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OBJECTIVE: To evaluate the feasibility of developing a computer vision algorithm that uses preoperative computed tomography (CT) scans to predict superior mesenteric artery (SMA) margin status in patients undergoing Whipple for pancreatic ductal adenocarcinoma (PDAC), and to compare algorithm performance to that of expert abdominal radiologists and surgical oncologists. SUMMARY BACKGROUND DATA: Complete surgical resection is the only chance to achieve a cure for PDAC; however, current modalities to predict vascular invasion have limited accuracy. METHODS: Adult patients with PDAC who underwent Whipple and had preoperative contrast-enhanced CT scans were included (2010-2022). The SMA was manually annotated on the CT scans, and we trained a U-Net algorithm for SMA segmentation and a ResNet50 algorithm for predicting SMA margin status. Radiologists and surgeons reviewed the scans in a blinded fashion. SMA margin status per pathology reports was the reference. RESULTS: Two hundred patients were included. Forty patients (20%) had a positive SMA margin. For the segmentation task, the U-Net model achieved a Dice Similarity Coefficient of 0.90. For the classification task, all readers demonstrated limited sensitivity, although the algorithm had the highest sensitivity at 0.43 (versus 0.23 and 0.36 for the radiologists and surgeons, respectively). Specificity was universally excellent, with the radiologist and algorithm demonstrating the highest specificity at 0.94. Finally, the accuracy of the algorithm was 0.85 versus 0.80 and 0.76 for the radiologists and surgeons, respectively. CONCLUSIONS: We demonstrated the feasibility of developing a computer vision algorithm to predict SMA margin status using preoperative CT scans, highlighting its potential to augment the prediction of vascular involvement.
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Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.
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OBJECTIVES: To explore the topic of Prostate Imaging-Reporting and Data System (PI-RADS) interobserver variability, including a discussion of major sources, mitigation approaches, and future directions. METHODS: A narrative review of PI-RADS interobserver variability. RESULTS: PI-RADS was developed in 2012 to set technical standards for prostate magnetic resonance imaging (MRI), reduce interobserver variability at interpretation, and improve diagnostic accuracy in the MRI-directed diagnostic pathway for detection of clinically significant prostate cancer. While PI-RADS has been validated in selected research cohorts with prostate cancer imaging experts, subsequent prospective studies in routine clinical practice demonstrate wide variability in diagnostic performance. Radiologist and biopsy operator experience are the most important contributing drivers of high-quality care among multiple interrelated factors including variability in MRI hardware and technique, image quality, and population and patient-specific factors such as prostate cancer disease prevalence. Iterative improvements in PI-RADS have helped flatten the curve for novice readers and reduce variability. Innovations in image quality reporting, administrative and organisational workflows, and artificial intelligence hold promise in improving variability even further. CONCLUSION: Continued research into PI-RADS is needed to facilitate benchmark creation, reader certification, and independent accreditation, which are systems-level interventions needed to uphold and maintain high-quality prostate MRI across entire populations.
