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Background: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient‐derived tumours, and had promising activity in a phase I study. Methods: Here, we investigated the impact of selinexor–gemcitabine–nab‐paclitaxel (Sel‐GemPac) combination on LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse model utilising digital spatial profiling (DSP) and single nuclear RNA sequencing (snRNAseq). Results: Sel‐GemPac synergistically inhibited the growth of the KPC tumour‐derived cell line. The Sel‐GemPac combination reduced the 2D colony formation and 3D spheroid formation. In the KPC mouse model, at a sub‐maximum tolerated dose (sub‐MTD) , Sel‐GemPac enhanced the survival of treated mice compared to controls (p <.05). Immunohistochemical analysis of residual KPC tumours showed re‐organisation of tumour stromal architecture, suppression of proliferation and nuclear retention of tumour suppressors, such as Forkhead Box O3a (FOXO3a). DSP revealed the downregulation of tumour promoting genes such as chitinase‐like protein 3 (CHIL3/CHI3L3/YM1) and multiple pathways including phosphatidylinositol 3'‐kinase‐Akt (PI3K‐AKT) signalling. The snRNAseq demonstrated a significant loss of cellular clusters in the Sel‐GemPac‐treated mice tumours including the CD44+ stem cell population. Conclusion: Taken together, these results demonstrate that the Sel‐GemPac treatment caused broad perturbation of PDAC‐supporting signalling networks in the KPC mouse model. Highlights: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin‐bound (nab)‐paclitaxel (GemPac).Exporter protein exportin 1 (XPO1) inhibitor selinexor (Sel) with GemPac synergistically inhibited the growth of LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx1‐Cre (KPC) mouse derived cell line and enhanced the survival of mice.Digital spatial profiling shows that Sel‐GemPac causes broad perturbation of PDAC‐supporting signalling in the KPC model. [ABSTRACT FROM AUTHOR]

Background: One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence. Methods: A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET‐h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two‐sided hypothesis tests. Results: Compared with patients expending <3.0 MET‐h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET‐h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42–0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%–69.2%) with <3.0 MET‐h/week of physical activity and 72.2% (95% CI, 63.1%–79.6%) with ≥18 MET‐h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2–20.8 percentage points). Conclusions: Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence. Among patients initially diagnosed with stage III colon cancer enrolled in a trial of postoperative treatment, higher postoperative physical activity is associated with improved overall survival after tumor recurrence. Oncologists may wish to include counseling about the potential benefits of physical activity in their postoperative treatment consultations. [ABSTRACT FROM AUTHOR]

The radiotracer 1‐(2‐[18F]fluoroethyl)‐L‐tryptophan (L‐[18F]FETrp or [18F]FETrp) is a substrate of indoleamine 2,3‐dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [18F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first‐in‐human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [18F]FETrp on a Synthra RNPlus research module, including a one‐pot two steps radiosynthesis, dual independent chiral and reverse‐phase semipreparative high‐performance liquid chromatography purifications, and solid‐phase extraction‐assisted formulation. The presented approach has led to its Investigational New Drug application and approval that allows the testing of this tracer in humans. [ABSTRACT FROM AUTHOR]

Background: The incidence of early‐onset colorectal cancer (EOCRC) is rising. Left‐sided colorectal cancer (LCC) is associated with better survival compared to right‐sided colon cancer (RCC) in metastatic disease. NCCN guidelines recommend the addition of EGFR inhibitors to KRAS/NRAS WT metastatic CRC originating from the left only. Whether laterality impacts survival in locoregional disease and EOCRC is of interest. Methods: 65,940 CRC cases from the National VA Cancer Cube Registry (2001–2015) were studied. EOCRC (2096 cases) was defined as CRC diagnosed at <50 years. Using ICD codes, RCC was defined from the cecum to the hepatic flexure (C18.0–C18.3), and LCC from the splenic flexure to the rectum (C18.5–18.7; C19 and C20). Results: EOCRC is more likely to originate from the left side (66.65% LCC in EOCRC vs. 58.77% in CRC). Overall, LCC has better 5‐year Overall Survival (OS) than RCC in stages I (61.67% vs. 58.01%) and III (46.1% vs. 42.1%) and better 1‐year OS in stage IV (57.79% vs. 49.49%). Stage II RCC has better 5‐year OS than LCC (53.39% vs. 49.28%). In EOCRC, there is no statistically significant difference between LCC and RCC in stages I‐III. Stage IV EOCRC patients with LCC and RCC have a 1‐year OS of 73.23% and 59.84%, respectively. Conclusion: In EOCRC, LCC is associated with better OS than RCC only stage IV. In the overall population, LCC is associated with better OS in all stages except stage II. The better prognosis of stage II RCC might be due to the high incidence of mismatch repair deficient tumors in this subpopulation. [ABSTRACT FROM AUTHOR]

