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As one of the most ubiquitous diagnostic imaging tests in medical practice, chest radiography requires timely reporting of potential findings and diagnosis of diseases in the images. Automated, fast, and reliable detection of diseases based on chest radiography is a critical step in radiology workflow. In this work, we developed and evaluated various deep convolutional neural networks (CNN) for differentiating between normal and abnormal frontal chest radiographs, in order to help alert radiologists and clinicians of potential abnormal findings as a means of work list triaging and reporting prioritization. A CNN-based model achieved an AUC of 0.9824 ± 0.0043 (with an accuracy of 94.64 ± 0.45%, a sensitivity of 96.50 ± 0.36% and a specificity of 92.86 ± 0.48%) for normal versus abnormal chest radiograph classification. The CNN model obtained an AUC of 0.9804 ± 0.0032 (with an accuracy of 94.71 ± 0.32%, a sensitivity of 92.20 ± 0.34% and a specificity of 96.34 ± 0.31%) for normal versus lung opacity classification. Classification performance on the external dataset showed that the CNN model is likely to be highly generalizable, with an AUC of 0.9444 ± 0.0029. The CNN model pre-trained on cohorts of adult patients and fine-tuned on pediatric patients achieved an AUC of 0.9851 ± 0.0046 for normal versus pneumonia classification. Pretraining with natural images demonstrates benefit for a moderate-sized training image set of about 8500 images. The remarkable performance in diagnostic accuracy observed in this study shows that deep CNNs can accurately and effectively differentiate normal and abnormal chest radiographs, thereby providing potential benefits to radiology workflow and patient care.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes ( POLA1 , POLE , GINS3 ) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation. ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.

Background Immunostimulatory effects of PARP inhibitors could increase sensitivity to immune checkpoint inhibitors. The previous Phase II trial (MEDIOLA) reported clinical benefits of durvalumab and olaparib (D + O) in patients with germline BRCA‐mutated (gBRCAm) HER2‐negative metastatic breast cancer. Yet, the clinical activity of D + O in germline BRCA wild‐type (gBRCAwt) triple‐negative breast cancer (TNBC) remains unknown. Methods This single‐arm Phase II study tested D + O in patients with metastatic TNBC. The primary objective was overall response rate (ORR). Secondary objectives were safety, disease control rate (DCR), progression‐free survival (PFS) and overall survival (OS). Based on gBRCA status, patients were assigned to either gBRCAwt or gBRCAm cohort and were treated with D (1500 mg iv q4w) and O (300 mg twice a day orally). Pretreatment fresh tissues and serial blood samples were collected for correlative studies. Results Fifteen patients (12 gBRCAwt and 3 gBRCAm) were enrolled. gBRCAm and gBRCAwt cohorts are reported as a combined dataset because of small sample size due to COVID‐19 and slow accrual. The median number of prior therapies was three (range 0–8). Among 14 RECIST‐evaluable patients (11 gBRCAwt and 3 gBRCAm), ORR was 28.6% (3 gBRCAm and 1 gBRCAwt). DCR was 64.3% (3 gBRCAm and 6 gBRCAwt). The median PFS and OS were 3.6 months (95% confidence interval [CI]: 1.8–5.7) and 10.7 months (95% CI: 5.9–38.9), respectively. There is one gBRCAm patient with ongoing durable PR (67.4+ months). There was no new safety concern. CD83 expression on Types 1 and 2 conventional dendritic cells in blood at baseline was low in the patients with PFS ≥ 4 months compared to those with PFS < 4 months. Conclusion Our study demonstrated modest clinical benefits of D + O with ORR of 28.6% in subsets of heavily pretreated TNBC. Further detailed classification of DCs to understand the predictive role of DCs and prospective validation in a large cohort is required. Trial Registration ClinicalTrials.gov identifier: NCT02484404

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.ConclusionIn patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained.Trial registration numberNCT04166383.

Background Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti‐PD1/PD‐L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti‐PD‐L1) and tremelimumab (anti‐CTLA‐4), with and without an interventional radiology (IR) procedure in advanced BTC. Methods Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6‐month progression‐free survival (PFS). Results Twenty‐three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3–3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9–4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5–6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9–40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1–2. Conclusion Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC. The purpose of this study was to explore the efficacy and safety of two ICIs, durvalumab and tremelimumab, with and without an interventional radiology (IR) procedure in patients with advanced BTC. Durva/Treme + IR showed no difference in efficacy compared with Durva/Treme alone, but the safety profile of both cohorts was manageable. Larger studies are needed to fully characterize efficacy of Durva/Treme with or without IR in advanced BTCs.

Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data. One hundred fifty-eight women with CDH1 variants were evaluated, of whom 48 (30%) also had an ILC diagnosis. The median age at CDH1 diagnosis was 45 years [interquartile range, IQR 34–57 years] whereas the median age at diagnosis of CDH1 with concomitant ILC (HLBC) was 53 [IQR 45–62] years. Among women with HLBC, 83% (40/48) were identified with CDH1 mutation after diagnosis of ILC. Among 76 women (48%, 76/158) undergoing surveillance for ILC with breast magnetic resonance imaging (MRI), 29% (22/76) had an abnormal MRI result with available biopsy data for comparison. MRI detected ILC in 7 out of 8 biopsy-confirmed cases, corresponding with high sensitivity (88%), specificity (75%), and negative predictive value (98%); however, false-positive and false-discovery rates were elevated also (25% and 68%, respectively). HLBC was most frequently diagnosed at age 40–49 years (44%, 21/48), significantly younger than the common age of diagnosis of ILC in SEER general population data (most frequent age range 60–69 years, 28%; p < 0.001). HLBC tumors were smaller than SEER-documented ILC tumors (median 1.40 vs. 2.00 cm; p = 0.002) and had a higher incidence of background lobular carcinoma in situ (88% vs. 1%; p < 0.001) as well as progesterone receptor positivity (95% vs. 81%, p = 0.032). These findings suggest that HLBC is often detected via conventional screening methods as an early-stage hormone receptor-positive tumor, thus the clinical benefit of intensive screening with MRI may be limited to a subset of women with germline CDH1 variants.