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Fibroblast activation protein (FAP), expressed in the tumor microenvironment of a variety of cancers, has become a target of novel PET tracers. The purpose of this report is to evaluate the imaging characteristics of 68Ga-FAP-2286, present the first-to our knowledge-dosimetry analysis to date, and compare the agent with 18F-FDG and FAPI compounds. Methods: Patients were administered 219 ± 43 MBq of 68Ga-FAP-2286 and scanned after 60 min. Uptake was measured in up to 5 lesions per patient and within the kidneys, spleen, liver, and mediastinum (blood pool). Absorbed doses were evaluated using MIM Encore and OLINDA/EXM version 1.1 using the International Commission on Radiological Protection publication 103 tissue weighting factor. Results: Forty-six patients were imaged with 68Ga-FAP-2286 PET. The highest average uptake was seen in sarcoma, cholangiocarcinoma, and colon cancer. The lowest uptake was found in lung cancer and testicular cancer. The average SUVmax was significantly higher on 68Ga-FAP-2286 PET than on 18F-FDG PET in cholangiocarcinoma (18.2 ± 6.4 vs. 9.1 ± 5.0, P = 0.007), breast cancer (11.1 ± 6.8 vs. 4.1 ± 2.2, P < 0.001), colon cancer (13.8 ± 2.2 vs. 7.6 ± 1.7, P = 0.001), hepatocellular carcinoma (9.3 ± 3.5 vs. 4.7 ± 1.3, P = 0.01), head and neck cancer (11.3 ± 3.5 vs. 7.6 ± 5.5, P = 0.04), and pancreatic adenocarcinoma (7.4 ± 1.8 vs. 3.7 ± 1.0, P = 0.01). The total-body effective dose was estimated at 1.16E-02 mSv/MBq, with the greatest absorbed organ dose in the urinary bladder wall (9.98E-02 mGy/MBq). Conclusion: 68Ga-FAP-2286 biodistribution, dosimetry, and tumor uptake were similar to those of previously reported FAPI compounds. Additionally,68Ga-FAP-2286 PET had consistently higher uptake than 18F-FDG PET. These results are especially promising in the setting of small-volume disease and differentiating tumor from inflammatory uptake.
Subject(s)
Fluorodeoxyglucose F18 , Gallium Radioisotopes , Neoplasms , Positron-Emission Tomography , Radiometry , Humans , Fluorodeoxyglucose F18/pharmacokinetics , Male , Female , Neoplasms/diagnostic imaging , Neoplasms/metabolism , Positron-Emission Tomography/methods , Middle Aged , Tissue Distribution , Aged , Adult , Radiopharmaceuticals/pharmacokinetics , Aged, 80 and over , QuinolinesABSTRACT
Background The Liver Imaging Reporting and Data System version 2018 (LI-RADS) treatment response algorithm (TRA) is a high-specificity, lower-sensitivity grading system to diagnose hepatocellular carcinoma (HCC) and recurrence after local-regional therapy. However, the emphasis on specificity can result in disease understaging, potentially leading to poorer posttransplant outcomes. Purpose To determine the negative predictive value (NPV) of pretransplant CT and MRI assessment for viable HCC on a per-patient basis using the LI-RADS TRA, considering explant pathology as the reference standard. Materials and Methods Patient records from 218 consecutive adult patients from a single institution with HCC who underwent liver transplant from January 2011 to November 2017 were retrospectively reviewed. Two readers blinded to the original report reviewed immediate (within 90 days) pretransplant imaging and characterized observations according to the LI-RADS TRA. Based on this, patients with LR-4, LR-5, or LR-TR (treatment response) viable tumors were designated as viable tumor; patients with solely LR-3 or LR-TR equivocal tumors were designated as equivocal; and patients with only LR-TR nonviable lesions were designated as no viable disease. Patients were designated as within or outside the Milan criteria. These per-patient designations were compared with the presence of viable disease at explant pathology. Fisher exact test was used to compare the differences between CT and MRI. Weighted κ values were used to calculate interreader reliability. Results Final study sample consisted of 206 patients (median age, 61 years [IQR, 57-65 years]; 157 male patients and 49 female patients). Per-patient LI-RADS TRA assessment of pretransplant imaging had an NPV of 32% (95% CI: 27, 38) and 26% (95% CI: 20, 33) (readers 1 and 2, respectively) for predicting viable disease. Seventy-five percent (reader 1) and 77% (reader 2) of patients deemed equivocal had residual tumors at explant pathology. Weighted interreader reliability was substantial (κ = 0.62). Conclusion Patient-based stratification of viable, equivocal, and nonviable disease at pretransplant CT or MRI, based on LI-RADS TRA, demonstrated low negative predictive value in excluding HCC at explant pathology. © RSNA, 2023 See also the editorial by Tamir and Tau in this issue.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Adult , Humans , Male , Female , Middle Aged , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/surgery , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Predictive Value of Tests , Retrospective Studies , Reproducibility of Results , Magnetic Resonance Imaging/methods , Algorithms , Tomography, X-Ray Computed/methods , Sensitivity and Specificity , Contrast MediaABSTRACT
