Pirus Ghadjar

The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer

Chemokines are a superfamily of small chemotactic cytokines, which interact with their G‐protein‐coupled receptors. These interactions regulate multiple physiological functions, particularly tissue architecture and compartment‐specific migration of white blood cells. It has been found that the chemokine/chemokine receptor system has been utilized by cancer cells for migration and metastasis. The chemokine receptor CCR6 is expressed in colorectal cancer and several other cancer types, and stimulation by its physiological chemokine ligand CCL20 has been reported to promote cancer cell proliferation and migration in vitro. Moreover, CCR6/CCL20 interactions apparently play a role in organ selectiveliver metastasis of colorectal cancer. Here, we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCR6 and CCL20 in the formation of colorectal cancer liver metastasis, providing a potential basis for novel treatment strategies.

Chemokine Receptor CCR6 Expression Level and Liver Metastases in Colorectal Cancer

PURPOSE The liver is the primary organ of metastasis in colorectal cancer (CRC). Chemokine receptor CCR6 is expressed on a subset of T cells and is associated with their migration into the liver. This study was performed to analyze a possible association between CCR6 expressed by primary CRC and liver metastases. PATIENTS AND METHODS CCR6 expression levels were evaluated by immunohistology in 64 CRC primary tumor specimens. Twenty-four of 64 patients had synchronous liver metastases. Evaluation of immunostaining was performed semiquantitatively by visual assessment and quantitatively by digital image analysis (DIA). Multiple logistic regression analysis was performed to assess relevant parameters for liver metastases. RESULTS CCR6 expression was verified in all 64 primary tumor specimens with considerable variations in intensity; 21 tumors (33%) demonstrated weak CCR6 staining, 32 (50%) demonstrated intermediate staining, and 11 (17%) demonstrated strong staining. Quantitative assessment by DIA showed an up to 5-log difference in CCR6 values. CCR6 staining was significantly stronger in tumor cells compared with adjacent colon epithelial cells (P < .0005). Multiple logistic regression analysis, controlling for age, sex, tumor stage, nodal status, pathologic grade, and preoperative carcinoembryonic antigen levels, revealed that CCR6 staining in the primary tumor was independently associated with the presence of liver metastases (odds ratio = 2.1; P = .002). CONCLUSION The association between expression level of CCR6 in primary CRC and synchronous liver metastases suggests that CCR6 and its ligand may be involved in the metastatic spread to the liver. Therefore, CCR6 may be a potential target for specific therapeutic interventions.

Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.

To compare tumour control and toxicity outcomes with the use of high‐dose intensity‐modulated radiation therapy (IMRT) alone or brachytherapy combined with IMRT (combo‐RT) for patients with intermediate‐risk prostate cancer.

Toxicity and early treatment outcomes in low- and intermediate-risk prostate cancer managed by high-dose-rate brachytherapy as a monotherapy

PURPOSE To determine the acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and present short-term biochemical no evidence of disease (bNED) rates after high-dose-rate brachytherapy (HDR-B) monotherapy. METHODS AND MATERIALS Between October 2003 and June 2006, 36 patients with low (28) and intermediate (8) risk prostate cancer (PCA) were treated by HDR-B monotherapy. All patients received one implant and four fractions of 9.5Gy within 48h for a total prescribed dose (PD) of 38Gy. Five patients received hormonal therapy (HT). Median age was 63.5 years and median followup was 3 years (range, 0.4-4 years). Toxicity was scored according to the CTCAE version 3.0. Biochemical failure was defined according to the Phoenix criteria. RESULTS Acute and late Grade 3 GU toxicity was observed in 1 (3%) and 4 (11%) patients, respectively. Grade 3 GI toxicity was absent. The three- year bNED survival rate was 100%. The sexual preservation rate in patients without HT was 75%. Late Grade 3 GU toxicity was associated with the planning target volume (PTV) V(100) (% PTV receiving > or =100% of the PD; p=0.036), D(90) (dose delivered to 90% of the PTV; p=0.02), and the urethral V(120) (urethral volume receiving > or =120% of the PD; p=0.043). The urethral V(120) was associated with increased PTV V(100) (p<0.001) and D(90) (p=0.003). CONCLUSIONS After HDR-B monotherapy, late Grade 3 GU toxicity is associated with the urethral V(120) and the V(100) and D(90) of the PTV. Decrease of the irradiated urethral volume may reduce the GU toxicity and potentially improve the therapeutic ratio of this treatment.

Nuclear expression of CXCR4 in tumor cells of non-small cell lung cancer is correlated with lymph node metastasis.

The stromal-derived factor 1alpha (CXCL12)/chemokine receptor CXCR4 system plays an important role in the metastatic process of a variety of cancers, with CXCR4 frequently expressed by tumor cells homing to CXCL12-rich compartments. The current study evaluated a possible association of CXCR4 expression with lymph node metastasis in primary non-small cell lung cancer. CXCR4 expression levels were evaluated using immunohistology in 46 non-small cell lung cancer specimens of patients without or with lymph node involvement (N0 = 24, N1/N2/N3 = 22). Evaluation of immunostaining was performed semiquantitatively by visual assessment. Statistical analyses with multiple testing adjustments for confirmatory comparisons were performed to assess relevant parameters associated with lymph node metastases. In all samples of non-small cell lung cancer, tumor cells stained positively for cytoplasmic CXCR4. The intensity of the CXCR4 staining varied considerably between specimens: 2 (4%) tumors demonstrated weak cytoplasmic CXCR4, 22 (48%) intermediate, and 22 (48%) strong staining. Membranous staining was absent; however, nuclear staining of CXCR4 was observed in 5 non-small cell lung cancer samples. Statistical analyses of the association between presence of lymph node metastases and CXCR4 expression levels revealed that cytoplasmic CXCR4 expression was not associated with the presence of lymph node metastases. However, nuclear CXCR4 was significantly correlated with increasing lymph node stage (P = .008), linear-to-linear association. The association between aberrant expression of CXCR4 in the nucleus of non-small cell lung cancer and metastasis to lymph nodes points toward a potential tumor metastasis promoting function of nuclear CXCR4.

Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry.

Abstract Purpose: Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry. Materials and methods: The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. Results: A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. Conclusions: In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.

Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10

PURPOSE Patients with biochemical failure (BF) after radical prostatectomy may benefit from dose-intensified salvage radiation therapy (SRT) of the prostate bed. We performed a randomized phase III trial assessing dose intensification. PATIENTS AND METHODS Patients with BF but without evidence of macroscopic disease were randomly assigned to either 64 or 70 Gy. Three-dimensional conformal radiation therapy or intensity-modulated radiation therapy/rotational techniques were used. The primary end point was freedom from BF. Secondary end points were acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and quality of life (QoL) according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and PR25. RESULTS Three hundred fifty patients were enrolled between February 2011 and April 2014. Three patients withdrew informed consent, and three patients were not eligible, resulting in 344 patients age 48 to 75 years in the safety population. Thirty patients (8.7%) had grade 2 and two patients (0.6%) had grade 3 genitourinary (GU) baseline symptoms. Acute grade 2 and 3 GU toxicity was observed in 22 patients (13.0%) and one patient (0.6%), respectively, with 64 Gy and in 29 patients (16.6%) and three patients (1.7%), respectively, with 70 Gy (P = .2). Baseline grade 2 GI toxicity was observed in one patient (0.6%). Acute grade 2 and 3 GI toxicity was observed in 27 patients (16.0%) and one patient (0.6%), respectively, with 64 Gy, and in 27 patients (15.4%) and four patients (2.3%), respectively, with 70 Gy (P = .8). Changes in early QoL were minor. Patients receiving 70 Gy reported a more pronounced and clinically relevant worsening in urinary symptoms (mean difference in change score between arms, 3.6; P = .02). CONCLUSION Dose-intensified SRT was associated with low rates of acute grade 2 and 3 GU and GI toxicity. The impact of dose-intensified SRT on QoL was minor, except for a significantly greater worsening in urinary symptoms.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: A study from the rare cancer network

