Fully Automated Deep Learning Model to Detect Clinically Significant Prostate Cancer at MRI.

Background Multiparametric MRI can help identify clinically significant prostate cancer (csPCa) (Gleason score ≥7) but is limited by reader experience and interobserver variability. In contrast, deep learning (DL) produces deterministic outputs. Purpose To develop a DL model to predict the presence of csPCa by using patient-level labels without information about tumor location and to compare its performance with that of radiologists. Materials and Methods Data from patients without known csPCa who underwent MRI from January 2017 to December 2019 at one of multiple sites of a single academic institution were retrospectively reviewed. A convolutional neural network was trained to predict csPCa from T2-weighted images, diffusion-weighted images, apparent diffusion coefficient maps, and T1-weighted contrast-enhanced images. The reference standard was pathologic diagnosis. Radiologist performance was evaluated as follows: Radiology reports were used for the internal test set, and four radiologists' PI-RADS ratings were used for the external (ProstateX) test set. The performance was compared using areas under the receiver operating characteristic curves (AUCs) and the DeLong test. Gradient-weighted class activation maps (Grad-CAMs) were used to show tumor localization. Results Among 5735 examinations in 5215 patients (mean age, 66 years ± 8 [SD]; all male), 1514 examinations (1454 patients) showed csPCa. In the internal test set (400 examinations), the AUC was 0.89 and 0.89 for the DL classifier and radiologists, respectively (P = .88). In the external test set (204 examinations), the AUC was 0.86 and 0.84 for the DL classifier and radiologists, respectively (P = .68). DL classifier plus radiologists had an AUC of 0.89 (P < .001). Grad-CAMs demonstrated activation over the csPCa lesion in 35 of 38 and 56 of 58 true-positive examinations in internal and external test sets, respectively. Conclusion The performance of a DL model was not different from that of radiologists in the detection of csPCa at MRI, and Grad-CAMs localized the tumor. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Johnson and Chandarana in this issue.

Application of high-density 2D receiver coil arrays for improved SNR in prostate MRI.

PURPOSE: To study if adaptive image receive (AIR) receiver coil elements can be configured into a 2D array with high (>45% by diameter) element-to-element overlap, allowing improved SNR at depth (0.7-1.5× element diameter) versus conventional (20%) overlap. METHODS: An anterior array composed of twenty 10-cm diameter elements with 45% overlap arranged into a 4 × 5 grid and a similar 3 × 7 twenty-one-element posterior array were constructed. SNR and g-factor were measured in a pelvic phantom using the new high-density (HD) arrays (41 total elements) and compared to vendor AIR-based arrays (30 total elements) with conventional overlap. T2-weighted fast-spin-echo (T2SE) images acquired using both arrays were compared in 20 subjects. SNR was estimated in vivo. Results were compared blindly by three uroradiologists using a five-point scale. Images using the HD arrays were also compared to a set of images acquired over a range of acceleration factors (R = 2.0, 2.5, 3.0) with the conventional arrays. RESULTS: SNR within the phantom was on average 15% higher for R = 1.0, 1.5, and 2.0 using the HD arrays. Across the 20 subjects SNR within the prostate was 11% higher and assessed radiologically as significantly higher (p < 0.001) for the HD versus conventional arrays. At all acceleration factors the new HD arrays outperformed the conventional arrays (p ≤ 0.01), allowing increased R for similar SNR. CONCLUSION: AIR elements can be configured into 2D arrays with high (45%) element-to-element overlap, consistently providing increased SNR at depth versus arrays with conventional (20%) overlap. The SNR improvement allows increased acceleration in T2SE prostate MRI.

Minimally Invasive Esophagectomy Provides Better Short- and Long-Term Outcomes Than Open Esophagectomy in Locally Advanced Esophageal Cancer.

