Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Hepatocellular Carcinoma Presenting as a Clival Mass

Introduction: Hepatocellular carcinoma (HCC) comprises the majority of primary liver cancer and has a poor prognosis. Clivus metastasis is rare with only a few reported cases in the medical literature. We report a case of a patient who presented with clival mass found to have metastatic HCC. Case Description/Methods: A 63-year-old woman presented for neurosurgical evaluation after she was found to have a skull base mass on computerized tomography (CT) of the head at an outside hospital. She endorsed dysphagia for three months, however denied headaches or visual disturbances. A magnetic resonance imaging (MRI) revealed a 5.4 cm by 2.9 cm by 3.6 cm mass in the clivus, which was deemed as the cause of dysphagia (Figure 1a). The patient subsequently underwent an endoscopic transsphenoidal resection of the clival mass. Histopathology from the tissue revealed a hepatoid carcinoma, concerning for metastatic HCC (Figure 1b and 2c). Immunohistochemical strains were positive for hepatocytic marker arginase-1 (Figure 1d). Laboratory studies revealed alpha fetoprotein (AFP) of 56,344 ng/mL, CA-125 of 376 ng/mL, normal B-HCG and carcinoembryonic antigen (CEA). Thereafter, a triple phase CT of the liver revealed two LI-RADS 5 lesions suggestive of HCC as the primary malignancy. Patient's case was discussed at multidisciplinary tumor board with recommendations for systemic immunotherapy with atezolimumab plus bevacizumab and radiation therapy to the clivus. Discussion(s): The incidence of HCC has almost tripled since the 1980s making it the fastest rising cause of cancer related deaths. Metastasis to the brain comprises 0.26% to 2.2% of cases and the skull base is the most rarely affected anatomical site. Although CNS presentation is rare, we may see more neurological manifestations of metastatic HCC with the persistence of chronic hepatitis infections, the rise of metabolic diseases such as NASH, and an increase in alcohol-related liver disease during the COVID-19 pandemic. Although exceedingly rare, metastasis to the clivus should be considered in the differential diagnosis of skull base masses. Despite detection and treatment, prognosis remains poor and emphasis should be placed on consistent HCC surveillance. This case emphasizes that skull masses must be evaluated diligently as they can be the first sign of underlying liver malignancy. Given the morbidity and mortality associated with HCC, recognition of atypical manifestations of HCC can lead to a prompt diagnosis and initiation of life-saving treatment. (Figure Presented).

Alcohol Use and the Risk of Colorectal Liver Metastasis: A Systematic Mapping Review.

The consumption of alcohol has long been associated with the development of liver disease as well as cancers including colorectal cancer (CRC). Leading healthcare concerns include the prevalent use of alcohol and the high burden of CRC mortality. Many CRC deaths are attributed to the development of colorectal liver metastasis (CRLM) as the liver is the foremost site of CRC spread. However, an association has not been defined for the role of alcohol intake and related liver injury with the development of CRLM. Here, a mapping review of recent research was undertaken to evaluate the relationship between alcohol consumption and the risk of CRLM. The literature search revealed 14 articles meeting the inclusion criteria that included patient database analyses and preclinical studies. Most of the human data analyses found alcohol use independently associates with worse CRC outcomes. The preclinical evaluations identified several pathways involved in the alcohol-mediated promotion of CRLM burden and CRC cell metastatic behavior. The limited number of studies identified exposes a significant need for more prospective analyses to define the role of alcohol intake and advanced CRC as well as the translation of preclinical research to fully characterize targetable mechanisms for the generation of new therapeutic options.

