CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma.

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity.

BACKGROUND AND AIMS: Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo-like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC. APPROACH AND RESULTS: An orally available PLK4 inhibitor, CFI-400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI-400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41-stimulator of interferon genes-interferon regulatory factor 3/7-NF-κß cytosolic DNA sensing pathway, thereby driving the transcription of senescence-associated secretory phenotypes, which recruit immune cells. CFI-400945 was evaluated in liver-specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor-infiltrated immune cells were analyzed. CFI-400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4-positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI-400945 with anti-programmed death-1 showed a tendency to improve HCC survival. CONCLUSIONS: We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late-stage mouse HCC.

Longitudinal evaluation of five nasopharyngeal carcinoma animal models on the microPET/MR platform.

PURPOSE: We longitudinally evaluated the tumour growth and metabolic activity of three nasopharyngeal carcinoma (NPC) cell line models (C666-1, C17 and NPC43) and two xenograft models (Xeno76 and Xeno23) using a micropositron emission tomography and magnetic resonance (microPET/MR). With a better understanding of the interplay between tumour growth and metabolic characteristics of these NPC models, we aim to provide insights for the selection of appropriate NPC cell line/xenograft models to assist novel drug discovery and evaluation. METHODS: Mice were imaged by 18F-deoxyglucose ([18F]FDG) microPET/MR twice a week for consecutive 3-7 weeks. [18F]FDG uptake was quantified by standardized uptake value (SUV) and presented as SUVmean tumour-to-liver ratio (SUVRmean). Longitudinal tumour growth patterns and metabolic patterns were recorded. SUVRmean and histological characteristics were compared across the five NPC models. Cisplatin was administrated to one selected optimal tumour model, C17, to evaluate our imaging platform. RESULTS: We found variable tumour growth and metabolic patterns across different NPC tumour types. C17 has an optimal growth rate and higher tumour metabolic activity compared with C666-1. C666-1 has a fast growth rate but is low in SUVRmean at endpoint due to necrosis as confirmed by H&E. NPC43 and Xeno76 have relatively slow growth rates and are low in SUVRmean, due to severe necrosis. Xeno23 has the slowest growth rate, and a relative high SUVRmean. Cisplatin showed the expected therapeutic effect in the C17 model in marked reduction of tumour size and metabolism. CONCLUSION: Our study establishes an imaging platform that characterizes the growth and metabolic patterns of different NPC models, and the platform is well able to demonstrate drug treatment outcome supporting its use in novel drug discovery and evaluation for NPC.

Using Occlusion-Based Saliency Maps to Explain an Artificial Intelligence Tool in Lung Cancer Screening: Agreement Between Radiologists, Labels, and Visual Prompts.

Occlusion-based saliency maps (OBSMs) are one of the approaches for interpreting decision-making process of an artificial intelligence (AI) system. This study explores the agreement among text responses from a cohort of radiologists to describe diagnostically relevant areas on low-dose CT (LDCT) images. It also explores if radiologists' descriptions of cases misclassified by the AI provide a rationale for ruling out the AI's output. The OBSM indicating the importance of different pixels on the final decision made by an AI were generated for 10 benign cases (3 misclassified by the AI tool as malignant) and 10 malignant cases (2 misclassified by the AI tool as benign). Thirty-six radiologists were asked to use radiological vocabulary, typical to reporting LDCT scans, to describe the mapped regions of interest (ROI). The radiologists' annotations were then grouped by using a clustering-based technique. Topics were extracted from the annotations and for each ROI, a percentage of annotations containing each topic were found. Radiologists annotated 17 and 24 unique ROIs on benign and malignant cases, respectively. Agreement on the main label (e.g., "vessel," "nodule") by radiologists was only seen in only in 12% of all areas (5/41 ROI). Topic analyses identified six descriptors which are commonly associated with a lower malignancy likelihood. Eight common topics related to a higher malignancy likelihood were also determined. Occlusion-based saliency maps were used to explain an AI decision-making process to radiologists, who in turn have provided insight into the level of agreement between the AI's decision and radiological lexicon.

Medical imaging and nuclear medicine: a Lancet Oncology Commission.

