Circulating immune-related proteins associated with immune checkpoint inhibitor efficacy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial. MATERIALS AND METHODS: The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included. RESULTS: High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy. CONCLUSIONS: Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.

Age-related Differences in Recall of Information and Handling of Chemotherapy-related Side Effects in Cancer Patients: The ReCap Study.

BACKGROUND: To prevent severe toxicity and hospital admissions, adequate management and recall of information about side effects are crucial and health literacy plays an important role. If age-related factors impact recall of given information and handling of side effects, revised ways to give information are required. PATIENTS AND METHODS: We undertook a questionnaire-based survey among 188 newly diagnosed patients with pancreatic cancer or colorectal cancer and chemo-naive patients with prostate cancer treated with adjuvant or first-line palliative chemotherapy comprising satisfaction with given information, recall of potential side effects, and handling of hypothetical side effect scenarios. We evaluated the association between baseline characteristics, ie, age, frailty (G8 score), comorbidity (Charlson Comorbidity Index), cognitive function (Mini-Cog), satisfaction, recall of information, and handling of side effects. RESULTS: Reduced ability to recall information about several side effects (eg, chest pain) was associated with older age (odds ratio adjusted for cancer [aOR] 0.94 [95% CI, 0.88-0.98]) and poor cognitive screening (aOR 0.56 [95% CI, 0.33-0.91]). Insufficient or dangerous handling of side effects was associated with older age (aOR 0.96 (95% CI, 0.92-0.99)) and cognitive impairment (aOR 0.70 [95% CI, 0.50-0.95]). CONCLUSION: Older age and poor cognitive screening may impact patients' ability to understand and adequately handle chemotherapy-related side effects. Cognitive screening and focus on individual ways to give information including assessment of recall and handling are needed.

Genomic landscape of treatment refractory metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a complex and heterogeneous disease with few standard and targeted treatment options. Next-generation sequencing of tumor tissue was performed to identify cancer driver mutations to discover possible personalized treatment options, as targeted treatment possibilities are limited for this patient population. Results of genomic sequencing in patients with treatment-refractory mCRC are described in this retrospective analysis. MATERIAL AND METHODS: Clinico-pathological characteristics and genomic sequence results of consecutive patients with refractory mCRC, referred to the Experimental Cancer Therapy Unit (ECTU) at Department of Oncology, Herlev & Gentofte Hospital in the period from 1 October 2015 to 14 December 2018 were reviewed in this retrospective analysis. Tumor tissue from the patients was analyzed by next-generation sequencing using the Oncomine Comprehensive primer panel to detect actionable variants of cancer driver mutations and microsatellite instability status. From August 2018 tumor mutational burden was also analyzed. RESULTS: A total of 80 patients with treatment-refractory mCRC and in a fairly good performance were referred to the ECTU during this period. Genomic sequencing of tumor tissue was performed for all 80 patients and a cancer driver mutation was identified in 90% (n = 72) of the patients. A total of 31.3% (n = 25) of the patients received therapy either as targetable therapy outside an available trial (n = 2), FDA approved therapy (n = 2), or treatment in phase 1 or 2 trials, independent of the genomic signature 26.3% (n = 21). CONCLUSION: Most mCRC patients refractory to standard anti-neoplastic therapies, presented with a cancer driver mutation, however, only a few of these mutations gave rise to matched therapies as only 2.5% of the patients from this period received targeted therapy.

Aspects of transition cow metabolomics-Part I: Effects of a metaphylactic butaphosphan and cyanocobalamin treatment on the metabolome in liver, blood, and urine in cows with different liver metabotypes.