BACKGROUND: Minimally invasive esophagectomy (MIE) has been increasingly performed for locally advanced esophageal cancer in place of open transthoracic esophagectomy (OE). This study explored the significance of MIE for esophageal squamous cell carcinoma (ESCC), focusing mainly on the depth of primary esophageal tumors. METHODS: This study retrospectively assessed short- and long-term outcomes of patients who underwent esophagectomy for ESCC from 2005 through 2021. The inverse probability of the treatment-weighting (IPTW) method was used to compare the outcomes between OE and MIE. The outcomes also were evaluated in the subgroups stratified by cT category. RESULTS: Among 1117 patients, 447 (40%) underwent OE and 670 (60%) underwent MIE. After IPTW adjustment, the incidence of any postoperative complications was significantly higher in the OE group than in the MIE group (60.8% vs 53.7%; p = 0.032), whereas the R0 resection rate was significantly higher in the MIE group (98.6% vs 92.7%; p < 0.001). The MIE group showed better 3 year overall and cancer-specific survival than the OE group (p < 0.001). The incidence of locoregional recurrence within the surgical field was significantly more frequent in the OE group (p < 0.001). In the subgroup analysis stratified by cT category, the R0 resection rate was significantly higher and the incidence of locoregional recurrence was lower in the MIE group among the patients with cT3-4 tumors. In the patients with cT1-2 tumors, MIE showed no significant benefit over OE. CONCLUSIONS: For the patients with cT3-4 tumors, MIE showed fewer postoperative complications, better locoregional control, and better prognosis than OE. Compared with OE, MIE is beneficial, especially for locally advanced ESCC.

DNA double-strand breaks enhance brassinosteroid signaling to activate quiescent center cell division in Arabidopsis.

In Arabidopsis roots, the quiescent center (QC), a group of slowly dividing cells located at the center of the stem cell niche, functions as an organizing center to maintain the stemness of neighboring cells. Recent studies have shown that they also act as a reservoir for backup cells, which replenish DNA-damaged stem cells by activating cell division. The latter function is essential for maintaining stem cells under stressful conditions, thereby guaranteeing post-embryonic root development in fluctuating environments. In this study, we show that one of the brassinosteroid receptors in Arabidopsis, BRASSINOSTEROID INSENSITIVE1-LIKE3 (BRL3), plays a major role in activating QC division in response to DNA double-strand breaks. SUPPRESSOR OF GAMMA RESPONSE 1, a master transcription factor governing DNA damage response, directly induces BRL3. DNA damage-induced QC division was completely suppressed in brl3 mutants, whereas QC-specific overexpression of BRL3 activated QC division. Our data also showed that BRL3 is required to induce the AP2-type transcription factor ETHYLENE RESPONSE FACTOR 115, which triggers regenerative cell division. We propose that BRL3-dependent brassinosteroid signaling plays a unique role in activating QC division and replenishing dead stem cells, thereby enabling roots to restart growing after recovery from genotoxic stress.

Multiparametric MRI Scoring System of the Pancreas for the Diagnosis of Chronic Pancreatitis.

BACKGROUND: Ductal features alone may not offer high diagnostic sensitivity or most accurate disease severity of chronic pancreatitis (CP). PURPOSE: Diagnose CP based on multiparametric MRI and MRCP features. STUDY TYPE: Prospective. POPULATION: Between February 2019 and May 2021, 46 control (23 males, 49.3 ± 14.1 years), 45 suspected (20 males, 48.7 ± 12.5 years), and 46 definite (20 males, 53.7 ± 14.6 years) CP patients were enrolled at seven hospitals enrolled in the MINIMAP study. CP classification was based on imaging findings and clinical presentation. FIELD STRENGTH AND SEQUENCES: 1.5 T. T1-weighted (T1W) spoiled gradient echo, T1 map with variable flip angle, dual-echo Dixon, secretin-enhanced MRCP before and after secretin infusion. ASSESSMENT: Dual-echo fat fraction (FF), T1 relaxation time, extracellular volume (ECV), T1 signal intensity ratio of the pancreas to the spleen (T1 score), arterial-to-venous enhancement ratio (AVR), pancreatic tail diameter (PTD), pancreas volume, late gadolinium enhancement, pancreatic ductal elasticity (PDE), and duodenal filling grade of secretin-enhanced MRCP were measured. STATISTICAL TESTS: Logistic regression analysis generated CP-MRI and secretin-enhanced CP-SMRI scores. Receiver operating characteristics analysis was used to differentiate definite CP from control. Interobserver agreement was assessed using Lin's concordance correlation coefficient. RESULTS: Compared to control, definite CP cohort showed significantly higher dual-echo FF (7% vs. 11%), lower AVR (1.35 vs. 0.85), smaller PTD (2.5 cm vs. 1.95 cm), higher ECV (28% vs. 38%), and higher incidence of PDE loss (6.5% vs. 50%). With the cut-off of >2.5 CP-MRI score (dual-echo FF, AVR, and PTD) and CP-SMRI score (dual-echo FF, AVR, PTD, and PDE) had cross-validated area under the curves of 0.84 (sensitivity 87%, specificity 68%) and 0.86 (sensitivity 89%, specificity 67%), respectively. Interobserver agreement for both CP-MRI and CP-SMRI scores was 0.74. CONCLUSION: The CP-MRI and CP-SMRI scores yielded acceptable performance and interobserver agreement for the diagnosis of CP. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Natural language processing pipeline to extract prostate cancer-related information from clinical notes.