The diagnosis and treatment of patients with cancer requires access to imaging to ensure accurate management decisions and optimal outcomes. Our global assessment of imaging and nuclear medicine resources identified substantial shortages in equipment and workforce, particularly in low-income and middle-income countries (LMICs). A microsimulation model of 11 cancers showed that the scale-up of imaging would avert 3·2% (2·46 million) of all 76·0 million deaths caused by the modelled cancers worldwide between 2020 and 2030, saving 54·92 million life-years. A comprehensive scale-up of imaging, treatment, and care quality would avert 9·55 million (12·5%) of all cancer deaths caused by the modelled cancers worldwide, saving 232·30 million life-years. Scale-up of imaging would cost US$6·84 billion in 2020-30 but yield lifetime productivity gains of $1·23 trillion worldwide, a net return of $179·19 per $1 invested. Combining the scale-up of imaging, treatment, and quality of care would provide a net benefit of $2·66 trillion and a net return of $12·43 per $1 invested. With the use of a conservative approach regarding human capital, the scale-up of imaging alone would provide a net benefit of $209·46 billion and net return of $31·61 per $1 invested. With comprehensive scale-up, the worldwide net benefit using the human capital approach is $340·42 billion and the return per dollar invested is $2·46. These improved health and economic outcomes hold true across all geographical regions. We propose actions and investments that would enhance access to imaging equipment, workforce capacity, digital technology, radiopharmaceuticals, and research and training programmes in LMICs, to produce massive health and economic benefits and reduce the burden of cancer globally.

CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis-Driven Hepatocarcinogenesis via ERK-Dependent PKM2 Nuclear Relocalization and Activation.

BACKGROUND AND AIMS: Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain-of-function and loss-of-function in vitro studies in patient-derived organoid and cell cultures as well as in vivo positron emission tomography-magnetic resonance imaging animal models, we showed that protein arginine N-methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. APPROACH AND RESULTS: We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal-regulated kinase (ERK)-mediated PKM2 translocation into the nucleus. This altered PRMT6-ERK-PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1-silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2-deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. CONCLUSIONS: Our findings indicate that the PRMT6-ERK-PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.

Association between MRI histogram features and treatment response in locally advanced cervical cancer treated by chemoradiotherapy.

OBJECTIVE: To examine the associations of histogram features of T2-weighted (T2W) images and apparent diffusion coefficient (ADC) with treatment response in locally advanced cervical cancer (LACC) following concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Fifty-eight patients who underwent a 4-week CCRT regimen with MRI prior to treatment (pre-CCRT) and after treatment (post-CCRT) were retrospectively analysed. Histogram features were calculated from volumes of interest (VOIs) from one radiologist on T2W images and ADC maps. VOIs from two radiologists were used to assess observer repeatability in delineation and feature values at both time-points with the Dice similarity coefficient (DSC) and intraclass correlation coefficient (ICC). Treatment response was defined as a 90% reduction in tumour volume. Paired Mann-Whitney U tests were used to determine if features changed significantly between examinations. Two-sample Mann-Whitney U tests were used to identify features that were significantly different between response groups. Receiver operating characteristic (ROC) analysis was done on significantly different MRI features between treatment response groups. RESULTS: Pre-CCRT delineation and feature repeatability were generally good (DSC > 0.700; ICC > 0.750). Post-CCRT repeatability was low (DSC < 0.700; ICC < 0.750), but ADC mean and percentiles retained good ICC scores. All features, except for T2WKurtosis, significantly changed between examinations. Post-CCRT ADC50 was the only feature that demonstrated both good observer variability and significant differences between treatment response groups (p = 0.036) and had an AUC of 0.701 with a cut-off of 1.357 × 10-6 mm2/s. CONCLUSION: ADC and T2W histogram features could be used to track changes in LACC tumours undergoing CCRT. Post-CCRT ADC50 was associated with treatment response with good observer repeatability. KEY POINTS: • Pre-treatment tumour delineation and histogram feature values had good observer repeatability, while these were less repeatable at post-treatment. • MRI histogram analysis could be used to track changes in the tumour as it undergoes concurrent chemoradiotherapy. • Post-treatment median ADC was associated with treatment response and had good repeatability.

Primary cardiac lymphoma: the management and outcome of a single-centre cohort of 22 patients.