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Imaging techniques such as CT, MRI, and bone scans have traditionally been used for diagnosis and staging. Molecular imaging modalities targeting the prostate-specific membrane antigen (PSMA) have recently gained attention due to their high affinity and accuracy. PSMA PET has been combined with other modalities such as multiparametric MRI for better diagnostic and prognostic performance. PSMA imaging has been studied at different clinical settings with a wide range of disease aggressiveness. In this review we will explore the role of PSMA PET in high-risk prostate cancer staging, biochemical recurrence, and castration-resistant prostate cancer. The primary focus of this review article is to examine the latest developments in the use of PSMA imaging and emphasize the clinical situations where its effectiveness has been demonstrated to significantly impact the treatment of prostate cancer. In addition, we will touch upon the potential future advancements of PSMA PET imaging and its evolving significance in the management of prostate cancer.
Subject(s)
Prostate-Specific Antigen , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/drug therapy , Prostate-Specific Antigen/analysis , Positron Emission Tomography Computed Tomography , Choline/analysis , Neoplasm Staging , Recurrence , Molecular Targeted TherapyABSTRACT
Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1-2) GEP-NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1-3 GEP-NET, we calculated baseline TGR (TGR0 ) from radiological images of metastases acquired prior to first-line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1-3 tumors combined was 5% (range = 0.1%-52%) and median TGR0 was 4.8%/month (m) (range = 0%-45.9%/m). TGR0 correlated with pretreatment Ki67 across G1-3 pooled and within G3 GEP-NET. Patients with higher TGR0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p = .03) and shorter overall survival (median, 4.1 years vs. not reached; p = .003). Independent of therapies given, higher TGR0 GEP-NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p = .02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p = .04) upon serial biopsy. Importantly, TGR0 , but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP-NETs, future clinical trials may benefit from stratification for TGR0 , particularly in G1-2 tumors, in which TGR0 does not correlate with Ki67. TGR0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR0 in larger and more homogeneously treated cohorts, and to ascertain if post-treatment TGR has value in previously treated patients starting a new line of therapy.
Subject(s)
Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Neuroendocrine Tumors/pathology , Ki-67 Antigen , Retrospective StudiesABSTRACT
Recent advances in positron emission tomography (PET) technology and reconstruction techniques have now made quantitative assessment using cardiac PET readily available in most cardiac PET imaging centers. Multiple PET myocardial perfusion imaging (MPI) radiopharmaceuticals are available for quantitative examination of myocardial ischemia, with each having distinct convenience and accuracy profile. Important properties of these radiopharmaceuticals ( 15 O-water, 13 N-ammonia, 82 Rb, 11 C-acetate, and 18 F-flurpiridaz) including radionuclide half-life, mean positron range in tissue, and the relationship between kinetic parameters and myocardial blood flow (MBF) are presented. Absolute quantification of MBF requires PET MPI to be performed with protocols that allow the generation of dynamic multiframes of reconstructed data. Using a tissue compartment model, the rate constant that governs the rate of PET MPI radiopharmaceutical extraction from the blood plasma to myocardial tissue is calculated. Then, this rate constant ( K1 ) is converted to MBF using an established extraction formula for each radiopharmaceutical. As most of the modern PET scanners acquire the data only in list mode, techniques of processing the list-mode data into dynamic multiframes are also reviewed. Finally, the impact of modern PET technologies such as PET/CT, PET/MR, total-body PET, machine learning/deep learning on comprehensive and quantitative assessment of myocardial ischemia is briefly described in this review.