Dairy cows in modern production systems are at risk to develop metabolic disorders during the transition period. Reasons for individual differences in susceptibility, as well as the underlying pathomechanisms, are still only partially understood. The development of metaphylactic treatment protocols is needed. In this context, an on-farm prospective 3-fold blinded randomized study involving 80 German Holstein cows was performed throughout 1 yr. The trial involved a thorough recording of the production and clinical traits, clinical chemistry, and liver biopsies and blood and urine sampling at d 14 (mean: 12 d, range: 1-26 d) antepartum (AP), and d 7 (7, 4-13) and 28 (28, 23-34) postpartum (PP) for metabolomics analyses. Two groups received a treatment with butaphosphan and cyanocobalamin (BCC) at either the dosage recommended by the manufacturer or the double dosage (5 or 10 mL/100 kg of body weight 10% butaphosphan and 0.005% cyanocobalamin (Catosal, Bayer Animal Health), n = 20 in each group, parity: 4.2 ± 2.0 and 3.4 ± 1.3, respectively (mean ± SD)] and one group a placebo treatment (NaCl 0.9%, n = 40, parity: 4.0 ± 1.9). The animals were treated at 6 time points (7, 6, and 5 d AP, and 1, 2, and 3 d PP) via intravenous injection. Mass spectroscopy-based targeted metabolomics analysis of blood plasma and liver samples were performed using the AbsoluteIDQ p180 kit (Biocrates Life Sciences), whereas the urine samples were analyzed by nuclear magnetic resonance spectroscopy. Statistical analysis was performed using multivariate [partial least squares discriminant analysis (PLS-DA)] and univariate methods (linear mixed model). Multivariate data analysis (PLS-DA plots) of the liver metabolome revealed 3 different metabotypes (A = medium, B = minor, C = large alterations in liver metabolome profile between AP and PP status). Metabotype B animals were characterized by higher PP lipomobilization (stronger PP body condition decrease and higher blood bilirubin, fatty acids, gamma-glutamyltransferase, and triglyceride levels) and a higher occurrence of transition cow diseases, compared with the animals in metabotype C. Analysis of the feeding data showed that the period of metabotype B animals (calving in a distinct time frame) was characterized by a decreased grass silage quality. The PP liver metabolome of the metabotype C animals was characterized by higher concentrations of AA, acylcarnitines, lysoPC and sphingomyelins compared with metabotype B. For the metaphylactic treatment with BCC a dose-dependent effect was confirmed, differing between the metabotypes. In all matrices and metabotypes at various time points significant treatment effects were observed, with different profiles in clinical chemistry and as well in metabolomics data. The most clear-cut treatment effect was observed in metabotype B in the liver at 7 d PP, characterized by an increase in several acylcarnitines and phosphatidylcholines, indicating a more efficient influx and oxidation of fatty acids in mitochondria and thereby an increase in energy supply and more efficient triglyceride export in the liver. The results from the liver metabolomics analysis support the application of an indication-based metaphylactic treatment with BCC.

An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine.

PURPOSE: Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. METHODS: The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5 mg/m2 once daily for 14 consecutive days in combination with capecitabine 800 mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. RESULTS: 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. CONCLUSIONS: Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics.

BACKGROUND: Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. METHODS: A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest. RESULTS: 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion. CONCLUSIONS: Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan.

Hepatic arterial therapy with oxaliplatin and systemic capecitabine for patients with liver metastases from breast cancer.

OBJECTIVES: Hepatic arterial treatment (HAT) for liver metastases in patients with metastatic breast cancer (MBC) has only been investigated in few studies. MATERIALS AND METHODS: Two phase II trials were initiated simultaneously to evaluate capecitabine in combination with oxaliplatin in patients with MBC and liver metastases. These two trials are reported together. Continuous capecitabine (1300 mg/m2) was combined with oxaliplatin (85 mg/m2) alternating between systemic treatment and HAT followed by degradable starch microspheres with EmboCept® S every second week. Four patients participated in a pharmacokinetic analysis of oxaliplatin. Each patient had samples taken when receiving oxaliplatin systemically and as HAT with and without EmboCept® S. RESULTS: Totally, 52 patients received HAT: 14 with liver metastases only and 38 patients with additional limited metastatic disease. The patients had previously received a median of 2 (range 0-6) chemotherapeutic regimens for MBC. The response rate was 42.3% (95% confidence interval (CI) 28.7-56.8%) with 7.7% complete and 34.6% partial responses. Median progression free survival was 10.8 months (95% CI 6.9-14.7 months) and median overall survival 27.6 months (95% CI 20.4-34.8 months). The toxicity was moderate with hand-foot syndrome (15.4%), neuropathy (9.6%), fatigue (9.6%), and abdominal pain (9.6%) being the most common grade 3 adverse events. There was no clear difference between systemic blood concentrations of oxaliplatin when given systemic or as HAT. CONCLUSION: HAT oxaliplatin in combination with capecitabine is safe and efficient in patients with MBC. The results are promising with high response rates and a long median progression free and overall survival.