Thore Thiesler

Computed tomography perfusion imaging of renal cell carcinoma: systematic comparison with histopathological angiogenic and prognostic markers.

PurposeThe aim of this study was to systematically analyze the correlation between computed tomography (CT) perfusion and histopathological angiogenic and prognostic markers in patients with renal cell carcinoma (RCC). Material and MethodsFifteen patients (12 men; mean age, 64.5 ± 9.4 years) with RCC underwent contrast-enhanced CT perfusion imaging (scan range, 10 cm; scan time, 40 seconds; dual-source 128-section CT) 1 day before surgery. The procedure for surgical specimen processing was modified to obtain an exact match with CT images. Microvessel density (MVD) was quantified by CD34 staining, and lymphatic vessel density (LVD) was stained with D2-40 antibodies. The CT perfusion values blood flow (BF), blood volume (BV), and flow extraction product (KTrans) were calculated using the maximum-slope and a delay-corrected modified Patlak approach and were correlated to MVD and LVD. The relationship between CT perfusion and the prognostic markers pT stage, Fuhrman grade, and tumor necrosis was evaluated. ResultsHistopathology revealed varying high MVD but low or absent intratumoral LVD. The BF and BV of RCC, both including and excluding necrotic regions, showed significant correlations with MVD (r = 0.600–0.829, P < 0.05 each). Significant correlations between MVD and KTrans were found only in small tumor areas exhibiting no necrosis (r = 0.550, P < 0.05). No significant correlation was found between BF, BV, and KTrans with intratumoral LVD (P = 0.35–0.82). With higher pT stage and Fuhrman grade, BF, BV, and KTrans were lower, similar to the MVD, but without reaching statistical significance. Blood flow, BV, and KTrans were significantly higher in RCCs with less than 50% necrosis than in those with 50% or grater necrosis (P < 0.05 each). ConclusionOur study indicates that BF and BV from CT perfusion reflect blood vessels of RCC. Computed tompgraphic perfusion parameters differ significantly depending upon the degree of tumor necrosis.

HIPEC ROC I: A phase i study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum‐based chemotherapy in patients with platinum‐sensitive recurrent epithelial ovarian cancer

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum‐sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum‐based intravenous chemotherapy. Twelve patients with operable, recurrent platinum‐sensitive EOC (recurrence ≥6 months after first‐line therapy) were included according to the classical 3+3 dose‐escalation design at three dose levels—60, 80 and 100 mg/m2. After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41–43°C. Postoperatively, all patients were treated with standard intravenous platinum‐based combination chemotherapy. One of six patients experienced a dose‐limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m2. The remaining five patients treated with 100 mg/m2 tolerated their treatment well. The recommended phase II dose was established at 100 mg/m2. The mean peritoneal‐to‐plasma AUC ratio was 19·5 at the highest dose level. Cisplatin‐induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1–3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum‐based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m2 has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum‐sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m2. The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer

Purpose: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. Results: In the training cohort (n = 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P < 0.001), Gleason score (P = 0.004), and androgen receptor (AR) expression (P < 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P = 0.004; HR, 2.37; 95% confidence interval (CI), 1.32–4.25]. In the test cohort (n = 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P = 0.011; HR, 1.49; 95% CI, 1.10–2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P < 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P = 0.007; HR, 1.46; 95% CI, 1.11–1.92). Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1–targeted therapy might be a treatment option for hormone-naïve prostate cancers. Clin Cancer Res; 22(8); 1969–77. ©2015 AACR.

The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice.

