Defining a high-risk subgroup with colon cancer stages I and II for possible adjuvant therapy

AimAdjuvant therapy is not routinely recommended in UICC stages I and II colon cancer, but may be considered for high-risk patients. Our aim is to identify clinicopathologic characteristics in colon cancer stages I and II, which are associated with an increased risk of tumour recurrence and tumour-related death.MethodsWe analysed our prospectively documented clinical database of 775 patients with colon cancer stages I and II, which underwent curative resection between 1982 and 2006. No adjuvant chemotherapy was applied. The median follow-up time was 80 months.ResultsFor the entire study group, 5- and 10-year tumour-specific survival probabilities were 94.8 ± 0.9% and 91.0 ± 1.4%, respectively. Multivariate analysis identified three tumour characteristics as independent prognostic factors: lymphatic vessel invasion (p = 0.034), poor tumour grading (G3/G4) (p = 0.020) and extended tumour length (?6 cm) (p = 0.042). Five-year (10-year) tumour-specific survival for patients without any of the poor prognostic tumour characteristics (ppTCs) was 96.0% (94.7%). There was a significantly increased risk for tumour-related death with increasing numbers of ppTCs (p < 0.001). While patients with only one ppTC had a 5-year (10-year) tumour-specific survival of 94.8% (88.9%), it decreased to 88.9% (78.4%) for patients with two ppTCs (hazard ratio (HR) 3.69, 95% confidence interval (CI) 1.67–8.13) and to 87.5% (72.9%) for patients with all three ppTCs (HR 6.56, 95% CI 1.50–26.62).ConclusionPatients with stage I or II colon cancer have a favourable prognosis after radical resection. The presence of two or three poor prognostic tumour characteristics identifies a small patient subgroup (12%) with an increased risk of tumour-related death that may be considered for adjuvant chemotherapy.     

HER3 expression in patients with primary colorectal cancer and corresponding lymph node metastases related to clinical outcome

AimTo evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases.Patient and methodsHER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed.ResultsHER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p = 0.026) and in the subgroup of patients with colon cancer stage II (p = 0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r = 0.9, p < 0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r = 0.6, p < 0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis.ConclusionA high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.     

The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: A North American validation

BackgroundA reclassification of the International Union Against Cancer (UICC) staging system for adrenocortical carcinoma (ACC) patients has recently been proposed by the European Network for the Study of Adrenal Tumors (ENSAT) to better discriminate between cancer-specific mortality (CSM) risk strata. We formally tested the validity of the modified staging system in a large North American population-based cohort.MethodsKaplan–Meier survival curves depicted CSM rates in the overall population and after stratification according to the 2004 UICC or the 2008 ENSAT-staging system. Cox regression models addressing CSM tested the prognostic value of respectively the UICC or the ENSAT-staging system. Harrell’s concordance index quantified the accuracy of the standard versus the modified staging system.ResultsIn the overall population (n = 573), the CSM-free survival rates at 1, 3, and 5 years were, respectively, 62.9%, 47.0%, and 38.1%. No statistically significant differences in survival were recorded between 2004 UICC stages II and III patients (p = 0.1). Conversely, a statistically significant difference was observed between 2008 ENSAT stage II and stage III patients (p < 0.001). The 2008 ENSAT-staging system showed higher accuracy (83.0%) in predicting 3-year CSM rates, relative to the 2004 UICC-staging system (79.5%) (p < 0.001).ConclusionOur study corroborates the superior accuracy of the ENSAT-staging system for ACC relative to the 2004 UICC-staging system. In consequence, the 2008 ENSAT-staging system may warrant consideration in the next update of staging manuals.     

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients

AimThe hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC.MethodsImmunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors.ResultsHIF-1α was positively correlated with HIF-2α (p < 0.0001), PHD1 (p = 0.024), PHD2 (p < 0.0001), PHD3 (p = 0.004), FIH (p < 0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p < 0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009).ConclusionThese results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.     

