Quality of life in breast cancer patients and surgical results of immediate tissue expander/implant-based breast reconstruction after mastectomy.

OBJECTIVES: The purpose of this study was to analyze the effects of prior radiotherapy (RT) as well as postmastectomy radiotherapy (PMRT) on patient-reported quality of life (QoL) and on surgical/aesthetic outcomes in patients with expander-/implant-based delayed immediate reconstruction (EIBR) compared to patients that underwent EIBR without any RT. MATERIAL AND METHODS: QoL was assessed by BREAST-Q, the surgical/aesthetic outcome by a structured examination and a picture analysis (BCCT.CORE software) and subsequently compared between the three cohorts. RESULTS: Of 161 eligible patients, 97 followed the invitation (no RT n = 54, 9 of them with bilateral EIBR; PMRT n = 26; history of RT n = 15). The surgical/aesthetic results were better in the RT-naive cohort than in the PMRT cohort, but satisfaction with outcome and psychosocial well-being were better in the PMRT cohort. The RT-naive cohort showed (significantly) higher scores in satisfaction with breast, satisfaction with implant and sexual well-being compared to the history of RT cohort, although satisfaction with outcome was comparable. The PMRT cohort reached significantly more points in almost all categories and better BCCT.CORE and examination results than the history of RT cohort. Of all patients, 92.7%, 84.6% and 78.6% (RT naive, PMRT, history of RT) would agree to undergo EIBR again. CONCLUSION: EIBR results in acceptable QoL and surgical results. In patients with a prior RT, QoL is significantly lower and surgical results are significantly worse. However, high acceptance rates suggest EIBR being a justifiable option even for this group. Prospective studies and long-term follow-up are required for definitive conclusions.

Paratesticular alveolar rhabdomyosarcomas do not harbor typical translocations: a distinct entity with favorable prognosis?

The alveolar subtype of rhabdomyosarcoma (RMA) is a strong risk factor. Cases of RMA located in paratesticular sites have however been reported to have similar outcomes to those of embryonal rhabdomyosarcoma (RME). We wanted to re-evaluate the impact of subtype in paratesticular rhabdomyosarcoma (PT-RMS). Patients from a population-based cohort diagnosed with paratesticular RMA in 1990-2013 were analyzed. All tumor samples were re-reviewed using conventional morphology, immunohistochemistry, and molecular testing. Seven patients were eligible. Four tumors showed focal areas morphologically compatible with RMA (mixed RMA/RME). One case was undifferentiated, with a solid round-cell morphology which had to be reclassified as poorly differentiated RME. Two cases had a "microalveolar" morphology which is today regarded as sclerosing RME. No tumor showed the characteristic gene fusion of RMA. Five children had localized disease, one bone metastases, and another lymph-node involvement. All primaries were grossly resected. One locoregional relapse occurred. At a median follow-up of 7 years, all patients were alive disease-free. PT-RMS can show a focal alveolar histology combined with typical features of RME. In current morphological classifications, all rhabdomyosarcomas qualify for the alveolar subtype if typical features of RMA are realized at least focally. Rhabdomyosarcomas consisting of pure RMA morphology were however not found in our patients with PT-RMS. The mixed RMA/RMEs identified in our population-based study did not show a translocation typical for RMA and had a good prognosis. Further prospective studies need to evaluate if mixed RMA/RMEs have a similar favorable outcome in non-paratesticular sites as well.

Neoadjuvant radiotherapy followed by mastectomy and immediate breast reconstruction : An alternative treatment option for locally advanced breast cancer.

BACKGROUND: The optimal sequence of mastectomy with immediate breast reconstruction (IBR) and radiotherapy (RT) for the treatment of locally advanced breast cancer (LABC) is still under debate. Increased rates of postoperative complications are described following postmastectomy RT. Neoadjuvant RT aims to improve the aesthetic results and simplify the reconstructive pathway. PATIENTS: A total of 22 patients diagnosed with LABC and treated with neoadjuvant RT followed by mastectomy and IBR between 04/2012 and 03/2015 were retrospectively analyzed. RT consisted of external beam RT to the breast and the regional lymphatics, if indicated. Both implant-based and autologous tissue-transfer reconstruction techniques were used. RESULTS: At the time of RT, 10 patients had no prior surgery and 12 patients had previously undergone breast-conserving surgery (BCS) with positive resection margins without the possibility to perform a second BCS. Additional neoadjuvant chemotherapy was administered in 18 patients prior to RT. A complete pathological response was achieved in 55.0% of patients. The 2­year overall survival rate was 89.3%, the 2­year disease-free-survival 79.8% and the local-recurrence-free survival was 95.2%. The cosmetic result was excellent or good in 66% of the patients treated with upfront mastectomy and 37% of the patients who had previously undergone BCS. Among patients who received implant-based IBR, 4 patients developed serious wound-healing problems with implant loss. The most satisfactory results were achieved with autologous tissue reconstruction. CONCLUSION: A sequential neoadjuvant chemo-/radiotherapy to allow IBR following mastectomy in selected cases of LABC seems feasible and can be safely attempted. Careful patient selection, close monitoring, and continuous patient support is mandatory to ensure compliance in this treatment strategy.

