Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.

BACKGROUND & AIMS: Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system. METHODS: To leverage this opportunity, we used plate-based single-cell RNA-seq to deeply profile myeloid cells from liver fine needle aspirates in patients with HCV before and after DAA treatment. We comprehensively characterised liver neutrophils, eosinophils, mast cells, conventional dendritic cells, plasmacytoid dendritic cells, classical monocytes, non-classical monocytes, and macrophages, and defined fine-grained subpopulations of several cell types. RESULTS: We discovered cell type-specific changes post-cure, including an increase in MCM7+STMN1+ proliferating CD1C+ conventional dendritic cells, which may support restoration from chronic exhaustion. We observed an expected downregulation of interferon-stimulated genes (ISGs) post-cure as well as an unexpected inverse relationship between pre-treatment viral load and post-cure ISG expression in each cell type, revealing a link between viral loads and sustained modifications of the host's immune system. We found an upregulation of PD-L1/L2 gene expression in ISG-high neutrophils and IDO1 expression in eosinophils, pinpointing cell subpopulations crucial for immune regulation. We identified three recurring gene programmes shared by multiple cell types, distilling core functions of the myeloid compartment. CONCLUSIONS: This comprehensive single-cell RNA-seq atlas of human liver myeloid cells in response to cure of chronic viral infections reveals principles of liver immunity and provides immunotherapeutic insights. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT02476617). IMPACT AND IMPLICATIONS: Chronic viral liver infections continue to be a major public health problem. Single-cell characterisation of liver immune cells during hepatitis C and post-cure provides unique insights into the architecture of liver immunity contributing to the resolution of the first curable chronic viral infection of humans. Multiple layers of innate immune regulation during chronic infections and persistent immune modifications after cure are revealed. Researchers and clinicians may leverage these findings to develop methods to optimise the post-cure environment for HCV and develop novel therapeutic approaches for other chronic viral infections.

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.

Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110ß blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

CT-Guided Percutaneous Needle Biopsy of Retroperitoneal and Pelvic Lymphadenopathy: Assessment of Technique, Diagnostic Yield, and Clinical Value.

PURPOSE: To assess the technical success rate, diagnostic yield, and clinical value of computed tomography (CT)-guided percutaneous needle biopsy (PNB) for retroperitoneal and pelvic lymphadenopathy. MATERIALS AND METHODS: This retrospective study included 344 patients evaluated for safety and technique and 334 patients evaluated for diagnostic yield and clinical analyses. PNBs were performed with fine-needle aspiration (FNA) in 315 patients and with core biopsy in 333 patients. Follow-up analyses, including repeat biopsy, open surgery, imaging, and clinical indicators, were conducted for 94 patients who had nonspecific malignant or benign results. Diagnostic yields were calculated based on biopsy and follow-up results. Factors associated with final diagnoses were compared and modeled by multivariate analysis. RESULTS: Technical success rate was 99.7%. Thirty-nine patients (11.3%) had minor complications. From biopsy results and follow-up analyses, final malignant diagnoses were determined for 281 patients (84.1%). Overall sensitivity, specificity, and accuracy rates of PNB were 91.5%, 100%, and 92.8%, respectively. For patients with a history of malignancy, the likelihood of nodal involvement was 84.6% and that of a new, different malignancy was 3.7%. Older age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.05), history of malignancy (OR, 3.44; 95% CI, 1.71-6.92), multiple lymph nodes (LNs; OR, 2.65; 95% CI, 1.38-5.09), and new or enlarging LNs (OR, 2.62; 95% CI, 1.25-5.48) were independent risk factors for malignancy diagnosis. CONCLUSIONS: CT-guided PNB is a safe, effective procedure that can achieve high diagnostic yields for patients with retroperitoneal and pelvic lymphadenopathy.

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.

BACKGROUND: Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. METHODS: In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. RESULTS: We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. CONCLUSION: Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. IMPLICATIONS FOR PRACTICE: Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.

Combined endoscopic trangastric drainage and video assisted retroperitoneal pancreatic debridement - The best of both worlds for extensive pancreatic necrosis with enteric fistulae.