Loss of Bcl-2 expression in colon cancer: A prognostic factor for recurrence in stage II colon cancer

AimsTo evaluate the prognostic value of immunohistochemical expression of Bcl-2 in colon cancers.Patients and methodsTwo hundred and twenty-six resected and paraffin-embedded colon carcinomas were analysed by immunostaining using monoclonal antibodies for Bcl-2. We evaluated whether the Bcl-2 staining patterns, semi-quantitatively assessed, could be correlated with the pTNM stage, size and tumour circumference, differentiation, appearance, vascular invasion, perineural invasion, colloid component, margins, involvement of adjacent structures, stromal appearance, flow cytometry and the S-phase.ResultsEighty patients (36%) were considered Bcl-2 positive. The extent of Bcl-2 expression by tumour cells decreased significantly with respect to increasing tumour size (P = 0.042), the extension of parietal invasion pT (P = 0.007), the invasive nature of the tumour (P = 0.024), and extent of the circumference (P = 0.024). In a multivariate analysis, Bcl-2 expression does not appear as an independent prognosis factor in the overall population as in the 166 patients with optimal resection. Of the 59 stage II patients, using univariate analysis, Bcl-2 appears to be predictive of relapse-free survival (P = 0.025) but not of overall survival (P = 0.09).ConclusionThe loss of Bcl-2 expression appears to be correlated with increase in number of relapses in the stage II colon cancers and could be a potential useful additional histo-prognostic marker in therapy decision making. Bcl-2 immunodetection seems to be associated with slower local tumour growth.     

Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: Results from the multicenter,randomised trial Fédération Francophone de Cancérologie Digestive 9601

ObjectiveTo assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC).DesignAmong the 294 patients with non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test.ResultsAmong the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p = 0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval [CI], 0.4–0.8; p = 0.0002) and OS (HR, 0.4; CI, 0.3–0.6; p < 0.0001). Both median PFS (5.1 [4.6–5.6] versus 2.9 [2.2–4.1] months; p = 0.001) and OS (16.3 [13.7–19.2] versus 9.6 [7.4–12.5]; p < 0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary (n = 43).ConclusionResection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.     

Tumour budding is a strong and independent prognostic factor in pancreatic cancer

IntroductionPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC.AimTo assess the frequency and prognostic impact of tumour budding in PDAC.MethodsWhole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10 buds across 10 HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines.ResultsInter-observer agreement was considered strong (ICC = 0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p = 0.0463), lymphatic invasion (p = 0.0192) and decreased disease-free (p = 0.0005) and overall survival (p < 0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p < 0.0001; HR (95% CI): 3.65 (2.1–6.4)).ConclusionsOur results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches.     

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

IntroductionAkt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER–) breast cancer with long-term follow-up.Material and methodsThe expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model.ResultsThe risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER– tumours to 68% risk reduction for the group with high ER-levels (P for trend = 0.042). Akt1 showed no significant prognostic information.ConclusionOur results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.     

Role of emphysema and airway obstruction in prognosis of lung cancer

Background and objectiveIt has been reported that the presence of COPD and emphysema is associated with an increased risk of lung cancer, but the prognosis significance of these two conditions is not well known. The aim of our study was to analyze the influence of COPD and emphysema in the prognosis of non-small cell lung cancer (NSCLC).MethodsThree hundred and fifty-three patients with cytohistologic diagnosis of NSCLC were prospectively collected. The relationship between survival at two years and the following variables: age, sex, smoking habit, comorbid diseases (cardiovascular diseases, previous tumour and COPD), weight loss, presence of emphysema on CT scan, performance status (PS) and treatment, was analyzed. The Kaplan–Meier method and log-rank test were used for survival analysis. A multivariate Cox proportional hazard model, stratified by TNM stage, was used to evaluate prognostic factors.ResultsEmphysema was present in 110 patients, associated with COPD in 78 (70.9%). In univariate analysis, survival decreased with age > 70 years (p = 0.01), presence of emphysema (p = 0.02), weight loss (p = 0.00001), PS ≥ 2 (p = 0.00001) and symptomatic treatment (p = 0.0001). Multivariate analyses identified emphysema (HR = 1.49 (95% CI 1.11–2.01)), PS ≥ 2 (HR = 2.12 (95% CI 1.31–3.38)) and treatment: surgery (HR = 0.3 (95% CI 0.15–0.56)) and chemotherapy (HR = 0.34 (95% CI 0.31–0.57)) as independent prognostic factors.ConclusionThe presence of emphysema affects the prognostic outcome of patients with non-small cell lung cancer. Emphysema should therefore be considered for prognostic studies on comorbidity.     