REAL WORLD DATA SUPPORTS POST-PANDEMIC CONTINUATION OF TELEMEDICINE SURVEILLANCE VISITS FOLLOWING RESECTION OF COLORECTAL LIVER METASTASES

INTRODUCTION The purpose of surveillance after resection of colorectal liver metastases (CLM) is to detect and treat recurrence using axial imaging, biomarker measurement, and a history/physical examination. In response to COVID-19 pandemic, telemedicine was used as a risk mitigation strategy to replace in-person visits, including for cancer surveillance. The objective of the study was to measure the uptake of telemedicine for cancer surveillance and outcomes following telemedicine surveillance after resection of CLM. METHODS Data from a prospective database was combined with real world data obtained from electronic health records using a cloud-based, data integration tool (Palantir Foundry) to identify patients in active surveillance following first surgical resection for CLM between April 2017 and April 2021. Telemedicine surveillance visit was defined as a follow-up visit >90 days following surgery using video or telephone. Recurrence was defined as detection of a new lesion. Bivariate statistical testing was performed using Student's t-test or chi-squared test. Retrospective chart review was used to validate identification of recurrence using the Foundry platform (100% interobserver agreement). RESULTS A total of 1,057 surveillance visits (306 patients) met our inclusion criteria. Prior to April 2020, 0% (0/686) visits utilized telemedicine. After April 2020, an average of 47.3% of visits per month utilized telemedicine (range 33.0 – 69.0%). The overall rate of identifying a recurrence during surveillance visit was 18.1% (191/1,057). There was no difference when comparing detection of recurrence using in-person (17.6%, 154/872) versus telemedicine visits (20.0%, 37/185, P=.371). The management of recurrence did not differ whether it was identified with an in-person or telemedicine visit;surgery, 36 (23%) vs. 10 (27%);ablation, 26 (17%) vs. 8 (22%);systemic therapy, 83 (54%) vs. 16 (43%);other, 9 (6%) vs. 3 (8%), respectively (P=.699). CONCLUSION Telemedicine was used in almost half of surveillance visits for CLM during the COVID- 19 pandemic. Detection and treatment of recurrence was similar for both telemedicine and in-person visits. Telemedicine-based follow-up is a safe and effective approach for surveillance after resection of CLM, supporting continued utilization beyond the pandemic.

15th Congress of the European Association for Clinical Pharmacology and Therapeutics, EACPT

The proceedings contain 294 papers. The topics discussed include: impact of the genotype and phenotype of CYP3A and P-GP on the apixaban and rivaroxaban blood concentrations in real-world setting;direct oral anticoagulant-related bleeding in atrial fibrillation patients alters DNA methylation of NOS3 and KDR genes;impact of obesity on dexamethasone pharmacokinetic in COVID-19 hospitalized patients: an observational exploratory study;intestinal permeability in transplant patients: are systemic short-chain fatty acids an early biomarker?;immunogenicity 5-months after homologous or heterologous booster vaccination in health care workers primed with Ad26.COV2.S;geographic variation in top-10 prescribed medication and potentially inappropriate prescription in Portugal: an ecological study of 2.2 million older adults;quantitative proteomics of hepatic drug-metabolizing enzymes and transporters in patients with colorectal cancer liver metastasis;pharmacological characterization of a novel lipid-rich breast cancer patient-derived xenograft;and multiple sclerosis drugs and dental and gingival disorders: an observational retrospective study and disproportionality analysis in the world pharmacovigilance database.

