oral opioid exposure versus epidural (135 MME vs. 7.5 MME, p < 0.001) and longer length of stay versus CWIS + methadone (9 vs. 7 days, p = 0.04), There were no CWIS or methadone-associated complications and one epidural abscess. CONCLUSIONS: CWIS + methadone safely offers better pain control with less in-hospital opioid use, shorter length of stay, and decreased resource utilization compared with epidural analgesia in patients undergoing CRS-HIPEC.

Stigmatization of people with addiction by health professionals: Current knowledge. A scoping review.

Background: Stigma of people with substance and non-substance use disorders (SNSUD) is a long-known phenomenon. The aim of this review was to assess the stigmatization, by health professionals, of people with SNSUD, its characteristics and change over time. Methods: A scoping review of literature reviews was conducted with systematic search of PubMed, Scopus and PsycINFO databases. Results: From the 19 selected reviews, all focused on people with SUD (PWSUD) only and 20 % to 51 % of health professionals had negative attitudes/beliefs about SUD. Addiction training and clinical experience with PWSUD were associated with a less negative attitude. Health professionals' negative beliefs, lack of time or support were associated with less involvement in addiction care. Tobacco use disorder, SUDs other than alcohol and tobacco, relapse, psychiatric comorbidity or criminal records were associated with a more negative attitude. The influence of several variables potentially related to stigmatization was inconsistent across selected reviews. The evolution of stigmatization over time was not systematically assessed and showed mixed results. Conclusions: The stigmatization of PWSUD has an impact on their care, and a change in some variables could reduce its importance: moral model of addiction, health professionals' negative beliefs, lack of training, time, and role support. Teaching what addiction is according to the medical chronic disease model, and developing stigma-focused training could improve caregivers' attitudes and further reduce stigma. Further studies are needed to determine whether stigma of PWSUD by health professionals has changed over time and to characterize stigma for people with non-substance use disorders.

Prediction of Early Recurrence Following CRS/HIPEC in Patients With Disseminated Appendiceal Cancer.

INTRODUCTION: In patients with disseminated appendiceal cancer (dAC) who underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), characterizing and predicting those who will develop early recurrence could provide a framework for personalizing follow-up. This study aims to: (1) characterize patients with dAC that are at risk for recurrence within 2 y following of CRS ± HIPEC (early recurrence; ER), (2) utilize automated machine learning (AutoML) to predict at-risk patients, and (3) identifying factors that are influential for prediction. METHODS: A 12-institution cohort of patients with dAC treated with CRS ± HIPEC between 2000 and 2017 was used to train predictive models using H2O.ai's AutoML. Patients with early recurrence (ER) were compared to those who did not have recurrence or presented with recurrence after 2 y (control; C). However, 75% of the data was used for training and 25% for validation, and models were 5-fold cross-validated. RESULTS: A total of 949 patients were included, with 337 ER patients (35.5%). Patients with ER had higher markers of inflammation, worse disease burden with poor response, and received greater intraoperative fluids/blood products. The highest performing AutoML model was a Stacked Ensemble (area under the curve = 0.78, area under the curve precision recall = 0.66, positive predictive value = 85%, and negative predictive value = 63%). Prediction was influenced by blood markers, operative course, and factors associated with worse disease burden. CONCLUSIONS: In this multi-institutional cohort of dAC patients that underwent CRS ± HIPEC, AutoML performed well in predicting patients with ER. Variables suggestive of poor tumor biology were the most influential for prediction. Our work provides a framework for identifying patients with ER that might benefit from shorter interval surveillance early after surgery.

Indications and possible limitations using medio-plantar plate systems in tarsometatarsal 1 fusions - A cadaveric study.