OBJECTIVES: To develop an automated pipeline for extracting prostate cancer-related information from clinical notes. MATERIALS AND METHODS: This retrospective study included 23,225 patients who underwent prostate MRI between 2017 and 2022. Cancer risk factors (family history of cancer and digital rectal exam findings), pre-MRI prostate pathology, and treatment history of prostate cancer were extracted from free-text clinical notes in English as binary or multi-class classification tasks. Any sentence containing pre-defined keywords was extracted from clinical notes within one year before the MRI. After manually creating sentence-level datasets with ground truth, Bidirectional Encoder Representations from Transformers (BERT)-based sentence-level models were fine-tuned using the extracted sentence as input and the category as output. The patient-level output was determined by compilation of multiple sentence-level outputs using tree-based models. Sentence-level classification performance was evaluated using the area under the receiver operating characteristic curve (AUC) on 15% of the sentence-level dataset (sentence-level test set). The patient-level classification performance was evaluated on the patient-level test set created by radiologists by reviewing the clinical notes of 603 patients. Accuracy and sensitivity were compared between the pipeline and radiologists. RESULTS: Sentence-level AUCs were ≥ 0.94. The pipeline showed higher patient-level sensitivity for extracting cancer risk factors (e.g., family history of prostate cancer, 96.5% vs. 77.9%, p < 0.001), but lower accuracy in classifying pre-MRI prostate pathology (92.5% vs. 95.9%, p = 0.002) and treatment history of prostate cancer (95.5% vs. 97.7%, p = 0.03) than radiologists, respectively. CONCLUSION: The proposed pipeline showed promising performance, especially for extracting cancer risk factors from patient's clinical notes. CLINICAL RELEVANCE STATEMENT: The natural language processing pipeline showed a higher sensitivity for extracting prostate cancer risk factors than radiologists and may help efficiently gather relevant text information when interpreting prostate MRI. KEY POINTS: When interpreting prostate MRI, it is necessary to extract prostate cancer-related information from clinical notes. This pipeline extracted the presence of prostate cancer risk factors with higher sensitivity than radiologists. Natural language processing may help radiologists efficiently gather relevant prostate cancer-related text information.

Imaging of Perirenal and Intrarenal Lymphatic Vessels: Anatomy-based Approach.

The lymphatic system (or lymphatics) consists of lymphoid organs and lymphatic vessels. Despite the numerous previously published studies describing conditions related to perirenal and intrarenal lymphoid organs in the radiology literature, the radiologic findings of conditions related to intrarenal and perirenal lymphatic vessels have been scarcely reported. In the renal cortex, interlobular lymphatic capillaries do not have valves; therefore, lymph can travel along the primary route toward the hilum, as well as toward the capsular lymphatic plexus. These two lymphatic pathways can be opacified by contrast medium via pyelolymphatic backflow at CT urography, which reflects urinary contrast agent leakage into perirenal lymphatic vessels via forniceal rupture. Pyelolymphatic backflow toward the renal hilum should be distinguished from urinary leakage due to urinary injury. Delayed subcapsular contrast material retention via pyelolymphatic backflow, appearing as hyperattenuating subcapsular foci on CT images, mimics other subcapsular cystic diseases. In contrast to renal parapelvic cysts originating from the renal parenchyma, renal peripelvic cysts are known to be of lymphatic origin. Congenital renal lymphangiectasia is mainly seen in children and assessed and followed up at imaging. Several lymphatic conditions, including lymphatic leakage as an early complication and acquired renal lymphangiectasia as a late complication, are sometimes identified at imaging follow-up of kidney transplant. Lymphangiographic contrast material accumulation in the renal hilar lymphatic vessels is characteristic of chylo-urinary fistula. Chyluria appears as a fat-layering fluid-fluid level in the urinary bladder or upper urinary tract. Recognition of the anatomic pathway of tumor spread via lymphatic vessels at imaging is of clinical importance for accurate management at oncologic imaging. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Factors associated with intrachoroidal cavitation and sinkhole formation in eyes with glaucomatous visual-field defects.

