Search

Cervical cancer is a deadly disease and the COVID-19 pandemic has the potential to further impact its lethality. Hypofractionated radiotherapy could mitigate this impact, however robust data in cervical cancer setting still is lacking. Information provided here could help institutions in reducing radiotherapy fractions for cervical cancer patients.

Purpose To compare CTVHR and OAR dimensions and inter-rater agreement between magnetic resonance (MR) and trans-rectal ultrasound (TRUS) images in IB cervical cancer patients. Methods IB cervical cancer patients treated with (chemo)radiotherapy plus MR-guided brachytherapy (BT) were prospectively enrolled in this study. Radiation oncologists contoured CTVHR and OARs in pre-BT MR images (MRI) and intra-operative TRUS images. These contours were subsequently compared in regard to volume and dimension. Contour inter-rater agreement analysis was also investigated using kappa index (KI). Stata 15.0 was used for statistical analysis and a p-value Results TRUS CTVHR volumes were statistically smaller than the respective MRI contoured volumes. TRUS CTVHR thickness was found to be consistently smaller than MRI contours in all patients. No statistical difference was seen in width and height between the two different imaging modalities. MRI contours had a median KI of 0.66 (range: 0.56–0.77) while TRUS-based contours had a median KI of 0.64 (range: 0.47–0.77). Bladder and rectum had very satisfactory KI in both imaging modalities. Vaginal contours had moderate agreement in MR (0.52) and in TRUS images (0.58). Conclusion TRUS images allow good visualization of CTVHR and OARs in IB cervical cancer patients. Inter-rater contour variability was comparable between TRUS and MR images. TRUS is a promising modality on its own for image-guided BT.

Adding a boost to whole breast radiation (WBI) following breast-conserving surgery (BCS) may help improve local control, but it increases the total cost of treatment and may worsen cosmetic outcomes. Therefore, it is reserved for patients whose potential benefit outweighs the risks; however, current evidence is insufficient to support comprehensive and consistent guidance on how to identify these patients, leading to a potential for significant variations in practice. The use of a boost in the setting of close margins and hypofractionated radiotherapy represents two important areas where consensus guidelines, patterns of practice, and current evidence do not seem to converge. Close margins were previously routinely re-excised, but this is no longer felt to be necessary. Because of this recent practice change, good long-term data on the local recurrence risk of close margins with or without a boost is lacking. As for hypofractionation, although there is guidance recommending that the decision to add a boost be independent from the whole-breast fractionation schedule, it appears that patterns-of-practice data may show underutilization of a boost when hypofractionation is used. The use of a boost in these two common clinical scenarios represents important areas of future study for the optimization of adjuvant breast radiation.

Background and purpose To identify a PSA threshold value at an intermediate follow-up time after low dose rate (LDR) prostate brachytherapy associated with cure, defined as long-term (10–15 year) freedom from prostate cancer. Materials and methods Data from 7 institutions for 14,220 patients with localized prostate cancer treated with LDR brachytherapy, either alone (8552) or with external beam radiotherapy (n = 1175), androgen deprivation (n = 3165), or both (n = 1328), were analyzed. Risk distribution was 42.4% favorable, 49.2% intermediate, and 8.4% high-risk. Patients with clinical failure before 3.5 years were excluded. Kaplan-Meier analysis was used with clinical failure (local, distant, regional or biochemical triggering salvage) as an endpoint for each of four PSA categories: PSA ≤ 0.2, >0.2 to ≤0.5, >0.5 to ≤1.0, and >1.0 ng/mL. PSA levels at 4 years (±6 months) in 8746 patients without clinical failure were correlated with disease status at 10–15 years. Results For the 77.1% of patients with 4-year PSA ≤ 0.2, the freedom-from-recurrence (FFR) rates were 98.7% (95% CI 98.3–99.0) at 10 years and 96.1% (95% CI 94.8–97.2) at 15 years. Three independent validation cohorts confirmed 97–99% 10-year FFR rates with 4-year PSA ≤ 0.2. Successive PSA categories were associated with diminished disease-free rates at 10 and 15 years. PSA category was strongly associated with treatment success (p Conclusions Since 98.7% of patients with PSA ≤ 0.2 ng/mL at 4 years after LDR prostate brachytherapy were disease-free beyond 10 years, we suggest adopting this biochemical definition of cure for patients with ≥4 years’ follow-up after LDR brachytherapy.

Purpose To describe and compare outcomes in men with initially presumed indolent prostate cancer receiving definitive radiation therapy after active surveillance (AS) versus those in a risk-matched cohort undergoing up-front radiation therapy. Methods and Materials Men prospectively enrolled in an AS program between 1992 and 2014 and subsequently undergoing curative radiation therapy (ie, image guided radiation therapy [IGRT] or low-dose-rate brachytherapy [LDR-BT]) were identified. Biochemical relapse–free rate (bRFR), metastasis-free rate (mFR), and overall survival (OS) were compared against a cohort of men treated up front, matched by age, clinical prognostic indices (risk group, prostate-specific antigen, cT category, Gleason score, percentage of involved biopsy cores), and radiation therapy modality. Results Of 1070 patients in the AS registry, 200 underwent definitive radiation therapy (143 IGRT and 57 LDR-BT) after a median of 32.9 (interquartile range [IQR] 20.6-59.8) months on surveillance. Main reasons for treatment were grade and volume upgrading (57.5% and 26%, respectively). Median follow-up after radiation therapy was 4.9 (IQR 3.1-7.5) years. At 5 years the bRFR, mFR, and OS were, respectively, 97%, 99%, and 98.5%. No patient died of prostate cancer. Adequate risk-matching was confirmed in an independent cohort comprising 359 patients receiving up-front IGRT (71%) or LDR-BT (29%) and followed for a median of 9 (IQR 3.1-7.5) years. There was no difference in the disease-specific outcomes (bRFR, mFR) between the 2 cohorts (Gray's P value of .257 and .934, respectively). In multivariate analyses, timing of radical radiation therapy (deferred vs up-front) was not correlated to biochemical relapse or metastases occurrence. Conclusions Curative-intent radiation therapy (ie, dose-escalated IGRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Deferring radical therapy after a period of AS does not seem to result in inferior oncologic outcomes compared with patients with similar risk characteristics undergoing up-front treatment.

