E. Boelke

Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation

Epidermal EGFR regulates skin inflammation and contributes to skin barrier function and host defense. Skin-Deep Search for the Effects of EGFR Inhibitors The goal of all medical interventions is to treat disease while minimizing the damage to healthy tissues in the body. This can be difficult to achieve for cancer drugs, however, especially when the effectiveness of a drug directly correlates with its side effects, as is the case for inhibitors of the epidermal growth factor receptor (EGFR). EGFR inhibitors are particularly known for causing a severe rash and skin damage, which sometimes forces patients to prematurely stop their treatments. Now, two papers by Mascia et al. and Lichtenberger et al. help clarify the mechanism of rash formation induced by EGFR inhibitors and uncover some of the skin components that contribute to this phenomenon. Both sets of authors used mouse models that lack EGFR only in the skin to replicate the pattern of injury seen in patients treated with EGFR inhibitors. They characterized the changes in chemokine expression in the skin of treated patients and study animals and examined the effects of EGFR inhibition on skin defenses and bacteria. They also investigated the effects of crossing mice that lack EGFR in the skin with mice deficient in different immune pathways and immune cell types to determine which ones are necessary for the rash phenotype. The findings of these two studies suggest that EGFR signaling is important for normal skin barrier function and antimicrobial defense, and that skin macrophages may contribute to the adverse effects of EGFR inhibitors. Additional work will be necessary to further expand our understanding of EGFR inhibitor toxicity and to continue the search for ways to prevent this disruptive side effect. The current studies provide mechanistic insights that should help guide further investigation in this area. The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient’s treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFRΔep) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.

Adjuvant radiotherapy of regional lymph nodes in breast cancer - a meta-analysis of randomized trials.

BackgroundRadiotherapy (RT) improves overall survival (OS) of breast cancer patients after breast conserving surgery and after mastectomy in patients with involved lymph nodes (LN). The contribution of RT to the regional LN to this survival benefit was poorly understood. Recently, the results of three large randomized trials addressing this question have become available.Material and methodsThe published abstracts (full publication pending) of the MA.20 (n=1832) and the EORTC 22922–10925 (EORTC) (n=4004) trial and the full publication of the French trial (n=1334) were basis of the meta-analysis. Main eligibility criteria were positive axillary LN (all trials), LN negative disease with high risk for recurrence (MA.20), and medial/central tumor location (French, EORTC). The MA.20 and the EORTC trial tested the effect of additional regional RT to the internal mammary (IM) LN and medial supraclavicular (MS) LN, whereas in the French trial all patients received RT to the MS-LN and solely RT to the IM-LN was randomized. Primary endpoint was OS. Secondary endpoints were disease-free survival (DFS) and distant metastasis free survival (DMFS).ResultsRegional RT of the MS-LN and the IM-LN (MA.20 and EORTC) resulted in a significant improvement of OS (Hazard Ratio (HR) 0.85 (95% CL 0.75 - 0.96)). Adding the results of the French trial and using the random effects model to respect the different design of the French trial, the effect on OS of regional radiotherapy was still significant (HR 0.88 (95% CL 0.80 - 0.97)). The absolute benefits in OS were 1.6% in the MA.20 trial at 5 years, 1.6% in the EORTC trial at 10 years, and 3.3% in the French trial at 10 years (not significant in single trials). Regional radiotherapy of the MS-LN and the IM-LN (MA.20 and EORTC) was associated with a significant improvement of DFS (HR 0.85 (95% CL 0.77 - 0.94)) and DMFS (HR 0.82 (95% CL 0.73 - 0.92)). The effect sizes were not significantly different between trials for any end point.ConclusionAdditional regional radiotherapy to the internal mammary and medial supraclavicular lymph nodes statistically significantly improves DFS, DMFS, and overall survival in stage I-III breast cancer.

Palliative Radiotherapy Tailored to Life Expectancy in End-Stage Cancer Patients: Reality or Myth?

The purpose of the study was to investigate the adequacy of palliative radiation treatment in end‐stage cancer patients.

A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against EGFR are currently used for therapy of recurrent or metastatic disease; however, their mode of action is not completely understood. To investigate the immunological effects of anti‐EGFR mAb, we generated a three‐dimensional spheroid model of EGFR‐expressing SCCHN and used this model to study the effect of anti‐EGFR mAb on leukocyte migration toward tumors. Pretreatment with the blocking anti‐EGFR mAb EMD 72000, its F(ab′)2 fragments or an EGFR tyrosine kinase inhibitor led to substantially increased leukocyte infiltration into EGFR overexpressing tumor spheroids, but not into those with low EGFR expression. Nonblocking anti‐EGFR mAb or fibroblast‐specific mAb did not affect leukocyte infiltration, suggesting that the observed increase in leukocyte infiltration depends on interference with EGFR activation. Using a human cytokine macroarray, we demonstrated that the blockade of EGFR by anti‐EGFR mAb in EGFR‐overexpressing SCCHN cells leads to differential expression of several cytokines and chemokines, including the chemokine MCP‐1/CCL‐2. The significant upregulation of MCP‐1/CCL2 on exposure to anti‐EGFR mAb was confirmed by quantitative PCR and enzyme‐linked immunospot analyses. Moreover, blocking anti‐MCP‐1 antibody inhibited leukocyte migration toward tumor cells induced by anti‐EGFR mAb, pointing to an important role of MCP‐1/CCL2 in anti‐EGFR mAb‐induced leukocyte migration. Our findings demonstrate that anti‐EGFR mAb induces leukocyte infiltration to tumor spheroids by upregulating chemokine expression. This novel mechanism for anti‐EGFR mAb action may contribute to the antitumor effects of anti‐EGFR mAb in vivo.

