Performance of OncoE6 cervical test with collection methods enabling self-sampling.

BACKGROUND: The paradigm shift from cytological screening to Human Papillomavirus (HPV)-based screening for cervical cancer allows the introduction of new technologies in sample collection and diagnostics. The OncoE6™ Cervical Test (OncoE6 Test) is a rapid, easy-to-use lateral flow method detecting HPV16/18 E6 oncoproteins that has proven to detect high-grade cervical lesions with high specificity. If compatible with self-collection samples, this technology might allow for decentralized screening of hard-to-reach populations. METHODS: For technical validation, cervicovaginal lavages were collected from 20 patients with confirmed HPV16+ or HPV18+ invasive cervical cancer. Cervical smears were collected by polyester-tipped swabs and cytobrushes. All samples were applied to the OncoE6 Test and cytobrush samples additionally genotyped. RESULTS: Lavage, swab, and cytobrush revealed concordant outcome in 18/20 samples. HPV types corresponded with the HPV genotyping by GP5+/6+ PCR analyses. Due to a rare mutation found in the E6 antibody binding site one sample was not detected, another sample had very low cellularity. CONCLUSIONS: Overall, vaginal lavages are technically adequate for the OncoE6 Test. Combining self-sampling with oncoprotein rapid testing to detect women with highest risk for severe dysplasia or cancer may allow for secondary cancer prevention in settings where other screening modalities were unsuccessful to date.

Interdisciplinary decision making in prostate cancer therapy - 5-years' time trends at the Interdisciplinary Prostate Cancer Center (IPC) of the Charité Berlin.

BACKGROUND: Patients with prostate cancer face the difficult decision between a wide range of therapeutic options. These men require elaborate information about their individual risk profile and the therapeutic strategies´ risks and benefits to choose the best possible option. In order to detect time trends and quality improvements between an early patient population (2003/2004) and a later reference group (2007/2008) data was analysed with regards to epidemiologic parameters, differences in diagnostics and the type and ranking of the recommended therapies taking into account changes to Gleason Grading System and implementation of new therapeutic strategies, particularly Active surveillance, in 2005. METHODS: Data from all 496 consecutive patients who received consultation in 2003/2004 (n = 280) and 2007/2008 (n = 216) was retrospectively evaluated. Categorical variables were compared using the Chi-square test. Dependent variables were analysed using the unpaired Students´ t-test and the Mann-Whitney U-test. RESULTS: The cohorts were comparable concerning clinical stage, initial PSA, prostate volume, comorbidities and organ confined disease. Patients in Cohort I were younger (66.44 vs. 69.31y; p < .001) and had a longer life expectancy (17.22 vs. 14.75y; p < .001). 50.9%, 28.2% and 20.9% in Cohort I and 37.2%, 39.6% and 23.2% in Cohort II showed low-, intermediate- and high-risk disease (D´Amico) with a trend towards an increased risk profile in Cohort II (p = .066). The risk-adapted therapy recommended as first option was radical prostatectomy for 91.5% in Cohort I and 69.7% in Cohort II, radiation therapy for 83.7% in Cohort I and 50.7% in Cohort II, and other therapies (brachytherapy, Active surveillance, Watchful waiting, high-intensity focused ultrasound) for 6.5% in Cohort I and 6.9% in Cohort II (p < .001). Radiation therapy was predominant in both cohorts as second treatment option (p < .001). Time trends showing quality improvement involved an increase in biopsy cores (9.95 ± 2.38 vs. 8.43 ± 2.29; p < .001) and an increased recommendation for bilateral nerve sparing (p < .001). CONCLUSION: In the earlier years, younger patients with a more favourable risk profile presented for interdisciplinary consultation. A unilateral recommendation for radical prostatectomy and radiation therapy was predominant. In the later years, the patient population was considerably older. However, this group may have benefitted from optimised diagnostic possibilities and a wider range of treatment options.

The phyllodes menace-Variation in course, therapy, and appearance of phyllodes tumors in a case series of three patients.