PURPOSE: To investigate factors associated with intrachoroidal cavitation (ICC) and sinkhole formation in eyes with glaucomatous visual-field defects. METHODS: This retrospective, cross-sectional study enrolled a total of 2808 eyes of 1482 patients who were diagnosed/treated for glaucoma and underwent swept-source optical coherence tomography (OCT). We first determined the prevalence of ICCs and sinkholes and their locations. Next, we selected one eye from each patient and compared the clinical characteristics of eyes with and without ICCs. Finally, in eyes with ICCs, we compared the clinical characteristics of eyes with and without sinkholes. Blood flow (BF), represented by laser speckle flowgraphy-measured tissue-area mean blur rate (MBR), was measured in the temporal optic nerve head (ONH), temporal peripapillary chorioretinal atrophy (PPA) zone, and in the ICC zone. ICC area and angle were analyzed in OCT en-face images. Mean deviation and total deviation in the central area (TD-central) were measured with Humphrey visual-field testing. RESULTS: A total of 86 eyes (3.1%) had ICCs and 52 eyes (1.9%) had sinkholes. ICC eyes had a lower spherical equivalent and longer axial length (AL) than non-ICC eyes (P < 0.05). Patients with eyes with sinkholes were more elderly and had worse best-corrected visual acuity, worse TD-central, a larger ICC, and lower tissue-area MBR in the temporal ONH, temporal PPA zone, and ICC zone (P < 0.05). CONCLUSION: In eyes with glaucoma, AL elongation might be linked to ICC formation. Sinkhole formation might be associated with ICC enlargement, impaired ocular BF, and impaired retinal structure and function involving the central area.

Anatomical factor associated with thoracic procedural difficulty in robot-assisted minimally invasive esophagectomy.

BACKGROUND: Robotic surgical systems with full articulation of instruments, tremor filtering, and motion scaling can potentially overcome the procedural difficulties in endoscopic surgeries. However, whether robot-assisted minimally invasive esophagectomy (RAMIE) can overcome anatomical difficulties during thoracoscopic esophagectomy remains unclear. This study aimed to clarify the anatomical and clinical factors that influence the difficulty of RAMIE in the thoracic region. METHODS: Forty-five patients who underwent curative-intent RAMIE with upper mediastinal lymph node dissection for esophageal cancer were included. Using preoperative computed tomography images, we calculated previously reported anatomical indices to assess the upper mediastinal narrowness and vertebral body projections in the middle thoracic region. The factors influencing thoracic operative time were then investigated. RESULTS: During the thoracic procedure, the median operative time was 215 (124-367) min and the median blood loss was 20 (5-190) mL. Postoperatively, pneumonia, anastomotic leakage, and recurrent laryngeal nerve palsy occurred in 17.8%, 2.2%, and 6.7% of the patients, respectively. The multiple linear regression model revealed that a narrow upper mediastinum and greater blood loss during the thoracic procedure were significant factors associated with a prolonged thoracic operative time (P = 0.025 and P < 0.001, respectively). Upper mediastinal narrowing was not associated with postoperative complications. CONCLUSIONS: A narrow upper mediastinum was significantly associated with a prolonged thoracic operative time in patients with RAMIE.

Gastric conduit reconstruction after esophagectomy.

A high risk of complications still accompanies gastric conduit reconstruction after esophagectomy. In this narrative review, we summarize the technological progress and the problems of gastric conduit reconstruction after esophagectomy. Several types of gastric conduits exist, including the whole stomach and the narrow gastric tube. The clinical outcomes are similar between the two types of conduits. Sufficient blood supply to the conduit is mandatory for a successful esophageal reconstruction. Recently, due to the availability of equipment and its convenience, indocyanine green angiography has been rapidly spreading. When the blood perfusion of the planning anastomotic site is insufficient, several techniques, such as the Kocher maneuver, pedunculated gastric tube with duodenal transection, and additional microvascular anastomosis, exist to decrease the risk of anastomotic failure. There are two different anastomotic sites, cervical and thoracic, and mainly two reconstructive routes, retrosternal and posterior mediastinal routes. Meta-analyses showed no significant difference in outcomes between the anastomotic sites as well as the reconstructive routes. Anastomotic techniques include hand-sewn, circular, and linear stapling. Anastomoses using linear stapling is advantageous in decreasing anastomosis-related complications. Arteriosclerosis and poorly controlled diabetes are the risk factors for anastomotic leakage, while a narrow upper mediastinal space and a damaged stomach predict leakage. Although standardization among the institutional team members is essential to decrease anastomotic complications, surgeons should learn several technical options for predictable or unpredictable intraoperative situations.