Enteric fistula is a serious complication of necrotizing pancreatitis. Endoscopic transluminal drainage and necrosectomy can significantly reduce the incidence of enterocutaneous fistula after pancreatic debridement. However, endoscopic necrosectomy may not be well-suited to debridement of necrosis that tracks laterally to the paracolic gutters, which is often more efficiently addressed by video-assisted retroperitoneal debridement (VARD). We report the combined use of endoscopic transgastric drainage and VARD for treatment of a 76 year old man with severe necrotizing acute pancreatitis complicated by infected, walled-off pancreatic necrosis. Computed tomography showed laterally tracking pancreatic necrosis and flouroscopic drain injection after percutaneous drainage demonstrated with fistulas to the stomach, duodenum, and colon. The infection and fistulas resolved completely. This approach combined the major advantage of VARD with the major advantage of endoscopic transluminal drainage. We are not aware of any reports of combining these techniques and believe the combination offers a minimally invasive approach for patients with extensive necrosis and a high likelihood of enteric or pancreatic fistulas.

A Quality Improvement Initiative to Reduce Catheter Exchange Rates for Fluoroscopically Guided Gastrostomy Tubes.

PURPOSE: To evaluate the effectiveness of a data-driven quality improvement initiative to reduce catheter exchange rates. MATERIALS AND METHODS: A single-institution retrospective analysis of all percutaneous radiologic gastrostomy (PRG) placement and replacement procedures between January 2010 and July 2015 was conducted. A statistical model predicting the risk for catheter exchange for any reason and exchanges specifically for tube malfunction was created; a quality improvement plan to reduce catheter exchanges was designed and implemented in June 2014. The outcomes for subsequent PRG procedures from July 2014 through March 2015 were followed until July 2015. RESULTS: Between 2010 and June 2014, 1,144 primary PRG procedures and 442 replacement procedures were performed in 1,112 patients. Of the 442 exchange procedures, 289 were "rescue" procedures secondary to catheter malfunction. A quality improvement plan was implemented in June 2014 that encouraged primary gastrojejunostomy catheter and balloon-retained PRG catheter placement and placement of skin sutures in patients considered high risk for catheter dislodgment. From July 2014 through March 2015, 229 PRG catheters were placed, and 71 exchange procedures were performed through July 2015. There was a statistically significant decrease in the number of rescue exchanges performed secondary to catheter malfunction (P = .036). CONCLUSIONS: Procedural and patient-specific risk factors for PRG complications were identified, and a statistical model to predict rates of minor complications was created. These findings were used to implement a quality improvement program that resulted in a decrease in PRG exchanges secondary to catheter malfunction.

CT-Guided Percutaneous Microwave Ablation of Tumors in the Hepatic Dome: Assessment of Efficacy and Safety.

PURPOSE: To evaluate the technique, efficacy, safety, and clinical outcomes of CT-guided microwave ablation of tumors in the hepatic dome. MATERIALS AND METHODS: Retrospective review was conducted of 46 consecutive patients (31 men and 15 women; mean age, 64 y) treated with CT-guided microwave ablation for hepatic-dome tumors between June 2011 and December 2014. Baseline demographics of sex, tumor diagnosis, tumor location, tumor size, and technical details were recorded. Technical success was evaluated. Treatment response was assessed per European Association for the Study of the Liver criteria. Overall success and overall survival were calculated, and complications were recorded. RESULTS: Forty-eight tumors were treated. Tumor locations included segments VIII (n = 32), VII (n = 10), and VIa (n = 6). Mean tumor size was 2.4 cm (range, 0.9-5.2 cm). Thirty-four tumors (70%) were treated following creation of artificial ascites with 0.9% normal saline solution (mean volume, 1,237 mL; range, 300-3,000 mL). The technical success rate was 100%, and the complete response rate was 94%. Overall survival rate was 73.9% over 24.7 months of follow-up. There were no major complications. Two patients experienced small, asymptomatic pneumothoraces that were aspirated at the time of the procedure and required no further treatment. CONCLUSIONS: CT-guided microwave ablation of tumors in the hepatic dome is associated with a high technical success rate, high complete response rate, and low complication rate.

Catecholamine Surge during Image-Guided Ablation of Adrenal Gland Metastases: Predictors, Consequences, and Recommendations for Management.