Background Osteoradionecrosis (ORN) of the jaws is among the most serious oral complications of head and neck cancer radiotherapy, arising from radiation-induced fibro-atrophic tissue injury, manifested by necrosis of osseous tissues and failure to heal, often secondary to operative interventions in the oral cavity. It is associated with considerable morbidity and has important quality of life ramifications. Since ORN is very difficult to treat effectively, preventive measures to limit the onset of this disease are needed; however, the effects of various preventive interventions has not been adequately quantified. Objectives To assess the effects of interventions for preventing ORN of the jaws in adult patients with head and neck cancer undergoing curative or adjuvant (i.e. non-palliative) radiotherapy. Search methods Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 5 November 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 10) in the Cochrane Library (searched 5 November 2019), MEDLINE Ovid (1946 to 5 November 2019), Embase Ovid (1980 to 5 November 2019), Allied and Complementary Medicine (AMED) Ovid (1985 to 5 November 2019), Scopus (1966 to 5 November 2019), Proquest Dissertations and Theses International (1861 to 5 November 2019) and Web of Science Conference Proceedings (1990 to 5 November 2019). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. Selection criteria We selected randomised controlled trials (RCTs) or quasi-RCTs of adult patients 18 years or older with head and neck cancer who had undergone curative or adjuvant radiotherapy to the head and neck, who had received an intervention to prevent the onset of ORN. Eligible patients were those subjected to pre- or post-irradiation dental evaluation. Management of these patients was to be with interventions independent of their cancer therapy, including but not limited to local, systemic, or behavioural interventions. Data collection and analysis Two review authors independently selected trials from search results, assessed risk of bias, and extracted relevant data for inclusion in the review. Authors of included studies were contacted to request missing data. We used standard methodological procedures expected by Cochrane. Main results Four studies were identified that met pre-determined eligibility criteria, evaluating a total of 342 adults. From the four studies, all assessed as at high risk of bias, three broad interventions were identified that may potentially reduce the risk of ORN development: one study showed no reduction in ORN when using platelet-rich plasma placed in the extraction sockets of prophylactically removed healthy mandibular molar teeth prior to radiotherapy (odds ratio (OR) 3.32, 95% confidence interval (CI) 0.58 to 19.09; one trial, 44 participants; very low-certainty evidence). Another study involved comparing fluoride gel and high-content fluoride toothpaste (1350 parts per million (ppm)) in prevention of post-radiation caries, and found no difference between their use as no cases of ORN were reported (one trial, 220 participants; very low-certainty evidence). The other two studies involved the use of perioperative hyperbaric oxygen (HBO) therapy and antibiotics. One study showed that treatment with HBO caused a reduction in the development of ORN in comparison to patients treated with antibiotics following dental extractions (risk ratio (RR) 0.18, 95% CI 0.43 to 0.76; one trial, 74 participants; very low-certainty evidence). Another study found no difference between combined HBO and antibiotics compared to antibiotics alone prior to dental implant placement (RR 3.00, 95% CI 0.14 to 65.16; one trial, 26 participants; very low-certainty evidence). Adverse effects of the different interventions were not reported clearly or were not important. Authors' conclusions Given the suboptimal reporting and inadequate sample sizes of the included studies, evidence regarding the interventions evaluated by the trials included in this review is uncertain. More well-designed RCTs with larger samples are required to make conclusive statements regarding the efficacy of these interventions.

BACKGROUND: At our institution, we have historically treated brain metastasis (BM) ≤2 cm in eloquent brain with a radiosurgery (SRS) lower prescription dose (PD) to reduce the risk of radionecrosis (RN). We sought to evaluate the impact of this practice on outcomes. METHODS: We analyzed a prospective registry of BM patients treated with SRS between 2008 and 2017. Incidences of local failure (LF) and RN were determined and Cox regression was performed for univariate and multivariate analyses (MVAs). RESULTS: We evaluated 1533 BM ≤2 cm. Median radiographic follow-up post SRS was 12.7 months (1.4–100). Overall, the 2-year incidence of LF was lower for BM treated with PD ≥21 Gy (9.3%) compared with PD ≤15 Gy (19.5%) (sub–hazard ratio, 2.3; 95% CI: 1.4–3.7; P = 0.0006). The 2-year incidence of RN was not significantly higher for the group treated with PD ≥21 Gy (9.5%) compared with the PD ≤15 Gy group (7.5%) (P = 0.16). MVA demonstrated that PD (≤15 Gy) and tumor size (>1 cm) were significantly correlated (P < 0.05) with higher rates of LF and RN, respectively. For tumors ≤1 cm, when comparing PD ≤15 Gy with ≥21 Gy, the risks of LF and RN are equivalent. However, for lesions >1 cm, PD ≥21 Gy is associated with a lower incidence of LF without significantly increasing the risk of RN. CONCLUSION: Our results indicate that rates of LF or RN following SRS for BM are strongly correlated with size and PD. Based on our results, we now, depending upon the clinical context, consider increasing PD to 21 Gy for BM in eloquent brain, excluding the brainstem.