Long-term Survival After Surgery for Primary Hepatic Sarcoma in Adults

HYPOTHESIS Patients with primary hepatic sarcomas benefit from resection, with possible long-term cure. DESIGN Retrospective and prospective cohort study. SETTING University hospitals of Hamburg-Eppendorf and Düsseldorf, Germany. PATIENTS Between 1985 and 2006, 22 patients (8 men and 14 women; median age at initial diagnosis, 54 years [range, 19-80 years]) were surgically treated for primary hepatic sarcomas. INTERVENTION Tumor resection with curative intent ranging from nonanatomical resection to liver transplant. MAIN OUTCOME MEASURES Effects on overall survival were analyzed using the log-rank test. RESULTS The majority of tumors were more than 5 cm (n = 19), with a median tumor size of 7 cm (range, 4-14 cm); of intermediate differentiation (G2; n = 15); and classified as leiomyosarcoma (n = 7). Ten patients received a hemihepatectomy. In 4 patients, a bisegmentectomy was performed and in 2 patients, a segmentectomy, while 4 patients received a nonanatomical resection. Liver transplant was performed in 2 patients. In 18 patients, complete tumor resection (R0) was achieved. Perioperative mortality was 0%. Median follow-up was 88 months (range, 6-246 months). Local recurrence occurred in 6 patients. Distant metastases were diagnosed in 10 patients, predominantly in the lung (n = 6). The 5-year survival after surgery was 65%, with 41% of the patients living more than 10 years without disease. Patients with angiosarcoma had a poor prognosis (P = .03). CONCLUSIONS Although primary hepatic sarcoma is a rare malignant tumor, no standard treatment is established. A long-term survival is possible after complete tumor resection in a preselected population with early-stage disease.

PSA after Incidental Irradiation of the Nonmalignant Prostate: Long-Term Changes

Background:Incidental irradiation of the prostate may affect serum prostate-specific antigen (PSA). However, scarce data exist on PSA changes after irradiation of noncancerous prostatic tissue. This is an update of a study on PSA after pelvic irradiation.Material and Methods:From 1997 to 2007, blood samples of 33 men were examined who had undergone pelvic irradiation for rectal or anal cancer. The planning target volume included the prostate in all cases. No patient had clinical evidence of prostatic disease. Radiotherapy was applied in fractions of 1.8–2 Gy up to 40–50 Gy (n = 3), 50–60 Gy (n = 21), and 60–65 Gy (n = 2). Seven patients received 5 × 5 Gy. Serum PSA was measured before, during, and after radiotherapy periodically. Median log (PSA) changes were calculated according to elapsed time from starting radiotherapy. The significance was tested with χ2-test.Results:18 patients died during follow-up. For 15 patients, long-term PSA data with a median follow-up of 9 years (2,546–3,528 days) are available. PSA levels rose during the first weeks of irradiation peaking at 2–4 weeks with a significant 2.7-fold increase (p < 0.01). 1 year after radiation therapy, PSA declined below (90%) the preirradiation level, but this difference was not significant (p = 0.36). On further follow-up PSA did not change up to 8.9 years after radiotherapy (p = 0.36).Conclusion:Irradiation of the prostate causes transient increase of serum PSA. By 1 year, PSA has returned near the preirradiation value and stays there for at least 9 years. A major interference with prostate cancer screening or surveillance after radiotherapy is therefore unlikely.Hintergrund:Die Bestrahlung der Prostata kann den Serumspiegel des prostataspezifischen Antigens (PSA) beeinflussen. Über radiogene PSA-Veränderungen ohne Prostatakarzinom gibt es allerdings kaum Daten.Material und Methodik:Von 1997 bis 2007 wurden Serumproben von 33 Männern ohne Prostataerkrankung untersucht, die wegen eines Rektum- oder Analkarzinoms bestrahlt wurden. Das Planungszielvolumen schloss in allen Fällen die Prostata ein. Die Bestrahlung erfolgte in Einzeldosen von 1,8–2 Gy bis 40–50 Gy (n = 3), 50–60 Gy (n = 21) bzw. 60–65 Gy (n = 2). Sieben Patienten wurden mit 5 × 5 Gy bestrahlt. PSA-Werte wurden vor, während und nach der Strahlentherapie bestimmt. Die zeitlichen Veränderungen des medianen logarithmierten PSA wurden analysiert. Die Signifikanz wurde mit dem χ2-Test geprüft.Ergebnisse:18 Patienten verstarben. Für 15 Patienten liegen PSA-Daten mit einer medianen Nachbeobachtungsdauer von 9 Jahren (2 546–3 528 Tage) vor. In den ersten Bestrahlungswochen stiegen die PSA-Werte auf ein Maximum vom 2,7fachen des Ausgangswerts nach 2–4 Wochen (p < 0,01). Nach 1 Jahr waren die Werte auf das 0,9fache des Ausgangswerts gefallen (p = 0,36). Im Weiteren änderten sich bei einer Nachbeobachtung von 8,9 Jahren die PSA-Werte nicht signifikant (p = 0,36).Schlussfolgerung:Nach Bestrahlung der gesunden Prostata steigen die PSA-Werte in den ersten Wochen vorübergehend an. Bereits nach 1 Jahr unterscheiden sie sich nicht mehr signifikant von den Ausgangswerten und ändern sich für wenigstens 9 Jahre nicht signifikant. Eine wesentliche Beeinflussung der PSA-Referenzwerte im Rahmen des Prostata-Screenings durch eine Beckenbestrahlung ist daher unwahrscheinlich.