BACKGROUND: The tarsometatarsal 1 arthrodesis is an adequate treatment for moderate to severe hallux valgus deformity and instability of the first ray. Plantar plating arthrodesis has been shown to provide better mechanical stability and fewer postoperative complications than screw fixation or medial plating. The medio-plantar plate is a new plate design for Lapidus arthrodesis. It could combine the biomechanical advantages of the plantar plate and the anatomical overview of a medial plate. However, the implanted material can cause irritation of the tibialis anterior, which in some cases may require removal of the material. The purpose of this study was to examine the possibility of tendon irritation following medio-plantar first tarsometatarsal joint arthrodesis using cadaveric specimens. METHODS: The study involved the simulated surgical procedure of medio-plantar plate arthrodesis on 30 lower extremities. After the plates were fixed, a thorough examination of the feet was conducted to assess any tendon irritation and to determine a recommendation for placement of the medio-plantar plate based on the Olewnik classification. RESULTS: Irritation of the tibialis anterior tendon components with the medio-plantar plate depends mainly on the anatomic norm variant, classified according to Olewnik et al. A medio-plantar plate is particularly recommended in TA tendon Olewnik type 3 and type 5. The positioning of a medio-plantar plate in Olewnik type 1 and type 2 tendons depends on the anatomic fit of the medio-plantar plate and the bony configuration of the TMT 1 joint. A large portion of the TA tendon must be detached, so a different plate design may be preferred in these patients. CONCLUSIONS: TMT 1 arthrodesis with medio-plantar plating of the first tarsometatarsal joint should be performed considering the anatomic TA tendon variations. LEVEL OF EVIDENCE: Level V, Expert Opinion includes Case Reports and Technique Tips.

Endoscopically Assisted Percutaneous Harvesting of the Flexor Hallucis Tendon in Zone 2: An Anatomical Study.

BACKGROUND: Flexor hallucis longus (FHL) transfer is a well-established method for treating chronic Achilles tendon ruptures and tendinopathy. Harvesting of the FHL tendon in zone 2 results in greater length but is also associated with an increased risk of injury to the medial plantar nerve and requires an additional plantar incision. Because of the anatomic proximity of the FHL tendon to the tibial neurovascular bundle in zone 2, the purpose of this study was to investigate the risk of vascular or nerve injury with arthroscopic assisted percutaneous tenotomy in zone 2 of the FHL tendon. METHODS: Endoscopically assisted percutaneous FHL transfer was performed on 10 right lower extremities from 10 cadaveric human specimens. The FHL tendon lengths and the relationship between FHL tendon and the tibial neurovascular bundle at zone 2 was analyzed. RESULTS: We observed a complete transection of the medial plantar nerve in 1 case (10%). The mean length of the FHL tendon was 54.7 ± 9.5 mm and the mean distance from the distal stump of the FHL tendon to local neurovascular structures was 1.3 ± 0.7 mm. CONCLUSION: There is a risk of neurovascular injury after endoscopic FHL tenotomy in zone 2. The tenotomy site is within 2 mm of the local neurovascular structures in the majority of cases. The additional length gained from this technique is unlikely to be required for the majority of FHL tendon transfer procedures. If additional length is needed, we would recommend the use of intraoperative ultrasonography or a mini-open approach to minimize injury risk. LEVEL OF EVIDENCE: Level V, expert opinion.

Validation of the AJCC 8th Edition Staging System for Disseminated Appendiceal Cancer Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-institutional Analysis.

BACKGROUND: The AJCC 8th edition stratifies stage IV disseminated appendiceal cancer (dAC) patients based on grade and pathology. This study was designed to externally validate the staging system and to identify predictors of long-term survival. METHODS: A 12-institution cohort of dAC patients treated with CRS ± HIPEC was retrospectively analyzed. Overall survival (OS) and recurrence-free survival (RFS) were analyzed by using Kaplan-Meier and log-rank tests. Univariate and multivariate cox-regression was performed to assess factors associated with OS and RFS. RESULTS: Among 1009 patients, 708 had stage IVA and 301 had stage IVB disease. Median OS (120.4 mo vs. 47.2 mo) and RFS (79.3 mo vs. 19.8 mo) was significantly higher in stage IVA compared with IVB patients (p < 0.0001). RFS was greater among IVA-M1a (acellular mucin only) than IV M1b/G1 (well-differentiated cellular dissemination) patients (NR vs. 64 mo, p = 0.0004). Survival significantly differed between mucinous and nonmucinous tumors (OS 106.1 mo vs. 41.0 mo; RFS 46.7 mo vs. 21.2 mo, p < 0.05), and OS differed between well, moderate, and poorly differentiated (120.4 mo vs. 56.3 mo vs. 32.9 mo, p < 0.05). Both stage and grade were independent predictors of OS and RFS on multivariate analysis. Acellular mucin and mucinous histology were associated with better OS and RFS on univariate analysis only. CONCLUSIONS: AJCC 8th edition performed well in predicting outcomes in this large cohort of dAC patients treated with CRS ± HIPEC. Separation of stage IVA patients based on the presence of acellular mucin improved prognostication, which may inform treatment and long-term, follow-up strategies.

Lens-specific ßA3/A1-conditional knockout mice: Phenotypic characteristics and calpain activation causing protein degradation and insolubilization.