Radiation-induced parenchymal lung changes after stereotactic body radiotherapy are common, and can obscure the primary tumor site. In this study we propose a structured radiographic reporting tool for characterization of these changes, pilot its feasibility in a group of radiation oncologists, and test the interrater agreement. We could demonstrate the applicability of the scale, with a fair to moderate agreement.The purpose of the study was to design and pilot a synoptic scale for characterization of late radiographic changes after lung stereotactic body radiotherapy (SBRT).A participatory design process involving 6 radiation oncologists and 2 thoracic radiologists was used in the scale's design. Seventy-seven early-stage non-small-cell lung cancer patients who were treated with SBRT were included, and after treatment their serial computed tomography (CT) images were scored by 6 radiation oncologists. Gwet's First-order Agreement Coefficient (AC1) and a leave-one-out (LOO) analysis was used to assess interrater reliability and variability among raters, respectively.The scale reports on 5 independent categories including "tumor in primary site," "tumor in involved lobe," "consolidation," "volume loss," and "ground-glass or interstitial changes." At each time point, each category is reported as "increased," "stable," "decreased," "obscured," or "not present," compared with the previous. The total number of rated images for the pilot ranged from 450 at 6 months to 84 at 48 months. The primary tumor site was scored as obscured in 38% to 40% of ratings from 12 months onward; 3% to 5% of primary tumors were scored as "increased." Consolidation, volume loss, and ground-glass or interstitial changes were increasingly marked as "stable" with time. At 24 months, AC1 was 0.28 (LOO, 0.22-0.42), 0.47 (LOO, 0.39-0.72), 0.45 (LOO, 0.42-0.50), 0.21 (LOO, 0.15-0.26), and 0.25 (LOO, 0.20-0.38) for the 5 categories listed, respectively.In a population of clinicians, this scale could be implemented to characterize evolving lung changes after SBRT, and had fair to moderate interrater agreement. Obscured tumor site is a common challenge of follow-up CT imaging, and new imaging techniques should be explored. This scale provides a tool for communicating changes after SBRT.

Pharmaceutical research and development is increasingly focused on niche markets, most notably treatments for rare diseases and “personalized” medicine. Drawing on the results of a qualitative study of 34 key Canadian stakeholders (including drug regulators, funders, scientists, policy experts, pharmaceutical industry representatives, and patient advocates), we explore the major trends that are reportedly contributing to the growing interest of the pharmaceutical industry in niche markets. Informed by both these key informant interviews and a review of the relevant literature, our paper provides a critical analysis of the many different—and sometimes conflicting—views on the reasons for and extent of the shift toward niche markets. We consider some of the potential advantages to industry, as well the important implications and risks that arise from the increasing pursuit of niche markets and pharmacogenomics. While there are many potential benefits associated with targeted therapies and drug development for historically neglected rare diseases, niche market therapies also present evidentiary challenges (e.g., smaller clinical trials and enrichment strategies) that can make approval decisions difficult, and uncertainties remain around the true benefits of many therapies.

Aim: To determine factors associated with home death in patients with cancer in Ontario, particularly to assess the association between death at home and (1) patients’ rural/urban residence and (2) neighborhood income in urban areas. Materials and Methods: We conducted a retrospective cross-sectional study in Ontario (2003-2010) using linked administrative databases. In order to account for clustering phenomenon, multivariable generalized estimating equation model was used to evaluate factors associated with home death. Analysis was performed in both rural and urban areas. For urban areas, neighborhood income was tested as a determinant of the place of death. Results: A total of 193 783 deaths were analyzed, 9.1% of which occurred at home. In urban areas, home death was more likely for patients living in richer neighborhoods (odds ratio 1.69 for the highest compared to lowest neighborhood income quintile, 95% confidence interval: 1.54-1.86). The odds of dying at home when living in a rural area were no different from those living in the poorest urban neighborhood. Other variables associated with lower odds of home death were comorbidity index, certain cancers, and year of death. Conclusion: The likelihood of dying at home significantly increases with living in higher-income urban neighborhoods and decreases with rural residence. Urban neighborhoods with lowest income have odds of home death similar to rural areas. These findings underline the importance of targeting proper populations for public support at the end of life.