256: New Aspects Regarding the Radiation of Thalamic Gliomas

Results: Three patterns of tumor spread were found. The first pattern followed the thalamic tributaries of the posterior part of the internal cerebral veins. These were the anterior and superior thalamic veins. For the second pattern the close proximity of the internal cerebral vein branches of the superior thalamic veins was a potential route of spread between the medial surfaces of the thalami. In addition to spread across the midline tumours could also spread along the adjacent tectal, pineal and/or vermian veins. The third pattern of thalamic tumor spread was found in gliomas which use the anterior tributaries of the internal cerebral venous architecture of the posterior and inferior branches from the basal vein of Rosenthal.

Acute and late side effects for intraoperative electron radiotherapy during breast-conserving surgery of breast cancer.

94 Background: Intraoperative boost irradiation as part of breast-conserving therapy is a perfect method to adequately capture the high risk tumor relapse area. The most homogeneous dose distribution is achieved with electrons. Intraoperative radiotherapy (IOERT) as a boost for breast cancer releases a high single dose of radiation to the breast tissue; therefore acute toxicity is of particular attention. To date there is only inadequate information available on breast cancer patients treated with IORT using electrons applied as a boost. We therefore analyzed the acute toxicity and late side effects after radiotherapy with 10 Gy as a boost with a minimum follow-up of 3 months. METHODS A total of 385 patients treated with IOERT (10 Gy with 5, 7 and 9 MeV electrons) with a dedicated robotic linac (NOVAC 7, New Radiant Technology, Aprilia, Italy) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT,50- 50.4 Gy; 1.8-2 Gy per fraction) were included in this study. All patients underwent a retrospective follow-up regarding acute and late side effects. Toxicities were documented using the common toxicity criteria (CTC 4.0 of the European Organization for Research and Treatment of Cancer). RESULTS The IOERT was well tolerated and the cosmetic results were good. As a side effect there were five patients with seroma. Two patients developed a secondary wound healing. Two patients developed chronic pain in the irradiated breast. Ten patients developed a grade 2 fibrosis. The remaining patients did not develop any grade 3 or 4 side effects. The observed toxicity rates were not influenced by age, tubus size, electron energy or systemic therapy. 80 patients had a follow up longer than 5 years. Three of them developed distant metastasis and one patient died. CONCLUSIONS After IOERT of the breast using electrons we did not find any unexpected acute and late toxicity rates.

Association of CD44s and CD44v6 expression with survival outcomes in malignant fibrious histiocytoma.

44 Background: New prognostic markers are being searched to determine the value of adjuvant and/or palliative treatment in soft tissue sarcomas (STS). Several studies showed that CD44 expression was associated with a better outcome in certain cancers, such as bladder tumors. The aim of this study was to evaluate the expression of CD44 in STS of the adult and to determine whether this correlates with the clinical outcome. METHODS We examined the clinical outcome of 34 adult MFH patients (19 males and 15 females, average age 62 years, median 63 years, ranged from 38 to 88 years) who underwent curative treatment The majority of patients received adjuvant radiotherapy (n = 25). No patients received initial adjuvant chemotherapy. The prognostic value of CD44s and isoform expression were evaluated by immunohistochemistry of tissue microarrays. RESULTS At first, we split the data for each variant of CD44 into two equally sized groups at the medians to the expression values (low and high). We apply a log rank test on the two groups and use the p value as an evaluation criterion for the usefulness of the grouping. CD44s and CD44v6 expression significantly correlated with an improved outcome whereas CD44v8 and h CD44 were not significant. CONCLUSIONS CD44s and CD44v6 expression seem to be associated with improved survival in malignant fibrous histiocytoma.

Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission: Results of a multivariate analysis.

154 Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. METHODS 315 LABC patients (cT1-cT4 /cN0-N1) were treated during 1991-1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or-in case of breast conservation-a 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. RESULTS The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p<0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p<0.001). CONCLUSIONS A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of a pCR after NRT-CHX.