ßA3/A1-crystallin is a lens structural protein that plays an important role in maintaining lens transparency via interactions with other crystallins. While the function of ßA3/A1-crystallin in the retina is well studied, its functions in the lens, other than as a structural protein, remain unclear. In the current study, we generated the lens-specific ßA3/A1-crystallin conditional knockout mouse (named ßA3/A1ckO) and explored phenotypic changes and the function of the crystallin in the lens. The ßA3/A1ckO mice showed congenital cataract at birth and exhibited truncation of lens proteins. Several truncated protein fragments were recovered as a pellet during a low-speed centrifugation (800 rpm, 70 x g) followed by a relatively higher speed centrifugation (5000 rpm, 2744 x g). Mass spectrometric analysis of pellets recovered following the two centrifugations showed that among the fragments with Mr < 20 kDa, the majority of these were from ß-tubulin, and some from phakinin, αA-crystallin, and calpain-3. Further, we observed that in vitro activation of calpain-3 by calcium treatment of the wild-type-lens homogenate resulted in the degradation of calpain-3, αA-crystallin and ß-tubulin and insolubilization of these proteins. Based on these results, it was concluded that the activation of calpain 3 resulted in proteolysis of ß-tubulin, which disrupted cellular microtubular structure, and caused proteolysis of other lens proteins (αA-crystallin and phakinin). These proteolyzed protein fragments become insoluble, and together with the disruption of microtubular structure, and could be the causative factors in the development of congenital nuclear cataract in ßA3/A1cKO mice.

Resonant laser ionization and mass separation of 225Ac.

[Formula: see text]Ac is a radio-isotope that can be linked to biological vector molecules to treat certain distributed cancers using targeted alpha therapy. However, developing [Formula: see text]Ac-labelled radiopharmaceuticals remains a challenge due to the supply shortage of pure [Formula: see text]Ac itself. Several techniques to obtain pure [Formula: see text]Ac are being investigated, amongst which is the high-energy proton spallation of thorium or uranium combined with resonant laser ionization and mass separation. As a proof-of-principle, we perform off-line resonant ionization mass spectrometry on two samples of [Formula: see text]Ac, each with a known activity, in different chemical environments. We report overall operational collection efficiencies of 10.1(2)% and 9.9(8)% for the cases in which the [Formula: see text]Ac was deposited on a rhenium surface and a ThO[Formula: see text] mimic target matrix respectively. The bottleneck of the technique was the laser ionization efficiency, which was deduced to be 15.1(6)%.

Influence of insurance status on the postoperative outcomes of cytoreductive surgery and HIPEC.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is increasingly performed for peritoneal surface malignancies but remains associated with significant morbidity. Scant research is available regarding the impact of insurance status on postoperative outcomes. METHODS: Patients undergoing CRS/HIPEC between 2000 and 2017 at 12 participating sites in the US HIPEC Collaborative were identified. Univariate and multivariate analyses were used to compare the baseline characteristics, operative variables, and postoperative outcomes of patients with government, private, or no insurance. RESULTS: Among 2268 patients, 699 (30.8%) had government insurance, 1453 (64.0%) had private, and 116 (5.1%) were uninsured. Patients with government insurance were older, more likely to be non-white, and comorbid (p < 0.05). Patients with government (OR: 2.25, CI: 1.50-3.36, p < 0.001) and private (OR: 1.69, CI: 1.15-2.49, p = 0.008) insurance had an increased risk of complications on univariate analysis. There was no independent relationship on multivariate analysis. An American Society of Anesthesiologists score of 3 or 4, peritoneal carcinomatosis index score >15, completeness of cytoreduction score >1, and nonhome discharge were factors independently associated with a postoperative complication. CONCLUSION: While there were differences in postoperative outcomes between the three insurance groups on univariate analysis, there was no independent association between insurance status and postoperative complications after CRS/HIPEC.

Conditional Survival Following Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: The long-term prognosis of patients who undergo cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies (PSM) varies considerably on the basis of histological and operative factors. While overall survival (OS) estimates are used to inform adjuvant therapy and surveillance strategies, conditional survival may provide more clinically relevant estimates of prognosis by accounting for disease-free time elapsed. PATIENTS AND METHODS: All patients from 12 academic institutions who underwent CRS ± HIPEC for PSM from 2000 to 2017 were retrospectively analyzed. OS and disease-free survival (DFS) rates were calculated using the Kaplan-Meier method while conditional overall (COS) and conditional disease-free survival (CDFS) rates were calculated at 1, 2, or 3 years from surgery for different tumor histologies. RESULTS: Overall, 1610 patients underwent CRS ± HIPEC. Among patients with benign appendiceal mucinous tumors (N = 460), 5-year OS and COS at 3 years were 92.1% and 96.3% (Δ4.2%), respectively. For patients with well-differentiated appendiceal cancers (N = 400), 5-year OS and COS at 3 years were 76.3% and 88.3% (Δ12.0%), respectively. For patients with high-grade appendiceal cancers (N = 258), 5-year OS and COS at 3 years were 43.8% and 75.4% (Δ31.6%), respectively. For patients with colorectal cancers (N = 362), 5-year OS and COS at 3 years were 31.8% and 67.3% (Δ35.5%), respectively. For patients with peritoneal mesothelioma (N = 130), 5-year OS and COS at 3 years were 67.6% and 89.7% (Δ22.1%), respectively. Similar trends were observed for DFS/CDFS. CONCLUSION: The conditional survival of patients undergoing CRS ± HIPEC for PSM is associated with tumor histology. COS and CDFS provide a more accurate, dynamic estimate of survival than OS and DFS, especially for patients with more aggressive histologies.

Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [153Sm]Sm-DOTA-TATE.

Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-Am 153Sm. In this proof-of-concept study, we further evaluated the potential of high-Am 153Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR2) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with 153Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR2-expressing CA20948 cells. In vitro biological evaluation showed that [153Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [153Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated 153Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.

Do Lymph Node Metastases Matter in Appendiceal Cancer with Peritoneal Carcinomatosis? A US HIPEC Collaborative Study.

BACKGROUND: Whether formal regional lymph node (LN) evaluation is necessary for patients with appendiceal adenocarcinoma (AA) who have peritoneal metastases is unclear. The aim of this study was to evaluate the prognostic value of LN metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: A retrospective analysis of the US HIPEC collaborative, a multi-institutional consortium comprising 12 high-volume centers, was performed to identify patients with AA who underwent CRS-HIPEC with adequate LN sampling (≥ 12 LNs). RESULTS: Two hundred-fifty patients with AA who underwent CRS-HIPEC were included. Outcomes were compared between LN - and LN + disease. Baseline patient characteristics between groups were similar, with most patients undergoing complete cytoreduction (0/1: 86.0% vs. 76.8%, p = 0.08), respectively. More adverse tumor factors were found in patients with LN + disease, including poor differentiation, signet ring cells, and lymphovascular invasion. Multivariate analysis of overall survival (OS) found LN + disease was independently associated with worse OS (HR: 2.82 95%CI: 1.25-6.34, p = 0.01), even after correction for receipt of systemic therapy. On Kaplan-Meier analysis, median OS was lower in patients with LN + disease (25.9 months vs. 91.4 months, p < 0.01). LN + disease remained associated with poor OS following propensity score matching (HR: 4.98 95%CI: 1.72-14.40, p < 0.01) and in patients with PCI ≥ 20 (HR: 3.68 95%CI: 1.54-8.80, p < 0.01). CONCLUSIONS: In this large multi-institutional study of patients with AA undergoing CRS-HIPEC, LN status remained associated with worse OS even in the setting of advanced peritoneal carcinomatosis. Formal LN evaluation should be performed for most patients with AA undergoing CRS-HIPEC.

Development and Validation of an Explainable Machine Learning Model for Major Complications After Cytoreductive Surgery.