PURPOSE: To identify retrospectively predictors of catecholamine surge during image-guided ablation of metastases to the adrenal gland. MATERIALS AND METHODS: Between 2001 and 2014, 57 patients (39 men, 18 women; mean age, 65 y ± 10; age range, 41-81 y) at two academic medical centers underwent ablation of 64 metastatic adrenal tumors from renal cell carcinoma (n = 27), lung cancer (n = 23), melanoma (n = 4), colorectal cancer (n = 3), and other tumors (n = 7). Tumors measured 0.7-11.3 cm (mean, 4 cm ± 2.5). Modalities included cryoablation (n = 38), radiofrequency (RF) ablation (n = 20), RF ablation with injection of dehydrated ethanol (n = 10), and microwave ablation (n = 4). Fisher exact test, univariate, and multivariate logistical regression analysis was used to evaluate factors predicting hypertensive crisis (HC). RESULTS: HC occurred in 31 sessions (43%). Ventricular tachycardia (n = 1), atrial fibrillation (n = 2), and troponin leak (n = 4) developed during HC episodes. HC was significantly associated with maximum tumor diameter ≤ 4.5 cm (odds ratio [OR], 26.36; 95% confidence interval [CI], 5.26-131.99; P < .0001) and visualization of normal adrenal tissue on CT or MR imaging before the procedure (OR, 8.38; 95% CI, 2.67-25.33; P < .0001). No HC occurred during ablation of metastases in previously irradiated or ablated adrenal glands. CONCLUSIONS: Patients at high risk of catecholamine surge during ablation of non-hormonally active adrenal metastases can be identified by the presence of normal adrenal tissue and tumor diameter ≤ 4.5 cm on pre-procedure CT or MR imaging.

Image-guided ovarian mass biopsy: efficacy and safety.

PURPOSE: Image-guided needle biopsy represents a minimally invasive method for pathologic diagnosis of a mass. This study evaluates the diagnostic yield, accuracy, and safety of ovarian mass biopsy with combined core and fine-needle technique. MATERIALS AND METHODS: Medical records of all women at least 18 years of age, referred from gynecologic oncology, who underwent image-guided ovarian mass biopsy from 2001 through 2011 were reviewed. Among 27 patients, ultrasound guidance was used in 13 (48%), six transabdominal and seven transvaginal; computed tomography guidance was used in 14 (52%), nine transabdominal and five transgluteal. Biopsy indications were suspected metastasis (n = 15; 56%), suspected ovarian cancer to be treated with neoadjuvant chemotherapy (n = 10; 37%), and relative contraindication to surgery (n = 2; 7%). Mean maximum lesion dimension was 9.9 cm (range, 2-23 cm), with solid composition in nine (33%), cystic in six (22%), and mixed in 12 (44%). Biopsy pathologic findings were compared versus those of the surgical specimen or, for masses that were not resected, versus the stability of benign masses and response to chemotherapy of malignant masses on follow-up. RESULTS: All biopsies yielded a diagnosis. No biopsy-related complications were noted. Eleven patients (41%) did not undergo lesion resection and were followed for an average of 28.8 months (range, 0.3-118.4 mo). In no patient did malignancy develop during clinical follow-up after a benign biopsy diagnosis. Sensitivity and specificity for diagnosis of malignancy were 100% ± 0 (19 of 19) and 88% ± 26 (seven of eight), respectively, for cancer detection. In nine patients (33%) with final pathologic diagnosis of epithelial ovarian cancer, tumor seeding was not observed during a mean follow-up of 44.6 months (range, 1.3-110.2 mo). CONCLUSIONS: Image-guided ovarian mass core needle biopsy results in a pathologic diagnosis of benign and malignant masses with high yield, accuracy, and safety.

Preventing inadvertent drain removal using a novel catheter securement device.

Percutaneous drains have provided a minimally invasive way to treat a wide range of disorders from abscess drainage to enteral feeding solutions to treating hydronephrosis. These drains suffer from a high rate of dislodgement of up to 30% resulting in emergency room visits, repeat hospitalizations, and catheter repositioning/replacement procedures, which incur significant morbidity and mortality. Using ex vivo and in vivo models, a force body diagram was utilized to determine the forces experienced by a drainage catheter during dislodgement events, and the individual components which contribute to drainage catheter securement were empirically collected. Prototypes of a skin level catheter securement and valved quick release system were then developed. The system was inspired by capstans used in boating for increasing friction of a line around a central spool and quick release mechanisms used in electronics such as the Apple MagSafe computer charger. The device was tested in a porcine suprapubic model, which demonstrated the effectiveness of the device to prevent drain dislodgement. The prototype demonstrated that the miniaturized versions of technologies used in boating and electronics industries were able to meet the needs of preventing dislodgement of patient drainage catheters.

Interventional radiology in pregnancy complications: indications, technique, and methods for minimizing radiation exposure.

Complications of pregnancy, whether they occur during gestation or postpartum, often pose complex challenges because they affect two patients (mother and fetus or infant) and because both short- and long-term outcomes must be considered in management decision making. Interventional radiologists play a critical role in treating complications such as ectopic implantation, postpartum hemorrhage, symptomatic ovarian cyst, post-cesarean section fluid collection, obstructive uropathy, and vesicouterine fistula. Interventional radiology offers therapeutic options that obviate surgery, thereby minimizing morbidity and mortality and maximizing the potential for fertility preservation. Such options include chemical injection of an ectopic gestational sac, uterine artery embolization, aspiration and drainage, percutaneous nephrostomy, and suprapubic cystostomy catheter placement. All these procedures are performed with the use of radiologic imaging for guidance. The levels of radiation to which the mother and fetus may be exposed during such procedures are of concern because of potential negative effects on long-term health. However, various methods can be used to lower maternal and fetal radiation dose levels to the minimum needed to accomplish the clinical objective.

