Combination Treatment of Intratumoral Vidutolimod, Radiosurgery, Nivolumab, and Ipilimumab for Microsatellite Stable Colorectal Carcinoma With Liver Metastases.

INTRODUCTION: Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response. PATIENTS AND METHODS: In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy. RESULTS: A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL (P = .01), and 66 versus 40 pg/mL (P = .03), respectively. CONCLUSIONS: The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

Incidental pulmonary embolism in CT scans of oncological patients with metastatic disease undergoing clinical trials: frequency and linkage with onset of disease progression (PE-PD association).

OBJECTIVES: We aimed to analyze the association between the onsets of PE and of progressive disease (PD) in CT scans of oncological patients undergoing clinical trials. METHODS: We retrospectively searched our oncological clinical trials database (1/2012 - 6/2017). We retrieved patients who underwent protocol baseline and follow-up CT scans. RECIST 1.1 categories of response were calculated for each scan at interpretation. The entire dataset was searched for reports with incidental PE.For patients with incidental PE, we collected all the scans conducted up to and including the scan with PE. For each scan, we retrieved the recorded RECIST 1.1 category. We excluded patients with PE at baseline.The frequency of incidental PE in oncological clinical trial patients was calculated. For patients with incidental PE, we evaluated the association between PE and PD. RESULTS: During the study period, 1,070 patients underwent 3,818 CTs. The total number of follow-up months was 7,292 months. 18 patients developed incidental PE during follow-up. Thus, the frequency of incidental PE in oncological clinical trial patients was 3% per year of follow-up. Patients with incidental PE underwent 60 scans up to development of PE. Of 42 non-baseline scans, 6/6 (100%) PD showed PE, and 5/36 (13.9%) non-PD showed PE, making PE onset associated with PD onset (p < 0.001). CONCLUSION: In oncological clinical trials, the frequency of incidental PE is 3% per year of follow-up. The onset of incidental PE is linked to the onset of PD. ADVANCES IN KNOWLEDGE: Incidental PE is associated with the onset of disease progression. Radiologists interpret oncological scans should be aware of the association between PE and PD.

Metastasis Initiation Precedes Detection of Primary Cancer-Analysis of Metastasis Growth in vivo in a Colorectal Cancer Test Case.

Most cases of deaths from colorectal cancer (CRC) result from metastases, which are often still undetectable at disease detection time. Even so, in many cases, shedding is assumed to have taken place before that time. The dynamics of metastasis formation and growth are not well-established. This work aims to explore CRC lung metastasis growth rate and dynamics. We analyzed a test case of a metastatic CRC patient with four lung metastases, with data of four serial computed tomography (CT) scans measuring metastasis sizes while untreated. We fitted three mathematical growth models-exponential, logistic, and Gompertzian-to the CT measurements. For each metastasis, a best-fitted model was determined, tumor doubling time (TDT) was assessed, and metastasis inception time was extrapolated. Three of the metastases showed exponential growth, while the fourth showed logistic restraint of the growth. TDT was around 93 days. Predicted metastasis inception time was at least 4-5 years before the primary tumor diagnosis date, though they did not reach detectable sizes until at least 1 year after primary tumor resection. Our results support the exponential growth approximation for most of the metastases, at least for the clinically observed time period. Our analysis shows that metastases can be initiated before the primary tumor is detectable and implies that surgeries accelerate metastasis growth.

Low rate of spleen involvement in sporadic Burkitt lymphoma at staging on PET-CT.