Microsatellite instability‐high (MSI‐H) and tumor mutational burden (TMB) are predictive biomarkers for immune‐checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI‐H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592‐gene panel; a subset of MSI‐H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene‐specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co‐expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P <.0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P <.0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P <.0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI. What's new? Immunotherapy based on checkpoint inhibitors shows promising results in a variety of cancer types, but still benefits a minority of patients. High microsatellite instability (MSI) and tumor mutational burden (TMB) have both been identified as biomarkers predictive of response to checkpoint inhibitors. Here, the authors investigated how the underlying causes of MSI influence TMB. Tumors lacking the mismatch repair protein duo MLH1/PMS2 had lower TMB than those lacking a different protein heterodimer, MLH2/MSH6. Even among tumors lacking the same mismatch repair proteins, the tissue of origin influenced mutational burden. [ABSTRACT FROM AUTHOR]

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead. [ABSTRACT FROM AUTHOR]

FAU, a pyrimidine nucleotide analogue, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU, which is incorporated into DNA, causing cell death. This study presents a model-based approach to integrating dynamic positron emission tomography (PET) and conventional plasma pharmacokinetic studies to characterize the plasma and tissue pharmacokinetics of FAU and FMAU. Twelve cancer patients were enrolled into a phase 1 study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50-1600 mg/m2) and dynamic PET assessment of 18F-FAU were performed. A parent-metabolite population pharmacokinetic model was developed to simultaneously fit PET-derived tissue data and conventional plasma pharmacokinetic data. The developed model enabled separation of PET-derived total tissue concentrations into the parent drug and metabolite components. The model provides quantitative, mechanistic insights into the bioactivation of FAU and retention of FMAU in normal and tumor tissues and has potential utility to predict tumor responsiveness to FAU treatment. [ABSTRACT FROM AUTHOR]