Key Clinical Message: Early and complete surgical resection is the most important therapeutic and diagnostic measure. Adjuvant radiation is suggested for malign phyllode tumors, phyllode tumors larger than 10 cm or those with a low distance to the resection margins. Abstract: Phyllodes tumors are rare fibroepithelial tumors of the breast. Histologically, they are usually classified as benign, borderline or malignant, though these classifications do not necessarily reflect the clinical course of the disease. These tumors may stay undetected for years, or show sudden and rapid progression. There is currently no consistent therapy recommendation based upon histological findings, the localization of the tumor and/or whether it is recurrent. Using the examples of three patients, we show how courses and therapy may differ widely, and discuss this in the context of the current state of the literature.

Intrasplenic Pancreatic Pseudocyst after Chemoradiation of a Pancreatic Adenocarcinoma Mimicking Progressive Disease: A Case Report and Review of the Literature.

Chemoradiation is one of the therapeutic options in palliative treatment of locally advanced pancreatic adenocarcinoma, with a well-known safety profile. In this case report, we describe the treatment-related occurrence of an intrasplenic pancreatic pseudocyst which was successfully removed by gastrocystic drainage. This rare complication should be considered in the follow-up and clinical management of patients, particularly if left-sided complaints occur.

Hormone-refractory and metastatic prostate cancer - palliative radiotherapy.

Prostate cancer progression is commonly manifested by obstructive uropathy, regional lymphatic metastases and hematogenous metastases to the axial skeleton. Radiotherapy is a mainstay in the palliation of symptomatic metastatic prostate cancer and is most often used for the palliation of painful metastatic bone lesions, resulting in a relief of pain in about 80-90% of patients and a reduction of analgesics. In metastatic disease compromising the integrity of the spinal cord or a nerve root, radiotherapy can be used as an urgent intervention to minimize neurological dysfunction and local progression or as an adjunct to surgical decompression. Local progression is often associated with hematuria, ureteric obstruction and perineal discomfort. Symptoms of metastatic lymphadenopathy like leg edema and back discomfort caused by pelvic or paraaortic metastases are related to the immediate anatomic structures affected. Radiotherapy for localized hormone-refractory prostate cancer has an excellent local control rate; nevertheless, the prognosis is poor, the majority of patients failing with distant metastasis within few years. The role of radiotherapy in hormone-refractory and metastatic prostate cancer, considering the patient's individual situation, are presented and discussed.

Radiotherapy in biochemical recurrences after surgery for prostate cancer.

A biochemical recurrence following prostatectomy is often diagnosed in relatively young and healthy men, and hence deemed very relevant concerning life, given the generally high life expectancy of these patients. Therefore, there is a need for a therapy that offers a long-term chance of cure. Following salvage radiotherapy in large multicenter series, about 45% of the patients treated are in biochemical complete remission 4 years after radiotherapy. The best chances of response are in those patients in whom none of the established risk factors, that will be discussed, are present. Given the established curative potential of salvage radiotherapy and the fact that there are no therapeutic alternatives with a realistic chance of cure, the rather moderate rates of side effects seem acceptable.

Neoadjuvant proton beam irradiation followed by transscleral resection of uveal melanoma in 106 cases.

AIMS: To describe results after neoadjuvant proton beam irradiation followed by transscleral resection of large uveal melanoma. METHODS: Retrospective interventional case series, including 106 consecutive patients. Local tumour control, enucleation and metastasis development were assessed with survival curves. Predictors of local recurrence and metastasis were investigated with log-rank testing. RESULTS: Mean follow-up was 3.2 years. Local recurrence occurred in five cases with an estimated risk of 4.2% and 10.4% at 3 and 5 years after treatment, respectively. Enucleation was performed in 10 cases with an estimated risk of 9.2% and 18.4% at 3 and 5 years, respectively. Significant risk factors for local recurrence were not evident. Metastasis was estimated to occur in 28.4% at 3 years and 40.3% at 5 years, correlating with patient's age only (p=0.01). Seventy four patients (69.8%) underwent vitreoretinal surgery for complications after tumour resection. Median visual acuity (VA) was 20/50 at diagnosis and 20/400 in the third year after treatment. VA preservation of 20/200 or better was achieved in 33 patients (31.1%). CONCLUSION: Neoadjuvant proton beam irradiation may help to prevent local recurrence after transscleral resection. Additional vitreoretinal surgery was frequently needed in the presented series. The majority of patients avoided enucleation and functional blindness.

