Björn L.D.M. Brücher

Time Course of Tumor Metabolic Activity During Chemoradiotherapy of Esophageal Squamous Cell Carcinoma and Response to Treatment

PURPOSE To evaluate the time course of therapy-induced changes in tumor glucose use during chemoradiotherapy of esophageal squamous cell carcinoma (ESCC) and to correlate the reduction of metabolic activity with histopathologic tumor response and patient survival. PATIENTS AND METHODS Thirty-eight patients with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) scheduled to undergo a 4-week course of preoperative simultaneous chemoradiotherapy followed by esophagectomy were included. Patients underwent positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) before therapy (n = 38), after 2 weeks of initiation of therapy (n = 27), and preoperatively (3 to 4 weeks after chemoradiotherapy; n = 38). Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUVs). Results Mean tumor FDG uptake before therapy was 9.3 +/- 2.8 SUV and decreased to 5.7 +/- 1.9 SUV 14 days after initiation of chemoradiotherapy (-38% +/- 18%; P <.0001). The preoperative scan showed an additional decrease of metabolic activity to 3.3 +/- 1.1 SUV (P <.0001). In histopathologic responders (< 10% viable cells in the resected specimen), the decrease in SUV from baseline to day 14 was 44% +/- 15%, whereas it was only 21% +/- 14% in nonresponders (P =.0055). Metabolic changes at this time point were also correlated with patient survival (P =.011). In the preoperative scan, tumor metabolic activity had decreased by 70% +/- 11% in histopathologic responders and 51% +/- 21% in histopathologic nonresponders. CONCLUSION Changes in tumor metabolic activity after 14 days of preoperative chemoradiotherapy are significantly correlated with tumor response and patient survival. This suggests that FDG-PET might be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.

Neoadjuvant therapy of esophageal squamous cell carcinoma: Response evaluation by positron emission tomography

ObjectiveTo evaluate the use of positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET) to assess the response to neoadjuvant radiotherapy and chemotherapy in patients with locally advanced esophageal cancer. Summary Background DataImaging modalities, including endoscopy, endoscopic ultrasound, computed tomography, and magnetic resonance imaging, currently used to evaluate response to neoadjuvant treatment in esophageal cancer do not reliably differentiate between responders and nonresponders. MethodsTwenty-seven patients with histopathologically proven squamous cell carcinoma of the esophagus, located at or above the tracheal bifurcation, underwent neoadjuvant therapy consisting of external-beam radiotherapy and 5-fluorouracil as a continuous infusion. FDG-PET was performed before and 3 weeks after the end of radiotherapy and chemotherapy (before surgery). Quantitative measurements of tumor FDG uptake were correlated with histopathologic response and patient survival. ResultsAfter neoadjuvant therapy, 24 patients underwent surgery. Histopathologic evaluation revealed less than 10% viable tumor cells in 13 patients (responders) and more than 10% viable tumor cells in 11 patients (nonresponders). In responders, FDG uptake decreased by 72% ± 11%; in nonresponders, it decreased by only 42% ± 22%. At a threshold of 52% decrease of FDG uptake compared with baseline, sensitivity to detect response was 100%, with a corresponding specificity of 55%. The positive and negative predictive values were 72% and 100%. Nonresponders to PET scanning had a significantly worse survival after resection than responders. ConclusionFDG-PET is a valuable tool for the noninvasive assessment of histopathologic tumor response after neoadjuvant radiotherapy and chemotherapy.

IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism

ObjectivesIndoleamine-2,3-Dioxygenase (IDO) is an immunosuppressive molecule inducible in various cells. In addition to classic IDO (IDO1), a new variant, IDO2, has recently been described. When expressed in dendritic cells (DCs) or cancer cells, IDO was thought to suppress the immune response to tumors. A novel therapeutic approach in cancer envisages inhibition of IDO with 1-methyl-tryptophan (1MT). The levo-isoform (l-1MT) blocks IDO1, whereas dextro-1MT (d-1MT), which is used in clinical trials, inhibits IDO2. Here we analyze IDO2 expression in human cancer cells and the impact of both 1-MT isoforms on IDO activity.MethodsSurgically extirpated human primary tumors as well as human cancer cell lines were tested for IDO1 and IDO2 expression by RT-PCR. IDO1 activity of Hela cells was blocked by transfection with IDO1-specific siRNA and analysed for tryptophan degradation by RP-HPLC. The impact of d-1MT and l-1MT on IDO activity of Hela cells and protein isolates of human colon cancer were studied.ResultsHuman primary gastric, colon and renal cell carcinomas constitutively expressed both, IDO1 and IDO2 mRNA, whereas cancer cells lines had to be induced to by Interferon-gamma (IFN-γ). Treatment of Hela cells with IDO1-specific siRNA resulted in complete abrogation of tryptophan degradation. Only l-1MT, and not d-1MT, was able to block IDO activity in IFN-γ-treated Hela cells as well as in protein isolates of primary human colon cancer.ConclusionsAlthough IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, d-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of d-1MT, this cannot be attributed to inhibition of IDO in tumor cells.