Stratification of resectable lung adenocarcinoma by molecular and pathological risk estimators

BackgroundMortality in early stage, resectable lung cancer is sufficiently high to warrant consideration of post-surgical treatment. Novel markers to stratify resectable lung cancer patients may help with the selection of treatment to improve outcome.MethodsPrimary tumour tissue from 485 patients, surgically treated for stage I–II lung adenocarcinoma, was analysed for the RNA expression of 31 cell cycle progression (CCP) genes by quantitative polymerase chain reaction (PCR). The expression average, the CCP score, was combined with pathological stage into a prognostic score (PS). Cox proportional hazards regression assessed prediction of 5-year lung cancer mortality above clinical variables. The PS threshold was tested for risk discrimination by the Mantel–Cox log-rank test.ResultsThe CCP score added significant information above clinical markers (all patients, P = 0.0029; stage I patients, P = 0.013). The prognostic score was a superior predictor of outcome compared to pathological stage alone (PS, P = 0.00084; stage, P = 0.24). Five-year lung cancer mortality was significantly different between the low-risk (90%, 95% confidence interval (CI) 81–95%), and high-risk groups (65%, 95% CI 57–72%), P = 4.2 × 10^–6).ConclusionsThe CCP score is an independent prognostic marker in early stage lung adenocarcinoma. The prognostic score provides superior risk estimates than stage alone. The threefold higher risk in the high-risk group defines a subset of patients that should consider therapeutic choices to improve outcome.     

Frequency of therapy-relevant staging shifts in colorectal cancer through the introduction of pN1c in the 7th TNM edition

BackgroundpN1c is a novel N-category introduced for colorectal cancer (CRC) in current TNM (Tumour, Node, Metastasis) classification. It represents cancers displaying tumour deposits (TDs) in the fat but no involvement of lymph nodes. pN1c is integrated into the UICC (International Union Against Cancer) staging system and shifts previous stage II cancers (6th edition) to stage III. We investigated the frequency of upstaging and TD prognostic significance.Methods414 CRCs, consecutively collected during a population-based epidemiological study, TNM classified and UICC staged according to the 6th TNM edition were reinvestigated for TD presence. The association with survival was investigated after a median follow-up time of 5 years in multivariate analyses among nodal negative and positive cases.ResultsTDs were found in 103 (24.9%) cancers and were strongly associated with T-, N- and M-stages (p < 0.0001, each). Upstaging of previous stage II cancers by the presence of TDs (pN1c) was found in six of 140 cases (4.3% of stage II, 1.4% of all tumours). For stage III CRC, strongly reduced overall, CRC-specific and recurrence-free survival were observed with the presence of TDs (hazard ratios (HR) 2.29, 95% confidence interval 1.27–4.10, HR 2.51, 1.27–4.98, and HR 2.43, 1.32–4.48, respectively).ConclusionsUpstaging of CRCs through the introduction of pN1c occurs in less than 5% of previous stage II and less than 2% of all cancers. Given the biologic relevance of TDs, integration into the UICC staging relevant N-category is justified. The high prognostic impact of TDs, however, is not reflected in nodal positive cancers in both the TNM and UICC staging systems.     

Molecular prediction of early recurrence after resection of hepatocellular carcinoma

The prognosis of hepatocellular carcinoma (HCC) remains poor. Vascular invasion, tumour multiplicity and large tumour size are the conventional poor prognostic indicators related to early recurrence. However, it is difficult to predict prognosis of each HCC in the absence of these indicators. The purpose of this study is to predict early recurrence of HCC after radical resection based on whole human gene expression profiling. Microarray analyses were performed in 139 HCC primary tumours. A total of 88 cases lacking the conventional poor prognostic indicators were analysed to establish a molecular prediction system characteristic for early recurrence in 42 training cases with two polarised prognoses, and to test its predictive performance in 46 independent cases (group C). Subsequently, this system was applied to another 51 independent cases with some poor prognostic indicators (group D). The molecular prediction system accurately differentiated HCC cases into poor and good prognoses in both the independent group C (disease-free survival [DFS]: p = 0.029, overall survival [OS]: p = 0.0043) and independent group D (DFS: p = 0.0011, OS, p = 0.035). Multivariate Cox regression analysis indicated that the clinical value of molecular prediction system was an independent prognostic factor (p < 0.0001, hazard ratio = 3.29). Gene expression pattern related to early intrahepatic recurrence inherited in the primary HCC tumour can be useful for the prediction of prognosis.     