Subject(s)
Myocardial Ischemia , Humans , Myocardial Ischemia/diagnostic imaging , Myocardial Perfusion Imaging/methods , Positron-Emission Tomography/methods , RadiopharmaceuticalsABSTRACT
PURPOSE: Pseudocirrhosis is a term used to describe changes in hepatic contour that mimic cirrhosis radiographically, but lack the classic pathologic features of cirrhosis. This radiographic finding is frequently found in patients with metastatic breast cancer (MBC), but the risk factors and clinical consequences are poorly understood. METHODS: In this retrospective study, we identified patients with MBC and pseudocirrhosis who were treated at a single center from 2002 to 2021. We used chart extraction and radiology review to determine demographic characteristics, treatment history, imaging features, and complications of pseudocirrhosis. RESULTS: 120 patients with MBC and pseudocirrhosis were identified with the following BC subtypes: hormone receptor (HR) positive, HER2 negative (n = 99, 82.5%), HR+/HER2+ (n = 14, 11.7%), HR- /HER2+ (n = 3, 2.5%), and triple negative (TNBC; n = 4, 3.3%). All patients had liver metastases and 82.5% (n = 99) had > 15 liver lesions. Thirty-six patients (30%) presented with de novo metastatic disease. Median time from MBC diagnosis to pseudocirrhosis was 29.2 months. 50% of patients had stable or responding disease at the time of pseudocirrhosis diagnosis. Sequelae of pseudocirrhosis included radiographic ascites (n = 97, 80.8%), gastric/esophageal varices (n = 68, 56.7%), splenomegaly (n = 26, 21.7%), GI bleeding (n = 12, 10.0%), and hepatic encephalopathy (n = 11, 9.2%). Median survival was 7.9 months after pseudocirrhosis diagnosis. Radiographic ascites was associated with shorter survival compared to no radiographic ascites (42.8 vs. 76.2 months, p = < 0.001). CONCLUSIONS: This is the largest case series of patients with MBC and pseudocirrhosis. Nearly all patients had HR+ MBC and extensive liver metastases. Survival was short after pseudocirrhosis and prognosis worse with radiographic ascites.
Subject(s)
Breast Neoplasms , Liver Neoplasms , Humans , Female , Breast Neoplasms/pathology , Retrospective Studies , Ascites , Prognosis , Liver Neoplasms/secondary , Receptor, ErbB-2ABSTRACT
Importance: National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. Objective: To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. Design, Setting, and Participants: This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Interventions: Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours). Main Outcomes and Measures: Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Results: Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. Conclusions and Relevance: This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02839343.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Adenocarcinoma/radiotherapy , Adenocarcinoma/surgery , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Fluorouracil/therapeutic use , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Male , Middle Aged , Neoadjuvant Therapy , Oxaliplatin/therapeutic use , Pancreas/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Prospective Studies , Pancreatic NeoplasmsABSTRACT
Patients with metastatic breast cancer are at high risk for developing vertebral compression fractures due to underlying bone metastases and bone density loss. Vertebral augmentation techniques including percutaneous vertebroplasty and percutaneous balloon kyphoplasty are techniques used to stabilize compression fractures and improve pain. However, rare complications from these interventions have been observed, including spinal cord compression, nerve root compression, venous cement embolism, and pulmonary cement embolism. These complications pose unique potential challenges for patients with cancer who may already have decreased lung function and potential for venous thromboembolism. In this review, we first describe the role of percutaneous vertebral augmentations in patients with metastatic cancer, with a particular focus on patients with breast cancer. Then, we describe complications of vertebral augmentation in two patients with metastatic breast cancer including long-term symptomatic and radiographic follow-up.