ABSTRACT Colorectal cancer (CRC) develops through a multistep process and is modulated by inflammation. However, the inflammatory pathways that support intestinal tumors at different stages remain incompletely understood. Interleukin (IL)-33 signaling plays a role in intestinal inflammation, yet its contribution to the pathogenesis of CRC is unknown. Using immunohistochemistry on 713 resected human CRC specimens, we show here that IL-33 and its receptor ST2 are expressed in low-grade and early-stage human CRCs, and to a lesser extent in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow (BM) chimera studies indicate that engagement of the IL-33/ST2 pathway on both the radio-resistant and radio-sensitive compartment is essential for CRC development. Mechanistically, activation of IL-33/ST2 signaling compromises the integrity of the intestinal barrier and triggers the production of pro-tumorigenic IL-6 by immune cells. Together, this data reveals a tumor-promoting role of IL-33/ST2 signaling in CRC.

Surfaceome of classical Hodgkin and non-Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is characterized by a low percentage of tumor cells in a background of diverse, reactive immune cells. cHL cells commonly derive from preapoptotic germinal‐center B cells and are characterized by the loss of B‐cell markers and the varying expression of other hematopoietic lineage markers. This phenotypic variability and the scarcity of currently available cHL‐specific cell surface markers can prevent clear distinction of cHL from related lymphomas.

Impact of using elastic stains for detection of venous invasion in the prognosis of patients with lymph node negative colorectal cancer

Purpose and methodsPatients with nodal negative colorectal cancer (CRC) suffer recurrent or metastatic disease in 40% of cases after surgical resection. To investigate a potential prognostic impact of vascular tumor infiltration, we retrospectively analyzed 185 nodal negative stage I and II CRC specimens for the presence of intra- and/or extramural venous invasion (V1IM/V1EM) using elastic stains of all tumor sections and correlated our findings with the clinical follow-up.ResultsVenous invasion was observed in 43 (23.2%) patients by elastic stains compared with six (3.2%) using HE only (p < 0.05). Venous invasion was more common in stage II than in stage I tumors (28.1% versus 5.1%; p < 0.05). However, survival analyses showed no significant differences in 5-year survival rates comparing patients with and without venous invasion (68% and 71%, p = 0.543) or patients with V1IM and V1EM (62% vs. 74%, p = 0.473), respectively.ConclusionsOur data emphasize the need for standardized criteria, including elastic stains, to reliably detect vascular invasion in CRC. Doing so, however, the prognostic impact of venous invasion in stage I and II CRC may be lower as previously anticipated.

Loss of Anterior Gradient-2 expression is an independent prognostic factor in colorectal carcinomas

AIMS The human Anterior Gradient-2 (AGR2) protein is strongly expressed in various human cancers, and it has been described to promote aggressive tumour features in some entities. So far, a comprehensive analysis of AGR2 expression in colorectal carcinomas has not been described. METHODS Normal intestinal cells and colorectal carcinoma cell lines were analysed for AGR2 expression. AGR2 protein expression was immunohistochemically analysed in 28 normal tissue samples and 1068 tissue samples of clinically well characterised colorectal carcinomas. For statistical analysis, chi square test, spearman rank correlations, Kaplan-Meier estimates (Log rank test) and Cox regression were applied to test for diagnostic or prognostic associations. RESULTS In the normal intestinal cell line and in normal colon mucosa AGR2 was found in all cases (n=28). In contrast, loss of AGR2 was found in all six analysed colorectal cancer cell lines and in 833/1068 (78%) of the colorectal carcinoma tissue samples analysed, and it was significantly associated with a higher tumour grade and tumour localisation in the left-sided colon. In addition to the conventional prognostic tumour parameters pT category, nodal status, metastasis and histological tumour grade the loss of AGR2 expression was significantly associated with reduced overall survival times in univariate and multivariate analyses, thus suggesting AGR2 as an independent prognostic factor in primary colorectal carcinoma. CONCLUSIONS AGR2 is frequently lost in colorectal carcinomas and might be a novel independent prognostic factor for overall patient survival.

