Inhibition of Wnt/ß-Catenin Signaling Sensitizes Esophageal Cancer Cells to Chemoradiotherapy.

The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to improve patients' outcome. In this study, we investigated the impact of Wnt/ß-catenin signaling on CRT resistance in esophageal cancer cells. Experiments were conducted in adenocarcinoma and squamous cell carcinoma cell lines with varying expression levels of Wnt proteins and Wnt/ß-catenin signaling activities. To investigate the effect of Wnt/ß-catenin signaling on CRT responsiveness, we genetically or pharmacologically inhibited Wnt/ß-catenin signaling. Our experiments revealed that inhibition of Wnt/ß-catenin signaling sensitizes cell lines with robust pathway activity to CRT. In conclusion, Wnt/ß-catenin activity may guide precision therapies in esophageal carcinoma patients.

Transoral laser microsurgery for T1b glottic cancer: review of 51 cases.

For the treatment of T1b glottic carcinoma, different treatment options, such as transoral laser microsurgery, open surgical techniques, and primary radiotherapy, are under discussion. In this context, the aim of the present study was to describe oncologic results and complication rates of transoral laser microsurgery in treatment of T1b glottic carcinoma. This is a retrospective unicenter chart review of patients treated at an academic tertiary referral center between 1986 and 2006. Fifty-one previously untreated T1b cases were exclusively treated by transoral laser microsurgery and included into this study, 47 were male, and 4 were female. The main outcome measures included local control rate and complications, overall, disease specific, and recurrence-free survival. The median follow-up period was 98 months. The 5-year local control rate was 90.2%; larynx preservation rate was 92.2%. No intra- or postoperative complications, such as wound infections, postoperative bleeding, hematoma, edema, and fistula development, were observed. A single patient required revision surgery due to synechia. Five-year survival rates were: overall 84.7%, disease specific 97.7%, and recurrence free 72.4%. Our data support the conclusion that transoral laser microsurgery is a considerable treatment option in T1b glottic carcinoma. The oncologic outcome was at least comparable to other treatment options, while the perioperative morbidity and complication rate were lower.

Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy.

Since the response to chemoradiotherapy in patients with locally advanced rectal cancer is heterogeneous, valid biomarkers are needed to monitor tumor response. Circulating microRNAs are promising candidates, however analyses of circulating microRNAs in rectal cancer are still rare. 111 patients with rectal cancer and 46 age-matched normal controls were enrolled. The expression levels of 30 microRNAs were analyzed in 17 pre-treatment patients' plasma samples. Differentially regulated microRNAs were validated in 94 independent patients. For 52 of the 94 patients a paired comparison between pre-treatment and post-treatment samples was performed. miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p, were significantly downregulated in pre-treatment plasma samples of patients with rectal cancer (p < 0.05). miR-29c, miR-30c, and miR-195 showed a trend of differential regulation. After validation, miR-31 and miR-30c were significantly deregulated by a decrease of expression. In 52 patients expression analyses of the 8 microRNAs in matched pre-treatment and post-treatment samples showed a significant decrease for all microRNAs (p < 0.05) after treatment. Expression levels of miR-31 and miR-30c could serve as valid biomarkers if validated in a prospective study. Plasma microRNA expression levels do not necessarily represent miRNA expression levels in tumor tissue. Also, expression levels of microRNAs change during multimodal therapy.

Prognostic Value of MicroRNAs in Preoperative Treated Rectal Cancer.

BACKGROUND: Patients with locally advanced rectal cancer are treated with preoperative chemoradiotherapy followed by surgical resection. Despite similar clinical parameters (uT2-3, uN+) and standard therapy, patients' prognoses differ widely. A possible prediction of prognosis through microRNAs as biomarkers out of treatment-naïve biopsies would allow individualized therapy options. METHODS: Microarray analysis of 45 microdissected preoperative biopsies from patients with rectal cancer was performed to identify potential microRNAs to predict overall survival, disease-free survival, cancer-specific survival, distant-metastasis-free survival, tumor regression grade, or nodal stage. Quantitative real-time polymerase chain reaction (qPCR) was performed on an independent set of 147 rectal cancer patients to validate relevant miRNAs. RESULTS: In the microarray screen, 14 microRNAs were significantly correlated to overall survival. Five microRNAs were included from previous work. Finally, 19 miRNAs were evaluated by qPCR. miR-515-5p, miR-573, miR-579 and miR-802 demonstrated significant correlation with overall survival and cancer-specific survival (p < 0.05). miR-573 was also significantly correlated with the tumor regression grade after preoperative chemoradiotherapy. miR-133b showed a significant correlation with distant-metastasis-free survival. miR-146b expression levels showed a significant correlation with nodal stage. CONCLUSION: Specific microRNAs can be used as biomarkers to predict prognosis of patients with rectal cancer and possibly stratify patients' therapy if validated in a prospective study.