Subject(s)
Breast Neoplasms , Fractures, Compression , Spinal Fractures , Vertebroplasty , Breast Neoplasms/complications , Breast Neoplasms/surgery , Female , Fractures, Compression/complications , Fractures, Compression/surgery , Humans , Spinal Fractures/etiology , Spinal Fractures/surgery , Treatment Outcome , Vertebroplasty/adverse effects , Vertebroplasty/methodsABSTRACT
BACKGROUND. Data are limited regarding utility of positive oral contrast material for peritoneal tumor detection on CT. OBJECTIVE. The purpose of this article is to compare positive versus neutral oral contrast material for detection of malignant deposits in nonsolid intraabdominal organs on CT. METHODS. This retrospective study included 265 patients (133 men, 132 women; median age, 61 years) who underwent an abdominopelvic CT examination in which the report did not suggest presence of malignant deposits and a subsequent CT examination within 6 months in which the report indicated at least one unequivocal malignant deposit. Examinations used positive (iohexol; n = 100) or neutral (water; n = 165) oral agents. A radiologist reviewed images to assess whether the deposits were visible (despite clinical reports indicating no deposits) on unblinded comparison with the follow-up examinations; identified deposits were assigned to one of seven intraabdominal compartments. The radiologist also assessed adequacy of bowel filling with oral contrast material. Two additional radiologists independently reviewed examinations in blinded fashion for malignant deposits. NPV was assessed of clinical CT reports and blinded retrospective readings for detection of malignant deposits visible on unblinded comparison with follow-up examinations. RESULTS. Unblinded review identified malignant deposits in 58.1% (154/265) of examinations. In per-patient analysis of clinical reports, NPV for malignant deposits was higher for examinations with adequate bowel filling with positive oral contrast material (65.8% [25/38]) than for examinations with inadequate bowel filling with positive oral contrast material (45.2% [28/62], p = .07) or with neutral oral contrast material regardless of bowel filling adequacy (35.2% [58/165], p = .002). In per-compartment analysis of blinded interpretations, NPV was higher for examinations with adequate and inadequate bowel filling with positive oral contrast material than for examinations with neutral oral contrast regardless of bowel filling adequacy (reader 1: 94.7% [234/247] and 92.5% [382/413] vs 88.3% [947/1072], both p = .045; reader 2: 93.1% [228/245] and 91.6% [361/394] vs 85.9% [939/1093], both p = .01). CONCLUSION. CT has suboptimal NPV for malignant deposits in intraabdominal nonsolid organs. Compared with neutral material, positive oral contrast material improves detection, particularly with adequate bowel filling. CLINICAL IMPACT. Optimization of bowel preparation for oncologic CT may help avoid potentially severe clinical consequences of missed malignant deposits.
Subject(s)
Contrast Media , Tomography, X-Ray Computed , Female , Humans , Intestines , Iohexol , Male , Middle Aged , Retrospective Studies , Sensitivity and Specificity , Tomography, X-Ray Computed/methodsABSTRACT
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
Subject(s)
Neoplasms , Proto-Oncogene Proteins p21(ras) , Animals , Cell Line, Tumor , Iron/pharmacology , Mutation/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins p21(ras)/genetics , Signal TransductionABSTRACT
INTRODUCTION: Disconnected pancreatic duct syndrome (DPDS) is a recognized complication of necrotizing pancreatitis (NP). Manifestations include recurrent peripancreatic fluid collections (R-PFC) and pancreatocutaneous fistulae (PC-Fistulae). Pancreatitis of the disconnected pancreatic segment (DPDS-P) and its relationship to new-onset diabetes after pancreatitis (NODAP) are not well characterized. METHODS: We performed a retrospective cohort study of consecutive patients with NP admitted to University of California, San Francisco from January 2011 to June 2019. A diagnosis of a disconnected pancreatic duct (PD) was confirmed using computed tomography and magnetic resonance cholangiopancreatography/endoscopic retrograde cholangiopancreatography. DPDS was defined as a disconnected PD presenting with R-PFC, PC-Fistulae, or DPDS-P. The primary outcome was NODAP, defined as diabetes mellitus (DM) occurring >3 months after NP. Cox proportional hazards regression was used to evaluate the relationship between DPDS and NODAP. RESULTS: Of 171 patients with NP in this study, the mean clinical follow-up was 46 ± 18 months and the imaging follow-up was 38 ± 20 months. Twenty-seven patients (16%) developed DPDS-P at a median of 28 months. New-onset DM occurred in 54 of the 148 patients (36%), with 22% developing DM within 3 months of NP and 14% developing NODAP at a median of 31 months after AP. DPDS-P was associated with NODAP when compared with non-DPDS patients (adjusted hazard ratio 5.63 95% confidence interval: 1.69-18.74, P = 0.005) while R-PFCs and PC-Fistulae were not. DISCUSSION: DPDS and NODAP occurred in 28% and 14% of the patients, respectively. Pancreatitis of the disconnected pancreas occurred in 16% of the patients and was associated with higher rates of NODAP when compared with patients with other manifestations of DPDS and patients without DPDS.
