Union For International Cancer Control Stage Research Articles

Immature central tumor tertiary lymphoid structures are associated with better prognosis in non-small cell lung cancer

Background & aimsTertiary lymphoid structures (TLSs) are predictive biomarkers of favorable clinical outcomes and immunotherapy response in several solid malignancies, including non-small cell lung cancer (NSCLC). However, the relationship between TLSs and NSCLC prognosis has not been eludicated from the aspects of location, density, and maturity. This study aimed to investigate the clinicopathological and prognostic significance of TLSs in NSCLC.MethodsA collection of 151 resected pulmonary nodules in patients with NSCLC was retrospectively analyzed. Two experienced pathologists reviewed hematoxylin-eosin (H&E) slides and assessed TLS scores at different anatomic subregions. Then, we analyzed their correlation with clinicopathologic parameters and CD8 staining intensity and assessed multiple clinicopathological factors affecting patient prognosis.ResultsCD8 expression was correlated with total (TLS-CT) (P = 0.000), aggregates (Agg) (TLS-CT) (P = 0.001), follicles (FOL)-I (TLS-CT) (P = 0.025), and TLS(overall) (P = 0.013). TLS scores in the central tumor (CT) and invasion margin (IM) areas were negatively correlated with distant metastasis and Union for International Cancer Control (UICC) stage in NSCLC patients, while TLS score in the CT area was positively correlated with CD8 expression. TLS (overall), Agg (TLS-CT), and FOL-I (TLS-CT) were positively correlated with distant metastasis, UICC stage, and CD8 expression in NSCLC patients. Agg (TLS-IM) was positively correlated with distant metastasis and UICC stage. FOL-I (TLS-IM) was positively correlated with UICC stage. FOL-II (TLS-IM) was positively correlated with distant metastasis (P < 0.05). Multivariate Cox regression analysis showed that unfavorable independent prognostic factors were associated with metastasis status and UICC stage. Independent prognostic factors with protective effects included Agg (TLS-CT), FOL-I (TLS-CT), total (TLS-CT), and overall TLS (P < 0.05).ConclusionHistological score assessment of H&E sections of Agg (TLS-CT), FOL-I (TLS-CT), total (TLS-CT), and overall TLS levels in NSCLC has prognostic value.

Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer.

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in Union for International Cancer Control (UICC) stage IV CRC patients. Insights into differential site-specific reconstitution of tumor cells and the corresponding tumor microenvironment are still missing. Here, we analyzed the transcriptome of single cells derived from murine multivisceral CRC and delineated the intermetastatic cellular heterogeneity regarding tumor epithelium, stroma, and immune cells. Interestingly, we found an intercellular site-specific network of cancer-associated fibroblasts and tumor epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell-dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and - based on the results of our analysis - provided an auspicious site-specific immunomodulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.

Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer

Management of colorectal cancer (CRC) has been updated continuously over the past 2 decades. While the combination of these initiatives has had implications for improved survival, the implications for rates of recurrence remain unexplored. To ascertain the rates of recurrence and describe time to recurrence within 5 years of surgery with curative intent for stages I to III CRC. This cohort study used the Danish Colorectal Cancer Group Database to identify patients with Union for International Cancer Control (UICC) stages I to III CRC who underwent primary surgery between January 1, 2004, and December 31, 2019. They were followed up until recurrence (event), death (competing event), diagnosis of a second cancer (competing event), emigration (censoring event), 5 years postoperatively (censoring event), or January 1, 2023 (censoring event), whichever came first. Recurrence status was ascertained through individual-level linked data from the Danish Cancer Registry, Danish National Patient Registry, and Danish Pathology Registry using a validated algorithm. Data were analyzed from January 1 to August 8, 2023. Primary surgery performed during 3 calendar periods (2004-2008, 2009-2013, and 2014-2019) stratified by tumor site (colon or rectum) and UICC stage (I, II, and III). Stage-specific 5-year recurrence reported as the cumulative incidence function (CIF) of recurrence, the association between calendar period of primary surgery and recurrence risk reported as subdistribution hazard ratios (sHRs), and the time from surgery to recurrence. Of the 34 166 patients with UICC stages I to III CRC (median [IQR] age, 70 [62-77] years); 18 552 males [54.3%]) included in the study, 7027 developed recurrence within 5 years after the primary surgery. For colon cancer, the 5-year CIF of recurrence decreased over the 3 calendar periods from 16.3% to 6.8% for UICC stage I, from 21.9% to 11.6% for UICC stage II, and from 35.3% to 24.6% for UICC stage III colon cancer. For rectal cancer, the 5-year CIF decreased over the 3 periods from 19.9% to 9.5% for stage I, from 25.8% to 18.4% for stage II, and from 38.7% to 28.8% for stage III disease. Patients with stage III disease had a shorter time from surgery to recurrence compared with those with stage I disease (time ratio stage III vs stage I = 0.30; 95% CI, 0.28-0.32). Cancers detected through screening were associated with lower stage-adjusted risks of recurrence (sHR, 0.81; 95% CI, 0.73-0.91) compared with cancers not detected through screening. In this cohort of patients with CRC, the risk of recurrence decreased in patients with stages I to III disease during the study period. Cancer detection by screening was associated with an even lower risk of recurrence. Time to recurrence differed according to UICC stage. Because the risk of recurrence was so low in selected patient groups, future research is warranted to explore risk-stratified surveillance protocols in patients with CRC.

Narrowing the therapeutic window?-A case-control study on the influence of the COVID-19 pandemic on the primary UICC stage of NSCLC.

General clinical perception suggests a decline in the diagnosis and treatment of lung cancer during the SARS-CoV-2 pandemic. Early diagnosis of non-small cell lung cancer (NSCLC) is crucial in therapeutic regimes as early stages are potentially curable by operation alone or with combined therapy. Pandemic-triggered overload of the healthcare system may have prolonged the diagnosis of NSCLC, possibly leading to higher tumor stages at first diagnosis. This study aims to identify how COVID-19 affected the distribution of the Union for International Cancer Control (UICC) stage in NSCLC at first diagnosis. A retrospective case-control study was conducted, including all patients receiving their first diagnosis of NSCLC in the regions of Leipzig and Mecklenburg-Vorpommern (MV) between January 2019 and March 2021. Patient data were retrieved from the clinical cancer registries of the city of Leipzig and the federal state of MV. Ethical approval for this retrospective evaluation of archived, anonymized patient data was waived by the Scientific Ethical Committee at the Medical Faculty, Leipzig University. Three investigation periods were defined to study the effects of high incidences of SARS-COV-2: the curfew period as an enacted security measure, the period of high incidence rates and the period of the aftermath of high incidences. Differences in the UICC stages between these pandemic periods were studied by Mann-Whitney-U-Test. Pearson's correlation was calculated to examine changes in operability. The number of patients diagnosed with NSCLC dropped substantially during investigation periods. There was a significant difference in the UICC status in the aftermath of high incidences and imposed security measures in Leipzig (P=0.016). N-status differed significantly in the aftermath of high incidences and imposed security measures (P=0.022) with a decrease of N0- and an increase of N3-status, respectively, while N1- and N2-status remained relatively unaffected. No pandemic phase showed a significant difference in operability. The pandemic led to a delay in the diagnosis of NSCLC in the two examined regions. This resulted in higher UICC stages upon diagnosis. However, no increase in inoperable stages was shown. It remains to be seen, how this will affect the overall prognosis of the involved patients.

Chemerin and Chemokine-like Receptor 1 Expression Are Associated with Hepatocellular Carcinoma Progression in European Patients.

The chemoattractant protein chemerin is protective in experimental hepatocellular carcinoma (HCC), and high expression in HCC tissues of Asian patients was related to a favorable prognosis. Studies from Asia found reduced expression of chemerin in HCC compared to para-tumor tissues while our previous analysis observed the opposite. Aim of this study was to correlate chemerin expression in HCC tissues with disease severity of European patients Hepatocyte chemerin protein expression was assessed by immunohistochemistry in HCC tissue of 383 patients, and was low in 24%, moderate in 49% and high in 27%. High chemerin protein in the HCC tissues was related to the T stage, vessel invasion, histologic grade, Union for International Cancer Control (UICC) stage and tumor size. Chemokine-like receptor 1 (CMKLR1) is a functional chemerin receptor. CMKLR1 protein in hepatocytes was low expressed in HCC tissues of 36%, moderate in tissues of 32% and high in 32% of the HCCs. Tumor CMKLR1 was associated with the T stage, vessel invasion, histologic grade and UICC stage. Notably, sex-specific analysis revealed that associations of chemerin and CMKLR1 expression with HCC progression were significant in males but not in females. The tumor chemerin and CMKLR1 protein expression were not related to steatosis, inflammation and fibrosis grades. In summary, chemerin as well as CMKLR1 protein were related to disease severity of European HCC patients, and this was significant in males. This observation is in contrast to Asian patients where higher chemerin in the tumors was protective. Current analysis provides evidence for ethnicity and sex-related differences of tumor expressed chemerin and HCC severity.

Elevated Levels of Circulating Hsp70 and an Increased Prevalence of CD94+/CD69+ NK Cells Is Predictive for Advanced Stage Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less than 16 months. It is well established that many aggressive tumor entities, including NSCLC, overexpress the major stress-inducible heat shock protein 70 (Hsp70) in the cytosol, present it on the plasma membrane in a tumor-specific manner, and release Hsp70 into circulation. Although high Hsp70 levels are associated with tumor aggressiveness and therapy resistance, membrane-bound Hsp70 can serve as a tumor-specific antigen for Hsp70-primed natural killer (NK) cells, expressing the C-type lectin receptor CD94, which is part of the activator receptor complex CD94/NKG2C. Therefore, we investigated circulating Hsp70 levels and changes in the composition of peripheral blood lymphocyte subsets as potential biomarkers for the advanced Union for International Cancer Control (UICC) stages in NSCLC. As expected, circulating Hsp70 levels were significantly higher in NSCLC patients compared to the healthy controls, as well as in patients with advanced UICC stages compared to those in UICC stage I. Smoking status did not influence the circulating Hsp70 levels significantly. Concomitantly, the proportions of CD4+ T helper cells were lower compared to the healthy controls and stage I tumor patients, whereas that of CD8+ cytotoxic T cells was progressively higher. The prevalence of CD3-/CD56+, CD3-/NKp30, CD3-/NKp46+, and CD3-/NKG2D+ NK cells was higher in stage IV/IIIB of the disease than in stage IIIA but were not statistically different from that in healthy individuals. However, the proportion of NK cells expressing CD94 and the activation/exhaustion marker CD69 significantly increased in higher tumor stages compared with stage I and the healthy controls. We speculate that although elevated circulating Hsp70 levels might promote the prevalence of CD94+ NK cells in patients with advanced-stage NSCLC, the cytolytic activity of these NK cells also failed to control tumor growth due to insufficient support by pro-inflammatory cytokines from CD4+ T helper cells. This hypothesis is supported by a comparative multiplex cytokine analysis of the blood in lung cancer patients with a low proportion of CD4+ T cells, a high proportion of NK cells, and high Hsp70 levels versus patients with a high proportion of CD4+ T cells exhibiting lower IL-2, IL-4, IL-6, IFN-γ, granzyme B levels.

Laparoscopic Complete Mesocolic Excision Without Routine Gastro-Pancreatico-Colic Trunk Dissection: Survival Outcomes and Morbidity for 567 Cases.

Purpose: It is unclear whether the principles of open complete mesocolic excision (CME) can be safely applied to laparoscopic surgery. Furthermore, definitions vary over how radical optimal CME surgery should be. We report morbidity and oncological outcomes for laparoscopic CME without routine gastro-pancreatico-colic trunk (GPCT) dissection. Materials and Methods: An observational study with consecutive data for patients with Union for International Cancer Control (UICC) stage I-III colon adenocarcinoma who underwent elective laparoscopic resection between 2006 and 2015. Data were retrieved for demographics, tumor characteristics, treatment, and histology from prospectively maintained databases. Standardized, routinely video recorded, laparoscopic resections were performed in two United Kingdom centers from The National Training Programme for Laparoscopic Colorectal Surgery. Overall survival and disease-free survival (DFS) were reported using Kaplan-Meier curves and Cox regression. Results: Laparoscopic CME was performed in 567 patients, 52.7% (288/546) women, median (interquartile range [IQR]) age 73 (65-80) years. Median (IQR) length of stay was 4 (3-5) days with 4.0 (2.2-5.7)-year follow-up. Significant DFS predictors (hazard ratio [HR]) by multivariable Cox regression were age >80 years (1.9), American Society of Anesthesiologists (ASA) 3 and 4 (HR = 1.1), right colon cancer (1.7), UICC stage III (3.4), and intramesocolic grade (2.2). Overall 4-year DFS (95% confidence interval) was 81.3% (77-85). Four-year DFS by UICC grades I, II, and III was 94.6% (89-99), 83.4% (77-88), and 72.2% (66-78), respectively (log-rank P = .001). Morbidity by Clavien-Dindo grade was III 18 (3.2%), IV 4 (0.7%) and V 7 (1.2%). Conclusion: This large series suggests standardized laparoscopic CME without routine GPCT dissection has a low morbidity and achieves equivalent outcomes to the most radical open CME techniques.

Pattern of breast cancer presentation during the COVID-19 pandemic: results from a cohort study in the UK.

Background: This study aimed to explore the hypothesis that the stage of breast cancer at initial diagnosis in 2020 is more advanced compared with 2019. Methods: Tumor, node, metastasis and Union for International Cancer Control (UICC) stages of new breast cancer diagnoses at the Bucks Breast Unit from May to October 2019 and 2020 were reviewed. A p < 0.05 was considered significant. Results: Average UICC stage increased from 1a in 2019 to 2a in 2020 (p < 0.01). Excluding cancers detected through screening, UICC stage still increased from 1b in 2019 to 2a in 2020 (p = 0.0184). There was a significant increase in the percentage of node-positive patients (p = 0.0063) and patients with metastatic disease (p = 0.0295) on initial presentation. Conclusion: Overall, patients presented with higher UICC stages and more node-positive and metastatic disease on initial diagnosis in 2020 compared with 2019.

Epidemiology and surgical treatment of pancreatic cancer in the State of Brandenburg : Analysis of 5418 cases

Pancreatic cancer is the second most frequent cause of death among all forms of cancer in Germany with more than 19,000 deaths per year. The evaluation of the nationwide clinical cancer register aims to depict the reality of treatment and to improve the quality of treatment in the future by targeted analyses. The data from the clinical cancer register of Brandenburg-Berlin for the diagnosis years 2001-2017 were analyzed with respect to the treatment of pancreatic cancer. Data from patients resident in the State of Brandenburg were evaluated with respect to epidemiological and therapeutic parameters. A total of 5418 patients with pancreatic cancer were documented in the register from 2001 to 2017 and 49.6% of the patients were diagnosed as having the Union for International Cancer Control (UICC) stage IV. A pancreas resection was carried out in 26.4% of the cases. In cases of cancer of the head of the pancreas the most frequent procedure was a pylorus-preserving resection with 51.8% and a pancreatectomy was carried out in 9.4%. The R0 resection rate of all pancreatic cancers in the period from 2014 to 2017 was 61.9%. After R0 resection the 5‑year survival was 19%. Relevant multivariate survival factors were age, UICC stage and the residual (R) tumor classification. The case numbers per hospital had no influence on the absolute survival of patients operated on in the State of Brandenburg. The treatment reality in the State of Brandenburg for patients with pancreatic cancer corresponds to the results of international publications with respect to the key performance indicators investigated. A qualitative internationally comparable treatment of these patients is also possible in nonmetropolitan regions.

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months in the pCTX + TACE group versus 13.1 months in the pCTX group (p = 0.008). Controlling for albumin, bilirubin, ECOG (Eastern Cooperative Oncology Group) performance status, and UICC (Union for International Cancer Control) stage, the addition of TACE still conferred an OS benefit of 12.95 months (p = 0.014). A propensity score matching analysis yielded an OS benefit of 14 months from the time of unresectability for the pCTX + TACE group (p = 0.020). The addition of TACE to pCTX may provide an OS benefit for patients with unresectable iCCA. Thus, patients with liver-dominant iCCA undergoing standard-of-care pCTX should be considered for additional treatment with TACE.

Complex Liver Resections for Intrahepatic Cholangiocarcinoma.

: BackgroundThe only curative treatment option for intrahepatic cholangiocarcinoma (iCCA) is liver resection. Due to central tumor localization and vascular invasion, complex liver resections play an important role in curative treatment. However, the long-term outcomes after complex liver resection are not known. Methods: A retrospective cohort study was conducted for all patients undergoing liver surgery for iCCA. Complex liver resections included ante situm resections, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and major liver resection with vascular reconstructions. Results: Forty-nine patients (34%) received complex liver resection, 66 patients (46%) received conventional liver resection and 28 patients (20%) were not resectable during exploration. Preoperative characteristics were not different between the groups, except for Union for International Cancer Control (UICC) stages. The postoperative course for complex liver resections was associated with more complications and perioperative mortality. However, long-term survival was not different between complex and conventional resections. Independent risk factors for survival were R0 resections and UICC stage. Four patients underwent ante situm resection without any mortality. Conclusions: Complex liver resections are justified in selected patients and survival is comparable with conventional liver resections. Survival in iCCA is affected by UICC stage or resections margins and not by the complexity of the case.

Chemoradiotherapy by intensity-modulated radiation therapy with simultaneous integrated boost in locally advanced or oligometastatic non-small-cell lung cancer\u2014a\xa0two center experience

PurposeIntegrating moderate hypofractionation to the macroscopic tumor with elective nodal irradiation while sparing the organs at risk (OAR) in chemoradiotherapy of locally advanced non-small-cell lung cancer.MethodsFrom 2010–2018, treatment, patient and tumor characteristics of 138 patients from two radiation therapy centers were assessed. Chemoradiotherapy by intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) to the primary tumor and macroscopic lymph node metastases was used.ResultsA total of 124 (90%) patients received concurrent chemotherapy. 106 (76%) patients had UICC (Union for International Cancer Control) stage ≥IIIB and 21 (15%) patients had an oligometastatic disease (UICC stage IV). Median SIB and elective total dose was 61.6 and 50.4 Gy in 28 fractions, respectively. Furthermore, 64 patients (46%) had an additional sequential boost to the primary tumor after the SIB-IMRT main series: median 6.6 Gy in median 3 fractions. The median cumulative mean lung dose was 15.6 Gy (range 6.2–29.5 Gy). Median follow-up and radiological follow-up for all patients was 18.0 months (range 0.6–86.9) and 16.0 months (range 0.2–86.9), respectively. Actuarial local control rates at 1, 2 and 3 years were 80.4, 68.4 and 57.8%. Median overall survival and progression-free survival was 30.0 months (95% confidence interval [CI] 23.5–36.4) and 12.1 months (95% CI 8.2–16.0), respectively. Treatment-related toxicity was moderate. Radiation-induced pneumonitis grade 2 and grade 3 occurred in 13 (9.8%) and 3 (2.3%) patients.ConclusionsChemoradiotherapy using SIB-IMRT showed promising local tumor control rates and acceptable toxicity in patients with locally advanced and in part oligometastatic lung cancer. The SIB concept, resulting in a relatively low mean lung dose, was associated with low numbers of clinically relevant pneumonitis. The overall survival appears promising in the presence of a majority of patients with UICC stage ≥IIIB disease.

Prognostic significance of extracellular volume fraction with equilibrium contrast-enhanced computed tomography for pancreatic neuroendocrine neoplasms

Background/Objectives: Identifying reliable pretreatment imaging biomarkers for pancreatic neuroendocrine neoplasm (PanNEN) is a key imperative. Extracellular volume (ECV) fraction quantified with equilibrium contrast-enhanced CT can be easily integrated into routine examinations. This study aimed to determine whether ECV fraction with equilibrium contrast-enhanced computed tomography (CECT) could predict long-term outcomes in patients with PanNEN. MethodsThis study was a retrospective observational study of 80 patients pathologically diagnosed with PanNEN at a single institution. ECV fraction of the primary lesion was calculated using region-of-interest measurement within PanNEN and the aorta on unenhanced and equilibrium CECT. The impact of clinical factors and tumor ECV fraction on progression-free survival (PFS) and overall survival (OS) was assessed with univariate and multivariate analyses using Cox proportional hazards models. The correlation between WHO classification and tumor ECV fraction was evaluated using Kendall rank correlation coefficients. ResultsPFS and OS rates were estimated as 93.4% and 94.6%, 78.7% and 86.2%, 78.7% and 77.0%, and 78.7% and 66.6% at 1, 3, 5, and 10 years, respectively. Multivariate analysis revealed that Union for International Cancer Control (UICC) stage (hazard ratio [HR] = 3.95, P = 0.003), WHO classification (HR = 12.27, P = 0.003), and tumor ECV fraction (HR = 11.93, P = 0.039) were independent predictors of PFS. Patient age (HR = 1.11, P < 0.001), UICC stage (HR = 3.14, P = 0.001), and tumor ECV fraction (HR = 5.27, P = 0.024) were independent significant variables for predicting OS. Tumor ECV fraction had a weak inverse relationship with WHO classification (P = 0.045, τ = −0.178). ConclusionsECV fraction determined by equilibrium CECT and UICC stage may predict survival in patients with PanNEN.

Abstract 3755: PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer

Abstract Anti-Epithelial/Vascular Endothelial Growth Factor (EGF/VEGF)-targeted therapy plays important roles in advanced stage colorectal cancer (CRC) patients but fails to show clinical efficacy in specific subgroups which lack of clear underlying mechanisms. In vitro studies indicated that cross-talk or alternative receptor/ligand activities can bypass anti-growth factor signaling arrest and therefore may explain failure of monoclonal antibody (mAb) targeted therapy. In this study we analyzed effects of Platelet Derived Growth Factor (PDGF)-mediated bypassed signaling in CRC. We first investigated human UICC (Union for International Cancer Control ) stage I-IV tumors (n=46) from our Center and found increased PDGFRβ and VEGFR1/2 gene expression (p&amp;lt;0.01/p&amp;lt;0.001). Interestingly, further analysis on human HT29 colon cancer in vitro showed upregulated VEGFR1/2 expression upon VEGF stimulation. This was even more pronounced upon stimulation with PDGF. Inhibition of VEGFR2 and EGFR resulted in decreased HT29 cell proliferation, while additional treatment with VEGF and particularly PDGF attenuated the inhibiting effect and resulted in altered downstream signaling events. Treatment with the tyrosine kinase inhibitor Regorafenib alone, that blocks VEGFR/EGFR+PDGFR, prevented PDGF and VEGF-induced proliferation. This effect was not observed for either VEGFR2 mAb treatment with Ramucirumab or EGFR mAb therapy with Cetuximab. To conclude, PDGF-induced human colon cancer proliferation in the absence of PDGFR and simultaneously inhibited VEGFR2 and EGFR expression in HT29 colon cancer cells suggests bypassed alternative PDGF receptor partners for ligand binding on the tumor cell surface and subsequent intracellular signaling. This may explain failure of anti-VEGF/EGF-targeted monoclonal antibody therapies in CRC patient subgroups and underlines the necessity to effectively inhibit PDGF-mediated signaling events beside VEGF/EGF blockade in patients with increased PDGF expression within their tumors. Citation Format: Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3755.

Benefit of adjuvant chemotherapy in high-risk colon cancer: A 17-year population-based analysis of 6131 patients with Union for International Cancer Control stage II T4N0M0 colon cancer

BackgroundThe benefit of adjuvant chemotherapy in Union for International Cancer Control (UICC) stage III colon cancer has been demonstrated in numerous studies. While adjuvant chemotherapy is generally not recommended in stage II patients, its role in high-risk UICC stage II disease (e.g. T4 tumours) remains controversial. MethodsThe present population-based multicenter cohort study investigated the influence of adjuvant chemotherapy on survival and recurrence rates in high-risk UICC stage II T4N0M0 tumours. Based on an anonymised nationwide ADT data set from 31 clinical cancer registries, we identified a total of 6651 patients with a T4 tumour of the colon, of whom 6131 were eligible for survival analysis. A matched-pair analysis based on propensity scores (PSM) was performed with a subset of 3986 patients. ResultsMultivariable analyses demonstrated a significant benefit of adjuvant chemotherapy for overall survival (OS) (hazard ratio [HR]: 0.711, 95% confidence interval [CI]: 0.643–0.785, p < 0.001), cumulative recurrence rate (HR: 0.780, 95% CI: 0.681–0.893, p < 0.001), and recurrence-free survival (HR: 0.715, 95% CI: 0.652–0.785, p < 0.001) further confirmed by the matched-pair cohort. ConclusionThis large and representative study demonstrated a significant advantage of adjuvant chemotherapy for patients with T4 UICC stage II colon cancer in terms of OS, recurrence rate, and relapse-free survival. Based on these results, adjuvant chemotherapy should be recommended for these patients.

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

The Potential of CD16 on Plasma-Derived Exosomes as a Liquid Biomarker in Head and Neck Cancer.

Head and neck squamous cell carcinomas (HNSCC) are highly immune suppressive and aggressive malignancies. As part of the tumor microenvironment, exosomes contribute to this immune suppression. The Fc receptor CD16 is widely expressed on monocytes, neutrophils, and natural killer (NK) cells and is involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Here, surface levels of CD16 on total exosomes and tumor-derived exosomes (TEX) from plasma of HNSCC patients were analyzed regarding their potential as liquid biomarkers for disease stage. Exosomes were isolated from plasma using mini size exclusion chromatography. TEX were enriched by immune affinity capture with CD44v3 antibodies. On-bead flow cytometry was used to measure CD16 levels on total exosomes and TEX. The results were correlated with clinicopathological parameters. Total exosomes from HNSCC patients had significantly higher CD16 levels compared to TEX. Further, CD16 surface levels of total exosomes, but not TEX, correlated with clinicopathological parameters. Patients with advanced tumor stages T3/4 and Union for International Cancer Control (UICC) stages III/IV had significantly higher CD16 levels on total exosomes compared to patients with early tumor stages T1/2 and UICC stages I/II, respectively. Overall, CD16 positive exosomes have the potential as liquid biomarkers for HNSCC tumor stage and aggressiveness.

Outcome in Patients Treated With Cytoreductive Surgery and HIPEC for Gastric Cancer With Peritoneal Carcinomatosis

We compared patients with advanced gastric cancer [Union for International Cancer Control (UICC) III] versus patients with stage UICC IV and peritoneal carcinomatosis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) versus patients with stage UICC IV treated without HIPEC to ascertain if CRS and HIPEC improve overall survival (OS). We retrospectively analysed thirty-seven advanced gastric cancer patients who had been treated at our department from 2012 to 2017. The endpoint was median OS. Eighteen (49%) patients with UICC stage III showed a median OS of 37.4 months. Eight (21%) patients in the HIPEC group reached a median OS of 33.8 months. Median OS in the UICC IV group (11 patients, 30%) treated with a palliative concept was 6.2 months and therefore significantly worse (p=0.004). A systemic approach combined with CRS and HIPEC in selected stage IV gastric cancer patients improves the OS comparable to patients in UICC stage III.

Prognostic implications of the eighth edition of the union for international cancer control - classification for gastric cancer patients from specialized treatment centers in Germany and Korea: A STOBE-Compliant large-scale cohort study.

The validity of the 8th edition of the Union for International Cancer Control (UICC) staging system for gastric cancer has been evaluated only in Asian cohorts and not in European cohorts. The aim of this study was to evaluate the prognostic performance of the 8th edition of the UICC staging system in German and Korean cohorts independently and compare it with that of the 7th edition.A total of 6121 patients (526 from Germany and 5595 from Korea) who underwent upfront surgery for gastric cancer were retrospectively reclassified according to the 8th edition. Survival according to the UICC stages was estimated by the Kaplan-Meier method and compared by log-rank tests. A Cox proportional hazards model was fitted after adjusting for clinicopathological factors, and receiver operating characteristics analysis was conducted.The 8th edition showed significant differences in survival between each adjacent stage in the Korean cohort but not in the German cohort. Multivariate analyses revealed that the 8th edition staging was an independent prognostic factor, and its C-statistics were >0.76 in both German and Korean patients. The results were comparable to those observed with the UICC seventh edition (C-statistics was 0.768 vs 0.767 in the German cohort and 0.789 vs 0.785 in the Korean cohort for the 7th vs the 8th edition).The 8th edition showed prognostic value in predicting the survival of gastric cancer patients in both German and Korean cohorts. However, the predictive ability of the 8th and 7th edition was similar.

Early Detection of Pancreatic Cancer in Patients With Chronic Liver Disease Under Hepatocellular Carcinoma Surveillance

ObjectiveTo evaluate whether patients with hepatitis B virus (HBV)– and hepatitis C virus (HCV)–related chronic liver disease were diagnosed as having pancreatic cancer (PC) at an early stage during abdominal imaging surveillance for hepatocellular carcinoma (HCC). Patients and MethodsWe retrospectively examined 447 patients with PC diagnosed at Ehime University Hospital and affiliated centers (2011-2013). Data were collected regarding HBV and HCV status, likelihood of PC diagnosis, and Union for International Cancer Control (UICC) stage. Intergroup comparisons were performed using the χ2 test. ResultsThe UICC stage distribution in the HCC surveillance group (n=16) was stage 0 (n=2, 12.5%), stage IA (n=3, 18.8%), stage IB (n=2, 12.5%), stage IIA (n=2, 12.5%), stage IIB (n=2, 12.5%), stage III (n=1, 6.3%), and stage IV (n=4, 25%). The UICC stage distribution in the nonsurveillance group (n=431) was stage 0 (n=4, 0.9%), stage IA (n=28, 6.5%), stage IB (n=27, 6.3%), stage IIA (n=86, 20.0%), stage IIB (n=48, 11.1%), stage III (n=56, 13.0%), and stage IV (n=182, 42.2%). The HCC surveillance group had significantly more patients with stage 0 disease than with stages IA through IV (P=.02). Similar results were observed when including stages IA (P=.007) and IB (P=.004) as early stages but not stage IIA (P=.10). A dilated pancreatic duct led to a PC diagnosis in all 6 patients with stage 0 disease. ConclusionPatients with HBV- and HCV-related chronic liver disease had an early PC diagnosis during HCC surveillance. Careful evaluation of the pancreas is warranted during HCC surveillance.