RARE CASE OF ILEOCOLIC MESENTERY PRIMARY MELANOMA WITH LIVER METASTASIS

Purpose/Background: Although GI melanoma is commonly a metastatic disease, it is very unusual to see the mesenteric mass of the cecum and terminal ileum as the primary origin of melanoma. Hypothesis/Aim: This is a case report and presentation showing a rare occasion of primary melanoma in the cecum and the terminal ileum mesentery along the ileocolic pedicle causing cecal complete bowel obstruction. Methods/Interventions: The reported case is a rare occasion of large bowel obstruction near the cecum resulted from primary mesenteric melanoma invading into the wall of the descending colon. Primary melanoma of the GI tract is still controversial and only a limited of cases have been reported in the literature. We added a review of the other published case reports to this case report using Endnote. Results/Outcome(s): This is a 68-year-old female who was seen in the outpatient setting with increasing abdominal girth in addition to nausea and vomiting and obstipation. The patient had alternating bowel habits for over 2 months which she felt this was related to Covid as she was tested Covid positive and diagnosed with Covid pneumonia at the same time. She was directly admitted from the office to the inpatient and she had a CAT scan of the abdomen pelvis that demonstrated cecal obstruction related to possibly cecal mass/mesenteric mass with multiple liver metastatic diseases. She underwent exploratory laparotomy which resulted in Right extended hemicolectomy en bloc with a loop of jejunum and part of the terminal ileum. We tested later serum S100 the protein and it was elevated to 18,000, she had serum negative alpha-fetoprotein and negative CEA. This is a 68-year-old female who was seen in the outpatient setting with increasing abdominal girth in addition to nausea and vomiting and obstipation. The patient had alternating bowel habits for over 2 months which she felt was related to Covid as she was tested Covid positive and diagnosed with Covid pneumonia at the same time. She was directly admitted from the office to the inpatient service and she had a CAT scan of the abdomen pelvis that demonstrated cecal obstruction related to possibly cecal mass/ mesenteric mass with multiple liver metastatic diseases. She underwent exploratory laparotomy which resulted in Right extended hemicolectomy en bloc with a loop of jejunum and part of the terminal ileum. She had also intraoperative liver biopsy that demonstrated metastasis of the melanoma to the liver. We tested later serum S100 the protein and it was elevated to 18,000, she had serum negative alpha-fetoprotein and negative CEA. Limitations: Case report study with reported cases reviewed. Conclusions/Discussion: Large bowel obstruction could be related to unusual diagnoses like melanoma of the bowel mesentery. Although, primary GI melanoma is rare this showed the possibility of such diagnosis. (Figure Presented).

Tumor marker study in pleural fluid and tumor heterogeneity

Background-aim: Tumor markers (TM) in body fluids have been studied for years and several authors have proposed different cut-off. An apparently more accurate strategy is the one proposed by Molina et al. considering that the ratio TM in fluid with regard to TM in serum >1.2 indicates local production in the pleura, however if the ratio is <1.2 the presence of TM in the fluid would be explained by serum extravasation. Despite enough evidence to manage this biomarkers in body fluids, the practice is not widely extended in the clinical setting yet. Methods: AFP, CA19.9, CA15.3, CEA, CA125, PSA and SCC were analyzed in Alinity i platform (Abbott diagnostics) HCG and NSE was performed in Cobas e411 (Roche diagnostics). Results: Here we describe the case of a 69-year-old patient attending the Emergency Room due to pain in both hemythoraxes. Also remarkable was a wasting syndrome (5 kg weight loss in the past month). In Emergency blood analysis: VSG 50, PT 75%, DD 765 ng/mL, ferritin 368 ng/mL and LDH 385 U/L were outsdanding. Thorax radiology showed a pleural effusion. The patient was diagnosed with COVID19 bronchitis.TC scan evidenced pleural solid metastasis, multiple bone lesions and hepatic M1. Serum TM: AFP, CA19.9, PSA, NSE, SCC and HCG were normal. CA125 2992,60 U/mL (<35), CA15.3 614,70 U/mL (<32), CEA 400.82 ng/mL (<5). Pleural fluid TM: CEA 284.32 ng/mL;CA15.3 2210.3 U/mL. TM ratio: CA15.3: 3.6 (>1.2) this result indicates local synthesis of CA15.3, therefore pleural metastasis;CEA: 0.7 (<1.2) indicates that the CEA found un the fluid was extravasated from serum. Pathological examination was only positive for CK7 and mixt CK. All other markers were negative. It was concluded to be an undifferentiated carcinoma, cytologically reminding of an adenocarcinoma. Due to TTF1 and napsine negativity lung neoplasm could not be discarded.The patient was diagnosed with undifferentiated lung cancer stage IV. Conclusions: This a good example of different molecular patterns reflecting tumor heterogeneity evidenced by protein expression by each lesion: Pleural metastases expressed high amounts of CA15.3, however not CEA. Hepatic metastases and probably main tumor in the lung expressed CEA and CA15.3. It is arguable whether CA15.3 was expressed at lower quantities from the main tumor or the dilution of the protein in the bloodstream results in lower concentrations in relation to the ones found in the pleura.