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. METHODS: In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. INTERPRETATION: Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Human papillomavirus DNA load and p16INK4a expression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy.

As the detection rate of HPV-DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long-term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin-fixed paraffin-embedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load (≤/> median) with local failure, distant metastases, cancer-specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16(INK4a) were evaluated for any correlation with HPV16 DNA load and were included in uni- and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31, 35, 39, 44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16(INK4a) expression (p = 0.001). Patients with HPV16 DNA load ≤ median and low p16(INK4a) expression showed significantly worse local control (HPV16 DNA load: univariate p = 0.023, multivariate p = 0.042; p16(INK4a): univariate p = 0.021), and OS (HPV16 DNA load: univariate p = 0.02, multivariate p = 0.03). Moreover, a combined HPV16 DNA load and p16(INK4a) variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p = 0.019, p = 0.04 and p = 0.031). In conclusion, these data indicate that HPV16 DNA load and p16(INK4a) expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.

High-grade acute organ toxicity and p16(INK4A) expression as positive prognostic factors in primary radio(chemo)therapy for patients with head and neck squamous cell carcinoma.

BACKGROUND: Superior treatment response and survival for patients with human papilloma virus (HPV)-positive head and neck cancer (HNSCC) are documented in clinical studies. However, the relevance of high-grade acute organ toxicity (HGAOT), which has also been correlated with improved prognosis, has attracted scant attention in HPV-positive HNSCC patients. Hence we tested the hypothesis that both parameters, HPV and HGAOT, are positive prognostic factors in patients with HNSCC treated with definite radiotherapy (RT) or radiochemotherapy (RCT). PATIENTS AND METHODS: Pretreatment tumor tissue and clinical records were available from 233 patients receiving definite RT (62 patients) or RCT (171 patients). HPV infection was analysed by means of HPV DNA detection or p16(INK4A) expression; HGAOT was defined as the occurrence of acute organ toxicity >grade 2 according to the Common Toxicity Criteria. Both variables were correlated with overall survival (OS) using Cox proportional hazards regression. RESULTS: Positivity for HPV DNA (44 samples, 18.9 %) and p16(INK4A) expression (102 samples, 43.8 %) were significantly correlated (p < 0.01), and HGAOT occurred in 77 (33 %) patients. Overall, the 5-year OS was 23 %; stratified for p16(INK4A) expression and HGAOT, OS rates were 47 %, 42 %, 20 % and 10 % for patients with p16(INK4A) expression and HGAOT, patients with HGAOT only, patients with p16(INK4A) expression only, and patients without p16(INK4A) expression or HGAOT, respectively. After multivariate testing p16(INK4A) expression (p = 0.003) and HGAOT (p < 0.001) were significantly associated with OS. CONCLUSION: P16(INK4A) expression and HGAOT are independent prognostic factors for OS of patients with HNSCC, whereas p16(INK4A) expression is particularly important for patients without HGAOT.

Preoperative Prediction of Lymph Node Status by Circulating Mir-18b and Mir-20a During Chemoradiotherapy in Patients with Rectal Cancer.

BACKGROUND: In locally advanced rectal cancer, therapeutic success of preoperative chemoradiotherapy (CRT) ranges from resistance to complete regression. For those patients that respond well to CRT, local resection (LR) procedures are currently under investigation to minimize surgical morbidity and to improve functional outcome. To maintain the oncologic benefit appropriate staging procedures are essential. However, current clinical assessment and imaging techniques need further improvement. METHODS: Five miRNAs associated with rectal cancer (miR-17, miR-18b, miR-20a, miR-31, and miR-193-3p) were analyzed in the plasma of rectal cancer patients (n = 42) using qPCR. Expression levels were assessed before, during and after CRT and analyzed in regard to patients' lymph node status obtained after total mesorectal excision and intensive histopathological work-up. RESULTS: Four of the five miRNAs revealed reliable results in the plasma. miR-31 was excluded due to its low expression. MicroRNA-17, 18b, 20a, and 193-3p showed altering expression levels at different time points. Only 43% (miR-17), 43% (miR-18b), 53% (miR-20a), and 60% (miR-193-3p) showed a continuous in- or decrease of miRNA expression. The reduced expression of miR-18b and miR-20a during CRT was found to be significantly associated with postoperative lymph node negativity (p < 0.05). CONCLUSION: MicroRNA expression in patient plasma changes during preoperative CRT. The alteration is not continuous and the meaning requires additional analysis on a larger patient cohort. The co-occurrence of reduced miR-18b and miR-20a expression with lymph node negativity after preoperative CRT could help to stratify the surgical procedure with respect to total mesorectal excision and LR if validated prospectively.