Prognostic impact of immune response in resectable colorectal liver metastases treated by surgery alone or surgery with perioperative FOLFOX in the randomised EORTC study 40983

AimTo investigate whether the immune response in colorectal liver metastases is related to progression free survival (PFS) and if this may be influenced by systemic therapy.MethodsA retrospective central collection of tumour tissue was organised for the European Organisation for Research and Treatment of Cancer (EORTC) study 40983, where patients with colorectal liver metastases were treated by either resection alone or resection with perioperative FOLFOX. Immunostaining on whole slides was performed to recognise T-lymphocytes (CD3+, CD4+, CD8+), B-lymphocytes (CD20+), macrophages (CD68+) and mast cells (CD117+) inside the tumour, at the tumour border (TNI) and in normal liver tissue surrounding the tumour (0.5–2 mm from the TNI). Immunological response was compared between treatment arms and correlated to PFS.ResultsTumour tissue and immune response profiles were available for 82 resected patients, 38 in the perioperative chemotherapy arm and 44 in the surgery alone arm. Baseline patient and disease characteristics were similar between the treatment arms. In response to chemotherapy, we observed increased CD3+ lymphocyte and mast cell counts inside the tumour (p < 0.01), lower CD4+ lymphocytes in the normal liver tissue (p = 0.02) and lower macrophage counts in normal tissue (p < 0.01) and at the TNI (p = 0.02). High number of CD3+ lymphocyte and mast cells, and high T-cell score were correlated with tumour regression grade (TRG). Prolonged PFS correlated with the presence of mast cells in the tumour (9.8 versus 16.5 months, Hazard ratio (HR) 0.54 p = 0.03), higher CD3+ lymphocyte count at the TNI (10.8 versus 22.8 months, HR 0.57, p = 0.03) and T-cell score >2 (10.8 versus 38.6 months, HR 0.51, p = 0.04).ConclusionOur analyses in the context of a randomised study suggest that chemotherapy influences immune cell profiles, independent of patient characteristics. Immune responses of lymphocytes and mast cells were associated with pathological response to chemotherapy and to increased PFS. High CD3+ lymphocytes at the tumour front and intratumoural mast cells appear to be prognostic for patients with colorectal liver metastases.     

443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011

BackgroundMalignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents.Methods443 patients ⩽18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan–Meier method.ResultsAge of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182).ConclusionPatient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used.     

αvβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I–II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma

BackgroundBased on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway.Patients and methodsPatients were treated with 200 mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome.ResultsFor the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4w (95%CI = [47.3; 97.6]) while median TTP was 18.1w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09–15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS.ConclusionAssociation of 200 mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.     

Small renal cell carcinomas – How dangerous are they really? Results of a large multicenter study

Aim of the studyModern diagnostic ultrasound and cross-sectional imaging has enabled the detection of increasing numbers of renal tumours. The aim of this study was to investigate the tumour- and patient-specific characteristics and prognosis of small renal cell carcinomas (RCCs) after surgical resection.MethodsThe study included 2197 patients who underwent surgical resection of histologically confirmed RCC ⩽4 cm between 1990 and 2011. Median (mean) follow-up was 56.2 (65.5) months.ResultsAt the time of surgery, tumours were staged as pT ⩾ 3a in 175 (8.0%) cases, 134 (6.2%) were poorly differentiated and 75 (3.5%) were metastasised. The larger the tumour size, the higher was the risk of presenting with stage pT ⩾ 3a (p < 0.001), poor tumour differentiation (p = 0.004), microscopic vascular involvement (p = 0.001) and collecting system invasion (p = 0.03). The 5-year cancer-specific survival (CSS) rate was 93.8% for stage pT1a versus 79.4% for stage pT ⩾ 3a (p < 0.001), and it was 93.7% for G1–2 versus 76.8% for G3–4 differentiation (p < 0.001). Multivariate analysis identified age in years (hazard ratio (HR) 1.04, p < 0.001), metastatic disease (HR 12.5, p < 0.001), tumour differentiation (HR 2.8, p < 0.001) and non-clear cell histology (HR 0.51, p = 0.02) as independent prognosticators for CSS in patients with small RCC. Interestingly, the 5-year cancer-specific mortality rate for pT1a N/M0 patients was 5.8%.ConclusionsThis large multicenter study has clearly shown that, though most small RCC have a low pathological stage and a good prognosis, there is also a small but significant subgroup of these tumours that are already locally advanced or poorly differentiated.     