BACKGROUND: The incidence of primary cardiac lymphoma (PCL) is increasing, but the optimal management approach remains unclear. We assessed the clinical characteristics of a single-centre cohort with the goal of determining the optimal management approach. The treatment outcomes and prognostic factors are reported. MATERIAL AND METHODS: All PCL patients were diagnosed via biopsy guided by whole-body imaging (positron emission tomography/computed tomography [PET/CT] and/or contrast-enhanced CT]. Curative therapy involved either surgery or prephase steroids followed by definitive immunochemotherapy, depending on the histological type. The primary outcomes were overall survival (OS) and progression-free survival (PFS); the secondary outcome was the treatment response. RESULTS: Twenty-two PCL patients (14 males, 8 females; age: 59.5 ± 14.7 years [mean ± S.D.]) were histologically confirmed to have diffuse large B-cell lymphoma (DLBCL; n = 17 [77.3%]), fibrin-associated DLBCL (FA-DLBCL) (n = 4 [18.2%]) and Burkitt lymphoma (n = 1 [4.5%]). Seven patients underwent cardiotomy (three for biopsy, four with curative intent). The median and longest follow-up periods were 16.3 and 180.0 months, respectively. The 16 patients who received curative therapy (complete response [CR], n = 15 [93.8%]; partial response [PR], n = 1 [6.2%]) showed better survival than those who did not (5-year OS: 83.0 ± 11.3% vs. 0%; hazard ratio [HR]: 0.025[95% confidence interval, CI: 0.003-0.187], p < 0.001); 5-year PFS: 78.7 ± 11.0% vs. 0%, HR= 0.010[0.001-0.093], p < 0.001). The left ventricular ejection fractions (LVEF) before and after definitive treatment was 63.6 ± 2.4% and 64.6 ± 4.5%, respectively (p = 0.275, power = 0.318). Extrapericardial lesions were associated with poorer survival (5-year OS: 40.0 ± 29.7% vs. 100%, p = 0.027; 5-year PFS:40.0 ± 21.9% vs. 100%, p = 0.010). CONCLUSIONS: Whole-body imaging is essential for diagnosis and prognosis. Curative therapy provided reasonable outcomes and survival; extrapericardial lesions were associated with a poorer treatment response.

Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease. METHOD: Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines. RESULTS: The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis. CONCLUSIONS: We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.

Low-dose pembrolizumab and nivolumab were efficacious and safe in relapsed and refractory classical Hodgkin lymphoma: Experience in a resource-constrained setting.

The efficacy and safety of low-dose anti-PD1 antibodies in relapsed/refractory classical Hodgkin lymphoma (cHL) require confirmation. Pembrolizumab (100 mg every 3 weeks, Q3W) or nivolumab (40 mg Q2W) were administered to patients with relapsed/refractory cHL. In the pembrolizumab cohort (N = 11), who had failed a median of three (1-6) therapies (brentuximab vedotin [BV]: 91%; autologous hematopoietic stem cell transplantation [auto-HSCT]: 18%), the overall response rate (ORR) by positron emission tomography-computed tomography was 100% (metabolic complete response [mCR]: 73%; partial response [PR]: 27%). Median cumulative dose for achieving best response was 400 (300-800) mg. Median progression-free survival (PFS) was 35 months. Median overall survival (OS) was not reached. Adverse events (AEs) of grade 1-2 were observed in three patients. In the nivolumab cohort (N = 6), who had failed a median of three (2-6) therapies (BV: 50%; auto-HSCT: 17%; allogeneic HSCT: 34%), the ORR was 100% (mCR: 67%; PR: 17%; indeterminate response: 17%). Median cumulative dose for achieving best response was 160 (160-360) mg. Median PFS was 33 months. Median OS was not reached. AEs of grade 1-2 were observed in four patients, two of whom had pre-existing autoimmune conditions. Five patients with Epstein-Barr virus (EBV) positive Reed-Sternberg cells underwent monitoring of plasma EBV DNA, which became negative in four mCR patients but remained positive in one PR patient who died ultimately from refractory lymphoma. Low-dose pembrolizumab and nivolumab were highly efficacious and safe in relapsed/refractory cHL. These observations have significant financial implications in resource-constrained settings.