The anti-TNF-α antibody infliximab inhibits the expression of fat-transporter-protein FAT/CD36 in a selective hepatic-radiation mouse model.

Previously, we reported a radiation-induced inflammation triggering fat-accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36) in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36-expression by anti-tumor necrosis factor-α (anti-TNF-α) (infliximab) was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray) and the effect of anti-TNF-α-therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1-3 h) induction of TNF-α-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6-12 h), compared to sham-irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6-12 h) increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-α. TNF-α-blockage by anti-TNF-α showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with α-smooth muscle actin (α-SMA+) cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-α-therapy prevented early radiation-induced expression of FAT/CD36 in vivo.

STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo.

Increased activity of signal transducer and activator of transcription 3 (STAT3) is common in human malignancies, including colorectal cancers (CRCs). We have recently reported that STAT3 gene expression correlates with resistance of CRC cell lines to 5-fluorouracil (5-FU)-based chemoradiotherapy (CT/RT). This is of considerable clinical importance, because a large proportion of rectal cancers are resistant to preoperative multimodal treatment. To test whether STAT3 contributes to CT/RT-resistance, we first confirmed that STAT3 protein expression correlated positively with increasing resistance. While STAT3 was not constitutively active, stimulation with interleukin-6 (IL-6) resulted in remarkably higher expression levels of phosphorylated STAT3 in CT/RT-resistant cell lines. A similar result was observed when we determined IL-6-induced expression levels of phosphorylated STAT3 following irradiation. Next, STAT3 was inhibited in SW480 and SW837 using siRNA, shRNA and the small-molecule inhibitor STATTIC. Successful silencing and inhibition of phosphorylation was confirmed using Western blot analysis and a luciferase reporter assay. RNAi-mediated silencing as well as STATTIC treatment resulted in significantly decreased clonogenic survival following exposure to 3 µM of 5-FU and irradiation in a dose-dependent manner, with dose-modifying factors of 1.3-2.5 at a surviving fraction of 0.37. Finally, STAT3 inhibition led to a profound CT/RT-sensitization in a subcutaneous xenograft model, with a significantly delayed tumor regrowth in STATTIC-treated mice compared with control animals. These results highlight a potential role of STAT3 in mediating treatment resistance and provide first proof of concept that STAT3 represents a promising novel molecular target for sensitizing resistant rectal cancers to CT/RT.

Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival.

BACKGROUND: The transmembrane glycoprotein CD133 (cluster of differentiation 133; also known as Prominin or PROM1) has been described as a potential stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study, CD133 expression was evaluated in pre-RCT tumor biopsies and the corresponding post-RCT surgical specimens from patients with locally advanced rectal adenocarcinoma, and expression levels were correlated with histopathologic features and clinical follow-up. METHODS: One hundred twenty-six patients with International Union Against Cancer (UICC) stage II/III rectal cancer who received preoperative 5-fluorouracil (5-FU)-based RCT within the German Rectal Cancer Trials were investigated. Pre-RCT and post-RCT CD133 expression levels were determined using immunohistochemistry and were correlated with histopathologic parameters, tumor regression grade, cancer recurrence, and patient survival. RESULTS: Compared with pre-RCT biopsies, significantly higher CD133 expression was observed in tumor specimens (P = .01). However, no correlations were observed for either biopsies or tumor specimens between CD133 expression levels, histopathologic characteristics, or survival. In matched analyses of corresponding biopsy/tumor pairs, patients who had an increased fraction of CD133-expressing (CD133+) cells after preoperative RCT had significantly higher residual tumor stages (P = .02) and lower histopathologic tumor regression (P < .01). Moreover, these patients had significantly reduced disease-free survival and cancer-specific overall survival in univariate analysis (P < .001 and P = .004, respectively) and multivariate analysis (P = .003 and P = .024, respectively). CONCLUSIONS: The enrichment of CD133+ cancer cells during preoperative RCT was correlated with minor local tumor response, increased distant cancer recurrence, and decreased survival. The current results indicate that the up-regulation of intratumoral CD133 expression, in contrast to absolute pre-RCT and post-RCT CD133 levels, plays an important role in tumor progression and metastasis in patients with rectal cancer who are receiving neoadjuvant RCT.

Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII.

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.

Organ preservation in T4a laryngeal cancer: is transoral laser microsurgery an option?

The main objective of this study is to assess the feasibility of transoral laser microsurgery (TLM) in the treatment of T4a laryngeal cancer and to report the oncological and functional outcomes. This is a retrospective case-series study, held in a single-institute, academic tertiary referral center. Seventy-nine patients with previously untreated T4a glottic (n = 31, 39 %) or supraglottic laryngeal carcinoma (n = 48, 61 %) were included in this study. Five patients (6 %) were treated exclusively by TLM, 16 (20 %) had TLM and unilateral neck dissection, 27 (35 %) had TLM and bilateral neck dissection. Adjuvant (chemo)radiotherapy was additionally administered in 26 (33 %) cases following TLM and neck dissection, and in 5 (6 %) cases after TLM without neck dissection. The main outcome measures included organ preservation, local control, functional outcome, overall, recurrence-free, and disease-specific survival. The median follow-up period was 49 months, 5 year organ preservation rate and local control rate were 80.0 and 67.2 %, 5 year overall, recurrence-free and disease-specific survival were 55.8, 61.9 and 71.8 %. The 5 year overall survival rates were 62.5 % in pN0 cases and 57.2 % in cases with pN-positive neck disease. With respect to survival, these results are comparable to total laryngectomy, while being superior to primary (chemo)radiotherapy. TLM results in a low morbidity, rapid recovery and good function and can be a valid option for organ preserving surgery of pT4a glottic and supraglottic cancer.

Oncologic and functional results after transoral laser microsurgery of tongue base carcinoma.

The objective of the study was to determine the oncological and functional results in patients after excision of tongue base carcinoma by transoral laser microsurgery. A retrospective unicenter study performed between 1986 and 2007. 82 patients with previously untreated squamous cell carcinoma of the tongue base (T1-4, N0-2, M0) underwent transoral laser surgery with curative intent. Stage distribution was as follows: stage I, 1 case (1 %): stage II, 6 cases (7 %): stage III, 14 cases (17 %): stage IV 61 cases (75 %). Main outcome measures are local control rate, overall survival, recurrence-free survival, complications, and feeding tube dependence. The results were Kaplan-Meier 5-year local control rate for all patients was 84 %. T-stage-related local control rate after 5 years was 94 % for stage I-II, 78 % for stage III and 81 % for stage IV. 5-year overall survival and recurrence-free survival were 59 and 69 %, respectively. UICC stage-related overall survival and recurrence-free survival were 70 and 86 % for stage I-II, 44 and 54 % for stage III and 58 and 69 % for stage IV. Postoperative bleeding at the primary tumor site occurred in 9 patients (11 %). Gastrostomy tubes remained in place permanently in 5 patients (6 %). Primary transoral laser microsurgery of tongue base carcinoma offers convincing oncological and functional results comparable to other treatment modalities, e.g., radio(chemo)therapy but has lower rates of morbidity.

Results of transoral laser microsurgery for supraglottic carcinoma in 277 patients.

The objective of the study was to evaluate the oncological and functional results of transoral laser microsurgery (TLM) in patients with supraglottic laryngeal squamous cell carcinoma. Between June 1980 and December 2006, 277 patients with squamous cell supraglottic carcinoma of all stages were treated by primary carbon dioxide laser microsurgery. All treatments were performed with curative intention. The goal was the complete tumor removal with preservation of functionally important structures of the larynx. The administered treatment was exclusively TLM with or without selective or modified radical neck dissection in 215 cases (78 %); TLM with postoperative radiotherapy was performed in 62 cases (22 %). Data were analyzed using the Kaplan-Meier method. The median follow-up was 65 months. We achieved a 5-year local control rate of 85% for pT1/pT2, 82% for pT3, and 76% for pT4. The 5-year overall, recurrence-free and disease-specific survival rates for stages I and II were 76, 81, and 92%, for stages III and IVa 59, 65, and 81%, respectively. With respect to local control and survival, these results are comparable with the results achieved by conventional partial and total resection of the larynx, while being superior to primary (chemo)radiotherapy. Transoral laser microsurgery results in a low morbidity, rapid recovery, and superior function compared with standard therapy.

Results of transoral laser microsurgery in 102 patients with squamous cell carcinoma of the tonsil.