Neuroendocrine cancer of the prostate. Two case reports

Background: Neuroendocrine cancer of the prostate can present in diverse clinical pictures, potentially hampering the diagnosis and probably leading to underdiagnosis. Methods: Two cases are presented corresponding respectively to two forms of the disease: de novo neuroendocrine cancer and dedifferenciation of an adenocarcinoma of the prostate to neuroendocrine cancer under long term luteinising hormone releasing hormone (LHRH) agonist treatment. Results: Suspicion of neuroendocrine cancer may be raised in prostate cancer patients presenting either clinical or radiological metastatic progression without prostate specific antigen (PSA) rise, or relatively extended metastatic disease right at diagnosis associated to relatively low PSA, yet any non-pulmonary visceral metastases. Neuroendocrine cancer of the prostate can also turn out to be the origin of an adenocarcinoma of unknown primary. Conclusion: In case these considerations are respected the risk of missing the correct diagnosis of a neuroendocrine cancer of the prostate may be minimised.

Diagnostic value of FDG-PET/CT in fever of unknown origin

Background: Fever of unknown origin (FUO) is a challenging clinical problem in medicine that needs collaboration of various diagnostic techniques to establish the accurate diagnosis. We evaluated the diagnostic performance of 18F-FDG PET/CT in patients who presented themselves with FUO. Our study included 40 patients with FUO who underwent PET/CT examination and their results were compared to the results of laboratory, histopathological, microbiological investigations and/or response to therapy. Results: The final diagnosis included malignancy in 20 patients (50%), infectious causes in 7 patients (17.5%) and non-infectious inflammatory causes in 6 patients (15%). Fever resolved without diagnosis in 4 patients (10%), while no definite diagnosis was reached in 3 patients (7%). PET/CT successfully contributed to diagnosis of 35 out of 40 patients with diagnostic accuracy of 87.5%. The sensitivity, specificity, positive predictive value and negative predictive value of PET/CT in our study were 93.5%, 66.7%, 90.6% and 75%, respectively. Conclusion: PET/CT is a useful tool to investigate and diagnose the cause of FUO. It provides information that can guide the treatment strategy of the patients.

Consequences of stopping a 4/6 cyclin D-dependent kinase Inhibitor in metastatic breast cancer patients with clinical benefit on endocrine treatment, in the context of the COVID-19 outbreak

Background: The impact of some medical decisions hurriedly taken during the COVID-19 first wave remains unknown. We tried to assess the consequences of one of these precautionary measures, namely the interruption of a 4/6 cyclin D-dependent kinase inhibitor (CDK4/6i) in metastatic patients with clinical benefit (complete response/partial response and patients with stable disease for at least 6 months) on endocrine treatment (ET). The main reason for this interruption was to limit the risk of myelosuppression (assumed as a serious risk factor for COVID-19) and other adverse effects that could overlap with symptoms and clinical signs described in the SARS-CoV-2 infection. Methods: We included 60 patients (median age: 64 years old) in whom the CDK4/6i was stopped during the first COVID-19 outbreak. It was a non-interventional, retrospective, multicentric study. A univariate analysis was performed to assess risk factors associated with disease progression: odds ratios (OR) were estimated along with their confidence intervals (CI). Key patient characteristics, all included in the statistical model, are presented in Table 1. Results: The average duration of a CDK4/6i interruption was 8 weeks. During this therapeutic break, 22 (37 %) patients Shad a radiological and/or clinical progression of the disease. Among them, CDK4/6i were taken back for the majority of patients (n=16/22;73 %) when the sanitary situation improved.For four patients (n=4/22;18 %), a new specific treatment (chemotherapy or targeted therapy) was initiated for rapid or symptomatic tumor progression. Two patients died while CDK4/6i was withdrawn. All the results of the univariate analysis are summarized in Table 2. During the CDK4/6i discontinuation, the risk of disease progression was significantly increased in the presence of liver metastases. This was the only variable with a significant effect in univariate analysis. Although not statistically significant, the risk of disease progression was higher when CDK4/6i withdrawal was longer, when patients had a more aggressive breast cancer (Luminal B) and when the tumor was considered as resistant to ET. Conclusions: The importance of maintaining the cell cycle inhibitor in addition to ET does not seem to be debatable as 36 % of patients progressed during CDK4/6i withdrawal. This is important in clinical practice when the question of CDK4/6i discontinuation arises for other reasons (analgesic radiotherapy or programmed surgery for example). Special attention should be paid to patients with liver metastases for whom stopping such a treatment seems to accelerate the natural course of the disease.