Molecular Imaging of Peritoneal Carcinomatosis in Ovarian Carcinoma.

OBJECTIVE. This article discusses the emerging roles of 18F-FDG PET/CT and DWI in the assessment of peritoneal carcinomatosis in ovarian carcinoma from diagnostic accuracy to disease prognostication with gross pathologic correlation. CONCLUSION. PET/CT and DWI have incremental clinical values over conventional modalities with high predictive values of incomplete cytoreduction in ovarian carcinoma. The respective quantitative metrics offer evaluation of tumor burden with prognostic value in ovarian carcinoma.

The addition of pretreatment plasma Epstein-Barr virus DNA into the eighth edition of nasopharyngeal cancer TNM stage classification.

The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity-modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein-Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five-year progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA-I (T1-T4 N0-N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA-II (T1-T4 N0-N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA-III (T1-T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA-IVA (T3-T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1-T2 N0-N2; II: T3-T4 N0-N2 or T1-T2 N3 and III: T3-T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA-based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups.

Negative plasma Epstein-Barr virus DNA nasopharyngeal carcinoma in an endemic region and its influence on liquid biopsy screening programmes.

BACKGROUND: Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) in endemic regions may have undetectable plasma EBV DNA. METHODS: We prospectively recruited 518 patients with non-metastatic NPC and measured their pre-treatment plasma EBV DNA. The stage distribution and prognosis between pre-treatment plasma EBV DNA-negative (0-20 copies/ml) and EBV DNA-positive (>20 copies/ml) patients following radical treatment were compared. RESULTS: Seventy-eight patients (15.1%) were plasma EBV DNA-negative, and 62 in this subset (12.0%) had 0 copy/ml. Only 23/78 (29.5%) plasma EBV DNA-negative patients with advanced NPC (stage III-IVA) had strong EBV encoded RNA (EBER) positivity (score 3) in their tumours compared to 342/440 (77.7%) EBV DNA-positive patients of the same stages (p < 0.001). Though EBV DNA-negative patients had more early-stage disease (p < 0.001) and smaller volumes of the primary tumour and the positive neck nodes (p < 0.001), they had similar 5-year overall survival and cancer-specific survival to those EBV DNA-positive counterparts by stage. Similar results were also seen when plasma EBV DNA cut-off was set at 0 copy/ml. CONCLUSIONS: Patients with low-volume NPC may not be identified by plasma/serum tumour markers and caution should be taken in its utility as a screening tool for NPC even in endemic regions. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02476669.

PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase.

Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3+CD4+ and CD3+CD8+ T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.

Frequency, location, and association with dental pathology of mucous retention cysts in the maxillary sinus. A radiographic study using cone beam computed tomography (CBCT).

OBJECTIVES: The purpose of the present study was to evaluate the frequency, locations, and dimensions of mucous retention cysts of the maxillary sinus and analyze potential associated dental pathology. MATERIALS AND METHODS: A total of 156 cone beam computed tomography (CBCT) scans were included in the analysis, resulting in an evaluation of 310 maxillary sinuses. The presence of mucous retention cysts (MRC) manifesting as dome-shaped radiopacities in the sinus was diagnosed. Their locations were recorded, and dimensions (mm) were measured in coronal and sagittal/axial slices. The patients were grouped into (a) patients/sinuses with MRCs (test), and (b) patients/sinuses with healthy or any other changes (control) for further comparison and evaluation. RESULTS: There were 40 sinuses (12.9%) with a presence of a total of 56 MRCs. The mean age of involved patients was 29.0 years. The analysis showed that gender, age, sinus side, status of dentition, endodontic status, and periodontal status did not have a significant influence on the presence of MRCs when compared between test and control groups. Age and endodontic status exhibited a significant association with cyst location. CONCLUSIONS: Most of the sinuses analyzed (79.5%) did not present any MRC, and only 28.6% of the cysts diagnosed were found on the floor of the maxillary sinus. The mean dimension of the MRCs measured 6.28 ± 2.93 mm. No influencing factors on the presence or absence of MRCs were found in the present study. CLINICAL RELEVANCE: Most MRCs were not located on the floor of maxillary sinus. Future studies should assess their impact on surgical interventions in the sinus.

