Molecular diagnostics is typically outsourced to well-equipped centralized laboratories, often far from the patient. We developed molecular assays and portable optical imaging designs that permit ...on-site diagnostics with a cost-effective mobile-phone-based multimodal microscope. We demonstrate that targeted next-generation DNA sequencing reactions and in situ point mutation detection assays in preserved tumour samples can be imaged and analysed using mobile phone microscopy, achieving a new milestone for tele-medicine technologies.
Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We ...used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.
•The NAR-score is a new surrogate endpoint to be used in clinical trials.•For early determination of treatment response to different preoperative therapies.•It can discriminate between two treatments ...with different cell killing effect.•The NAR-score score appears to work irrespective of therapy given.
The Neoadjuvant rectal (NAR) score is a new surrogate endpoint to be used in clinical trials for early determination of treatment response to different preoperative therapies. The aim is to further validate the NAR-score, primarily developed using chemoradiotherapy (CRT) with a delay to surgery 6–8 weeks, and explore its value using other schedules.
The study included all 9978 patients diagnosed with non-metastasized RC in 2007–2015 that had undergone surgery and was registered in the Swedish Colorectal Cancer Registry. The patients of interest had either short-course radiotherapy (scRT)/CRT + delayed surgery, long-course radiotherapy (RT) + delayed surgery, (C)RT + additional chemotherapy, primary surgery, or scRT + immediate surgery. The scRT/CRT + delayed surgery groups were further divided based on time to surgery.
Mean NAR-score differed significantly (p < 0.0001) between different treatments. (C)RT + additional chemotherapy had the lowest mean score of 16.3 and CRT + delayed surgery had 17.7. There was a significant difference (p < 0.05) in overall survival (OS) and time to recurrence (TTR) of patients with a Low NAR-score (<8) compared to those with a High score (>16) for both CRT- and scRT, with a stronger correlation for CRT-patients. C-index for the NAR-score model (0.623) was not superior to when only pathological T- and N-stage was used (0.646).
The NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NAR-score can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.
Background
The purpose of this study was to investigate whether pT3–4 and pN-subclassifications, lymph-node ratio (LNR), tumour deposits, pre- and postoperative carcinoembryonic antigen (CEA), and ...C-reactive protein (CRP)—all parameters commonly collected in clinical management—add information about recurrence risk against a background of routine clinicopathological parameters as defined by the NCCN.
Methods
The prospective cohort consisted of all 416 patients diagnosed with colon cancer stage I–III in Uppsala County between 2010 and 2015. Cox proportional hazard models were used to calculate hazard ratios for time to recurrence and overall survival. The results were compared with the entire Swedish population concerning parameters recorded in the national quality registry, SCRCR, during the same time period.
Results
The Uppsala cohort was representative of the entire Swedish cohort. In unadjusted analyses, pT3-subclassification, pN-subclassification, LNR, tumour deposits, elevated postoperative CEA, and preoperative CRP correlated with recurrence. After adjusting for T-, N-stage, and NCCN risk factors, pN-subclassification, sidedness, and elevated postoperative CEA levels correlated with recurrence. Survival correlated with parameters associated with recurrence, LNR, and elevated postoperative CRP.
Conclusions
Additional information on recurrence risk is available from several routinely recorded parameters, but most of the risk is predicted by the commonly used clinicopathological parameters.
N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamineN-acetyltransferase that mainly converts ...aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamineN-acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased intracellular concentrations of mono- and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselectiveN(8)-acetylation of monoacetylated spermidine by NAT2 answers the long-standing question of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine-containing drugs by NAT2, which may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2, and we suggest that this enzyme should be considered for re-classification.
The completeness and accuracy of the registration of synchronous metastases and recurrences in the Swedish Colorectal Cancer Registry has not been investigated. Knowing how accurate these parameters ...are in the registry is a prerequisite to adequately measure the current recurrence risk.
All charts for patients diagnosed with stage I-III colorectal cancer (CRC) in two regions were reviewed. In one of the regions, all registrations of synchronous metastases were similarly investigated. After the database had been corrected, recurrence risk in colon cancer was calculated stratified by risk group as suggested by ESMO in 2020.
In patients operated upon more than five years ago (N = 1235), there were 20 (1.6%) recurrences not reported. In more recent patients, more recurrences were unreported (4.0%). Few synchronous metastases were wrongly registered (3.6%) and, likewise, few synchronous metastases were not registered (about 1%). The five-year recurrence risk in stage II was 6% for low-risk, 11% for intermediate risk, and 23% for high-risk colon cancer patients. In stage III, it was 25% in low- and 45% in high-risk patients. Incorporation of risk factors in stage III modified the risks substantially even if this is not considered by ESMO. Adjuvant chemotherapy lowered the risk in stage III but not to any relevant extent in stage II.
The registration of recurrences in the registry after 5 years is accurate to between 1 and 2% but less accurate earlier. A small number of unreported recurrences and falsely reported recurrences were discovered in the chart review. The recurrence risk in this validated and updated patient series matches what has been recently reported, except for the risk of recurrence in stage II low risk colon cancers which seem to be even a few percentage points lower (6 vs. 9%).
The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their ...contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGFβ/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer.
Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated ...with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.
Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at ...diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio OR = 0.3 in the targeted sequencing and OR = 0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR = 6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, non-responding tumors with initially small sizes carried a higher risk of recurrence. The findings, even if limited in addition to the imperfect clinical factors, offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.
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