Structure-Activity Relationship Study of CYM51010, an agonist for the µ-δ Opioid Receptor Heterodimer.

Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to develop safer analgesics. Although some heterodimer-preferring agonists have been reported so far, it is still difficult to activate the MOR/DOR heterodimer selectively in the presence of MOR or DOR monomers/homodimers. To gain insights to develop selective agonists for MOR/DOR, herein we prepared analogs of CYM51010, one of the reported heterodimer-preferring agonists, and collected structure-activity relationship information. We found that the ethoxycarbonyl group was needed for the activity for the heterodimer, although this group could be substituted with functional groups with similar sizes, such as an ethoxycarbonyl group. As for the acetylaminophenyl group, not a type of substituent, but rather a substituent located at a specific position (para-position) was essential for the activity. Changing the linker length between the acetylaminophenyl group and the piperidine moiety also had deleterious effects on the activity. On the other hand, the substitution of the acetylamino group with a trifluoroacetylamino group and the substitution of the phenethyl group with a benzyl group diminished the activities for the monomers/homodimers while keeping the activity for MOR/DOR, which enhanced the selectivity. Our findings herein will play an important role in developing selective agonists for MOR/DOR and for elucidating the physiological roles of this heterodimer in analgesic processes and in the establishment of side effects.

Clinical Characteristics of Corynebacterium ulcerans Infection, Japan.

Corynebacterium ulcerans is a closely related bacterium to the diphtheria bacterium C. diphtheriae, and some C. ulcerans strains produce toxins that are similar to diphtheria toxin. C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. Infection with C. ulcerans can cause respiratory or nonrespiratory symptoms in patients. Recently, the microorganism has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in Japan. To clarify the overall clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection, we analyzed 34 cases of C. ulcerans that occurred in Japan during 2001-2020. During 2010-2020, the incidence rate of C. ulcerans infection increased markedly, and the overall mortality rate was 5.9%. It is recommended that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection.

Combined Drainage and Protocolized Necrosectomy Through a Coaxial Lumen-apposing Metal Stent for Pancreatic Walled-off Necrosis: A Prospective Multicenter Trial.

OBJECTIVE: We evaluated a protocolized endoscopic necrosectomy approach with a lumen-apposing metal stent (LAMS) in patients with large symptomatic walled-off pancreatic necrosis (WON) comprising significant necrotic content, with or without infection. SUMMARY BACKGROUND DATA: Randomized trials have shown similar efficacy of endoscopic treatment compared with surgery for infected WON. DESIGN: We conducted a regulatory, prospective, multicenter single-arm clinical trial examining the efficacy and safety of endoscopic ultrasound -guided LAMS with protocolized necrosectomy to treat symptomatic WON ≥6 cm in diameter with >30% solid necrosis. After LAMS placement, protocolized WON assessment was conducted and endoscopic necrosectomy was performed for insufficient WON size reduction and persistent symptoms. Patients with radiographic WON resolution to ≤ 3 cm and/or 60-day LAMS indwell had LAMS removal, then 6-month follow-up. Primary endpoints were probability of radiographic resolution by 60 days and procedure-related serious adverse events. RESULTS: Forty consecutive patients were enrolled September 2018 to March 2020, of whom 27 (67.5%) were inpatients and 19 (47.5%) had clinical evidence of infection at their index procedure. Mean WON size was 15.0 ± 5.6 cm with mean 53.2% ± 16.7% solid necrosis. Radiographic WON resolution was seen in 97.5% (95% CI, 86.8%, 99.9%) by 60 days, without recurrence in 34 patients with 6-month follow-up data. Mean time to radiographic WON resolution was 34.1 ± 16.8 days. Serious adverse events occurred in 3 patients (7.5%), including sepsis, vancomycin-resistant enterococcal bacteremia and shock, and upper gastrointestinal bleeding. There were no procedure-related deaths. CONCLUSIONS: Endoscopic ultrasound-guided drainage with protocolized endoscopic necrosectomy to treat large symptomatic or infected walled-off necrotic pancreatic collections was highly effective and safe. Clinicaltrials.-gov no: NCT03525808.