Intravoxel incoherent motion MRI assessment of chemoradiation-induced pelvic bone marrow changes in cervical cancer and correlation with hematological toxicity.

PURPOSE: To investigate bone marrow changes after chemoradiation (CRT) using intravoxel incoherent motion magnetic resonance imaging (IVIM-MRI) and correlate imaging changes with hematological toxicity (HT) in patients with locally advanced cervical cancer. MATERIALS AND METHODS: Thirty-nine patients with newly diagnosed cervical cancer were prospectively recruited for two sequential 3.0T IVIM-MRI studies: before treatment (MRI-1) and 3-4 weeks after standardized CRT (MRI-2). The irradiated pelvic bone marrow was outlined as the regions of interest to derive the true diffusion coefficient (D) and perfusion fraction (f) based on a biexponential model. The apparent coefficient diffusion (ADC) was derived using the monoexponential model. Changes in these parameters between MRI-1 and MRI-2 were calculated as ΔD, Δf, and ΔADC. HT was defined accordingly to NCI-CTCAE (v. 4.03) of grade 3 and above. Statistical analysis was performed using Mann-Whitney U-test. RESULTS: The median age of patients was 54 years old (range 27-83 years old); 14 patients suffered from HT. Early bone marrow changes (3-4 weeks) of ΔD showed a significant difference between HT and non-HT groups (6.4 ± 19.7% vs. -6.4 ± 19.4%, respectively, P = 0.041). However, no significant changes were noted in Δf (3.7 ± 13.3% vs. 1.5 ± 12.5% respectively, P = 0. 592) and ΔADC (5.5 ± 26.3% vs. -3.3 ± 27.0% respectively, P = 0.303) between the HT and non-HT groups. Δf increased insignificantly for both groups. CONCLUSION: ΔD was the only significant parameter to differentiate early cellular environment changes in bone marrow after CRT, suggestive that ΔD was more sensitive than Δf and ΔADC to reflect the underlying microenvironment injury. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1491-1498.

Low-dose pembrolizumab for relapsed/refractory Hodgkin lymphoma: high efficacy with minimal toxicity.

Five patients with refractory/relapsed classical Hodgkin lymphoma (cHL), four having failed multiple lines of chemotherapy and brentuximab vedotin, were treated with low-dose pembrolizumab (median dose 100 mg, range: 100-200 mg, every 3 weeks). Complete response (CR) was achieved in four patients (80%), after a median cumulative dose of merely 495 (300-800) milligrams. Three CR patients have continued to receive pembrolizumab for a median of 16 (14-25) cycles, remaining in CR for a median of 18 (9-18) months. One CR patient underwent autologous hematopoietic stem cell transplantation and has remained in CR for 9 months. Partial response (PR) was achieved in one patient (20%), after a cumulative dose of 400 mg. The overall response rate was therefore 100% (CR: 80%; PR: 20%). Toxicity was virtually absent, with only grade 1 diarrhea and eczema each observed in one patient. Low-dose pembrolizumab was highly efficacious, achieving responses with minimal toxicity and at much lower costs.

Successful Treatment of a Pararenal Pregnancy Using High-Dose Methotrexate Regimen: A Case Report.

Background: Upper abdominal pregnancy is rare. Most patients present with hemoperitoneum, requiring emergency laparotomy. Case: A 32-year-old woman presented with acute abdominal pain and an elevated beta-human chorionic gonadotropin (ß-hCG) level. Ultrasound, computerized tomography (CT) scans, and laparoscopy failed to locate the source of elevated hCG. Subsequent positron emission tomography (PET)-CT demonstrated a cystic mass in the left pararenal region with no increased uptake. Repeated ultrasound scan revealed a live fetus implanted laterally to the abdominal aorta. After failing to respond to methotrexate at the usual dosage, a regimen used in gestational trophoblastic neoplasia was given. The pregnancy underwent miscarriage afterwards, and the hCG level gradually returned to normal. Conclusion: The site of an ectopic pregnancy should be sought thoroughly to avoid missing an abdominal pregnancy and hence disastrous hemoperitoneum. While medical therapy with high-dose methotrexate is not a standard treatment, it can be considered after failing the traditional therapy, provided that there is adequate treatment monitoring and expertise in handling the side effects of the medication.