PURPOSE To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). METHODS AND MATERIALS A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. RESULTS Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). CONCLUSIONS After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

Patterns and Predictors of Amelioration of Genitourinary Toxicity After High-dose Intensity-modulated Radiation Therapy for Localized Prostate Cancer: Implications for Defining Postradiotherapy Urinary Toxicity

BACKGROUND Treatment-related toxicity and quality of life (QoL) considerations are important when counseling patients with localized prostate cancer (PCa). OBJECTIVE To determine the incidence and longitudinal pattern of late genitourinary (GU) toxicity and QoL after high-dose, intensity-modulated radiotherapy (IMRT). DESIGN, SETTING, AND PARTICIPANTS A total of 268 patients with localized PCa were treated between June 2004 and December 2008 at a tertiary referral center. Median follow-up was 5 yr (range: 3-7.7 yr). INTERVENTION Patients underwent IMRT to a total dose of 86.4Gy; 50% of patients underwent neoadjuvant and concurrent androgen-deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Patients were evaluated with the prospectively obtained International Prostate Symptom Score (IPSS) questionnaire. GU toxicity was also scored using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0; toxicity events were defined as increase over baseline. Differences in increases in IPSS sums and QoL index between baseline IPSS sum and QoL index groups were analyzed using the Kruskal-Wallis and Mann-Whitney tests. Univariate and multivariate Cox regression models were applied. RESULTS AND LIMITATIONS The overall median IPSS sum increase during follow-up was 3 and was less pronounced among patients with severe baseline symptoms compared with those with mild baseline symptoms (median increase: 0 vs 4; p<0.0001). Overall QoL index was unchanged after IMRT but appeared to improve in patients with dissatisfied baseline QoL compared with satisfied baseline QoL (p<0.0001). Fifty-five (20%) and 2 (1%) patients developed grade 2 and 3 late GU toxicities, respectively; however, in 28 of 57 patients (49%), toxicity resolved during follow-up. Even though the IPSS data were prospectively obtained, most patients were not treated within a prospective protocol. CONCLUSIONS Late GU toxicity after high-dose IMRT was mild; severe, late GU toxicity was rare. Changes in IPSS sum and QoL index were dependent on the baseline GU function, which might be useful for future patient counseling.

Concomitant Cisplatin and Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Cancer: 10-Year Follow-Up of a Randomized Phase III Trial (SAKK 10/94)

PURPOSE To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer. METHODS AND MATERIALS From July 1994 to July 2000, a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to receive either hyperfractionated radiotherapy alone (median total dose, 74.4 Gy; 1.2 Gy twice daily; 5 days per week) or the same radiotherapy combined with two cycles of cisplatin (20 mg/m(2) for 5 consecutive days during weeks 1 and 5). The primary endpoint was the time to any treatment failure; secondary endpoints were locoregional failure, metastatic failure, overall survival, and late toxicity assessed according to Radiation Therapy Oncology Group criteria. RESULTS Median follow-up was 9.5 years (range, 0.1-15.4 years). Median time to any treatment failure was not significantly different between treatment arms (hazard ratio [HR], 1.2 [95% confidence interval {CI}, 0.9-1.7; p = 0.17]). Rates of locoregional failure-free survival (HR, 1.5 [95% CI, 1.1-2.1; p = 0.02]), distant metastasis-free survival (HR, 1.6 [95% CI, 1.1-2.5; p = 0.02]), and cancer-specific survival (HR, 1.6 [95% CI, 1.0-2.5; p = 0.03]) were significantly improved in the combined-treatment arm, with no difference in major late toxicity between treatment arms. However, overall survival was not significantly different (HR, 1.3 [95% CI, 0.9-1.8; p = 0.11]). CONCLUSIONS After long-term follow-up, combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control, distant metastasis-free survival, and cancer-specific survival compared to that of hyperfractionated radiotherapy alone, with no difference in major late toxicity.