Cancer Cell Death-Inducing Radiotherapy: Impact on Local Tumour Control, Tumour Cell Proliferation and Induction of Systemic Anti-tumour Immunity.

Radiotherapy (RT) predominantly is aimed to induce DNA damage in tumour cells that results in reduction of their clonogenicity and finally in tumour cell death. Adaptation of RT with higher single doses has become necessary and led to a more detailed view on what kind of tumour cell death is induced and which immunological consequences result from it. RT is capable of rendering tumour cells immunogenic by modifying the tumour cell phenotype and the microenvironment. Danger signals are released as well as the senescence-associated secretory phenotype. This results in maturation of dendritic cells and priming of cytotoxic T cells as well as in activation of natural killer cells. However, RT on the other hand can also result in immune suppressive events including apoptosis induction and foster tumour cell proliferation. That's why RT is nowadays increasingly combined with selected immunotherapies.

14th St. Gallen International Breast Cancer Conference 2015: Evidence, Controversies, Consensus - Primary Therapy of Early Breast Cancer: Opinions Expressed by German Experts.

The key topics of this year's 14th St. Gallen Consensus Conference on the diagnosis and therapy of primary breast cancer were again questions about breast surgery and axillary surgery, radio-oncology and systemic therapy options in consideration of tumor biology, and the clinical application of multigene assays. This year, the consensus conference took place in Vienna. From a German perspective, it makes sense to substantiate the results of the vote of the international panel representing 19 countries in light of the updated national therapy recommendations of the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie). Therefore, 14 German breast cancer experts, 3 of whom are members of the International St. Gallen Panel, have commented on the voting results of the St. Gallen Consensus Conference 2015 in relation to clinical routine in Germany.

The in vitro immunogenic potential of caspase-3 proficient breast cancer cells with basal low immunogenicity is increased by hypofractionated irradiation.

BACKGROUND: Radiotherapy is an integral part of breast cancer treatment. Immune activating properties of especially hypofractionated irradiation are in the spotlight of clinicians, besides the well-known effects of radiotherapy on cell cycle and the reduction of the clonogenic potential of tumor cells. Especially combination of radiotherapy with further immune stimulation induces immune-mediated anti-tumor responses. We therefore examined whether hypofractionated irradiation alone or in combination with hyperthermia as immune stimulants is capable of inducing breast cancer cells with immunogenic potential. METHODS: Clonogenic assay, AnnexinA5-FITC/Propidium iodide assay and ELISA analyses of heat shock protein 70 and high mobility group box 1 protein were applied to characterize colony forming capability, cell death induction, cell death forms and release of danger signals by breast cancer cells in response to hypofractionated radiation (4x4Gy, 6x3Gy) alone and in combination with hyperthermia (41.5 °C for 1 h). Caspase-3 deficient, hormone receptor positive, p53 wild type MCF-7 and caspase-3 intact, hormone receptor negative, p53 mutated MDA-MB231 breast cancer cells, the latter in absence or presence of the pan-caspase inhibitor zVAD-fmk, were used. Supernatants of the treated tumor cells were analyzed for their potential to alter the surface expression of activation markers on human-monocyte-derived dendritic cells. RESULTS: Irradiation reduced the clonogenicity of caspase deficient MCF-7 cells more than of MDA-B231 cells. In contrast, higher amounts of apoptotic and necrotic cells were induced in MDA-B231 cells after single irradiation with 4Gy, 10Gy, or 20Gy or after hypofractionated irradiation with 4x4Gy or 6x3Gy. MDA-B231 cells consecutively released higher amounts of Hsp70 and HMGB1 after hypofractionated irradiation. However, only the release of Hsp70 was further increased by hyperthermia. Both, apoptosis induction and release of the danger signals, was dependent on caspase-3. Only supernatants of MDA-B231 cells after hypofractionated irradiation resulted in slight changes of activation markers on dendritic cells; especially that of CD86 was upregulated and HT did not further impact on it. CONCLUSIONS: Hypofractionated irradiation is the main stimulus for cell death induction and consecutive dendritic cell activation in caspase proficient breast cancer cells. For the assessment of radiosensitivity and immunological effects of radio- and immunotherapies the readout system is crucial.