Characterization of an Iodinated Rectal Spacer for Prostate Photon and Proton Radiation Therapy.

PURPOSE: Conventional rectal spacers (nonI-SPs) are low-contrast on computed tomography (CT), often necessitating magnetic resonance imaging for accurate delineation. A new formulation of spacers (I-SPs) incorporates iodine to improve radiopacity and CT visualization. We characterized placement, stability, and plan quality of I-SPs compared to nonI-SPs. METHODS AND MATERIALS: Patients with intact prostate cancer (n = 50) treated with I-SPs and photons were compared to randomly selected patients (n = 50) with nonI-SPs (photon or proton therapy). The I-SP was contoured on the planning CT and cone beam CTs at 3 timepoints: first, middle, and final treatment (n = 200 scans). I-SPs Hounsfield units (HU), volume, surface area (SA), centroid position relative to prostate centroid, and distance between prostate/rectum centroids were compared on the planning CTs between each cohort. I-SP changes were evaluated on cone beam CTs over courses of treatment. Dosimetric evaluations of plan quality and robustness were performed. I-SP was tested in a phantom to characterize its relative linear stopping power for protons. RESULTS: I-SPs yielded a distinct visible contrast on planning CTs compared to nonI-SPs (HU 138 vs 12, P < .001), allowing delineation on CT alone. The delineated volume and SA of I-SPs were smaller than nonI-SPs (volume 8.9 vs 10.6 mL, P < .001; SA 28 vs 35 cm2, P < .001), yet relative spacer position and prostate-rectal separation were similar (P = .79). No significant change in HU, volume, SA, or relative position of the I-SPs hydrogel occurred over courses of treatment (all P > .1). Dosimetric analysis concluded there were no significant changes in plan quality or robustness for I-SPs compared to nonI-SPs. The I-SP relative linear stopping power was 1.018, necessitating HU override for proton planning. CONCLUSIONS: I-SPs provide a manifest CT contrast, allowing for delineation on planning CT alone with no magnetic resonance imaging necessary. I-SPs radiopacity, size, and relative position remained stable over courses of treatment from 28 to 44 fractions. No changes in plan quality or robustness were seen comparing I-SPs and nonI-SPs.

CT-guided celiac plexus neurolysis: a review of anatomy, indications, technique, and tips for successful treatment.

The celiac plexus is the largest visceral plexus and is located deep in the retroperitoneum, over the anterolateral surface of the aorta and around the origin of the celiac trunk. It serves as a relay center for nociceptive impulses that originate from the upper abdominal viscera, from the stomach to the proximal transverse colon. Celiac plexus neurolysis, with agents such as ethanol, is an effective means of diminishing pain that arises from these structures. Percutaneous imaging-guided celiac plexus neurolysis has been established as an invaluable therapeutic option in the management of intractable abdominal pain in patients with upper abdominal malignancy. The use of multidetector computed tomography (CT) for imaging guidance has superseded other modalities and allows direct visualization of the spread of the neurolytic agent in the antecrural space. Accurate depiction of the retroperitoneal anatomy and the position of the needle tip helps avoid crucial anatomic structures such as the pancreas, aorta, celiac artery, and superior mesenteric artery. Proper patient education, meticulous preprocedure planning, use of optimal multidetector CT techniques, adjunctive CT maneuvers, and postprocedure care are integral to successful celiac plexus neurolysis. Celiac plexus neurolysis does not completely abolish pain; rather, it diminishes pain, helping to reduce opioid requirements and their related side effects and improving survival in patients with upper abdominal malignancy.

A Step-Up Approach to Infected Abdominal Fluid Collections: Not Just for Pancreatitis.