Patients with Low Prostate-Specific Antigen Levels (≤4 ng/ml) Would Benefit from a Twelve-Core Biopsy Protocol for Prostate Cancer Detection

Introduction: Prostate biopsy protocols using twelve cores rather than the standard six cores have consistently shown improved prostate cancer detection rates. The aim of our study was to evaluate whether the improved rate of prostate cancer detection in patients with low prostate-specific antigen levels warrants the standardization of a twelve-core biopsy protocol in this group. Patients and Methods: The clinical and pathological records from 241 patients treated between 2000 and 2003 were evaluated, and the impact of a twelve-core biopsy protocol on the prostate cancer detection rate relative to prostate-specific antigen levels compared to the standardized six-core biopsies was analyzed. Results: Prostate cancer was detected in 34% (81/241) of the patients who underwent transrectal ultrasound-guided biopsy. An additional 23.5% (19/81) of the carcinomas were diagnosed using the twelve-core biopsy protocol, and 84.2% (16/19) of these fulfilled the clinical significance criterion developed by Epstein and coworkers (see text). Interestingly, the greatest increase was found in the patient group with prostate-specific antigen levels ≤4 ng/ml. Conclusions: Patients with low prostate-specific antigen levels (≤4 ng/ml) would benefit from the standardized use of a twelve-core biopsy protocol using peripheral cores.

The impact of pulmonary bone component embolism: an autopsy study

Aims Pulmonary bone marrow embolism (BME) and pulmonary bone fragment embolism (BFE) are two types of non-thrombotic pulmonary embolism (NTPE). While BME can be found consistently in autopsies, BFE is a rarely observed event. Both these conditions have bone lesions as source of embolism and are not considered to be causative for death. Methods A retrospective autopsy study was performed and lung whole tissue slides were reviewed for the presence of pulmonary embolism. Clinicopathological data were screened for osseous lesions considered as risk factors for BME and BFE. Results We reviewed 985 consecutive, unselected autopsies and identified 29 cases of BME (2.9%) and 5 cases of BFE (0.5%). Both conditions were mutually exclusive. While BME showed a significant association with costal fractures, BFE was significantly associated with osteomyelitis and previously performed femur nailing. There were between 1 and 346 bone emboli in BFE with a density ranging from 0.74 to 30.5 emboli/cm2 with mean embolic diameter of 45.8±37.6 μm. In two patients, BFE contributed significantly to fatal outcome. Conclusions BME was associated with costal fractures, while BFE was associated with orthopaedic procedures and osteomyelitis. BFE can result in patient death. Both conditions appeared exclusively, indicating that although they originate from osseous lesions their underlying pathogenesis may likely be different.

Quantitative perineural invasion is a prognostic marker in prostate cancer

This study aimed to investigate the prognostic value of a quantitative, detailed, yet practical analysis of perineural invasion in radical prostatectomy specimens in a high-risk prostate cancer cohort. A total of 114 patients with prostate cancer who underwent radical prostatectomy between 2000 and 2013 were analysed. Using S100 protein immunohistochemistry assisted in the detection of nerves. In the area of closest proximity of the tumour to the dorso-lateral margins, nerves were counted and the infiltration of nerves was categorised (0-3). Category 0 was nerves without immediate tumour-cell-contact. All nerves being fully surrounded by tumour (classical perineural carcinosis) were categorised group 3. Two further categories discriminated between nerves that were touched either by carcinoma cells below 50% of the circumference (category 1) or above (category 2). Perineural carcinosis (Pn1) was seen in 61.4% of cases and correlated positively with ISUP grades, pT categories and presence of intraductal carcinoma but failed significance on Kaplan-Meier analysis. A more quantitative analysis of percentual perineural involvement did demonstrate significant survival differences: cases with less than one Pn1-positive nerve in 5 high power fields had longer survival times. Incomplete perineural involvement (category 1-2) did not have a prognostic value, endorsing the current definition of perineural carcinosis as full circumferential encasement of a nerve by tumour cells. A quantitative analysis of the percentage of nerves positive for perineural invasion has a higher prognostic value than the classical dichotomous statement on the mere presence of perineural invasion.