Proton beam radiotherapy of diffuse iris melanoma in 54 patients.

BACKGROUND: Treatment modalities in iris melanoma include excision, plaque radiotherapy, photon or proton beam therapy and enucleation. In extensive tumours and diffuse seeding, radiotherapy remains as an alternative to enucleation. METHODS: This study is a retrospective, consecutive, interventional, single-institutional case series. 54 patients with a diffuse and non-resectable iris melanoma diagnosed from September 1998 to June 2012 were included. A 68-megaelectron volt proton beam was used to treat the anterior segment with a total dose of 4×12.5 cobalt grey equivalent. The cases were evaluated for local tumour control, eye retention, functional outcome and local complications after treatment. RESULTS: During a mean follow-up of 62.7 months (median 54.8 months, range 5.5-159.6 months), local tumour control was achieved in 96.3% of the patients. Cataract and glaucoma were the main complications developing after irradiation in 42.6% and 55.6%, respectively. In 34 of 44 patients (77.3%) who underwent cataract removal, a visual acuity of 20/40 or better following surgery was preserved. Enucleation was performed in three patients. The reason was suspected tumour recurrence in one and glaucoma in two. Hepatic metastasis occurred in one patient. CONCLUSIONS: As an alternative to enucleation, whole anterior segment fractionated proton beam radiotherapy offered excellent local tumour control in diffuse iris melanoma. Given the limited alternatives, the rate of complications appears acceptable and visual function could be preserved in the majority of the patients during follow-up.

Long-term results after proton beam therapy for retinal papillary capillary hemangioma.

PURPOSE: To evaluate the potential benefit and risk of proton beam therapy in the treatment of symptomatic retinal papillary capillary hemangioma. DESIGN: Retrospective interventional case series. METHODS: This study included patients presenting with symptomatic exudative retinal papillary capillary hemangioma with or without association with von Hippel-Lindau disease. All patients were treated either as a first or a secondary treatment option by proton beam therapy between 2001 and 2009. The minimum follow-up was 30 months. RESULTS: Eight eyes of 8 patients (3 male and 5 female, with a mean age of 36 years [range 22-80 years]) were treated for symptomatic papillary retinal hemangioma. The median interval between onset of macular edema and proton beam therapy was 1.7 months (range 0.5-3.3 months). The median follow-up period was 84 months (range 32-106 months) between proton beam treatment and last follow-up. Exudation completely resolved in all but 1 patient after 4.2 months on average (range 2.8-7.2 months). Mean visual acuity prior to proton beam irradiation was 0.7 logMAR (0.2 DIN (DIN 58220 norm)) (range 2-0.3 logMAR) and declined to 0.8 logMAR (0.16 DIN; range 2-0.1 logMAR) at last follow-up examination (no statistical significance, P=.071). CONCLUSION: The anatomic outcome after proton beam therapy for retinal papillary hemangioma is convincing, whereas functional outcome may be compromised because of tumor location, long-persisting macular edema, extensive exudation, and poor initial visual acuity. In patients with extended retinal detachment surgical intervention was still necessary. Although proton beam therapy is proven to be a therapeutic option, treatment will remain challenging.

Proton beam therapy leads to excellent local control rates in choroidal melanoma in the intermediate fundus zone.