Alcohol consumption is associated with a modest increased risk of colon cancer, but its relationship with colon cancer survival has not been elucidated. Using data from a phase III randomized adjuvant trial, we assessed the association of alcohol consumption with colon cancer outcomes. Patients completed a risk factor questionnaire before randomization to FOLFOX or FOLFOX + cetuximab ( N = 1984). Information was collected on lifestyle factors, including smoking, physical activity and consumption of different types of alcohol. Cox models assessed the association between alcohol consumption and outcomes of disease-free survival (DFS), time-to-recurrence (TTR) and overall survival (OS), adjusting for age, sex, study arm, body mass, smoking, physical activity and performance status. No statistically significant difference in outcomes between ever and never drinkers were noted [hazard ratio (HR)DFS = 0.86, HRTTR = 0.87, HROS = 0.86, p-values = 0.11-0.17]. However, when considering alcohol type, ever consumers of red wine ( n = 628) had significantly better outcomes than never consumers (HRDFS = 0.80, HRTTR = 0.81, HROS = 0.78, p-values = 0.01-0.02). Favorable outcomes were confirmed in patients who consumed 1-30 glasses/month of red wine ( n = 601, HR = 0.80-0.83, p-values = 0.03-0.049); there was a suggestion of more favorable outcomes in patients who consumed >30 glasses/month of red wine ( n = 27, HR = 0.33-0.38, p-values = 0.05-0.06). Beer and liquor consumption were not associated with outcomes. Although alcohol consumption was not associated with colon cancer outcomes overall, mild to moderate red wine consumption was suggestively associated with longer OS, DFS and TTR in stage III colon cancer patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Carbohydrate antigen 19-9 (CA19-9) is a widely used biomarker in pancreatic cancer. There is no consensus on the interpretation of the change in CA19-9 serum levels and its role in the clinical management of patients with pancreatic cancer. METHODS: Individual patient data from 6 prospective trials evaluating gemcitabine-containing regimens from 3 different institutions were pooled. CA19-9 values were obtained at baseline and after successive cycles of treatment. The objective of this study was to correlate a decline in CA19-9 with outcomes while undergoing treatment. RESULTS: A total of 212 patients with locally advanced (n = 50) or metastatic (n = 162) adenocarcinoma of the pancreas were included. Median baseline CA19-9 level was 1077 ng/mL (range, 15-492,241 ng/mL). Groups were divided into those levels below (low) or above (high) the median. Median overall survival (mOS) was 8.7 versus 5.2 months ( P = .0018) and median time to progression (mTTP) was 5.8 versus 3.7 months ( P = .082) in the low versus high groups, respectively. After 2 cycles of chemotherapy, up to a 5% increase versus ≥ 5% increase in CA19-9 levels conferred an improved mOS (10.3 vs 5.1 months, P = .0022) and mTTP (7.5 vs 3.5 months, P = 0.0005). CONCLUSIONS: In patients who have advanced pancreatic cancer treated with gemcitabine-containing regimens baseline CA19-9 is prognostic for outcome. A decline in CA19-9 after the second cycle of chemotherapy is not predictive of improved mOS or mTTP; thus, CA19-9 decline is not a useful surrogate endpoint in clinical trials. Clinically, a ≥ 5% rise in CA19-9 after 2 cycles of chemotherapy serves as a negative predictive marker. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background. In patients with hepatocellular carcinoma, selection criteria for transarterial hepatic selective internal radiotherapy are imprecise. Additionally, radiographic parameters to predict outcome of transarterial hepatic selective internal radiotherapy have not been fully characterized. Patients and methods. Computed tomography (CT) scans of 23 patients with unresectable primary hepatocellular carcinoma before and after transarterial hepatic selective internal radiotherapy with yttrium-90 microspheres were retrospectively reviewed. Selected radiographic parameters were evaluated and correlated with progression-free survival and overall survival. Response to treatment was assessed with Response RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria. Results. On the post-SIRT CT, 68% of tumors demonstrated decreased size (median decrease of 0.8 cm, P = 0.3); 64% had decreased attenuation (median decrease 5.7HU, P = 0.06), and 48% demonstrated increased tumor necrosis (P < 0.001). RECIST-defined partial response was seen in 10% patients, stable disease in 80%, and 10% had disease progression. Median progression-free survival was 3.9 months (range, 3.3 to 7.3), and median overall survival was 11.2 months (7.1 to 31.1). Pretreatment lower hepatopulmonary shunt fraction, central hypervascularity, and well-defined tumor margins were associated with improved progression-free survival. Conclusion. In patients with unresectable hepatocellular carcinoma, pretreatment CT parameters may predict favorable response to SIRT and improve patient selection. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to determine the predictive role of pretreatment carbohydrate antigen 19-9 (CA19-9) measurement and its change after one cycle of gemcitabine-based therapy for response, time to progression (TTP) and overall survival (OS). Methods: Analyses were derived from three consecutive gemcitabine-containing phase II clinical trials between 1997 and 2004. Results: A total of 111 patients with pancreas cancer was studied. Baseline CA19-9 concentrations were dichotomized near the median. Lower baseline CA19-9 levels were positively associated with OS (median 9.1 vs 6.1 months, P = 0.0057) and TTP (median 6.4 vs 4.2 months, P = 0.0044).The covariate adjusted hazard ratio (HR) for progression among patients with baseline CA19-9 ≥ 1000 ng/mL was HR = 1.94 (95% CI 1.24–3.02), with P = 0.0035. The covariate adjusted risk of death among patients with baseline CA19-9 ≥ 1000 ng/ml was similarly elevated: HR = 1.90 (95% CI 1.23–2.94), with P = 0.0039. Change in CA19-9 levels from baseline to the end of treatment cycle 1 did not predict objective response ( P = 0.75). There was somewhat longer OS (median 8.7 vs 7.1 months) and TTP (median 7.1 vs 5.4 months) in patients with ≥50% reduction in serum CA19-9 concentrations, but this was not statistically significant ( P = 0.74 and 0.81, respectively). Conclusion: Baseline CA19-9 levels may predict survival in patients with advanced pancreas cancer. The change in CA19-9 levels determined within 1 month of the initiation of therapy did not predict treatment outcome. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography (PET) performed during cancer therapy (treatment monitoring) has shown promise for predicting treatment outcome. However, when used for this purpose, PET generally is not considered standard care. Under the Medicare 'coverage with evidence development' policy, PET (and integrated PET/computed tomography) became a covered service for treatment monitoring if prospective registry data were collected. Methods: The National Oncologic PET Registry collected questionnaire data on intended patient management before and after PET. Data were available from 8240 patients who had 10,497 treatment-monitoring PET scans at 946 centers; these studies were used to monitor chemotherapy alone (82%), radiation therapy alone (6%), or combined-modality treatment (12%). Ovarian, pancreatic, and lung cancers accounted for 37% of the cohort. In 54% of scans, the pre-PET summary stage was metastatic disease. Results: If PET had not been available, then the pre-PET plan would have been other imaging (53%), ongoing treatment (41%), or biopsy or watching (6%). Change in the post-PET intended management was similar in the imaging and treatment groups: 26% to 28% of scans to switching to another therapy, and 16% to 19% scans led to adjustment of the dose or duration of therapy. Changes in management were more frequent if the referring physician judged that the post-PET prognosis was worse rather than improved or unchanged (78% vs 40%). The physicians indicated that PET enabled 91% of their patients to avoid future tests. Conclusions: Physicians often report plans to modify their therapeutic plans in elderly cancer patients when PET is used for treatment monitoring. [ABSTRACT FROM AUTHOR]

The article presents a research which examines the impact of positron emission tomography (PET) on cancer treatment management. Researchers examined 8240 patients for their study. Researchers after doing quantitative analysis concludes that, physicians often report plans to modify their therapeutic plans in elderly cancer patients when PET is used for treatment monitoring.