Combining CRP and CA19-9 in a novel prognostic score in pancreatic ductal adenocarcinoma.

Inflammation promotes tumor progression, induces invasion and metastatic spread. This retrospective study explored CRP, CA19-9, and routine laboratory values as preoperative prognostic factors in pancreatic cancer patients. Between 2000 and 2016, there were 212 surgically treated pancreatic cancer patients at Helsinki University Hospital, Finland. Out of these, 76 borderline resectable patients were treated with neoadjuvant therapy (NAT); 136 upfront resected patients were matched for age and sex at a 1:2 ratio. We analyzed preoperative CRP, CA19-9, CEA, leukocytes, albumin, bilirubin and platelets. CRP and CA19-9 were combined into a prognostic score: both CRP and CA19-9 below the cut-off values (3 mg/l and 37 kU/l, respectively), either CRP or CA19-9 above the cut-off value, and finally, both CRP and CA19-9 above the cut-off values. Among all patients, median disease-specific survival times were 54, 27 and 16 months, respectively (p < 0.001). At 5 years, among patients with CRP and CA19-9 levels below the cut-off values, 49% were alive and 45% were disease-free. Among NAT patients the corresponding survival rates were 52% and 45% and among those undergoing upfront surgery 45% and 40%, respectively. This novel prognostic score combining CRP and CA19-9 serves as a useful preoperative tool estimating survival.

Postoperative serum CA19-9, YKL-40, CRP and IL-6 in combination with CEA as prognostic markers for recurrence and survival in colorectal cancer.

BACKGROUND: In colorectal cancer (CRC) patients, guidelines only recommend measurement of preoperative carcinoembryonic antigen (CEA), although postoperative CEA may be more informative. However, the sensitivity of both preoperative and postoperative CEA in identifying relapse is limited. We studied whether CA19-9, YKL-40, C-reactive protein (CRP) and interleukin (IL)-6 add prognostic information combined with postoperative CEA. MATERIAL AND METHODS: This post-hoc analysis included 147 radically resected stage II (n = 38), III (n = 91) and IV (n = 18) CRC patients treated with adjuvant 5-fluorouracil (5-FU)-based therapy in the phase III LIPSYT study (ISRCTN98405441). We collected postoperative blood samples a median of 48 days after surgery. We analysed relapses, sensitivity, positive predictive value (PPV) and disease-free (DFS) and overall survival (OS) by bootstrap, Kaplan-Meier and adjusted Cox-models in the elevated vs. normal biomarker groups. RESULTS: Elevated postoperative CEA associated with impaired DFS (HR 7.23; CI95% 3.85-13.58), impaired OS (HR 7.16; CI95% 3.76-13.63), and more relapses (HR 7.9; CI95% 3.4-18.2); but sensitivity for CEA in finding relapses was only 31% (CI95% 21-48%). Normal CEA combined with an elevated YKL-40 or elevated CRP showed more relapses (HR for YKL-40 2.13 [CI95% 1.10-4.13], HR for CRP 3.14 [CI95% 1.21-8.16]), impaired DFS (HR 2.18 [CI95% 1.12-4.24] or 3.23 [CI95% 1.34-7.82]), and impaired OS (2.33 [CI95%1.24-4.40] or 2.68 [CI95%1.12-6.44]). Elevated CEA combined with a concomitantly elevated CA19-9, YKL-40, CRP or IL-6 showed a respective PPV of 100, 90, 100, and 100%. CONCLUSION: In radically operated stage II to IV CRC patients who received adjuvant 5-FU-based chemotherapy, a postoperatively elevated CEA alone or in combination with CA19-9, YKL-40, CRP, or IL-6, or a normal CEA combined with an elevated YKL-40 or with an elevated CRP, may indicate patients at high risk of relapse.

Immunohistochemical Expression of Somatostatin Receptor Subtypes in a Panel of Neuroendocrine Neoplasias.

Neuroendocrine neoplasias (NENs) are known to express somatostatin receptors (SSTRs) 1-5, which are G-protein-coupled cell membrane receptors. Somatostatin receptor imaging and therapy utilizes the SSTR expression. Synthetic somatostatin analogs with radioligands are used to detect primary tumors, metastases, and recurrent disease. Receptor analogs are also used for treating NENs. Furthermore, commercially available SSTR antibodies can be used for the immunohistochemical (IHC) detection of SSTRs. We investigated different SSTR antibody clones applying diverse IHC protocol settings to identify reliable clones and feasible protocols for NENs. A tissue microarray including NENs from 12 different primary sites were stained. Only UMB clones were able to localize SSTR on the cell membranes of NENs. SSTR2 (UMB1) emerged as the most common subtype followed by SSTR5 (UMB4) and SSTR1 (UMB7). SSTR3 (UMB5) expression was mainly cytoplasmic. Yet, SSTR4 expression was weak and located primarily in the cytoplasm. Thus, appropriate IHC protocols, including proper positive and negative controls, represent requirements for high-quality NEN diagnostics and for planning personalized therapy.

Toll-like receptor 2 and Toll-like receptor 4 predict favorable prognosis in local pancreatic cancer.