PURPOSE: To evaluate long-term outcomes of proton beam radiotherapy in the treatment of choroidal melanoma of the intermediate zone of the fundus. DESIGN: Retrospective interventional single-center study. METHODS: The study was a retrospective analysis with long-term follow-up of 62 patients with a minimum tumor-to-disc and tumor-to-fovea distance of 2 mm of choroidal melanoma in the intermediate zone of the fundus. Mean values of tumor prominence, largest basal diameter, and tumor distances to the optic disc and fovea were 7.6, 12.8, 5.2, and 4.6 mm, respectively. All patients were irradiated with a total proton dose of 60 cobalt gray equivalents. RESULTS: After proton beam radiotherapy, 71.0% of the patients received subsequent endoresection of the tumor. Only 18 patients (29.0%) did not require additional tumor resection and were analyzed as a separate group. For the total of patients, the median follow-up time was 70.3 months. The 5-year Kaplan-Meier rates of local tumor relapse, enucleation, and distant metastasis were 3.9%, 3.7%, and 13.4%, respectively. Cataract surgery was the most frequent secondary treatment in our cohort. CONCLUSIONS: In this study we demonstrate the effectiveness of proton beam irradiation in tumor control and preservation of the globe in the analyzed patients. The rate of metastasis was not higher than previously described. Nevertheless, consecutive tumor surgery is frequently required to maintain the eye in patients with large-sized choroidal melanomas. In conclusion, proton beam radiotherapy allows preservation of the eye in mid-zone choroidal melanomas.

Salvage proton beam therapy in local recurrent uveal melanoma.

PURPOSE: To evaluate survival and ocular outcome in recurrent uveal melanoma treated with proton beam therapy as salvage therapy. DESIGN: Retrospective, interventional case series. METHODS: We evaluated 48 patients with local recurrence of uveal melanoma after primary treatment with brachytherapy, transpupillary thermotherapy, proton beam therapy, laser photocoagulation, CyberKnife radiation, or photodynamic therapy. All patients received proton beam therapy as a salvage therapy at the Helmholtz Zentrum Berlin between July 2000 and December 2010. Kaplan-Meier analysis was used to obtain survival rates. RESULTS: The Kaplan-Meier estimator for local tumor control was 92.1% at 10 years after secondary treatment with proton beam therapy. Local recurrence developed in 3 patients; 1 of them underwent enucleation. During follow-up, 20.8% of the patients died (16.7% of metastasis, 4.1% of other causes or not specified). The most frequent surgical interventions were phacoemulsification (20.8%) and pars plana vitrectomy (10.4%). The Kaplan-Meier estimators were 77.4% for survival and 70.1% for the absence of metastasis 10 years after the primary treatment. CONCLUSIONS: Proton beam therapy as a salvage treatment resulted in high local tumor control rates in recurrent uveal melanoma, especially if the primary therapy was transpupillary thermotherapy or plaque brachytherapy. Preservation of the globe was possible in most patients. Enucleations were indicated only in case of re-recurrences of uveal melanoma, but not because of secondary complications like intractable pain or secondary glaucoma. Retreatment was associated with vision deterioration, but loss of vision remained exceptional. Further larger prospective studies are needed to confirm the presented results of our retrospective analysis.

Proton beam therapy of parapapillary choroidal melanoma.

PURPOSE: To analyze the functional outcome with regard to the development of visual acuity and radiation-induced optic neuropathy of patients with parapapillary choroidal melanoma treated with proton beam therapy. DESIGN: Clinical case series, retrospective study. METHODS: We evaluated 147 consecutive patients with parapapillary choroidal melanoma who received proton beam therapy as primary tumor treatment at the Helmholtz Center in Berlin from 1998 to 2005. A cumulative dose of 60 Cobalt Gray Equivalents (CGE) was delivered to the tumor and the optic disc received a minimum of 50 CGE. Kaplan-Meier analysis was used to assess ocular outcome and survival rates. For trend analysis of functional development, Wilcoxon-Mann-Whitney U test was used to compare the medians of 2 groups and Kruskal-Wallis test was used in the case of more than 2 groups. RESULTS: The mean follow-up time was 6.5 years (range 0.3-11.7 years). The most common side effects were radiation-induced optic neuropathy, retinopathy, and cataract. The median visual acuity before and within the first year after therapy was 0.4 logMAR (20/50), lapsing to 1.3 logMAR (20/400) after 3 years and 1.4 logMAR (20/500) after 5 years. During follow-up, no light perception developed in 17 cases (11.6%), mostly attributed to radiation-induced retinopathy, optic neuropathy, and secondary glaucoma. Enucleation was carried out in 14 patients (9.5%) because of local recurrence or severe side effects. CONCLUSION: Radiation-induced optic neuropathy is an expected issue after proton beam therapy of parapapillary choroidal melanoma, and visual impairment is common during long-term follow-up, but some useful vision can be preserved in a considerable number of patients.