The objective of this study is to assess the feasibility of transoral laser microsurgery (TLM) in the treatment of squamous cell cancer of the tonsil and to report the oncological and functional outcomes, using retrospective chart review in the setting of single-institute, academic tertiary referral center. Between October 1987 and December 2006, 102 patients were eligible for this study, mostly suffering from advanced disease: 13% presented with stage I and II (UICC/AJCC 2002) tumors and 87% with stages III and IVa. The median follow-up was 63 months. All patients were treated by TLM with (or without) neck dissection (95%) and with (66%) postoperative radiotherapy. Overall survival, recurrence-free survival, disease-free survival, local control and loco-regional control were analyzed as end points. Rate of tracheotomies, postoperative complications and swallowing function were also analyzed. 5-year Kaplan-Meier local and loco-regional control was 78% for pT1 and pT2 and 75 % for pT3 and pT4a tumors. 5-year Kaplan-Meier disease-free survival, recurrence-free survival, and overall survival and was 74, 64 and 59% for stage I and II, 68, 60 and 56 % for stage III and IVa, respectively. Our data supports the conclusion, that TLM should be considered as a therapeutic option for the treatment of cancer of the tonsil. The oncological and functional results are comparable to any other treatment regimen, while the morbidity and complications tend to be lower.

The molecular basis of chemoradiosensitivity in rectal cancer: implications for personalized therapies.

INTRODUCTION: Preoperative chemoradiotherapy represents the standard treatment for patients with locally advanced rectal cancer. Unfortunately, the response of individual tumors to multimodal treatment is not uniform and ranges from complete response to complete resistance. This poses a particular problem for patients with a priori resistant tumors because they may be exposed to irradiation and chemotherapy, treatment regimens that are both expensive and at times toxic, without benefit. Accordingly, there is a strong need to establish molecular biomarkers that predict the response of an individual patient's tumor to multimodal treatment and that indicate treatment-associated toxicities prior to therapy. Such biomarkers may guide clinicians in choosing the best possible treatment for each individual patient. In addition, these biomarkers could be used to identify novel molecular targets and thereby assist in implementing novel strategies to sensitize a priori resistant tumors to multimodal treatment regimens. OBJECTIVE: The aim of this review is to summarize recent findings about the molecular basis of treatment resistance and treatment toxicity in patients with rectal cancer. Whole-genome, as well as single-biomarker or multibiomarker, analyses and their potential implications will be highlighted. At the end, we will outline a future vision of rectal cancer treatment in the era of personalized medicine.

Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy.

A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a ß-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.

Gender-specific acute organ toxicity during intensified preoperative radiochemotherapy for rectal cancer.

Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil-based (5-FU-based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity. All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5-FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade ≥3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone. Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5-FU+oxaliplatin. A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity. These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity.

High-grade acute organ toxicity as positive prognostic factor in adjuvant radiation and chemotherapy for locally advanced head and neck cancer.

PURPOSE: To test for an association between high-grade acute organ toxicity during adjuvant radiation and chemotherapy and treatment outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. From September 1994 to October 2008, 294 HNSCC patients were treated with adjuvant radiation and chemotherapy at the authors' department. They received normofractionated (2 Gy per fraction) irradiation to include associated nodal drainage sites, for a cumulative dose of 60-64 Gy. From January 2002 to December 2009, 91 patients received additional concomitant cisplatin-based chemotherapy. Toxicity during treatment was monitored weekly according to the common toxicity criteria (CTC); any CTC toxicity grade 3 or higher, including mucositis, dysphagia, or skin reaction, was considered high-grade acute organ toxicity. The influence of possible prognostic factors on overall survival and locoregional control was studied by means of uni- and multivariate Cox regression. RESULTS: A statistically significant association was found between high-grade acute organ toxicity and both overall survival and locoregional control. Patients with CTC grade 3 or greater acute organ toxicity had a 5-year overall survival and locoregional control rate of 90% and 97%, respectively, as compared with 24% and 74%, respectively, in patients without such toxicity (P < .01). Multivariate analyses revealed that this association was independent from other factors that may influence treatment toxicity, especially concomitant chemotherapy and/or radiation therapy. CONCLUSION: The data suggest that normal tissue and tumor tissue may behave similarly with respect to treatment response, as high-grade acute organ toxicity during radiation and chemotherapy was associated with better outcomes in the patient population; therefore, the hypothesis should be further analyzed on the biomolecular and clinical level and with other tumor entities in prospective clinical trials.