We have previously demonstrated a significant negative impact of intratumoral neutrophils in metastatic renal cell carcinoma. This study assessed intratumoral neutrophils in localized clear cell ...renal cell carcinoma (RCC).
The study comprised 121 consecutive patients who had a nephrectomy for localized RCC. Biomarkers (intratumoral CD8+, CD57+ immune cells, CD66b+ neutrophils, and carbonic anhydrase IX CA IX) were assessed by immunohistochemistry, and the relationship with clinical and histopathologic features and patient outcome was evaluated.
The intratumoral neutrophils ranged from zero to 289 cells/mm(2) tumor tissue. The presence of intratumoral neutrophils was statistically significantly associated with increasing tumor size, low hemoglobin, high creatinine, and CA IX < or = 85%. In multivariate analysis, the presence of intratumoral neutrophils (hazard ratio HR, 3.0; 95% CI, 1.7 to 5.4; P < .0001), pT stage T3b/T4 (HR, 2.1; 95% CI, 1.2 to 3.6; P = .007), and low hemoglobin (HR, 1.8; 95% CI, 1.0 to 3.1; P = .03) were independent prognostic factors significantly associated with short recurrence-free survival. The presence of intratumoral neutrophils was also an independent prognostic factor for cancer-specific survival (HR, 3.5; 95% CI, 1.9 to 6.4; P < .0001) and overall survival (HR, 3.1; 95% CI, 1.9 to 5.0; P < .0001). Applying the prognostic value of intratumoral neutrophils to the Leibovich low-/intermediate-risk group (n = 78) showed a 5-year recurrence-free survival of 53% (95% CI, 34.6% to 71.8%; presence of intratumoral neutrophils) versus 87% (95% CI, 77.8% to 96.8%; absence of intratumoral neutrophils). The estimated concordance index was 0.74 using the Leibovich risk score and 0.80 when intratumoral neutrophils were added.
The presence of intratumoral neutrophils is a new, strong, independent prognostic factor for short recurrence-free, cancer-specific, and overall survival in localized clear cell RCC.
Aim
To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer.
Methods
We performed a post hoc analysis of the CRITICS trial, in which 788 ...patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data.
Results
In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11–1.85,
p
< 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42–2.25,
p
< 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (
p
< 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters.
Conclusion
CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position.
Trial registration
ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.
To analyze the relationship between pre-treatment measurements of tumor oxygen tension (pO
2) and survival in advanced head and neck cancer.
Eppendorf pO
2 measurements in 397 patients from seven ...centers were analyzed using the fraction of pO
2 values ≤2.5
mmHg (HP
2.5), ≤5
mmHg (HP
5) and median tumor pO
2 (mmHg) as descriptors. All patients had intended curative radiation therapy alone or as pre- or post-operative radiotherapy or radio-chemotherapy according to the practice at each center.
The degree of hypoxia varied between tumors with an overall median tumor pO
2=9
mmHg (range 0–62
mmHg), a median HP
2.5=19% (range 0–97%) and HP
5=38%, (range 0–100%). By quadratic regression median tumor pO
2 correlated with Hb (2
P=0.026,
n=357), while HP
2.5 or HP
5 did not. HP
2.5 above the population median was the only parameter that associated with poor overall survival (Kaplan Meier analysis,
P=0.006). In a multivariate Cox Proportional Hazards analysis, stratified according to institution HP
2.5 was by far the most statistically significant factor in explaining the variability in survival. After adjusting for HP
2.5, clinical stage, radiation dose and surgery hemoglobin concentration was not significant in the model. The prognostic model shows that the 5-year survival is almost constant for HP
2.5 values in the range from 0 to 20%, whereas the 5-year survival approaches 0% in the most hypoxic tumors.
This study provides evidence that tumor hypoxia is associated with a poor prognosis in patients with advanced head and neck cancer.
•Posterior beam proton spot scanning secures a high robustness towards anatomical changes.•Robust optimization in combination with full PTV coverage yields the highest robustness.•Posterior beam ...proton spot scanning maintains significant sparring of dose to normal tissue compared to IMRT.
SFUD strategies with one or two posterior proton beams and three target coverage strategies are compared with IMRT and tested for robustness towards anatomical changes by recalculation on surveillance CTs during treatment. We find posterior beam SFUD combining PTV coverage with robust optimization increases robustness towards anatomical changes compared to IMRT.
Introduction: In a previous report of 35 patients we suggested that pretreatment tumour pO
2 measured by Eppendorf electrodes was predictive of loco-regional control after primary radiotherapy in ...advanced head and neck squamous cell carcinomas. Radiother Oncol 41 (1996) 31.