Purpose Radiographic changes after lung stereotactic body radiation therapy (SBRT) have been categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis; (B), scar-like fibrosis (C), and no evidence of increased density (D). The purpose of this study was to assess the interrater reliability of this categorization system in patients with early-stage non-small cell lung cancer (NSCLC). Methods and Materials Seventy-seven patients were included in this study, all treated with SBRT for early-stage (T1/2) NSCLC at a single institution, with a minimum follow-up of 6 months. Six experienced clinicians familiar with post-SBRT radiographic changes scored the serial posttreatment CT images independently in a blinded fashion. The proportion of patients categorized as A, B, C, or D at each interval was determined. Krippendorff's alpha (KA), Multirater kappa (M-kappa), and Gwet's AC1 (AC1) scores were used to establish interrater reliability. A leave-one-out analysis was performed to demonstrate the variability among raters. Interrater agreement of the first and last 20 patients scored was calculated to explore whether a training effect existed. Results The number of ratings ranged from 450 at 6 months to 84 at 48 months of follow-up. The proportion of patients in each category was as follows: A, 45%; B, 16%; C, 13%; and D, 26%. KA and M-kappa ranged from 0.17 to 0.34. AC1 measure range was 0.22 to 0.48. KA increased from 0.24 to 0.36 at 12 months with training. The percent agreement for pattern A peaked at 12 month with a 54% chance of having >50% raters in agreement and decreased over time, whereas that for patterns B and C increased over time to a maximum of 20% and 22%, respectively. Conclusion This post-SBRT radiographic change categorization system has modest interrater agreement, and there is a suggestion of a training effect. Patterns of fibrosis evolve after SBRT and alternative categorization systems should be evaluated.

Histopathological evaluation and grading of meningioma give important prognostic information. We evaluated retrospectively monotonous sheeting, necrosis, hypercellularity, nuclear pleomorphism, small cell changes, brain invasion, mitosis, mast cells, psammoma bodies, MIB-1 labeling index (MIB-1 LI) and histological grade of 230 primary meningioma tumors according to the latest World Health Organization (WHO) classification. To reveal any possible association between clinical features and promoter hypermethylation of O(6)-methylguanine-DNA methyltransferase (MGMT) as an important epigenetic modification in many human cancers, we also evaluated the methylation status of MGMT in meningiomas by a SYBR-green-based real-time PCR method. There was a female predominance (2.38 to 1) in the meningiomas. The mean age of the patients was 49.9 ± 12.6 years (range 16 to 78 years). Transitional meningiomas were the most common subtype of the meningiomas (35.21%, n=81). Most of the meningiomas were located in the falx and parasagital area. There was a significant correlation between histopathological features of malignancy. These features were observed more frequently and with statistical relation to grade II rather than grade I. Mast cells, psammoma bodies and nuclear pleomorphism had poor associations (P>0.05). When we re-evaluated the tumor grading, 31 patients with grade I meningiomas were upgraded to grade II. None of the meningiomas tested by MSQP were methylated in MGMT promoter sequence. High MIB-1 LI could be indicative for higher grade of meningioma. Continuous revision of the classification system is needed to improve the accuracy of prognostic judgments in meningioma. The data confirm that there is no rationale to test meningiomas for MGMT methylation status.

Adjuvant radiotherapy (ART) after prostatectomy for patients with high risk features (extracapsular extension [ECE], seminal vesicle invasion [SVI] and positive margin) has been shown to be associated with improved biochemical disease free survival in three large randomized trials, and with improved overall survival in one. Similarly, salvage radiotherapy (SRT) can effectively achieve biochemical-control in a significant proportion of patients with a rising PSA after surgery. Nonetheless, both approaches of post-operative RT remain highly underutilized. This might be partly due to concerns with overtreatment inherent to adjuvant approaches, and/or hesitance about causing radiation toxicities and their subsequent effects on the patient’s quality of life. Herein, we review the literature lending evidence to these arguments. We show recent series of ART/SRT and their low rates of acute and long-term toxicities, translating only in transient decline in quality of life (QoL) outcomes. We conclude that concerns with side effects should not preclude the recommendation of an effective and curative-intent therapy for men with prostate cancer initially treated with radical surgery.