BACKGROUND: Burkitt lymphoma is a highly aggressive B cell non-Hodgkin lymphoma. Cross-sectional imaging techniques that are used to detect liver and spleen involvement by lymphoma have high rates of false negative and false positive findings, and as such may reduce the accuracy of staging. PURPOSE: This retrospective study evaluated the use of FDG PET-CT in determining splenic involvement at staging, in a relatively large cohort of adult patients with the sporadic form of Burkitt lymphoma (SBL). PATIENTS AND METHODS: All adult patients who underwent FDG PET-CT for staging of SBL at one medical center during 2005-2014 were enrolled for this retrospective study. RESULTS: Data were analyzed of 20 patients, with median age 49 years; 17 were male. PET-CT revealed highly intense FDG uptake, mean SUV max 11.4 ± 7.49 (range 4.3-38) in various tissues. None of the 20 patients had either focal or diffuse increased uptake of FDG in the spleen parenchyma. In 2 patients, there were highly FDG-avid soft tissue masses adjacent to the spleen, both in the context of direct peritoneal disease extension. CONCLUSION: The spleen is rarely involved in SBL at the time of staging, according to PET-CT, except in cases with direct extension from adjacent peritoneal mass. The low rate of spleen involvement according to PET-CT may serve as a specific characteristic of SBL. Larger-scale clinical studies incorporating PET-CT scans in SBL are needed to confirm our observation.

Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.

CT Image-based Decision Support System for Categorization of Liver Metastases Into Primary Cancer Sites: Initial Results.

RATIONALE AND OBJECTIVES: This study aimed to provide decision support for the human expert, to categorize liver metastases into their primary cancer sites. Currently, once a liver metastasis is detected, the process of finding the primary site is challenging, time-consuming, and requires multiple examinations. The proposed system can support the human expert in localizing the search for the cancer source by prioritizing the examinations to probable cancer sites. MATERIALS AND METHODS: The suggested method is a learning-based approach, using computed tomography (CT) data as the input source. Each metastasis is circumscribed by a radiologist in portal phase and in non-contrast CT images. Visual features are computed from these images, combined into feature vectors, and classified using support vector machine classification. A variety of different features were explored and tested. A leave-one-out cross-validation technique was conducted for classification evaluation. The methods were developed on a set of 50 lesion cases taken from 29 patients. RESULTS: Experiments were conducted on a separate set of 142 lesion cases taken from 71 patients with four different primary sites. Multiclass categorization results (four classes) achieved low accuracy results. However, the proposed system was found to provide promising results of 83% and 99% for top-2 and top-3 classification tasks, respectively. Moreover, when compared to the experts' ability to distinguish the different metastases, the system shows improved results. CONCLUSIONS: Automated systems, such as the one proposed, show promising new results and demonstrate new capabilities that, in the future, will be able to provide decision and treatment support for radiologists and oncologists, toward more efficient detection and treatment of cancer.

The Role of Liver Segment-to-Spleen Volume Ratio in the Staging of Hepatic Fibrosis in Patients with Hepatitis C Virus Infection.

BACKGROUND: Accurate assessment of liver fibrosis is crucial for the management of patients with hepatitis C virus (HCV) infection. OBJECTIVES: To evaluate the performance of liver segment-to-spleen volume ratio in predicting the severity of liver fibrosis. METHODS: Sixty-four consecutive HCV patients were enrolled in this retrospective study. All patients underwent contrast-enhanced computed tomography (CT) and were divided into three groups based on their hepatic fibrosis stage evaluated by shear-wave elastography (SWE): non-advanced (F0-F1, n=29), advanced (F2, n=19) and severe fibrosis (F3-F4, n=16). Using semi-automated liver segmentation software, we calculated the following liver segments and spleen volumes for each participant: total liver volume (TLV), caudate lobe (CV), left lateral segment (LLV), left medial segment (LMV), right lobe (RV) and spleen (SV), a well as their ratios: CV/SV, RV/SV, LLV/SV, LMV/SV and TLV/SV. RESULTS: RV/SV was found to discriminate between patients with non-advanced and advanced fibrosis (P = 0.001), whereas SV, CV, RV, TLV/SV, LMV/SV and RV/SV discriminated between patients with advanced and severe fibrosis (P < 0.05). RV/SV ≤ 3.6 and RV ≤ 2.9 were identified as the best cutoff values to differentiate non-advanced from advanced fibrosis and advanced from severe fibrosis with sensitivities of 72.2% and 92.7%, specificities of 72.7% and 77.8%, and with an area under the receiver operating characteristic (ROC) curve of 0.797 and 0.847, respectively (P ≤ 0.002). CONCLUSIONS: RV/SV may be used for the assessment and monitoring of liver fibrosis in HCV patients prior to the administration of antiviral therapy, considering SWE as the reference method.