Materials and methods: The aim of the present study was to test this hypothesis. Therefore, pretreatment tumour pO
2 was measured using the same assay in a new cohort of 35 patients that received an identical treatment being primary radiation along with a total dose of 66–68 Gy as 2 Gy per fraction over 5.5 or 6.5 weeks. Treatment outcome was evaluated as loco-regional control probability at 2 years using the same oxygenation parameter and applying the cut-off value from the first study.
Results: In agreement with the hypothesis generating study we found that the loco-regional tumour control probability was significantly higher (90%) among well oxygenated tumours as compared with the hypoxic subgroup (45%) (
P=0.04).
Conclusion: This study confirmed that pretreatment tumour oxygenation status was prognostic of loco-regional tumour control after primary radiation alone in advanced head and neck squamous cell carcinoma.
Purpose: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory
immune cells, thus potentially compromising this treatment option ...for patients with metastatic renal cell carcinoma. The impact
of IL-2–based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal
cell carcinoma is unknown.
Experimental Design: Baseline ( n = 58) and on-treatment ( n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before
and during IL-2–based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique
and correlated with other immune cell subsets and overall survival.
Results: A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm 2 ; range, 0-183) and on-treatment biopsies (median, 89 cells/mm 2 ; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively
correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment
( P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm 2 ) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months ( n = 11), whereas patients with low numbers (<180 cells/mm 2 ) of on-treatment FOXP3-positive cells ( n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive
cells.
Conclusion: Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2–based immunotherapy, and high numbers
of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.
Background
Epstein–Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of ...perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV−/MSS GCs who received either surgery only or perioperative treatment.
Methods
EBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival.
Results
In the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV−/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV−/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV−/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype.
Conclusions
In resectable GC, MSI-high had favorable outcome compared to EBV−/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients.
miRNAs might be potentially useful biomarkers for prediction of response to chemotherapeutic agents, radiotherapy and survival. The aim of this retrospective study was to validate miRNA response ...predictors in a cohort of patients with gastrooesophageal cancer in order to predict overall survival (OS) and disease-specific survival (DSS).
The study population encompassed 53 patients treated with curative intend for loco-regional gastrooesophageal cancer. miRNA expression was quantified from pre-therapeutic and diagnostic, formalin-fixed, paraffin embedded tumour specimens using Affymetrix GeneChip miRNA 1.0 Array. Based on growth inhibition of the NCI60 panel in the presence of cisplatin, epirubicine and capecitabine, a miRNA based response predictor was developed. The Cox proportional hazards model was applied to assess the correlations of the response predictor with OS and DSS.
A univariate analysis demonstrated a statistical significant improvement of OS for patients who had undergone surgical resection with prediction scores above the median prediction score (HR: 0.41 (95% CI: 0.17-0.96). Adjusting for surgery and stage, this predictor was identified to be independently associated with both OS (HR: 0.37 (95% CI: 0.16-0.87)) and DSS (HR: 0.32 (0.12-0.87)).
The miRNA profile predictive for sensitivity to cisplatin, epirubicine and capecitabine was shown to be independently associated with OS and DSS in patients with gastrooesophageal cancer.
Background and purpose: Hypoxic tumor cells are known to be relatively radioresistant. The aim of the study was to correlate oxygenation status and radiation response in advanced squamous cell ...carcinomas of head and neck.
Methods and patients: Pretreatment oxygenation status was measured in 34 lymph nodes and one primary tumor neck using oxygen electrodes. The primary oxygenation endpoint was the fraction of pO
2 values less than 2.5 mmHg. Patients received standardized, conventional, external radiotherapy 66–68 Gy in 33–34 fractions.
Results: Sixteen patients had loco-regional failure. Among these 16 patients the median of the fraction of pO
2 values less than 2.5 mmHg was 22% (range 0–95%) as compared to 6% (range 0–51%) among patients with loco-regional tumor control. When separating all 35 patients by the median of the fraction of pO
2 values less than 2.5 mmHg and comparing the 2 years actuarial tumor control probability using Kaplan-Meier estimates, the most hypoxic subgroup had significantly lower loco-regional tumor control (
P=0.013, Logrank test). By univariate regression analysis the fraction of pO
2 values less than 2.5 mmHg was found to be significant as continuous variable (
P=0.010). Finally, by Cox multiple regression analysis the fraction of pO
2 values less than 2.5 mmHg was found to be the strongest independent variable in predicting radiation response when using tumor control in the site of pO
2 assessment as treatment endpoint (
P=0.018).
Conclusion: These results suggest that pretreatment tumor oxygenation status is predictive of radiation response, when using the fraction of pO
2 values less than 2.5 mmHg as endpoint.
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