Importance: Cytoreductive surgery (CRS) is one of the most complex operations in surgical oncology with significant morbidity, and improved risk prediction tools are critically needed. Machine learning models can potentially overcome the limitations of traditional multiple logistic regression (MLR) models and provide accurate risk estimates. Objective: To develop and validate an explainable machine learning model for predicting major postoperative complications in patients undergoing CRS. Design, Setting, and Participants: This prognostic study used patient data from tertiary care hospitals with expertise in CRS included in the US Hyperthermic Intraperitoneal Chemotherapy Collaborative Database between 1998 and 2018. Information from 147 variables was extracted to predict the risk of a major complication. An ensemble-based machine learning (gradient-boosting) model was optimized on 80% of the sample with subsequent validation on a 20% holdout data set. The machine learning model was compared with traditional MLR models. The artificial intelligence SHAP (Shapley additive explanations) method was used for interpretation of patient- and cohort-level risk estimates and interactions to define novel surgical risk phenotypes. Data were analyzed between November 2019 and August 2021. Exposures: Cytoreductive surgery. Main Outcomes and Measures: Area under the receiver operating characteristics (AUROC); area under the precision recall curve (AUPRC). Results: Data from a total 2372 patients were included in model development (mean age, 55 years [range, 11-95 years]; 1366 [57.6%] women). The optimized machine learning model achieved high discrimination (AUROC: mean cross-validation, 0.75 [range, 0.73-0.81]; test, 0.74) and precision (AUPRC: mean cross-validation, 0.50 [range, 0.46-0.58]; test, 0.42). Compared with the optimized machine learning model, the published MLR model performed worse (test AUROC and AUPRC: 0.54 and 0.18, respectively). Higher volume of estimated blood loss, having pelvic peritonectomy, and longer operative time were the top 3 contributors to the high likelihood of major complications. SHAP dependence plots demonstrated insightful nonlinear interactive associations between predictors and major complications. For instance, high estimated blood loss (ie, above 500 mL) was only detrimental when operative time exceeded 9 hours. Unsupervised clustering of patients based on similarity of sources of risk allowed identification of 6 distinct surgical risk phenotypes. Conclusions and Relevance: In this prognostic study using data from patients undergoing CRS, an optimized machine learning model demonstrated a superior ability to predict individual- and cohort-level risk of major complications vs traditional methods. Using the SHAP method, 6 distinct surgical phenotypes were identified based on sources of risk of major complications.

Is Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemotherapy Still Indicated in Patients With Extraperitoneal Disease?

INTRODUCTION: The role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with extraperitoneal disease (EPD) is controversial. METHODS: Among patients with peritoneal metastases from appendiceal cancer (AC) and colorectal cancer (CRC) who underwent CRS-HIPEC, those with EPD (liver, lung, or retroperitoneal lymph nodes [RP LN]) were retrospectively compared to those without EPD. Overall (OS) and recurrence-free survival (RFS) analyses were performed before/after propensity score matching (PSM). RESULTS: Among 1341 patients with AC (64%) or CRC (36%) who underwent CRS ± HIPEC, 134 (10%) had EPD whereas 1207 (90%) did not. EPD was located in the lungs (47%), RP LN (28%), liver (18%), or multiple (6%). Patients with EPD experienced worse median OS (34 versus 63 mo; P = 0.002) and RFS (12 versus 19 mo; P < 0.001). On a multivariable analysis, EPD was associated with worse RFS (P = 0.003), but not OS (P = 0.071). After PSM, the association of EPD with OS (P = 0.204) and RFS (P = 0.056) was no longer significant. In the multivariable analysis of the PSM cohort, EPD was not associated with OS (P = 0.157) or RFS (P = 0.110). CONCLUSIONS: The findings of this large retrospective multi-institutional study suggest that EPD alone, while a negative prognostic indicator, should not be considered an absolute contraindication to CRS ± HIPEC for otherwise well-selected patients with peritoneal surface malignancies. Further research is needed to delineate whether location of EPD influences OS and RFS following CRS-HIPEC.

Targeted exon skipping of NF1 exon 17 as a therapeutic for neurofibromatosis type I.

We investigated the feasibility of utilizing an exon-skipping approach as a genotype-dependent therapeutic for neurofibromatosis type 1 (NF1) by determining which NF1 exons might be skipped while maintaining neurofibromin protein expression and GTPase activating protein (GAP)-related domain (GRD) function. Initial in silico analysis predicted exons that can be skipped with minimal loss of neurofibromin function, which was confirmed by in vitro assessments utilizing an Nf1 cDNA-based functional screening system. Skipping of exons 17 or 52 fit our criteria, as minimal effects on protein expression and GRD activity were noted. Antisense phosphorodiamidate morpholino oligomers (PMOs) were utilized to skip exon 17 in human cell lines with patient-specific pathogenic variants in exon 17, c.1885G>A, and c.1929delG. PMOs restored functional neurofibromin expression. To determine the in vivo significance of exon 17 skipping, we generated a homozygous deletion of exon 17 in a novel mouse model. Mice were viable and exhibited a normal lifespan. Initial studies did not reveal the presence of tumor development; however, altered nesting behavior and systemic lymphoid hyperplasia was noted in peripheral lymphoid organs. Alterations in T and B cell frequencies in the thymus and spleen were identified. Hence, exon skipping should be further investigated as a therapeutic approach for NF1 patients with pathogenic variants in exon 17, as homozygous deletion of exon 17 is consistent with at least partial function of neurofibromin.