Subject(s)
Diabetes Mellitus , Pancreatitis , Diabetes Mellitus/epidemiology , Diabetes Mellitus/etiology , Drainage/methods , Humans , Pancreas/diagnostic imaging , Pancreatic Ducts/diagnostic imaging , Pancreatic Ducts/pathology , Pancreatitis/diagnosis , Pancreatitis/etiology , Pancreatitis/pathology , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. METHODS: We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. RESULTS: Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. CONCLUSIONS: The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.
ABSTRACT
Müllerian duct anomalies (MDAs) have important implications for the reproductive health of female patients. In patients with both infertility and recurrent pregnancy loss, the incidence of MDAs is as high as 25%. Congenital uterine anomalies are often only part of a complex set of congenital anomalies involving the cervix, vagina, and urinary tract. Multiple classification systems for MDAs exist, each with different criteria that vary most for the diagnosis of septate uterus. Recognizing the features that guide clinical management is essential for interpretation. Identification of an MDA should prompt evaluation for associated urinary tract anomalies. In patients with infertility who seek to use assisted reproductive technologies such as intrauterine insemination, recognition of MDAs may have an affect on reproductive success, particularly in patients who have an incomplete and clinically occult septum that divides the cervix. Two-dimensional US is the first-line modality for evaluating the uterus and adnexa. Three-dimensional (3D) US or MRI may help to visualize the external uterine fundal contour and internal indentation of the endometrial cavity, which are two morphologic characteristics that are keys to the diagnosis of congenital uterine anomalies. Hysterosalpingo contrast-enhanced US may be performed in conjunction with 3D US to evaluate uterine morphologic characteristics, the endometrial cavity, and tubal patency in a single examination. MRI helps to characterize rudimentary uteri in patients with müllerian hypoplasia and allows assessment for ectopic ureters, abnormally positioned ovaries, or associated deep infiltrative endometriosis. Online supplemental material is available for this article. ©RSNA, 2021.