Of every five newly diagnosed cancers, one is a gastrointestinal (GI) malignancy in origin. Lower GI cancers are among the top three most frequent cancers in the United States and many western countries while upper GI cancers rank as the most prevalent type in many Asian countries, especially in central and eastern Asia. GI cancers are usually diagnosed in more advanced stages and in the absence of effective early diagnostic tools and therapeutic modalities, the survival rates are generally disappointingly low. Considering the high mortality rate, tremendous effort has been directed to address the urgent need for discovery of effective early diagnostic tools, efficient therapeutic targets, and treatment monitoring markers for GI malignancies. Biomarkers are one of these favorite tools with several potential applications in various aspects of clinical management of cancers. A plethora of biomarkers has been studied in GI cancers, of which only a handful have found their way from bench to bed. Guidelines have been published by different cancer societies and groups, such as American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and European Group on Tumour Markers (EGTM), with recommendations regarding clinical applications of available markers for gastrointestinal tumors [1–3]. CEA, K-RAS, HER2, and KIT are among the biomarkers with validated clinical implications in management of colorectal cancer (CRC), gastric cancer, and gastrointestinal stromal tumors [1, 4–6]. Nonetheless, there is a growing list of emerging markers with promising clinical results that need to be validated for routine clinical applications and current data are insufficient to recommend them as part of the clinical guidelines. The current special issue tackles this important area of cancer research. In this issue, S.-F. Chiang et al. report their investigation of bone marrow stromal antigen 2 (BST2; also known as CD317, tetherin, and HM1.24) as a plasma biomarker in 152 patients with CRC. They show that, compared to the controls, BST2 was significantly elevated in plasma samples from CRC patients. In addition, high BST2 expression in CRC tissue, as assessed by immunohistochemistry, was associated with poorer 5-year survival. BST2 has also been under investigation as a potential target for immunotherapy for over a decade [7]. In fact, a humanized monoclonal antibody targeting BST2 has been tested in Phase 1 trial of multiple myeloma (MM) but the response rate was low [8]. More recently, BST2-specific cytotoxic T lymphocytes targeting MM cells have been developed [9, 10]. Therefore, it is possible that BST2 could be a potential therapeutic target in CRC. However, given its detection in the plasma, future studies should also examine BST2 as a novel biomarker to noninvasively monitor therapeutic response. In another study, T. Xue et al. have investigated the clinical significance of miRNA-20b as a marker in hepatocellular carcinoma (HCC) and reported its association with poor survival. They confirmed HIF-1α and VEGF as the targets of miRNA-20b in vitro and showed their regulation in both normal and hypoxic conditions, suggesting miRNA-20b as an adaptation mechanism that may play a role in tumor progression. This study was performed on a small retrospective cohort and the intriguing results should be validated in future larger prospective studies. Also the functional studies need to be expanded to better understand its role in tumor progression. Thomsen-Friedenreich (TF) antigen is one of the tumor-associated glycans (TAG), which is normally overexpressed in cancer cells, and has a role in cell adhesion to endothelium. In search of a serologic biomarker for gastric cancer, O. Kurtenkov and K. Klaamas looked into the presence and avidity of anti-TF antibodies in serum samples of cancer patients and normal controls. Drawing on their prior study showing increased sialylation of anti-TF antibodies in gastric cancer, they assessed the following: (1) serum levels of anti-TF antibodies by ELISA; (2) reactivity of anti-TF antibodies to Sambucus nigra agglutinin (SNA); (3) avidity of anti-TF antibodies by ELISA; and (4) avidity of SNA-reactive anti-TF antibodies in 104 patients and 49 controls. They showed, for the first time, that SNA-reactive—and therefore aberrantly sialylated—TF-specific antibodies have a significantly higher avidity in cancer patients, with a diagnostic accuracy of 73.2%, and a sensitivity of 70.3% in stage I patients. While these results provide an exciting venue of further investigation for a serum-based marker for gastric cancer, all these biomarkers need prospective evaluation and validation studies for determining the clinical impact, which is missing for many of the newly diagnosed markers. The clinical application would need stringent prospective validation of specificity, sensitivity, and cost-effectiveness. The neutrophil-to-lymphocyte ratio (NLR) has been proposed as a potential inflammation-based prognostic indicator in various malignancies but there have been controversial reports of its prognostic values in gastric cancer. Sun et al. are here reporting the results of a meta-analysis including 19 studies with 5431 patients and concluded that pretreatment NLRs can predict the prognosis of gastric cancer. The clinical significance of these findings still needs to be validated in a larger independent study. In an effort to highlight the implications of HER2, a marker which is now accepted as part of practice guidelines in advanced gastric cancer, A. Ieni et al. have reviewed the HER2 status in various stages of gastric tumorigenesis and their clinical significance, suggesting a potential role in early steps of gastric carcinogenesis and offering potential clinical implications in both early and advanced gastric adenocarcinoma. Further on serum-based markers H. Kishikawa et al. review the current evidence about the use of “ABC method,” a combination of anti-Helicobacter pylori antibody and serum pepsinogen (PG), for gastric cancer screening. In this method, based on H. pylori (HP) titre and PG, subjects are subdivided into 4 groups (A, HP−/PG−; B, HP+/PG−; C, HP+/PG+; D, HP−, PG+), with recommendation for endoscopy surveillance in B, C, and D groups every 3, 2, and 1 year, respectively. After discussing the available evidence, the authors conclude that gastric cancer risk is not the same in each of the above categories and recommend that HP antibody titre measurement should be done to categorize patients into low-negative, high-negative, low-positive, and high-positive groups. They further recommend endoscopic surveillance in high-negative antibody titres in group A every 3 years, high-positive titres in group B every 2 years, and low-positive titres in group C every year. Recommending a tumor marker as part of a practice guideline requires a multistep complex process that starts with discovery and introduction of the biomarker in preclinical phase followed by a rigorous analytical validation that comprises assay development, strong methodology, and robust statistical and bioinformatics tools. The ultimate path toward FDA or other regulatory approval is an unequivocal clinical validation with independent prospective studies. This process can take two to three decades and there are many examples of overoptimistic interpretation of the promising early results [11–13], which eventually failed to succeed achieving FDA clearance due to lack of accuracy or robustness in at least one of the above-mentioned steps. While we all review, observe, and contribute to the expanding body of literature of the emerging tumor markers, learning the lessons from the stories of failures and successes will create a pragmatic and realistic path toward the ultimate goal of recognizing a tumor marker as an effective tool with a significant clinical outcome. Omeed Moaven Hamid Raziee Wilbur Bowne Mohammad Reza Abbaszadegan Bryan C. Fuchs

O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes alkyl groups from the O(6) position of guanine. MGMT is transcriptionally silenced by promoter hypermethylation in several human neoplasia. We used methylation-specific PCR (MSP) to analyze the MGMT promoter methylation status of 50 glioblastoma tumors. Hypermethylation was detected in 24 of 50 (48%) samples. We also analyzed mutant p53 expression by immunohistochemical analysis of glioblastoma tissue samples. A significant association was found between MGMT methylation and p53 mutation status (p.05). These results suggested that epigenetic inactivation of MGMT plays an important role in the survival of glioblastoma patients and this inactivated gene involved in p53 mutation.