Toll-like receptors play an essential role in our innate immune system and are a focus of interest in contemporary cancer research. Thus far, Toll-like receptors have shown promising prognostic value in carcinomas of the oral cavity, colon, and ovaries, but the prognostic role of Toll-like receptors in pancreatic ductal adenocarcinoma has not been established. We set out to investigate whether Toll-like receptor expression could serve in prognostic evaluation in pancreatic ductal adenocarcinoma, as well. Our study comprised 154 consecutive stage I-III pancreatic ductal adenocarcinoma patients surgically treated at Helsinki University Hospital between 2002 and 2011. Patients who received neoadjuvant therapy were excluded. Tissue microarrays and immunohistochemistry allowed assessment of the expression of Toll-like receptor 2 and Toll-like receptor 4 in pancreatic ductal adenocarcinoma tissue, and we matched staining results against clinicopathological parameters using Fisher's test. For survival analysis, we used the Kaplan-Meier method and the log-rank test, and the Cox regression proportional hazard model for univariate and multivariate analyses. The hazard ratios were calculated for disease-specific overall survival. Strong Toll-like receptor 2 expression was observable in 51 (34%) patients and strong Toll-like receptor 4 in 50 (33%) patients. Overall, neither marker showed any direct coeffect on survival. However, strong Toll-like receptor 2 expression predicted better survival when tumor size was less than 30 mm (hazard ratio = 0.30; 95% confidence interval = 0.13-0.69; p = 0.005), and strong Toll-like receptor 4 expression predicted better survival in patients with lymph-node-negative disease (hazard ratio = 0.21; 95% confidence interval = 0.07-0.65; p = 0.006). In conclusion, we found strong Toll-like receptor 2 and Toll-like receptor 4 expressions to be independent factors of better prognosis in pancreatic ductal adenocarcinoma patients with stage I-II disease.

Vascular invasion is an early event in pathogenesis of Merkel cell carcinoma.

This study investigated vascular and especially lymphovascular invasion in primary Merkel cell carcinoma and its value as a prognostic factor. Paraffin-embedded blocks prepared from tumor samples obtained from 126 patients diagnosed with Merkel cell carcinoma in 1979-2004 were immunohistochemically stained using antibodies CD31 and D2-40 to detect intravascular tumor emboli. This finding was compared with the clinical data and the disease outcome. Intravascular tumor cells were observed in 117 (93%) of the samples. The majority, 83 (66%), showed only lymphovascular invasion. Only blood vascular invasion was seen in four (3%) samples. In all, 30 (24%) samples demonstrated both lymphovascular invasion and blood vascular invasion. In only nine (7%) samples, there was no invasion within the vascular structures. The tumors lacking invasion were significantly smaller (P<0.01 and alpha=0.050) than those with vascular invasion, although lymphovascular invasion was observed even in the smallest tumor (0.3 cm) of this study. Already in the early stages of the disease, Merkel cell carcinoma seems to have the capacity to penetrate vessel walls. Our finding of the high frequency of lymphovascular invasion might therefore explain the extremely aggressive clinical behavior of Merkel cell carcinoma. This may support the role of sentinel node biopsy even in the case of very small primary Merkel cell carcinoma tumors.

P75 nerve growth factor receptor is expressed in regenerating human nerve grafts.

BACKGROUND: The purpose of this study was to elucidate the expression of p75 nerve growth factor receptor (p75NGFR) in human cross-facial nerve grafts and to compare the immunohistological findings with patient data and the functional outcome in facial reanimation. MATERIALS AND METHODS: The study comprised 37 sural nerve graft specimens. All of the patients had long-lasting complete facial paralysis and were operated on by the standard two-stage procedure involving cross-facial nerve grafts and microneurovascular muscle transfer. Nerve biopsies were taken 4 to 20 months (mean, 8 months) after the cross-facial nerve grafting. Immunohistochemistry for p75NGFR as well as for Schwann cells (S-100; Dako, Glostrup, Denmark) and for Neurofilament-200 (NF-200; Boehringer, Mannheim, Germany) was performed. RESULTS: In graft biopsies, the mean number of NF-200-positive axons amounted to 38% (range, 6-81%) of that in control samples. Further, regenerated axons were thinner than in control samples. Morphologically, the grafted nerves were characterized by fibrosis and invasion of inflammatory cells. A longer time between cross-facial nerve grafting and biopsy sampling correlated with a higher number of viable axons (NF-200) (P = 0.002). In all cases, expression of p75NGF receptor was clearly higher at the distal end of the grafted nerve. Expression of p75NGFR was lower in older than in younger patients (P = 0.003). A high expression of p75NGFR was often seen with better function of the transplanted muscle. CONCLUSION: Increased expression of p75NGFR in human nerve grafts was noted, especially in younger patients. We suggest that p75NGFR expression might be a contributing factor in a successful axonal regeneration and eventual recovery of muscle function.

AMES, MACIS and TNM prognostic classifications in papillary thyroid carcinoma.

The need for total thyroidectomy and extended for lymphadenectomy and the need for postoperative radioiodine ablation in the treatment of papillary thyroid carcinoma is continuously debated. Since less aggressive treatment in low-risk patients has been suggested, several scoring systems have been developed to identify low-risk patients. In the current study, we compared the AMES, MACIS and TNM staging systems in predicting carcinoma-specific mortality in papillary thyroid carcinoma. Between 1967 and 1994, 495 patients with papillary thyroid carcinoma were treated at the Department of Surgery, Helsinki University Central Hospital. Carcinoma-specific mortality in the AMES low-risk group, comprising 89.7% of these patients, was 2.4%. Corresponding figures for the MACIS were 89.9%, and 2.4%, and for the TNM 85.9% and 1.2%. The mortality ratio, at 10 years, between low-risk and high-risk patients was 22.2 for the AMES, 25.0 for the MACIS and 41.8 for the TNM system. The proportion of explained variance in the Cox model was 16.3 for the AMES, 30.0 for the MACIS taken as a conitinuous variable and 28.9 for the TNM stage. The TNM stage was on average superior to the MACIS or AMES score in predicting cancer-specific mortality of patients with papillary thyroid carcinoma. This may be explained by the fact that the TNM system includes the prognostic effect of nodal metastases, which is included in neither the MACIS nor AMES systems.