Subject(s)
Mullerian Ducts , Urogenital Abnormalities , Cervix Uteri/diagnostic imaging , Female , Fertility , Humans , Mullerian Ducts/diagnostic imaging , Pregnancy , Urogenital Abnormalities/diagnostic imaging , Uterus/diagnostic imagingABSTRACT
IMPORTANCE: The presence of pelvic nodal metastases at radical prostatectomy is associated with biochemical recurrence after prostatectomy. OBJECTIVE: To assess the accuracy of prostate-specific membrane antigen (PSMA) 68Ga-PSMA-11 positron emission tomographic (PET) imaging for the detection of pelvic nodal metastases compared with histopathology at time of radical prostatectomy and pelvic lymph node dissection. DESIGN, SETTING, AND PARTICIPANTS: This investigator-initiated prospective multicenter single-arm open-label phase 3 imaging trial of diagnostic efficacy enrolled 764 patients with intermediate- to high-risk prostate cancer considered for prostatectomy at University of California, San Francisco and University of California, Los Angeles from December 2015 to December 2019. Data analysis took place from October 2018 to July 2021. INTERVENTIONS: Imaging scan with 3 to 7 mCi of 68Ga-PSMA-11 PET. MAIN OUTCOMES AND MEASURES: The primary end point was the sensitivity and specificity for the detection pelvic lymph nodes compared with histopathology on a per-patient basis using nodal region correlation. Each scan was read centrally by 3 blinded independent central readers, and a majority rule was used for analysis. RESULTS: A total of 764 men (median [interquartile range] age, 69 [63-73] years) underwent 1 68Ga-PSMA-11 PET imaging scan for primary staging, and 277 of 764 (36%) subsequently underwent prostatectomy with lymph node dissection (efficacy analysis cohort). Based on pathology reports, 75 of 277 patients (27%) had pelvic nodal metastasis. Results of 68Ga-PSMA-11 PET were positive in 40 of 277 (14%), 2 of 277 (1%), and 7 of 277 (3%) of patients for pelvic nodal, extrapelvic nodal, and bone metastatic disease. Sensitivity, specificity, positive predictive value, and negative predictive value for pelvic nodal metastases were 0.40 (95% CI, 0.34-0.46), 0.95 (95% CI, 0.92-0.97), 0.75 (95% CI, 0.70-0.80), and 0.81 (95% CI, 0.76-0.85), respectively. Of the 764 patients, 487 (64%) did not undergo prostatectomy, of which 108 were lost to follow-up. Patients with follow-up instead underwent radiotherapy (262 of 379 [69%]), systemic therapy (82 of 379 [22%]), surveillance (16 of 379 [4%]), or other treatments (19 of 379 [5%]). CONCLUSIONS AND RELEVANCE: This phase 3 diagnostic efficacy trial found that in men with intermediate- to high-risk prostate cancer who underwent radical prostatectomy and lymph node dissection, the sensitivity and specificity of 68Ga-PSMA-11 PET were 0.40 and 0.95, respectively. This academic collaboration is the largest known to date and formed the foundation of a New Drug Application for 68Ga-PSMA-11. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03368547, NCT02611882, and NCT02919111.
Subject(s)
Prostate , Prostatic Neoplasms , Aged , Gallium Isotopes , Gallium Radioisotopes , Humans , Lymph Node Excision/methods , Lymph Nodes/pathology , Lymphatic Metastasis/diagnostic imaging , Lymphatic Metastasis/pathology , Male , Middle Aged , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography , Prospective Studies , Prostate/pathology , Prostatectomy/methods , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgeryABSTRACT
OBJECTIVES: The Pancreatitis Activity Scoring System (PASS) is an objective tool validated in acute pancreatitis but not in infected pancreatic necrosis (IPN). Our aim was to evaluate the role of PASS in IPN. METHODS: We performed a retrospective cohort study of IPN patients admitted to the University of California, San Francisco from January 2011 to March 2019. Daily PASS scores were calculated for each patient. Receiver operator characteristic analysis was used to define the optimal cutoff PASS score to predict outcomes. The primary and secondary outcomes were 72 hours postintervention multiorgan failure (MOF) and early readmission (within 30 days), respectively. RESULTS: One hundred and four patients underwent intervention (median age, 55 years). Thirty-five patients (33.6%) developed MOF postintervention. A 72-hour postintervention PASS greater than 250 was strongly associated with postintervention MOF (area under curve, 0.87; adjusted odds ratio, 26.83; 95% confidence interval, 6.37-112.86; P < 0.001). Discharge PASS greater than 150 was associated with 30-day readmission (area under curve, 0.82; adjusted odds ratio, 26.44; 95% confidence interval, 8.48-82.43; P < 0.001). CONCLUSIONS: The PASS score was associated with postintervention clinical outcomes and early readmission, suggesting it is a valid measure of disease activity in patients with IPN. Further prospective validation of PASS in IPN is needed.