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces immune response and disrupts neovascularization.1–4 Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and anti-tumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis is a phase II study of adult patients with histologically confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1x1013 viral particles was given intravenously two weeks prior to starting biweekly nivolumab 240mg and continued every 6 weeks. The combination was continued until disease progression or unacceptable toxicity. Primary endpoints were ORR and safety/tolerability. Secondary endpoints included mPFS and mOS. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, fourteen patients were enrolled with median age 50.5y (40–75), and 14% were female. Of the ten evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, two patients had stable disease. After median follow-up of 5.5 months (m), mOS was 5.5m (95%CI: 2.3–10.8m), and mPFS was 1.8m (95%CI: 1.4–1.9 m) (figure 1). The most common grade 3–4 treatment-related adverse events were fever/chills, flu-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (25.7m). Immune analysis of PBMCs showed an increase of PD1highKi67highCD8+ T-cells and HLA-DRhigh T-cells after VB-111 priming dose (figure 2). Plasma cytokines IL-10 and TNFα increased after treatment with both drugs.ConclusionsIn patients with MSS CLM, VB-111 and nivolumab did not improve objective response rate or survival but was tolerated with minimal toxicities. While challenging to distinguish between anti-viral or anti-tumor, correlative studies demonstrated an antigen-specific immune response with activation and proliferation of CD8+ T-cells systemically; however, this was poorly sustained and immune infiltration was sparsely seen within on-treatment tumor biopsies[5]. With its transient immunogenicity and limited clinical efficacy, a single priming dose may not be the optimal strategy for viral-mediated therapies; rather, multiple sequential doses of viral vector and earlier administration of checkpoint inhibition may be required to elicit a stronger immune response to result in tumor killing.Abstract 585 Figure 1Kaplan-Meier survival analyses of progression-free survival (PFS) and overall survival (OS). All patients who received at least one dose of both study drugs were included (n=12); one patient was excluded due to disease progression prior to nivolumab initiation, and one patient was taken off protocol due to malignant bowel perforation with abdominal sepsis. Time-to-event started from date of enrollment until disease progression or death, respectively. After median potential follow-up of 22.9 months, median progression-free survival was 1.8 months (95% CI 1.4–1.9), and median overall survival was 5.5 months (95% CI 2.3–10.8). MSS mCRC = microsatellite stable metastatic colorectal cancer, PFS = progression- free survival, and OS = overall survival.Abstract 585 Figure 2Immune and T cell profiling of peripheral blood mononuclear cells (PBMC) after treatment with VB-111 and nivolumab. PBMCs were collected at baseline, after receiving VB-111 alone (C2D1), and after receiving both VB-111 and nivolumab (C4D1). A high-dimensional full-spectrum flow cytometry panel for immunophenotyping was performed to study different immune cell subsets and activation status. The stacked bar graphs show the frequency of distinct immune (top) and T cell (bottom) clusters across treatment by patient with their best radiographic response shown below. T cell cluster 5 represents proliferating T cells (PD1high Ki67highCD8+ T-cells), which in a conventional supervised analysis (not shown) demonstrated a statistically significant increase after VB-111 that decreased at next time point, two weeks later (n=9, p<0.05, Friedman test).

Cell-free DNA (cfDNA) sequence analysis to screen for fetal aneuploidy can incidentally detect maternal cancer. Additional data are needed to identify DNA-sequencing patterns and other biomarkers that can identify pregnant persons who are most likely to have cancer and to determine the best approach for follow-up. In this ongoing study we performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (i.e., the fetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories in North America. We used a uniform cancer-screening protocol including rapid whole-body magnetic resonance imaging (MRI), laboratory tests, and standardized cfDNA sequencing for research purposes with the use of a genomewide platform. The primary outcome was the presence of cancer in participants after the initial cancer-screening evaluation. Secondary analyses included test performance. Cancer was present in 52 of the 107 participants in the initial cohort (48.6%). The sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively. Physical examination and laboratory tests were of limited use in identifying participants with cancer. Research sequencing showed that 49 participants had a combination of copy-number gains and losses across multiple (≥3) chromosomes; cancer was present in 47 of the participants (95.9%) with this sequencing pattern. Sequencing patterns of cfDNA in which there were only chromosomal gains (multiple trisomies) or only chromosomal losses (one or more monosomies) were found in participants with nonmalignant conditions, such as fibroids. In this study, 48.6% of participants who received unusual or nonreportable clinical cfDNA-sequencing results had an occult cancer. Further study of DNA-sequencing patterns that are suggestive of occult cancer during prenatal screening is warranted. (Funded by the NIH Intramural Research Programs; ClinicalTrials.gov number, NCT04049604.).