Histopathological regression grading matches excellently with local and regional spread after neoadjuvant therapy of rectal cancer.

Histopathological regression grading has been shown to predict outcome in chemoradiated rectal cancer. Lymph node spread is still considered the most important single prognostic parameter. Therefore, we investigated the association of regression grading with tumor spread in a single center retrospective cohort. 102 consecutive patients who had undergone neoadjuvant therapy for rectal adenocarcinoma were included. Surgery was performed, including total mesorectal excision. Pathological examination included UICC staging and Dworak's five-tier tumor regression grading. Histological complete response was achieved in 16.7% of cases. Dworak's regression grading and a simplified two tier scheme both correlated excellently with ypT, ypN and UICC stage. However, cases with poor histological response were strongly represented in ypN0. Tumor regression grading is a reliable method for assessment of response to neoadjuvant therapy, but the optimal cut-off for separating good and poor response remains to be established based on clinical outcome.

Adjuvant and neoadjuvant chemoradiation or radiotherapy in rectal cancer--a review focusing on open questions.

BACKGROUND: The therapy of rectal cancer has been a matter of debate since decades, especially with regard to the benefits of neoadjuvant or adjuvant therapies. Principles of additional therapies have been established nearly two decades ago and are questioned nowadays on the basis of more recently modified operative techniques. Benefits and sequelae of therapies have to be balanced against each other, and it seems somewhat likely that a more differentiated strategy than simply stating that every patient with stage II and III rectal cancer needs chemoradiation or radiotherapy will, in long term, be recommended. CONCLUSION: It should be kept in mind that results of centers of excellence and of phase-III studies with their positively selected patient populations are not representative for all the patients with rectal cancer and physicians treating them.

Predominant activation of endothelin-dependent cardiac hypertrophy by norepinephrine in rat left ventricle.

Locally released endothelin (ET)-1 has been recently identified as an important mediator of cardiac hypertrophy. It is still unclear, however, which primary stimulus specifically activates ET-dependent signaling pathways. We therefore examined in adult rats (n = 51) the effects of a selective ET(A) receptor antagonist in experimental models of cardiac hypertrophy, in which myocardial growth is predominantly initiated by a single primary stimulus. Rats were exposed to mechanical overload (ascending aortic stenosis), increased levels of circulating ANG II (ANG II infusion combined with hydralazine), or adrenergic stimulation (infusion of norepinephrine in a subpressor dose) for 7 days. All experimental treatments significantly increased left ventricular weight/body weight ratios compared with untreated rats, whereas systolic left ventricular peak pressure was increased only after ascending aortic stenosis. ET(A) receptor blockade exclusively reduced norepinephrine-induced cardiac hypertrophy and atrial natriuretic peptide gene expression. Blood pressure levels and heart rates remained unaffected during ET(A) receptor blockade in all experimental groups. These data indicate that in rat left ventricle, the ET-dependent signaling pathway leading to early development of cardiac hypertrophy and fetal gene expression is primarily activated by norepinephrine.

Virtual simulation of a boost field in adjuvant radiotherapy of the breast.

BACKGROUND AND PURPOSE: In CT-based adjuvant radiotherapy of the breast, virtual simulation techniques have been developed. This paper demonstrates a simple virtual simulation of a boost field. MATERIAL AND METHODS: 41 fields were planned virtually, 26 as electron beams, 15 as tangential photon beams. RESULTS: Depending on the user's expertise the geometric accuracy was high; possible sources of error are illustrated. Resulting field sizes tended to be slightly larger compared to conventional simulation when applying the same rules of field definition. Differences in focus-skin distances with consecutive divergence effects as well as partial volume effects were discussed to be causal. CONCLUSION: Virtual simulation of a boost field has the potential to elegantly link the simplicity of a conventional simulation with the accurate tumor bed identification provided by a CT data set. It was shown to be feasible and favorable with regard to the patient, the medical staff, and the simulator time. Moreover, it offers a visualization of dose distributions, which was found helpful in some cases.