Association between Enlarged Axillary Lymph Nodes and Silicone Breast Implant Ruptures seen on Magnetic Resonance Imaging.

BACKGROUND: Silicone breast augmentation is a common cosmetic surgery. Previous case reports demonstrated lymphadenopathy in the presence of implant ruptures. OBJECTIVES: To investigate the association between enlarged axillary lymph nodes and silicone implant ruptures as seen on breast magnetic resonance imaging (MRI). METHODS: Two groups were derived retrospectively from breast MRI reports in our institution for the period December 2011-May 2014. A search of our hospital records for "silicone" and "lymph node" was performed (group A), and the relationship between the presence of enlarged nodes and ruptures was evaluated. The prevalence of ruptures in the presence of nodes was calculated and the association between MRI imaging features and ruptures evaluated. A search for "silicone" and "implant rupture" was performed (group B) and, as for group A, the relationship between the presence of ruptures and nodes was evaluated and the prevalence of enlarged nodes in the presence of ruptures calculated. RESULTS: Group A comprised 45 women with enlarged nodes. Intracapsular ruptures were associated with nodes (P = 0.005), while extracapsular ruptures showed a trend of association with nodes (P = 0.08). The prevalence of ruptures in the presence of nodes was 31.4%. Nodes associated with ruptures showed a strong silicone signal (P = 0.008) and absent enhancement (P = 0.005). Group B comprised 73 women with ruptures. Enlarged nodes were associated with both intra- and extracapsular ruptures (P < 0.001 and P = 0.002 respectively). The prevalence of nodes in the presence of ruptures was 22.2%. CONCLUSIONS: Enlarged axillary nodes were associated with ruptures in two groups of patients. This finding can guide clinical decisions when either enlarged nodes or ruptures are encountered in patients with silicone implants. The association between silicone lymphadenopathy and implant rupture raises concerns regarding the role of rupture in silicone-induced systemic disease.

RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients.

PURPOSE: The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC). METHODS: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death. RESULTS: Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%. CONCLUSIONS: The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785.

Perfusion-weighted imaging of peritumoral edema can aid in the differential diagnosis of glioblastoma mulltiforme versus brain metastasis.

BACKGROUND: MRI differentiation between metastases and high grade gliomas is a challenging task. Contrast enhancement and size of edema do not provide clear-cut differentiators. The differences in the properties of the peritumoral edema between these tumor types may be exploited to distinguish between them, using MRI perfusion sequences, which are capable of imaging edema in the clinical setting and may be a reliable method to make this differentiation. OBJECTIVES: To assess the ability of perfusion-weighted imaging to differentiate between high grade gliomas andbrain metastases. METHODS: During 5 months, 21 patients (age 40-85, median age 61, 16 males and 5 females) with either glioblastoma multiforme (GBM) or metastasis (pathology proven), underwent MRI for assessment of the tumor prior to surgery. Most of the scans were done at 3 Tesla. The scans included perfusion-weighted imaging sequences. Perfusion in the tumor, in the peritumoral edema and in normal tissue were assessed using Functool software. The ratios of tumor perfusion and peritumoral edema perfusion to normal tissue perfusion were calculated and compared. RESULTS: Bleeding artifact precluded perfusion assessment in four patients. There was no statistically significant difference between the tumor perfusion ratios of high grade gliomas and those of metastases. The edema perfusion ratios were higher in GBM than in metastases (P = 0.007). CONCLUSIONS: Perfusion-weighted imaging of peritumoral edema can help to differentiate between GBM and metastases.

Complex aortic valve repair following excision of a papillary fibroelastoma.

Complex aortic valve repair after mass lesion resection, in an otherwise normal, thin leafleted valve, is rarely described in the literature. We present a 68-year-old woman who underwent resection of an asymptomatic aortic valve papillary fibroelastoma. Due to extensive involvement of her left coronary cusp, the resection resulted in a significant defect in the leaflet, requiring a complex repair to preserve her otherwise normal aortic valve. We describe the operative findings, repair technique, and associated literature.

Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids.

Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls. These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease.