Mitogen-activated protein kinase-activated protein kinase-2 (MK2) and its role in cell survival, inflammatory signaling, and migration in promoting cancer.

Cancer and the immune system share an intimate relationship. Chronic inflammation increases the risk of cancer occurrence and can also drive inflammatory mediators into the tumor microenvironment enhancing tumor growth and survival. The p38 MAPK pathway is activated both acutely and chronically by stress, inflammatory chemokines, chronic inflammatory conditions, and cancer. These properties have led to extensive efforts to find effective drugs targeting p38, which have been unsuccessful. The immediate downstream serine/threonine kinase and substrate of p38 MAPK, mitogen-activated-protein-kinase-activated-protein-kinase-2 (MK2) protects cells against stressors by regulating the DNA damage response, transcription, protein and messenger RNA stability, and motility. The phosphorylation of downstream substrates by MK2 increases inflammatory cytokine production, drives an immune response, and contributes to wound healing. By binding directly to p38 MAPK, MK2 is responsible for the export of p38 MAPK from the nucleus which gives MK2 properties that make it unique among the large number of p38 MAPK substrates. Many of the substrates of both p38 MAPK and MK2 are separated between the cytosol and nucleus and interfering with MK2 and altering this intracellular translocation has implications for the actions of both p38 MAPK and MK2. The inhibition of MK2 has shown promise in combination with both chemotherapy and radiotherapy as a method for controlling cancer growth and metastasis in a variety of cancers. Whereas the current data are encouraging the field requires the development of selective and well tolerated drugs to target MK2 and a better understanding of its effects for effective clinical use.

Routine histopathologic characteristics can predict oncotype DX(TM) recurrence score in subsets of breast cancer patients.

This study assessed whether routine pathologic parameters could predict Oncotype DX(TM) recurrence score (RS) in 72 breast cancers diagnosed from 2008-2012. Comparing patients with low RS (0-17) vs. intermediate RS (18-30) vs. high RS (>30), the mean Nottingham score increased (5.5 vs. 6.3 vs. 7.2, respectively, p = .001) and the mean PR Allred score decreased (6.7 vs. 4.9 vs. 3.3, respectively, p = .001). A high RS was least likely for low-grade tumors (0% had high RS, p = .005), and strong PR positivity (9% had high RS, p = .017). A low RS was least likely for cancers that were both high grade and PR weak/negative.

Proton therapy for prostate cancer online: patient education or marketing?

INTRODUCTION: Proton therapy (PT) for prostate cancer is an expensive treatment with limited evidence of benefit over conventional radiotherapy. We sought to study whether online information on PT for prostate cancer was balanced and whether the website source influenced the content presented. MATERIALS AND METHODS: We applied a systematic search process to identify 270 weblinks associated with PT for prostate cancer, categorized the websites by source, and filtered the results to 50 websites using predetermined criteria. We then used a customized version of the DISCERN instrument, a validated tool for assessing the quality of consumer health information, to evaluate the remaining websites for balance of content and description of risks, benefits and uncertainty. RESULTS: Depending on the search engine and key word used, proton center websites (PCWs) made up 10%-47% of the first 30 encountered links. In comparison, websites from academic and nonacademic medical centers without ownership stake in proton centers appeared much less frequently as a search result (0%-3%). PCWs scored lower on DISCERN questions compared to other sources for being balanced/unbiased (p < 0.001), mentioning areas of uncertainty (p < 0.001), and describing risks of PT (p < 0.001). PCWs scored higher for describing the benefits of treatment (p = 0.003). CONCLUSIONS: Patients should be aware that online information regarding PT for prostate cancer may represent marketing by proton centers rather than comprehensive and unbiased patient education. An awareness of these results will also better prepare clinicians to address the potential biases of patients with prostate cancer who search the Internet for health information.

The Anatomical Biological Value on Pretreatment (18)F-fluorodeoxyglucose Positron Emission Tomography Computed Tomography Predicts Response and Survival in Locally Advanced Head and Neck Cancer.

(18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) has become increasingly relevant in the staging of head and neck cancers, but its prognostic value is controversial. The objective of this study was to evaluate different PET/CT parameters for their ability to predict response to therapy and survival in patients treated for head and neck cancer. A total of 28 consecutive patients with a variety of newly diagnosed head and neck cancers underwent PET/CT scanning at our institution before initiating definitive radiation therapy. All underwent a posttreatment PET/CT to gauge tumor response. Pretreatment PET/CT parameters calculated include the standardized uptake value (SUV) and the anatomical biological value (ABV), which is the product of SUV and greatest tumor diameter. Maximum and mean values were studied for both SUV and ABV, and correlated with response rate and survival. The mean pretreatment tumor ABVmax decreased from 35.5 to 7.9 (P = 0.0001). Of the parameters tested, only pretreatment ABVmax was significantly different among those patients with a complete response (CR) and incomplete response (22.8 vs. 65, respectively, P = 0.021). This difference was maximized at a cut-off ABVmax of 30 and those patients with ABVmax < 30 were significantly more likely to have a CR compared to those with ABVmax of ≥ 30 (93.8% vs. 50%, respectively, P = 0.023). The 5-year overall survival was 80% compared to 36%, respectively, (P = 0.028). Multivariate analysis confirmed that ABVmax was an independent prognostic factor. Our data supports the use of PET/CT, and specifically ABVmax, as a prognostic factor in head and neck cancer. Patients who have an ABVmax ≥ 30 were more likely to have a poor outcome with chemoradiation alone, and a more aggressive trimodality approach may be indicated in these patients.

Comparison study of intensity modulated arc therapy using single or multiple arcs to intensity modulated radiation therapy for high-risk prostate cancer.

PURPOSE: Intensity modulated arc therapy (IMAT) is a form of intensity modulated radiation therapy (IMRT) that delivers dose in single or multiple arcs. We compared IMRT plans versus single-arc field (1ARC) and multi-arc fields (3ARC) IMAT plans in high-risk prostate cancer. MATERIALS AND METHODS: Sixteen patients were studied. Prostate (PTV P ), right pelvic (PTV RtLN ) and left pelvic lymph nodes (PTV LtLN ), and organs at risk were contoured. PTV P , PTV RtLN , and PTV LtLN received 50.40 Gy followed by a boost to PTV B of 28.80 Gy. Three plans were per patient generated: IMRT, 1ARC, and 3ARC. We recorded the dose to the PTV, the mean dose (D MEAN ) to the organs at risk, and volume covered by the 50% isodose. Efficiency was evaluated by monitor units (MU) and beam on time (BOT). Conformity index (CI), Paddick gradient index, and homogeneity index (HI) were also calculated. RESULTS: Average Radiation Therapy Oncology Group CI was 1.17, 1.20, and 1.15 for IMRT, 1ARC, and 3ARC, respectively. The plans' HI were within 1% of each other. The D MEAN of bladder was within 2% of each other. The rectum D MEAN in IMRT plans was 10% lower dose than the arc plans (p < 0.0001). The GI of the 3ARC was superior to IMRT by 27.4% (p = 0.006). The average MU was highest in the IMRT plans (1686) versus 1ARC (575) versus 3ARC (1079). The average BOT was 6 minutes for IMRT compared to 1.3 and 2.9 for 1ARC and 3ARC IMAT (p < 0.05). CONCLUSION: For high-risk prostate cancer, IMAT may offer a favorable dose gradient profile, conformity, MU and BOT compared to IMRT.

Case series analysis of post-brachytherapy prostate edema and its relevance to post-implant dosimetry. Post-implant prostate edema and dosimetry.

PURPOSE: We evaluated the post-operative pattern of prostate volume (PV) changes following prostate brachytherapy (PB) and analyzed variables which affect swelling. MATERIAL AND METHODS: Twenty-nine patients treated with brachytherapy (14) or combined brachytherapy and external beam radiotherapy modality (15) underwent pre- and post-implant computed tomography (CT). Prostate volume measurements were done on post-operative days 1, 9, 30, and 60. An observer performed 139 prostate volume (PV) measurements. We analyzed the influence of pre-implant PV, number of needles and insertion attempts, number and activity of seeds, Gleason score, use of hormonal therapy and external beam radiation therapy on the extent of edema. We computed a volume correction factor (CF) to account for dosimetric changes between day 1 and day 30. Using the calculated CF, the dose received by 90% (D(90)) of the prostate on day 30 (D(90)Day30) was obtained by dividing day 1 (D(90)Day1) by the CF. RESULTS: The mean PV recorded on post-operative day 1 was 67.7 cm(3), 18.8 cm(3) greater than average pre-op value (SD 15.6 cm(3)). Swelling returned to pre-implant volume by day 30. Seed activity, treatment modality, and Gleason score were significant variables. The calculated CF was 0.76. After assessment using the CF, the mean difference between estimated and actual D(90)Day30 was not significant. CONCLUSIONS: We observed maximum prostate size on post-operative day 1, returning to pre-implant volume by day 30. This suggests that post-implant dosimetry should be obtained on or after post-operative day 30. If necessary, day 30 dosimetry can be estimated by dividing D(90)Day1 by a correction factor of 0.76.

The role of PET/CT in decreasing inter-observer variability in treatment planning and evaluation of response for cervical cancer.

We have previously introduced anatomic biologic contouring (ABC) with PET/CT, using a distinct "halo" to unify contouring methods in treatment planning for lung and head and neck cancers. The objective of this study is to assess the utility of PET/CT in planning and treatment response for cervical cancer. Forty-two patients with stages II-IIIB cervix cancer were planned for irradiation using PET/CT. A CT-based Gross Tumor Volume (GTV-CT) was delineated by two independent observers while the PET remained obscured. The Planning Target Volume (PTV) was obtained by adding a 1.5 cm margin around the GTV. The same volumes were recontoured using PET/CT data and termed GTV-ABC and PTV-ABC, respectively. The values of GTV-CT and GTV-ABC and the absolute differences between the two observers were analyzed. Additionally, 23 of these patients had PET/CT performed 3 months after treatment. The anatomic biologic value (ABV) was calculated using the product of maximum diameter and mean SUV of the cervical tumor. The pre- and post-treatment ABVs were compared. A "halo" was observed around areas of maximal SUV uptake. The mean halo SUV was 1.91 ± 0.56 (SD). The mean halo thickness was 2.12 ± 0.5 (SD) mm. Inter-observer GTV variability decreased from a mean volume difference of 55.36 cm(3) in CT-based planning to 12.29 cm(3) in PET/CT-based planning with a respective decrease in standard deviation (SD) from 55.78 to 10.24 (p <0.001). Comparison of mean pre-treatment and post-treatment ABV's revealed a decrease of ABV from 48.2 to 7.8 (p<0.001). PET/CT is a valuable tool in radiation therapy planning and evaluation of treatment response for cervical cancer. A clearly visualized "halo" was successfully implemented in GTV contouring in cervical cancer, resulting in decreased inter-observer variability in planning. PET/CT has the ability to quantify treatment response using anatomic biologic value.

Management of acral myxoinflammatory fibroblastic sarcoma.

BACKGROUND: Acral myxoinflammatory fibroblastic sarcoma (AMFS) is a rare, low-grade sarcoma that commonly affects the distal extremities. From the published cases, therapy for AMFS to date has been comprised of excision or amputation, with limited use of radiotherapy (RT) or chemotherapy. In this report, the outcome of 17 patients with AMFS treated at the study institution was reported. METHODS: A retrospective review of all cases of AMFS identified in the Sarcoma Database in the Department of Radiation Oncology at the study institution was conducted. Treatment records and data from follow-up visits of patients were reviewed. RESULTS: Seventeen patients were identified. All the patients underwent surgical resection (15 excisions and 2 amputations). Positive surgical margins after excisions were noted in 5 patients and were widely positive in 1 patient. Of the 17 patients, 14 patients received some form of RT. The average total dose was 56.4 Gray (Gy). Eight patients received preoperative RT alone, 5 patients received preoperative RT and postoperative RT, and 1 patient received preoperative RT and intraoperative RT. Median follow-up was 24.5 months. One patient presented with recurrent disease and was treated with resection, and both pre- and postoperative RT. He was free of disease 23 months after his last treatment. No local recurrence was noted in the remaining patients. Of the 14 patients undergoing preoperative RT, complete pathologic necrosis or no tumor was noted in 1 of the patients. No metastatic disease was observed in any of the patients. There was no significant radiation toxicity observed in any of the patients. CONCLUSIONS: Data were consistent with local control of distal extremity sarcomas with resection and RT, suggesting that limb-sparing surgery with this treatment combination is an appropriate option in the limb-sparing control of patients with AMFS, even those with positive surgical margins.

Increased risk of high-grade dermatologic toxicities with radiation plus epidermal growth factor receptor inhibitor therapy.

BACKGROUND: The addition of epidermal growth factor receptor (EGFR) inhibitors to radiotherapy has produced increased locoregional control and has reduced mortality from various solid tumors with few additional toxicities. Although anecdotal reports have suggested increased radiation dermatitis, the overall effect of these regimens on dermatologic toxicities has not been ascertained. METHODS: Dermatologic toxicity data were analyzed from abstracts presented at the annual meetings of the American Society of Clinical Oncology, the American Society of Therapeutic Radiology and Oncology, Cochrane Collaboration, MEDLINE, and EMBASE databases. Phase 1, 2, and 3 trials that reported on radiation dermatitis, rash, and mucositis were included. Collaborative group, phase 3, randomized radiotherapy and chemoradiation trials served as controls. The summary incidence rate and relative risk were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of included studies. RESULTS: The summary incidence of high-grade radiation dermatitis in patients who received radiation plus EGFR inhibitors was 31.3% (95% confidence interval [95% CI], 17.7%-49.1%), rash in 16.1% (95% CI, 12.8%-20.1%), and mucositis occurred in 52.7% (95% CI, 38.1%-66.9%). When the combination of radiotherapy plus EGFR inhibitors was compared with radiation alone, the risk ratio for radiation dermatitis was 2.38 (95% CI, 1.8-3.2; P<.001), rash was 3.01 (95% CI, 2.0-4.6; P<.001), for mucositis it was 1.76 (95% CI, 1.5-2.0; P<.001), suggesting that there was an increased risk of dermatologic toxicities with the combined regimen. CONCLUSIONS: EGFR inhibitors combined with radiation were associated with a significant increase in the risk for high-grade radiation dermatitis, rash, and mucositis. Although increased rash is expected with EGFR inhibitors, in-field dermatitis and mucositis represent new safety concerns. Improved reporting and management strategies are critical for quality of life and the optimization of radiation plus EGFR inhibitor protocols.