Phase Ib study of BI 836880 (VEGF/Ang2 inhibitor) plus ezabenlimab (BI 754091;anti-PD-1 antibody) in patients (pts) with advanced hepatocellular carcinoma (HCC)

Background: Combination of anti-VEGF compounds and immune checkpoint inhibitors is an approved therapy across multiple solid tumors, including advanced HCC. This phase Ib study (NCT03468426) is assessing BI 836880 (bispecific VEGF/Ang2 nanobody) + ezabenlimab (anti-PD-1 antibody) in pts with advanced solid tumors. The recommended phase 2 dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg given IV every 3 weeks was determined in Part 1. In Part 2, RP2D was assessed in 7 expansion cohorts. We report data from cohorts in HCC after prior sorafenib/lenvatinib (cohort F) and untreated unresectable HCC (cohort G). Methods: Pts with locally advanced or metastatic HCC, Child-Pugh class A, not eligible for surgical or locoregional therapies were enrolled. Cohort F enrolled pts who had progressed on or after first-line treatment with sorafenib or lenvatinib or who had discontinued due to poor tolerability after ≥2 weeks of treatment. Cohort G enrolled pts who had received no prior systemic therapy for HCC. Treatment continued until disease progression, undue toxicity or consent withdrawal. Primary endpoint is objective response rate (ORR) by RECIST 1.1. Results: As of Aug 2021, 30/31 pts have been treated in cohorts F/G: 87/77% male;median age 65/64 yrs. Follow-up is ongoing in both cohorts. 9/19 pts in cohorts F/G remain on treatment;median (range) duration of treatment is 175 (42-532)/ 169 (42-336) days in cohorts F/G. All pts were evaluable for response in cohort F: confirmed ORR to date is 40% (1 complete response;11 partial responses [PRs]). Of 28 evaluable pts in cohort G, confirmed ORR to date is 21% (6 PRs). 12 (40%) pts in cohort F and 18 (64%) in cohort G have stable disease. In cohort F, AEs were reported in 28 (93%) pts, most frequently hypertension and proteinuria (each 30%). In cohort G, AEs occurred in 26 (84%) pts, most frequently ascites (26%) and thrombocytopenia (19%). 24 (80%) pts in cohort F and 15 (48%) in cohort G had treatmentrelated AEs (TRAEs). Most frequent TRAEs were proteinuria (27%), infusion-related reactions (IRRs) and hypertension (each 20%) in cohort F, and hypertension (13%), IRRs, hypothyroidism and diarrhea (each 10%) in cohort G. There were 3 pts with G5 AEs in cohort F (COVID-19 pneumonia [n = 1];low Glasgow coma score and dyspnea [n = 1];hepatic cirrhosis [n = 1]) and 1 G5 AE in cohort G (hepatic failure);none were considered related to treatment. AEs leading to discontinuation occurred in 2 pts in cohort F (G3 hepatic encephalopathy and G2 duodenal ulcer) and 3 in cohort G (G5 hepatic failure [n = 1];G2 acute kidney injury and G1 decreased appetite [n = 1];G2 diarrhea [n = 1]). Conclusions: BI 836880 + ezabenlimab had a manageable safety profile and showed promising activity in pts with untreated and second-line post-sorafenib/lenvatinib advanced HCC. Data continue to mature, particularly in cohort G. Cohort F has been expanded by a further 30 pts.