Background: More than 145,500 abdominal abscesses occur annually in the U.S. Percutaneous catheter drainage (PCD) is the primary treatment for clinically significant intra-abdominal collections (IACs), but only approximately 90% of all IACs are treatable with PCD. This leaves a significant number of patients facing long courses of management, including multiple interventions. Minimally invasive debridement techniques are now employed regularly for the treatment of infected necrosis caused by acute pancreatitis. We describe the use of minimally invasive videoscopic debridement techniques employed as part of a "step-up" approach to resolve IACs of other etiologies that are unresponsive to PCD. Methods: Data of all patients undergoing this procedure at a tertiary referral academic center from 2015 to 2017 after failure of different PCD techniques were analyzed retrospectively. Results: Four men and two women, mean age 54.6 years (range 26-70 years), with refractory IACs (mean drainage time 91.3 days; mean number of drainage procedures 4.6) following a variety of surgical interventions and inflammatory conditions underwent either video-assisted retroperitoneal debridement or sinus tract endoscopic debridement with a rigid or flexible endoscope. Technical success was achieved in all cases, and clinical success was observed in five cases. No immediate procedural complications were detected. The mean hospital stay and post-procedure drainage times were 5.5 and 25.2 days, respectively. There were no recurrent IACs. Conclusion: Minimally invasive debridement techniques can safely resolve IACs refractory to standard PCD techniques. Employment of these techniques as part of a step-up approach may reduce the morbidity and duration of drainage for the thousands of patients treated annually who have refractory IACs, whatever their etiology.

Magnetic resonance imaging/transrectal ultrasonography fusion guided seed placement in a phantom: Accuracy between 2-seed versus 1-seed strategies.

PURPOSE: To investigate whether the 2-seed placement per Magnetic Resonance Imaging (MRI) suspicious lesion yields a higher seed placement accuracy than a 1-seed strategy on a phantom. METHODS: Eight olives embedded in gelatin, each simulating a prostate, underwent MRI. Three virtual spherical lesions (3, 5, and 8 mm diameters) were marked in each olive on the MRI images and co-registered to the MRI/Transrectal Ultrasonography (TRUS) fusion biopsy system. Two radiologists placed 0.5 mm fiducials, targeting the center of each virtual lesion under fusion image guidance. Half of the 8 olives in each phantom were assigned either to the 1-seed or 2-seeds per lesion strategy. Post-procedure Computed Tomography (CT) images identified each seed and were fused with MR to localize each virtual lesion and collected the seed placement error - distance between the virtual target and the corresponding seed (using the closer seed for the 2-seed strategy). Seed placement success is defined as fiducial placement within a lesion boundary. RESULTS: Each operator repeated the procedure on three different phantoms, and data from 209 seeds placed for 137 lesions were analyzed, with an overall error of 3.03 ±â€¯1.52 mm. The operator skill, operator phantom procedural experience, lesion size, and number of seeds, were independently associated with the seed placement error. Seed placement success rate was higher for the 2-seed group compared to 1-seed, although the difference was not statistically significant. CONCLUSIONS: Placing 2 seeds per MRI lesion yielded a significantly lower error compared to 1-seed strategy, although seed placement success rate was not significantly different.

Improved Mortality in Necrotizing Pancreatitis with a Multidisciplinary Minimally Invasive Step-Up Approach: Comparison with a Modern Open Necrosectomy Cohort.

BACKGROUND: A minimally invasive step-up (MIS) approach has been associated with reduced morbidity compared with open surgical necrosectomy (OSN) for treatment of necrotizing pancreatitis. We sought to determine whether transitioning from an OSN to an MIS-based approach would result in reduced mortality. MIS interventions included percutaneous drainage, endoscopic transgastric necrosectomy, video-assisted retroperitoneal debridement, sinus tract endoscopic necrosectomy, or a combination of techniques, with selective use of OSN. STUDY DESIGN: We conducted an observational cohort study with retrospective comparison at a single tertiary referral center (2006 through 2019). Eighty-eight patients were treated with OSN and 91 were treated with an MIS-based approach. Baseline characteristics and clinical outcomes were compared between groups. The primary end point was 90-day mortality. RESULTS: There was no difference in baseline characteristics. Ninety-day mortality was 2% with MIS compared with 10% with OSN (p = 0.03). One-year mortality was 3% with MIS compared with 15% with OSN (p = 0.012). The rate of organ failure was lower with MIS (30% vs 45%; p = 0.029), but there was a higher bleeding rate (19% vs 9%; p = 0.064). In the MIS group, 9% were treated with percutaneous drainage, 32% with endoscopic transgastric necrosectomy, 8% with video-assisted retroperitoneal debridement, 15% with sinus tract endoscopic necrosectomy, and 27% with a combination of techniques. CONCLUSIONS: Adoption of a multidisciplinary MIS-based approach to necrotizing pancreatitis resulted in a 5-fold decrease in mortality compared with OSN.

Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers.

PURPOSE: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer. EXPERIMENTAL DESIGN: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response. RESULTS: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001). CONCLUSIONS: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.