Objective: Cancer represents the second cause of mortality in the world. Saffron as a medicinal plant is known for its anti-cancer and anti-depressant properties. In this randomized double blind clinical trial, the effects of saffron on response to treatment in patients suffering from liver metastasis were evaluated. Materials and Methods: Thirteen patients suffering from liver metastases who referred to Ghaem and Imam Reza hospital, Mashhad, Iran were included in this study and then divided into two different groups. Both groups received chemotherapy regimen. Patients in group one were treated with saffron capsule (50 mg, twice daily) during chemotherapy periods whereas patients in group two received placebo. A sum of the longest diameter were calculated and compared for all lesions in IV contrast CT scan before and after the treatment. Results: from 13 patients included in this study, six patients quit and seven continued until the end. In saffron-treated group, two patients showed partial and complete response (50%) whereas in placebo group, no response was seen. Also, two deaths in placebo and one in saffron group occurred. Conclusion: This research suggests that saffron might be useful in patients suffering from liver metastasis. However, further investigations with larger sample size are required.

Aim. Detection of methylation in the p16 gene, an inhibitor of cyclin D-dependent protein kinase, as a new tumor marker for early detection of esophageal squamous cell carcinoma (ESCC) in DNA derived from blood and serum.

42 Background: To evaluate the oncologic outcomes and potential impact of delayed radical treatment in the form of radiotherapy (RT), in men with localized prostate cancer progressing after active surveillance (AS). Methods: We identified patients on AS subsequently treated with state-of-the-art RT (either dose-escalated image-guided intensity modulated radiotherapy [IG-IMRT] or low-dose-rate brachytherapy [LDR-BT]). Based on the clinical characteristics at time of AS progression, we compared the oncologic outcomes to matched patients treated with upfront RT after diagnose. One to two matching patients per AS case were identified from existing RT databases based on: age (+/- 3 years), clinical prognostic factors (NCCN risk group; PSA +/- 2ng/mL; cT category; primary and secondary Gleason score; percentage of diagnostic cores involved dichotomized at < or > 50%), and treatment modality (IG-IMRT or LDR-BT). We aimed to determine whether patients on AS have potentially compromised outcomes. Results: We identified 215 patients (out of 1070 AS cohort) undergoing RT after a median of 26 months (IQR 16-52.5) on AS. Median follow-up post RT was 4.8 years (IQR 2.9-7.2). No patient died of prostate cancer. At 5-years, the biochemical relapse free-, metastases free- and overall-survival rate were respectively 98.6%, 99.1%, 98.6% in the AS cohort. Matched cohort comprised 400 patients treated with IG-IMRT (71%) or LDR-BT (29%). Adequate matching was confirmed. The median follow-up post RT was 8.2 years (IQR 4.7-10). At 5-years, biochemical relapse free-, metastases free- and overall-survival rates of 98.5%, 98.7%, 93.7% respectively, which were not statistically different compared to those patients treated upon AS progression. Conclusions: Curative-intent radiotherapy (i.e. dose-escalated IG-IMRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Moreover, the delay of therapy after a period of AS does not appear to result in inferior oncologic outcomes compared to patients with similar risk characteristics undergoing upfront radical radiotherapy.

Gastric cancer is the second leading cause of cancer-related deaths worldwide and the most common gastrointestinal cancer in Iran. Chemokine ligand 5 (CCL5/RANTES) is one of the most potent angiogenic factors that plays an important role in tumor growth, invasion, and metastasis. We aimed to assess the serum level of CCL5 in patients with gastric adenocarcinoma and its relation with histological grade and tumor stage, as well as the disease prognosis. Seventy-four patients with gastric adenocarcinoma that had undergone gastrectomy and 96 non-tumoral cases in which gastric cancer was ruled out by gastroscopy and biopsy were enrolled. Demographic and epidemiological characteristics and patient survival data were reviewed. Histological type, grade, and tumor stage (TNM) were determined by a single expert pathologist. Helicobacter pylori infection status and CCL5 serum level were measured by ELISA. Data were analyzed using SPSS software version 16. Patients with gastric adenocarcinoma had significantly higher serum CCL5 level compared with control group (P

Background B-cell non-Hodgkin’s lymphoma (NHL) is a common malignancy of lymphoid tissues. Different types of NHL show various behaviors, prognoses, and responses to treatment. Evaluation of disease activity in NHL can be helpful in managing and even increasing the patient’s survey. Methods and Results In total, 121 patients (76 males and 45 females), and their age range were 18-53 years, were evaluated in this study. The mean level of serum carbohydrate antigen 125 (CA-125) was 89.3±18.5 u/ml, ranging from 27 to 135 u/ml. There were significant differences in International Prognostic Index (IPI) score (p=0.002), stage of the disease (p=0.006), mortality rate (p=0.02), and relapse rate (p=0.04) between patients with serum CA-125 level 35 u/ml. Conclusion CA-125 seems to be a useful and reliable tumor marker for monitoring a patient with NHL. It might be the time to consider CA-125 in staging, prognostic scoring, or decision making about NHL treatment.