Adjuvant radiotherapy after breast conserving surgery - a comparative effectiveness research study.

PURPOSE: The purpose of this retrospective outcome study was to validate the effectiveness of postoperative radiotherapy in breast conserving therapy (BCT) and to evaluate possible causes for omission of radiotherapy after breast conserving surgery (BCS) in a non-trial population. METHODS: Data were provided by the population-based Munich Cancer Registry. The study included epidemiological data of 30.811 patients diagnosed with breast cancer from 1998 to 2012. The effect of omitting radiotherapy was analysed using Kaplan-Meier-estimates and Cox proportional hazard regression. Variables predicting omission of radiotherapy were analysed using multivariate logistic regression. RESULTS: Use of postoperative radiotherapy after BCS was associated with significant improvements in local control and survival. 10-year loco-regional recurrence-free-survival was 90.8% with postoperative radiotherapy vs. 77.6% with surgery alone (p<0.001). 10-year overall survival rates were 55.2% with surgery alone vs. 82.2% following postoperative radiotherapy (p<0.001). Variables predicting omission of postoperative radiotherapy included advanced age (women ⩾80 years; OR: 0.082; 95% CI: 0.071-0.094, p<0.001). CONCLUSIONS: This study shows a decrease in local control and a survival disadvantage if postoperative radiotherapy after breast conserving surgery is omitted in an unselected cohort of primary breast cancer patients. Due to its epidemiological nature, it cannot answer the question in whom postoperative radiotherapy can be safely omitted.

Reirradiation as part of a salvage treatment approach for progressive non-pontine pediatric high-grade gliomas: preliminary experiences from the German HIT-HGG study group.

BACKGROUND AND PURPOSE: The aim of the present analysis was to assess the feasibility, toxicity, and the tumor control of reirradiation as a salvage treatment for progressive pediatric non-pontine high-grade gliomas (HGG). PATIENTS AND METHODS: The database of the Reference Center for Radiation Oncology of the German HIT (HIT = German acronym for brain tumor) treatment network for childhood brain tumors was screened for children who were reirradiated for progressive non-pontine HGG. RESULTS: We identified eight patients (WHO grade III: n = 5; WHO grade IV: n = 3) who underwent reirradiation between April 2006 and July 2012. Median age was 13.5 years at primary diagnosis and 14.8 years at first progression. All patients initially underwent surgery (incomplete resection, n = 7; biopsy, n = 1) followed by radiochemotherapy. Relapses occurred inside (n = 2), at the margin (n = 4), and outside of the preirradiated area (n = 2). In all patients, reirradiation was tolerated well without significant acute toxicity. Temporary clinical improvement and tumor regression on magnetic resonance imaging (MRI) following reirradiation was reported (n = 3). However, all patients finally died by disease progression. Median survival time was 26.2 months from initial diagnosis and 11.4 months after first progression. Median time interval between initial radiotherapy and first reirradiation was 9.0 months. In six patients, all macroscopic tumor deposits were reirradiated. In these patients, median progression-free (overall) survival from the start of reirradiation was 2.4 (4.6) months. CONCLUSION: Our analysis, although based on a limited patient number, suggests that reirradiation of progressive non-pontine HGG is feasible in children. Benefit in terms of quality of life and/or survival needs to be assessed in a prospective and ideally in a randomized manner.

Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy.

Besides the direct, targeted effects of ionizing irradiation (x-ray) on cancer cells, namely DNA damage and cell death induction, indirect, nontargeted ones exist, which are mediated in large part by the immune system. Immunogenic forms of tumor cell death induced by x-ray, including immune modulating danger signals like the heat shock protein 70, adenosine triphosphate, and high-mobility group box 1 protein are presented. Further, antitumor effects exerted by cells of the innate (natural killer cells) as well as adaptive immune system (T cells activated by dendritic cells) are outlined. Tumor cell death inhibiting molecules such as survivin are introduced as suitable target for molecularly tailored therapies in combination with x-ray. Finally, reasonable combinations of immune therapies with radiotherapy are discussed.