A Protocolized Management of Walled-Off Necrosis (WON) Reduces Time to WON Resolution and Improves Outcomes.

BACKGROUND AND AIMS: Patients with infected or symptomatic walled-off necrosis (WON) have high morbidity and health care utilization. Despite the recent adoption of nonsurgical treatment approaches, WON management remains nonalgorithmic. We investigated the impact of a protocolized early necrosectomy approach compared with a nonprotocolized, clinician-driven approach on important clinical outcomes. METHODS: Records were reviewed for consecutive patients with WON who underwent a protocolized endoscopic drainage with a lumen-apposing metal stent (cases), and for patients with WON treated with a lumen-apposing metal stent at the same tertiary referral center who were not managed according to the protocol (control subjects). The protocol required repeat cross-sectional imaging within 14 days after lumen-apposing metal stent placement, with regularly scheduled endoscopic necrosectomy if WON diameter reduction was <50%. Control patients were treated according to their clinician's preference without an a priori strategy. Inverse probability of treatment weighting-adjusted analysis was used to evaluate the influence of being in the protocolized group on time to resolution. RESULTS: A total of 24 cases and 47 control subjects were included. There were no significant differences in baseline characteristics. Although numbers of endoscopies and necrosectomies were similar, cases had lower adverse event rates, shorter intensive care unit stay, and required nutritional support for fewer days. On matched multivariate Cox regression, cases had earlier WON resolution (hazard ratio, 5.73; 95% confidence interval, 2.62-12.5). This was confirmed in the inverse probability of treatment weighting-adjusted analysis (hazard ratio, 3.4; 95% confidence interval, 1.92-6.01). CONCLUSIONS: A protocolized strategy resulted in faster WON resolution compared with a discretionary approach without the need for additional therapeutic interventions, and with a better safety profile and decreased health care utilization.

Pancreatic involvement due to immune checkpoint inhibitors: a proposed classification.

BACKGROUND: Drug-induced acute pancreatitis (AP) is uncommon and pancreatic involvement due to immune checkpoint inhibitors (ICI) in published reports relied on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). CTCAE definition of AP differs from the revised Atlanta classification diagnostic criteria. This study aims to classify the spectrum of pancreatic involvement in patients receiving ICI therapy into categories built on the revised Atlanta classification. METHODS: A retrospective cohort study of cancer patients receiving cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors between 2011 and 2020. Pancreas-specific immune-related adverse events (irAEs) were categorized into AP and pancreatic injury. RESULTS: Forty-seven patients on ICI therapy met selection criteria. Twenty patients (43%) had AP, while 27 (57%) had pancreatic injury. Fifteen patients (75%) developed mild AP. Five patients progressed to pancreatic atrophy, and two patients (4%) developed exocrine pancreatic insufficiency. In both groups, most patients received nivolumab therapy (70% vs. 67%, p = 0.08) with no difference in mean number of nivolumab doses (9 vs. 10, p = 0.69). There was no correlation between the mean number of nivolumab or pembrolizumab doses and AP events (OR 0.94, p = 0.26, and OR 0.98, p = 0.86), but the duration of ICI therapy was significantly related to pancreatic atrophy (OR 1.01, p = 0.05; 95% CI 1.00-1.02). CONCLUSION: Based on the novel classification, majority of pancreatic irAEs were classified as asymptomatic pancreatic injury but with some risk of pancreatic atrophy. This classification can help in assessing patterns of pancreatic involvement, pathogenesis, and treatment decisions.

Cytokinin signaling promotes root hair growth by directly regulating RSL4 expression.

Root hairs are single-celled tubular structures produced from the epidermis, which play an essential role in water and nutrient uptake from the soil. Therefore, root hair formation and elongation are controlled not only by developmental programs but also by environmental factors, enabling plants to survive under fluctuating conditions. Phytohormones are key signals that link environmental cues to developmental programs; indeed, root hair elongation is known to be controlled by auxin and ethylene. Another phytohormone, cytokinin, also affects root hair growth, while whether cytokinin is actively involved in root hair growth and, if so, how it regulates the signaling pathway governing root hair development have remained unknown. In this study, we show that the two-component system of cytokinin, which involves the B-type response regulators ARABIDOPSIS RESPONSE REGULATOR 1 (ARR1) and ARR12, promotes the elongation process of root hairs. They directly up-regulate ROOT HAIR DEFECTIVE 6-LIKE 4 (RSL4) encoding a basic helix-loop-helix (bHLH) transcription factor that plays a central role in root hair growth, whereas the ARR1/12-RSL4 pathway does not crosstalk with auxin or ethylene signaling. These results indicate that cytokinin signaling constitutes another input onto the regulatory module governed by RSL4, making it possible to fine-tune root hair growth in changing environments.

Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. METHODS: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. DISCUSSION: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. TRIAL REGISTRATION: jRCTs041220120.

Artificial intelligence assisted whole organ pancreatic fat estimation on magnetic resonance imaging and correlation with pancreas attenuation on computed tomography.

BACKGROUND: Fatty pancreas is associated with inflammatory and neoplastic pancreatic diseases. Magnetic resonance imaging (MRI) is the diagnostic modality of choice for measuring pancreatic fat. Measurements typically use regions of interest limited by sampling and variability. We have previously described an artificial intelligence (AI)-aided approach for whole pancreas fat estimation on computed tomography (CT). In this study, we aimed to assess the correlation between whole pancreas MRI proton-density fat fraction (MR-PDFF) and CT attenuation. METHODS: We identified patients without pancreatic disease who underwent both MRI and CT between January 1, 2015 and June 1, 2020. 158 paired MRI and CT scans were available for pancreas segmentation using an iteratively trained convolutional neural network (CNN) with manual correction. Boxplots were generated to visualize slice-by-slice variability in 2D-axial slice MR-PDFF. Correlation between whole pancreas MR-PDFF and age, BMI, hepatic fat and pancreas CT-Hounsfield Unit (CT-HU) was assessed. RESULTS: Mean pancreatic MR-PDFF showed a strong inverse correlation (Spearman -0.755) with mean CT-HU. MR-PDFF was higher in males (25.22 vs 20.87; p = 0.0015) and in subjects with diabetes mellitus (25.95 vs 22.17; p = 0.0324), and was positively correlated with age and BMI. The pancreatic 2D-axial slice-to-slice MR-PDFF variability increased with increasing mean whole pancreas MR-PDFF (Spearman 0.51; p < 0.0001). CONCLUSION: Our study demonstrates a strong inverse correlation between whole pancreas MR-PDFF and CT-HU, indicating that both imaging modalities can be used to assess pancreatic fat. 2D-axial pancreas MR-PDFF is variable across slices, underscoring the need for AI-aided whole-organ measurements for objective and reproducible estimation of pancreatic fat.

Novel classification system for walled-off necrosis: a step toward standardized nomenclature and risk-stratification framework.

BACKGROUND AND AIMS: The optimal therapeutic approach for walled-off necrosis (WON) is not fully understood, given the lack of a validated classification system. We propose a novel and robust classification system based on radiologic and clinical factors to standardize the nomenclature, provide a framework to guide comparative effectiveness trials, and inform the optimal WON interventional approach. METHODS: This was a retrospective analysis of patients who underwent endoscopic management of WON by lumen-apposing metal stent placement at a tertiary referral center. Patients were classified according to the proposed QNI classification system: quadrant ("Q"), represented an abdominal quadrant distribution; necrosis ("N"), denoted by the percentage of necrosis of WON; and infection ("I"), denoted as positive blood culture and/or systemic inflammatory response syndrome reaction with a positive WON culture. Two blinded reviewers classified all patients according to the QNI system. Patients were then divided into 2 groups: those with a lower QNI stratification (≤2 quadrants and ≤30% necrosis; group 1) and those with a higher stratification (≥3 quadrants, 2 quadrants with ≥30% necrosis, or 1 quadrant with >60% necrosis and infection; group 2). The primary outcome was mean time to WON resolution. Secondary procedural and clinical outcomes between the groups were compared. RESULTS: Seventy-one patients (75% men) were included and stratified by the QNI classification; group 1 comprised 17 patients and group 2, 54 patients. Patients in group 2 had a higher number of necrosectomies, longer hospital stays, and more readmissions. The mean time to resolution was longer in group 2 than in group 1 (79.6 ± 7.76 days vs 48.4 ± 9.22 days, P = .02). The mortality rate was higher in group 2 (15% vs 0%, P = .18). CONCLUSIONS: Despite the heterogeneous nature of WON in severe acute pancreatitis, a proposed QNI system may provide a standardized framework for WON classification to inform clinical trials, risk-stratify the disease course, and potentially inform an optimal management approach.