Histopathological evaluation and grading of meningioma give important prognostic information. We evaluated retrospectively monotonous sheeting, necrosis, hypercellularity, nuclear pleomorphism, small cell changes, brain invasion, mitosis, mast cells, psammoma bodies, MIB-1 labeling index (MIB-1 LI) and histological grade of 230 primary meningioma tumors according to the latest World Health Organization (WHO) classification. To reveal any possible association between clinical features and promoter hypermethylation of O(6)-methylguanine-DNA methyltransferase (MGMT) as an important epigenetic modification in many human cancers, we also evaluated the methylation status of MGMT in meningiomas by a SYBR-green-based real-time PCR method. There was a female predominance (2.38 to 1) in the meningiomas. The mean age of the patients was 49.9 ± 12.6 years (range 16 to 78 years). Transitional meningiomas were the most common subtype of the meningiomas (35.21%, n=81). Most of the meningiomas were located in the falx and parasagital area. There was a significant correlation between histopathological features of malignancy. These features were observed more frequently and with statistical relation to grade II rather than grade I. Mast cells, psammoma bodies and nuclear pleomorphism had poor associations (P0.05). When we re-evaluated the tumor grading, 31 patients with grade I meningiomas were upgraded to grade II. None of the meningiomas tested by MSQP were methylated in MGMT promoter sequence. High MIB-1 LI could be indicative for higher grade of meningioma. Continuous revision of the classification system is needed to improve the accuracy of prognostic judgments in meningioma. The data confirm that there is no rationale to test meningiomas for MGMT methylation status.

Complete resection is the only definitive treatment available for gastric cancer. Factors associated with positive margins and their survival effects have been the subject of many studies, but the appropriate management for these patients is still debated. The objective of this review is to examine positive margins after gastric cancer resections by exploring predictive factors, impact on survival, and optimal strategies for re-resection.A systematic electronic literature search was conducted using Medline and EMBASE from January 1, 1998, to December 31, 2009. Studies on gastric or gastroesophageal junction adenocarcinoma that either investigated the predictors for positive margin or employed multivariate methods to analyze the survival effects of positive margins were selected.Twenty-two studies incorporating 19355 patients were included in this review. Positive margins were associated with larger tumor size, deeper wall penetration, more extensive gastric involvement, greater nodal involvement, higher stage, diffuse histology, higher Borrmann type, lymphatic vessel involvement, and total gastrectomy. Patient survival was independently associated with margin status, and this survival effect was more prominent in early cancers in most studies that performed subgroup analyses.The probability of acquiring positive margins is highly dependent on the biology and the extent of the tumor. There is a significant negative effect on survival, which is more prominent in cancers at early stages, making re-resection or a second operation important. Patients with more advanced disease can be offered more extensive surgery to remove disease, but this should be balanced against the risks of more extensive resections.

Aims and background The prognosis of glioblastoma multiforme (GBM) remains poor despite advances in surgery and adjuvant therapies. TP53 and O6-methylguanine-DNA methyltransferase (MGMT) are tumor suppressor genes that are implicated in GBM resistance to radiation and chemotherapy. In order to assess the expression of the protein products of these two genes, 50 GBM samples were analyzed in this study. Methods Demographic and clinical data along with postsurgery tumor samples from 50 GBM patients were collected from the pathology archive. MGMT and p53 protein expression was evaluated by immunohistochemistry. Results 52% of cases had mutated p53, predominantly expressed in the nuclei of tumor cells. MGMT immunohistochemistry was negative in 35 (70%) patients and positive in 15 (30%) others. Immunohistochemistry-negative specimens for MGMT expression showed a significantly higher expression of mutant p53 (P = 0.03). Conclusion MGMT expression was significantly lower in cells bearing p53 mutation. This indicates that there is a tendency for p53 activity to decline with MGMT inactivation. However, this study could not deduce which protein was the regulator of the other. Free full text available at www.tumorionline.it

To evaluate the relation of cluster of differentiation 44 (CD44) expression with clinicopathological features of gastric adenocarcinoma, and also its effect on prognosis with an emphasis on the differences between intestinal and diffuse types.From 2000 to 2006, 100 patients with gastric adenocarcinoma, who had undergone total or subtotal gastrectomy without any prior treatment, were studied. Haematoxylin and eosin (HE) staining was used for histological evaluation, including the type (Lauren's classification) and grading of the tumor. The expression of CD44 in the gastric adenocarcinoma mucosa and the adjacent mucosa were determined by immunohistochemistry. The survival analysis was obtained using the Kaplan-Meier test.Of 100 patients, 74 (74%) patients were male. The tumors were categorized as intestinal type (78%) or diffuse type (22%). Sixty-five percent of patients were CD44-positive. CD44 expression was not detected in normal gastric mucosa. Rather, CD44 was more commonly expressed in the intestinal subtype (P=0.002). A significant relation was seen between the grade of tumor and the expression of CD44 (P=0.014). The survival analysis showed a poor prognosis of patients with CD44-positive tumors (P=0.008); and this was more prominent in the intestinal (P=0.001) rather than diffuse type.Cell adhesion molecule CD44 is highly expressed in gastric adenocarcinoma. CD44 expression is correlated with a poor prognosis in patients with the intestinal type of gastric adenocarcinoma. CD44 can, therefore, be utilized as a prognostic marker for this group of patients.