Hepatocellular carcinoma: surveillance CT schedule after hepatectomy based on risk stratification.

PURPOSE: To evaluate alternative schedules for surveillance computed tomography (CT) for patients who underwent hepatectomy for hepatocellular carcinoma ( HCC hepatocellular carcinoma ) and to demonstrate an appropriate schedule on the basis of stratification for risk of recurrence. MATERIALS AND METHODS: CT and pathologic reports for consecutive patients with HCC hepatocellular carcinoma who underwent hepatectomy at one institution were evaluated with institutional review board approval. Univariate and multivariate analyses were performed to identify risk factors for recurrence. Patients were categorized into risk groups on the basis of classification and regression tree analysis. Average recurrence detection rates ( RDR recurrence detection rate s) between consecutive CT scans were calculated for existing and alternative surveillance schedules for each risk group, and the difference in RDR recurrence detection rate was determined by using the Student t test. A P value of less than .05 was considered to indicate a significant difference. Expected delay in diagnosis was also computed for the alternative surveillance schedules for each risk group. RESULTS: Two hundred sixty patients (216 men; mean age, 56.0 years ± 22.5) underwent 2705 CT studies. Independent risk factors for recurrence were microvascular invasion (P = .001), cirrhosis (P = .007), and tumor multiplicity (P = .001). Three risk groups (low, intermediate, and high) were identified. For low- and intermediate-risk groups, average RDR recurrence detection rate was not significantly different in the first 2 years after hepatectomy when the interval was extended from 3 months (3.3% and 4.6%, respectively) to 4 months (4.3% [expected delay, 16 days] and 6.1% [expected delay, 18 days], respectively) or for the subsequent 3 years when the interval was extended from 6 months (1.3% and 3.5%, respectively) to 12 months (2.5% [expected delay, 72 days] and 7.0% [expected delay, 103 days], respectively). This alternative schedule included five (35.7%) fewer CT scans than the 14 in the original schedule, and a reduction in radiation dose and cost during the 5-year follow-up period. CONCLUSION: Posthepatectomy surveillance CT schedules may be tailored and optimized according to stratification by risk of recurrence to reduce the frequency of CT scans without compromising surveillance benefits.

Relationship between intravoxel incoherent motion diffusion-weighted MRI and dynamic contrast-enhanced MRI in tissue perfusion of cervical cancers.

PURPOSE: To investigate the relationship between intravoxel incoherent motion (IVIM) diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI (DCE-MRI) in cervical cancer perfusion. MATERIALS AND METHODS: Prospective newly diagnosed cervical cancer patients underwent diffusion-weighted MRI (13 b-values: 1-1000 s/mm(2) ) and DCE-MRI. The IVIM perfusion parameters, perfusion fraction (f), pseudodiffusion coefficient (D*), and flow-related parameter (fD*), were derived from a biexponential decay model. DCE-MRI was analyzed with a pharmacokinetic model and signal-time curve to derive the amplitude factor (A), estimated volume transfer constant between blood plasma, and the extravascular extracellular space (est K(trans) ), maximum relative enhancement (MaxRE), and area under the signal-time curve (AUC). Spearman's rank correlation coefficient (r) evaluated the correlative relationships. RESULTS: The f = 13.51% ± 1.76%, D* = 71.72 ± 7.55 × 10(-3) mm(2) /s, fD* = 9.64 ± 1.28 × 10(-3) mm(2) /s, A = 1.41 ± 0.43, est K(trans) = 0.19 ± 0.06 s(-1) , MaxRE of 120.02 ± 21.07%, and AUC 212,393 ± 54,423 was found in 25 cervical cancer patients. Statistically significant positive correlations were found between fD* and est K(trans) (r = 0.42, P = 0.038), fD* and A (r = 0.50, P = 0.011), fD* and MaxRE (r = 0.52, P = 0.008), f and AUC (r = 0.58, P = 0.003). CONCLUSION: The IVIM perfusion parameters showed moderate to good correlations with quantitative and semiquantitative perfusion parameters derived from DCE-MRI in cervical cancer.