Early increase in circulating carbonic anhydrase IX during neoadjuvant treatment predicts favourable outcome in locally advanced rectal cancer

Background Locally advanced rectal cancer (LARC) comprises heterogeneous tumours with predominant hypoxic components. The hypoxia-inducible metabolic shift causes microenvironmental acidification generated by carbonic anhydrase IX (CAIX) and facilitates metastatic progression, the dominant cause of failure in LARC. Methods Using a commercially available immunoassay, circulating CAIX was assessed in prospectively archived serial serum samples collected during combined-modality neoadjuvant treatment of LARC patients and correlated to histologic tumour response and progression-free survival (PFS). Results Patients who from their individual baseline level displayed serum CAIX increase above a threshold of 224 pg/ml (with 96 % specificity and 39 % sensitivity) after completion of short-course neoadjuvant chemotherapy (NACT) prior to long-course chemoradiotherapy and definitive surgery had significantly better 5-year PFS (94 %) than patients with below-threshold post-NACT versus baseline alteration (PFS rate of 56 %; p < 0.01). This particular CAIX parameter, ΔNACT, was significantly correlated with histologic ypT0–2 and ypN0 outcome (p < 0.01) and remained an independent PFS predictor in multivariate analysis wherein it was entered as continuous variable (p = 0.04). Conclusions Our results indicate that low ΔNACT, i.e., a weak increase in serum CAIX level following initial neoadjuvant treatment (in this case two cycles of the Nordic FLOX regimen), might be used as risk-adapted stratification to postoperative therapy or other modes of intensification of the combined-modality protocol in LARC. Trial registration ClinicalTrials.gov NCT0027869

Pro-survival responses to the dual inhibition of anti-apoptotic Bcl-2 family proteins and mTOR-mediated signaling in hypoxic colorectal carcinoma cells

Background The use of targeted agents to impel dual inhibition of anti-apoptotic mechanisms and mTOR-mediated pro-survival signaling in colorectal carcinoma (CRC) cell lines with KRAS or BRAF mutation has been shown to induce apoptosis, a timely result given CRC entities harboring such mutations are in need of new therapies. Since CRC comprises heterogeneous tumors with predominant hypoxic components, we investigated effects of an inhibitor of anti-apoptotic Bcl-2 family proteins (ABT-737) in combination with an mTOR inhibitor (AZD8055)—collectively referred to as combo-Rx, in hypoxic CRC cell lines. Methods Cell viability measures, expression of proteins implicated in apoptosis and MAPK/PI3K-AKT/mTOR pathway signaling, and profiling of composite kinase activities were undertaken in a panel of 14 cell lines. Results In hypoxic conditions, combo-Rx suppressed viability of 13 of the cell lines, albeit ABT-737 did not significantly potentiate the inhibitory effect of single-agent AZD8055 in six of the models. Hypoxic KRAS/PIK3CA-mutant HCT-116 and HCT-15 cell lines (both with low endogenous expression of the anti-apoptotic Mcl-1 protein and showing augmented inhibition of viability following the addition of ABT-737 to AZD8055) responded to combo-Rx by induction of apoptosis but with the simultaneous strong Mcl-1 up-regulation and activation of MAPK/PI3K-conducted signaling. In contrast, in hypoxic KRAS-mutant LoVo (devoid of PIK3CA mutation), BRAF/PIK3CA-mutant RKO, and wild-type Colo320DM cell lines (all with high endogenous Mcl-1 expression and being resistant to the additional effect of ABT-737 to AZD8055), combo-Rx did not elicit apoptotic or pro-survival responses. Conclusions The concurrent inhibition of anti-apoptotic proteins and mTOR-mediated signaling in hypoxic KRAS/PIK3CA-mutant CRC cell lines resulted in pro-survival responses in parallel with the intended anti-proliferative effects, a finding that should be of note if considering combinatory targeting of multiple pathways in this CRC entity

Sex disparities in vitamin D status and the impact on systemic inflammation and survival in rectal cancer