Sentinel lymph node (SLN) identification by lymphoscintigraphy (LS) and biopsy are the standard method for axillary lymph node staging in low stage breast cancer patients. Many previous studies did not compare the number of SLN on LS with SLN detected during surgery. We aimed to study the accuracy of pre-operative LS for the prediction of the number of SLN detected by surgical gamma probe and the dye technique during surgery. Sixty patients were included in our study. SLN biopsy was performed using the combined radioactive and blue dye methods. Patients without previous excisional biopsy of the tumor (45 patients) received periareolar intra-dermal injections of 17.5MBq/0.2mL technetium-99m-antimony sulfide colloid ((99m)Tc ASC). The remainder of the patients, with the history of excisional biopsy of the tumor (15 patients); received two intra-dermal injections of 17.5MBq/0.2mL (99m)Tc-ASC in both ends of the surgical incision. All injections were done 2-4 h before surgery and gentle massage was applied to the injection site. Results showed that the number of SLN was correctly detected by LS in 58 patients. Eighty SLN were totally detected during surgery. All these SLN were radioactive and could be identified by surgical gamma probe. No SLN was detected only by the blue dye. Of the 80 detected SLN, 60 (75%) were both radioactive and colored. Pre-operative LS correctly predicted the number of harvested SLN during surgery in 77.5% of the patients. Only 78.7% (63/80) of the total harvested SLN were detected by pre-operative LS. We conclude that pre- operative LS identifies 78.7% and the blue dye technique can identify 75% of the SLN found by the gamma probe during surgery. The pre-operative LS technique can correctly identify the number of SLN in 77.5% of the patients.

Detection of methylation in the p16 gene, an inhibitor of cyclin D-dependent protein kinase, as a new tumor marker for early detection of esophageal squamous cell carcinoma (ESCC) in DNA derived from blood and serum.A large family with clustering of ESCC was assessed in Khorasan province in northeastern Iran. The family had three histologically proven cases of ESCC in two consecutive generations and several other deceased cases with histories of ESCC. DNA from blood of 28 living family members in three consecutive generations, 30 sporadic ESCC cases (from serum, blood, and tumor tissues), and 30 healthy volunteers (from blood) were examined for the methylation status of p16 promoter using methylation-specific PCR (MSP).Aberrant p16 promoter methylation was found in 64.3% (n = 28) of ESCC family members and none (n = 30) of our normal volunteers. Five of the 28 family members with esophageal cancer symptoms had negative endoscopy results for ESCC, while four of these members had p16 hypermethylation in their blood. The family members with negative endoscopy and positive p16 promoter methylation are being monitored closely for signs of ESCC development through regular check-ups and chromoendoscopies. In sporadic ESCC in northeastern Iran, 73.3% (n = 30) of tumor tissue samples had p16 hypermethylation. Serum and blood samples from the same patients showed p16 hypermethylation in 26.6% and 43.3% of the samples, respectively.Aberrant p16 methylation may be a valuable diagnostic tool as a tumor marker for the early identification of individuals in high risk ESCC families.

AIM: To determine p16 promoter hypermethylation in gastric tumoral tissue and serum samples, its impact on p16-protein expression, and correlation with clinical and histological features. METHODS: Samples were obtained from 52 histologically confirmed cases of gastric adenocarcinoma. Gastric tissue and serum of 50 age- and sex-matched individuals with normal gastroscopy and biopsy were obtained as control samples. Methylation-specific polymerase chain reaction (MSP) was used to evaluate methylation status of p16 promoter. p16-protein expression was analyzed by immunohistochemical staining on paraffin-embedded sections. RESULTS: Methylation was detected in 44.2% (23/52) of tumoral tissues. 60.9% of them were also methylated in serum, i.e., 26.9% of all patients (14/52). Methylation was not detected in tissue and sera of control samples. p16-protein expression was decreased in 61.5% of cases (32/52), and was significantly associated with promoter hypermethylation (P < 0.001). Methylation was significantly more frequent in higher pathological grades (P < 0.05). Methylation was not associated with other clinicopathological features and environmental factors including H pylori infection and smoking. CONCLUSION: p16 promoter hypermethylation is an important event in gastric carcinogenesis. It is the principle mechanism of p16 gene silencing. It is related to malignant tumor behavior. Detection of DNA methylation in serum may be a biomarker for early detection of gastric cancer.

BackgroundFas (Apo-1/CD95) and its specific ligand (FasL) are key elements in apoptosis. They have been studied in different malignancies but there are few published studies about the soluble forms of these markers (i.e. sFas/sFasL) in gastric cancer. We have compared the serum levels of sFas/sFasL in gastric adenocarcinoma patients and cases with pre-neoplastic lesions as potential markers for early diagnosis, and investigated their relation with clinicopathological characteristics.MethodsFifty-nine newly-diagnosed cases of gastric adenocarcinoma who had undergone gastrectomy, along with 62 endoscopically- and histologically-confirmed non-cancer individuals were enrolled in this study. sFas/sFasL serum levels were detected by Enzyme Linked Immunosurbent Assay.ResultsMean serum sFas level was significantly higher in gastric cancer patients than in control group (305.97 ± 63.71 (pg/ml) vs. 92.98 ± 4.95 (pg/ml), P < 0.001); while the mean serum level of sFasL was lower in patients with gastric adenocarcinoma (0.138 ± 0.04 (pg/ml) vs. 0.150 ± 0.02 (pg/ml), P < 0.001). Mean serum levels of sFas/sFasL were significantly different in both intestinal/diffuse and cardiac/non-cardiac subtypes when compared to the control group (P < 0.001). There was an increase in the serum level of sFas from the first steps of pre-neoplastic lesions to gastric adenocarcinoma (P < 0.001). Patients who had no lymph node involvement (N0) showed significantly higher serum levels of sFas compared to others (P = 0.044).ConclusionsProduction of sFas may play a critical role in the carcinogenesis of intestinal-type gastric cancer. sFas serum level may serve as a non-invasive tool for early diagnosis of gastric cancer.