Subject(s)
Pancreas/pathology , Pancreatitis, Acute Necrotizing/diagnosis , Pancreatitis, Acute Necrotizing/surgery , Severity of Illness Index , Adult , Female , Humans , Male , Middle Aged , Multiple Organ Failure/complications , Multiple Organ Failure/diagnosis , Outcome Assessment, Health Care , Pancreas/diagnostic imaging , Pancreatitis, Acute Necrotizing/complications , Prognosis , Retrospective Studies , Sensitivity and Specificity , Tomography, X-Ray Computed/methodsABSTRACT
OBJECTIVES/HYPOTHESIS: To assess the accuracy and utility of positron emission tomography/computed tomography (PET/CT) compared with magnetic resonance imaging (MRI) for detecting head and neck cancer (HNC) recurrence after microvascular reconstructive surgery. STUDY DESIGN: Retrospective cohort study. METHODS: Analysis of HNC patients who underwent microvascular reconstruction at a single, tertiary academic center following ablative surgery from 1998 to 2015. Forty-six patients aged 61.4 ± 15.8 years with both PET/CT and MRI examinations were identified. Two radiologists were blinded and interpreted each imaging study. Recurrence certainty scores were determined via continuous (0-100) and Likert ("Likely" to "Unlikely") scales, with larger values indicating a higher likelihood of recurrence. Pathologic confirmation of recurrence was confirmed in 23 patients (50%). RESULTS: Among those with primary site recurrences, mean recurrence certainty was significantly higher with PET/CT versus MRI on the continuous scale (63.9 vs. 44.4, P = .006). A receiver operating characteristic analysis for predicting primary site recurrence demonstrated a significantly larger area under the curve of 0.79 for PET/CT compared to 0.64 for MRI (P = .044). Categorization of "Likely" primary site recurrence on PET/CT, versus MRI, had higher sensitivity (0.63 vs. 0.40), but lower specificity (0.90 vs. 1.0). MRI demonstrated higher sensitivity (1.0 vs. 0.78) at detecting regional site recurrences. CONCLUSION: PET/CT demonstrates greater sensitivity than MRI as a surveillance tool for primary site recurrence following microvascular reconstruction where clinical evaluation is hindered by anatomical distortion. Therefore, PET/CT should be pursued as first-line imaging, with MRI utilized for confirmation of positive imaging findings at the primary site. LEVEL OF EVIDENCE: 2 Laryngoscope, 131:2713-2718, 2021.
Subject(s)
Head and Neck Neoplasms/surgery , Neoplasm Recurrence, Local/diagnosis , Positron Emission Tomography Computed Tomography/statistics & numerical data , Aged , Female , Fluorodeoxyglucose F18/administration & dosage , Head and Neck Neoplasms/diagnosis , Humans , Magnetic Resonance Imaging , Male , Microsurgery , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals/administration & dosage , Retrospective StudiesABSTRACT
BACKGROUND/AIM: The majority of colorectal cancer (CRC) cases, which are microsatellite stable (MSS) and do not harbor mismatch repair deficiency/microsatellite instability, are resistant to immunotherapy. Identification of patients with exceptional responses in MSS CRC and predictive biomarkers is an unmet need that needs to be addressed. CASE REPORT: We report three cases of MSS CRC with durable clinical benefit from immunotherapy with anti-PD-1 checkpoint inhibitors. Two cases bear a POLE P286R mutation, which has been associated with lack of immunotherapy response in MSS CRC. Two cases bear alterations in Ataxia-Telangiectasia Mutated (ATM) which may contribute to observed responses, including interaction with a co-administered intratumoral stimulator of interferon genes (STING) pathway agonist in one patient. CONCLUSION: Novel DNA damage repair alterations, including mutations in ATM, can provide insight into additional mechanisms by which genomic alterations can sensitize MSS CRC to diverse immunotherapies.