Background We reported previously that rectal cancer patients given curative-intent chemotherapy, radiation, and surgery for non-metastatic disease had enhanced risk of metastatic progression and death if circulating levels of 25-hydroxyvitamin D [25(OH) D] were low. Here we investigated whether the association between the vitamin D status and prognosis pertains to the general, unselected population of rectal cancer patients. Methods Serum 25(OH) D at the time of diagnosis was assessed in 129 patients, enrolled 2013–2017 and representing the entire range of rectal cancer stages, and analyzed with respect to season, sex, systemic inflammation, and survival. Results In the population-based cohort residing at latitude 60°N, 25(OH) D varied according to season in men only, who were overrepresented among the vitamin D-deficient (< 50 nmol/L) patients. Consistent with our previous findings, the individuals presenting with T4 disease had significantly reduced 25(OH) D levels. Low vitamin D was associated with systemic inflammation, albeit with distinct modes of presentation. While men with low vitamin D showed circulating markers typical for the systemic inflammatory response (e.g., elevated erythrocyte sedimentation rate), the corresponding female patients had elevated serum levels of interleukin-6 and the chemokine (C-X-C motif) ligand 7. Despite disparities in vitamin D status and the potential effects on disease attributes, significantly shortened cancer-specific survival was observed in vitamin D-deficient patients irrespective of sex. Conclusion This unselected rectal cancer cohort confirmed the interconnection of low vitamin D, more advanced disease presentation, and poor survival, and further suggested it may be conditional on disparate modes of adverse systemic inflammation in men and women. Trial registration ClinicalTrials.gov NCT01816607; registration date: 22 March 2013

High level of circulating vitamin D during neoadjuvant therapy may lower risk of metastatic progression in high-risk rectal cancer

Background Following curative-intent neoadjuvant therapy in locally advanced rectal cancer, metastatic progression is still dominant. We investigated if patients’ circulating 25-hydroxyvitamin D [25(OH)D] levels were associated with outcome. Methods Serum 25(OH)D concentration was assessed by liquid chromatography-mass spectrometry in samples collected from 84 patients at baseline, completion of the neoadjuvant therapy, and treatment evaluation before surgery, and analyzed with respect to season, disease presentation, and treatment effects. Results In the cohort of patients residing at latitude 58–62°N, baseline 25(OH)D differed significantly over the seasons, with highest measures (mean of 71.2 ± 5.6 nmol/L) in summer and lowest (48.7 ± 4.5 nmol/L) in spring, and changed over the three-month neoadjuvant period till response evaluation solely owing to season. The patient subgroup with slightly reduced performance status, anemia, and T4 disease that did not respond to the neoadjuvant therapy (ypT4 cases), had significantly lower baseline 25(OH)D (below 50 nmol/L) than T4 cases with response (ypT0–3) and T2–3 cases (above 60 nmol/L). Compared to the T4 patients with levels above 50 nmol/L, regarded as sufficient for a healthy bone status, those presenting levels below had significantly heightened risk of disease progression (mainly metastasis) and death, with hazard ratio of 3 and 17, respectively, on adjustment for age, sex, body mass index, and season. Conclusion Rectal cancer T4 cases had high risk of metastatic progression and death if circulating 25(OH)D levels were insufficient but obtained short-term and long-term outcome to neoadjuvant treatment no worse than patients with T2–3 disease when 25(OH)D was sufficient. Trial registration ClinicalTrials.gov NCT00278694; registration date: 16 January 2006, retrospective to enrollment of the first 10 patients of the current report

Quantitative imaging for radiotherapy purposes

Quantitative imaging biomarkers show great potential for use in radiotherapy. Quantitative images based on microscopic tissue properties and tissue function can be used to improve contouring of the radiotherapy targets. Furthermore, quantitative imaging biomarkers might be used to predict treatment response for several treatment regimens and hence be used as a tool for treatment stratification, either to determine which treatment modality is most promising or to determine patient-specific radiation dose. Finally, patient-specific radiation doses can be further tailored to a tissue/voxel specific radiation dose when quantitative imaging is used for dose painting. In this review, published standards, guidelines and recommendations on quantitative imaging assessment using CT, PET and MRI are discussed. Furthermore, critical issues regarding the use of quantitative imaging for radiation oncology purposes and resultant pending research topics are identified