Release of monocyte migration signals by breast cancer cell lines after ablative and fractionated γ-irradiation.

BACKGROUND: Radiotherapy, administered in fractionated as well as ablative settings, is an essential treatment component for breast cancer. Besides the direct tumor cell death inducing effects, there is growing evidence that immune mechanisms contribute - at least in part - to its therapeutic success. The present study was designed to characterize the type and the extent of cell death induced by fractionated and ablative radiotherapy as well as its impact on the release of monocyte migration stimulating factors by dying breast cancer cells. METHODS: Cell death and senescence assays were employed to characterize the response of a panel of breast cancer cell lines with different receptor and p53 status towards γ-irradiation applied in a fractionated (daily doses of 2 Gy) or ablative setting (single dose of 20 Gy). Cell-free culture supernatants were examined for their monocyte migration stimulating potential in transwell migration and 2D chemotaxis/chemokinesis assays. Irradiation-induced transcriptional responses were analyzed by qRT-PCR, and CD39 surface expression was measured by flow cytometry. RESULTS: Fast proliferating, hormone receptor negative breast cancer cell lines with defective p53 predominantly underwent primary necrosis in response to γ-irradiation when applied at a single, ablative dose of 20 Gy, whereas hormone receptor positive, p53 wildtype cells revealed a combination of apoptosis, primary, and secondary (post-apoptotic) necrosis. During necrosis the dying tumor cells released apyrase-sensitive nucleotides, which effectively stimulated monocyte migration and chemokinesis. In hormone receptor positive cells with functional p53 this was hampered by irradiation-induced surface expression of the ectonucleotidase CD39. CONCLUSIONS: Our study shows that ablative radiotherapy potently induces necrosis in fast proliferating, hormone receptor negative breast cancer cell lines with mutant p53, which in turn release monocyte migration and chemokinesis stimulating nucleotides. Future studies have to elucidate, whether these mechanisms might be utilized in order to stimulate intra-tumoral monocyte recruitment and subsequent priming of adaptive anti-tumor immune responses, and which breast cancer subtypes might be best suited for such approaches.

Endometrial cancer - reduce to the minimum. A new paradigm for adjuvant treatments?

BACKGROUND: Up to now, the role of adjuvant radiation therapy and the extent of lymph node dissection for early stage endometrial cancer are controversial. In order to clarify the current position of the given adjuvant treatment options, a systematic review was performed. MATERIALS AND METHODS: Both, Pubmed and ISI Web of Knowledge database were searched using the following keywords and MESH headings: "Endometrial cancer", "Endometrial Neoplasms", "Endometrial Neoplasms/radiotherapy", "External beam radiation therapy", "Brachytherapy" and adequate combinations. CONCLUSION: Recent data from randomized trials indicate that external beam radiation therapy - particularly in combination with extended lymph node dissection - or radical lymph node dissection increases toxicity without any improvement of overall survival rates. Thus, reduced surgical aggressiveness and limitation of radiotherapy to vaginal-vault-brachytherapy only is sufficient for most cases of early stage endometrial cancer.

Hyperfractionated, accelerated chemoradiation with concurrent mitomycin-C and cisplatin in locally advanced head and neck cancer, a phase I/II study.

BACKGROUND: To determine the outcome, acute and late toxicity in locally advanced head and neck cancer stage IVA with mitomycin-C (MMC), cisplatin (DDP) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART). PATIENTS AND METHODS: Thirty-five patients, with squamous cell cancer of the oral cavity (20%), oropharynx (37%), hypopharynx (26%) and larynx (17%), received 30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with MMC 10mg/m(2) (day 1 plus 36) and DDP 6 mg/m(2) given Mondays through Fridays during weeks 1-3. Median follow up was 19 months. RESULTS: C-HART was given as planned in 12 of 35 patients, with radiotherapy completed per protocol in 91%. Overall, patients received 70% of the intended dose of MMC and 91% of DDP. Mucositis CTC III/IV occurred in 27%, leucopenia CTC III/IV in 47%, and three early deaths were observed. Osteoradionecrosis occurred in 14% with cT4-tumours. At 3 years the locoregional control and survival rates were 60% and 46%, respectively. CONCLUSION: C-HART resulted in promising overall response with acceptable toxicity. Mucositis is a frequent, severe toxicity in patients treated with C-HART for head and neck cancer. While it appears that mucositis and hematological toxicity may lead to hospitalization and omitting of the second dose of mitomycin C, its impact on radiotherapy interruptions is marginal.