Comparable survival for young rectal cancer patients,despite unfavourable morphology and more advanced-stage disease

BackgroundYoung patients with rectal cancer tend to present with more advanced-stage disease and unfavourable tumour morphology. The effects of these tumour characteristics on survival in this particular patient group are unclear.MethodsPopulation-based data from the Netherlands Cancer Registry (NCR) were used. Data from patients diagnosed with rectal cancer between 1989 and 2010 were selected. Younger patients (⩽40 years) were compared with middle-aged patients (41–70 years) with respect to disease stage, tumour characteristics, treatment and outcomes. Patients aged older than 70 years were excluded. Relative excess risk (RER) models were used to perform uni- and multivariate survival analyses.FindingsA total of 37.056 patients were included (⩽40 years n = 1.102). Compared with middle-aged patients, young patients were more likely to have stage III (33.8% versus 27.8%) and stage IV (24.3% versus 19.6%) disease (p < 0.001). Young patients also presented more frequently with mucinous tumours (10.8% versus 9.0%), signet cell carcinomas (2.6% versus 0.6%) and poorly differentiated tumours (16.6% versus 12.3%) (p = 0.001). The treatment of stage I–III patients did not differ between the two groups, except regarding adjuvant chemotherapy, which was more often given to young patients (24.3% versus 14.4%, p < 0.001). Young age was a prognostic factor for better survival in stage I–III patients (RER 0.82 CI 0.71–0.94). Adjuvant chemotherapy was associated with improved survival in stage I–III patients (RER 0.76, 95%CI 0.70–0.83). In an exploratory analysis, adjuvant chemotherapy in young stage III and pN1 patients was associated with improved survival.Concluding statementYoung patients present with more advanced disease and have more unfavourable tumour characteristics compared with middle-aged patients. Despite these characteristics, survival rates are equal, and young age is a prognostic factor for better survival. Although the use of adjuvant chemotherapy is controversial, a positive correlation with survival was found in this study.     

High RNA-binding motif protein 3 expression is an independent prognostic marker in operated prostate cancer and tightly linked to ERG activation and PTEN deletions

BackgroundThe RNA-binding motif protein 3 (RBM3) has recently been suspected as a prognostic biomarker in several cancers.MethodsRBM3 expression was analysed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers.ResultsRBM3 expression was more often detectable in malignant compared to benign prostate. RBM3 immunostaining was found in 64% of the interpretable prostate cancers and was considered strong in 25.6%. High RBM3 expression was linked to advanced tumour stage, high Gleason score, positive nodal involvement and positive surgical margin status (p < 0.0001 each). There was a remarkable accumulation of strong RBM3 expression in v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) positive prostate cancers and tumours harbouring PTEN deletions (p < 0.0001 each). Moreover, RBM3 staining was tightly related to early biochemical recurrence if all tumours or subgroups of ERG negative and ERG positive cancers were analysed (p < 0.0001 each). In multivariate analysis, including RBM3 staining, Gleason grade, pT stage, prostate-specific antigen (PSA), surgical margin status, and nodal status, the prognostic impact of RBM3 staining retained statistically significance (p = 0.0084).ConclusionOur observations indicate that high RBM3 expression is an independent prognostic marker in prostate cancer. The tight link to ERG activation and PTEN deletions suggest interaction with key molecular pathways in prostate cancer.     

The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy

BackgroundLymphangiogenesis and angiogenesis are essential for tumour development and progression. The lymphatic vessel density (LVD) and blood vessel density (BVD) and their relationship to outcome have been studied extensively, however the clinical significance of the location of LVD/BVD in tumour is not known. In the present study, the location and degree of LVD/BVD and their relationship to preoperative radiotherapy (RT), clinicopathological, histopathological and biological factors were studied in rectal cancer patients participating in a Swedish clinical trial of preoperative RT.Patients and methodsThe location and degree of LVD/BVD were analysed in primary tumours (n = 138/140) and in their subgroups of non-RT (n = 74) and RT (n = 64/66). Further, the degree of LVD/BVD was examined in the corresponding distant normal mucosa (n = 35/31) and adjacent normal mucosa (n = 72/91). All sections were immunohistochemically examined by using D2-40 and CD34 antibodies.ResultsIn the whole series of the patients, a higher LVD at the periphery was related to negative p53 expression (P = 0.03) and favourable survival independent of tumour–node–metastasis stage, differentiation and p53 expression (P = 0.03). LVD was increased in p53-negative tumours after RT (P = 0.01).ConclusionLVD at the periphery of the tumour was an independent prognostic factor in rectal cancer patients.