The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas

The objectives of this study were to investigate histomorphologic features as a response classification after neoadjuvant radiochemotherapy (RTx/CTx) and to correlate the results with clinical outcome parameters (e.g., postoperative morbidity and mortality, recurrence, and survival) in patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment.

The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication.

Transient Lower Esophageal Sphincter Relaxation in Morbid Obesity

BackgroundThere is strong evidence that morbid obesity is often accompanied by gastroesophageal reflux. Gastroesophageal reflux is caused predominantly by transient lower esophageal sphincter relaxations (TLESRs). Only few data are available about TLESRs in patients with stage III obesity (body mass index > 35). The aim of this study was to analyze the frequency and types of TLESRs in patients with morbid obesity in different physiological stages (postprandial: upright and recumband) compared to patients with normal weight gastroesophageal reflux disease (GERD) and diffuse esophagus spasm (DES).MethodsIn order to measure TLESRs in obese patients with and without GERD, three subgroups were prospectively performed: group I consisted of seven healthy controls, group II consisted of seven obese patients, group III consisted of seven non-obese patients with GERD, and in group IV, five patients were recruited with diffuse esophageal spasm. All participants underwent both conventional water-perfused stationary esophagus manometry and a 24-h ambulatory esophagus manometry, 24-h ambulatory pH monitoring, and esophago-gastroscopy. In order to measure the lower esophageal sphincter pressure (LESP) over a prolonged time under physiological conditions, a special solid-state sleeve catheter was used. Additionally, all patients were interviewed using a standardized questionnaire.ResultsCompared to normal subjects, patients with morbid obesity and patients with gastroesophageal reflux show a substantial increase of TLESRs in the postprandial phase. There was a tendency towards more TLESRs per hour in patients with DES than in healthy subjects, but the difference was not statistically significant. The types of TLESRs differed with the LESP. The majority of isolated TLESRs were complete and incomplete. Some of the isolated TLESRs were accompanied by contractions of the tubular esophagus.ConclusionMorbid obesity is associated with gastroesophageal reflux. The frequency of TLESRs has significantly increased compared to healthy subjects and does not differ statistically from patients with GERD. Isolated TLESRs are mostly incomplete in patients with a hypotonic LES.

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patients prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P=0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P=0.0061) and p53-phospho (P=0.0064). Expression of p53 correlated with expression of p53-phospho (P<0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma.

Phosphoglycerate Kinase 1 a Promoting Enzyme for Peritoneal Dissemination in Gastric Cancer

Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate‐generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and β‐catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and β‐catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and β‐catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid‐mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and β‐catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.

PGK1 a potential marker for peritoneal dissemination in gastric cancer.

Background/Aims: Peritoneal carcinomatosis, which is caused by the dissemination of cancer cells into the abdominal cavity is a frequent finding in patients with primary gastric cancer, and it is associated with a poor prognosis. The mechanisms that mediate peritoneal carcinomatosis in diffuse primary gastric tumours require definition. Methods: We therefore compared the gene expression profile in diffuse primary gastric cancer patients with and without peritoneal carcinomatosis (n=13). Human specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated using oligonucleotide microarrays. Differentially expressed genes of interest were further evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: The results reveal a significant overexpression of phosphoglycerate kinase 1 (PGK1), the chemokine CXCR4 and its ligand CXCL12 in specimens from diffuse gastric cancer patients with peritoneal carcinomatosis. Overexpression of PGK1 is known to increase the expression of CXCR4. CXCR4 on its part can increase CXCL12 expression. Elevated levels of CXCR4 and CXCL12 are associated with an increase in the metastatic rate and play an important role in the metastatic homing of malignant cells. Conclusion: The overexpression of PGK1 and its signalling targets may be a expression-pathway in diffuse primary gastric carcinomas promoting peritoneal dissemination and may function as prognostic markers and/or be potential therapeutic targets to prevent the migration of gastric carcinoma cells into the peritoneum.

Early Detection of Colorectal Cancer Recurrence in Patients Undergoing Surgery with Curative Intent: Current Status and Challenges

Despite advances in neoadjuvant and adjuvant therapy, attention to proper surgical technique, and improved pathological staging for both the primary and metastatic lesions, almost half of all colorectal cancer patients will develop recurrent disease. More concerning, this includes ~25% of patients with theoretically curable node-negative, non-metastatic Stage I and II disease. Given the annual incidence of colorectal cancer, approximately 150,000 new patients are candidates each year for follow-up surveillance. When combined with the greater population already enrolled in a surveillance protocol, this translates to a tremendous number of patients at risk for recurrence. It is therefore imperative that strategies aim for detection of recurrence as early as possible to allow initiation of treatment that may still result in cure. Yet, controversy exists regarding the optimal surveillance strategy (high-intensity vs. traditional), ideal testing regimen, and overall effectiveness. While benefits may involve earlier detection of recurrence, psychological welfare improvement, and greater overall survival, this must be weighed against the potential disadvantages including more invasive tests, higher rates of reoperation, and increased costs. In this review, we will examine the current options available and challenges surrounding colorectal cancer surveillance and early detection of recurrence.