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Byline: Henrik. Hauswald, Eugen. Petrow, Falk. Roeder, Juergen. Debus, Felix. Zwicker, Peter. Huber Background: To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with [...]

Background:Pancreatic cancer is a highly aggressive malignancy and will become the second leading cause of cancer-related death in the USA and also in Germany by 2030. Furthermore, the majority of patients with pancreatic ductal adenocarcinoma (PDAC) will present with distant metastases, limiting surgical management in this population as there is little evidence available to support surgical or ablative treatment options for advanced-stage disease. However, highly selected patients suffering from synchronous and metachronous oligometastatic PDAC may potentially benefit from a surgical resection with an acceptable morbidity. Methods:This review summarizes and discusses the current literature on the management of oligometastatic disease regarding PDAC, focusing on para-aortic lymph nodes as well as isolated hepatic and pulmonary metastases. Results and Conclusion:In order to further investigate the feasibility and efficacy of such an approach, a prospective multicenter trial, in which survival and quality of life after metastatic resection and systemic chemotherapy is evaluated, has to be initiated. Additionally, local and locoregional ablation techniques or stereotactic body radiation therapy as therapeutic options for isolated metastases in PDAC need further research in order to determine their significance and benefit.

Zusammenfassung.Dieser Review fasst die aktuelle Datenlage zu strahlentherapeutischen Ansätzen beim Pankreaskarzinom zusammen. Obwohl eine alleinige adjuvante Chemotherapie als durch randomisierte Studien gut abgesicherter Standard gelten muss, kann auf Basis hervorragender single-center Ergebnisse eine (additive) adjuvante Radiochemotherapie bei selektionierten Patienten durchaus erwogen werden. Im neoadjuvanten Setting beim resektablen Pankreaskarzinom stellt die Radiochemotherapie aktuell keinen Therapiestandard dar und sollten deshalb nur im Rahmen von Studien angeboten werden. Beim lokal-fortgeschrittenen, primär nicht- oder borderline-resektablen Pankreaskarzinom stellt sich die Situation unterschiedlich dar. In Abwesenheit eindeutiger Ergebnisse aus randomisierten Studien legen die publizierten Arbeiten nahe, dass eine neoadjuvante Radiochemotherapie in einem substantiellen Anteil der Patienten (30 – 40 %) zu sekundärer Resektabilität und damit zu einer deutlichen Verbesserung der Prognose führt. Hierbei werden Überlebensraten erreicht (median ~24 Monate), welche denjenigen bei primärer Resektabilität einschließlich adjuvanter Therapie entsprechen können. Selbst bei Nicht-Erreichen sekundärer Resektabilität kann zumindest eine Verbesserung der Lebensqualität durch dauerhafte Verhinderung einer lokalen Problematik resultieren. Eine Kombination mit einer Induktionschemotherapie scheint dabei insbesondere bei Verwendung moderner potenter Systemtherapieansätze (Folfirinox, Gem/nab-Paclitaxel) sinnvoll und wird derzeit in größeren Studien untersucht. Moderne perkutane Radiotherapietechniken (IMRT, IGRT, SBRT), neue Strahlqualitäten (Protonen, Schwerionen) oder die Kombination mit alternativen Boostverfahren (IORT) können die therapeutische Breite erhöhen und zur Steigerung der Effektivität und/oder zur Reduktion der Toxizität beitragen. Sie eröffnen innovative Therapiemöglichkeiten, welche in kontrollierten Studien untersucht werden sollten.

BackgroundDesmoid-type fibromatosis (DF) is an aggressive (myo)fibroblastic neoplasm with an infiltrative growth pattern and a tendency for local recurrence. It is rarely seen at the foot. The aim of this retrospective study was to analyze clinical presentation, therapy, and outcomes in a consecutive series of four patients with DF at the foot.MethodsFrom 1994 to 2014, four patients had been surgically treated. The resection margin was marginal or even intralesional in all. One patient already had local recurrence at first presentation. The end point was either local recurrence or progression of residual disease.ResultsThe mean patient age was 27 years. In one patient, marginal excision healed the disease. In another patient, local recurrence after marginal resection necessitated distal phalanx amputation. Two other patients showed stable disease after either adjuvant radiotherapy or treatment with nonsteroidal anti-inflammatory drugs and tamoxifen.ConclusionsIf surgery is necessary, operative margins are less important than keeping function for the patient. Radiotherapy might be an option to avoid major amputation. The role of adjuvant radiotherapy is controversially discussed. A watchful wait-and-see policy seems to be justified by the published data but may be difficult for DF at the foot.

ABSTRACTBackground: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined inhibition of TGFβ and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the TGFβ-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of TGFβ and PDGF signaling and the attenuation of SPP1 (Osteopontin) expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis (IPF), our study suggests that the combined application of small molecule inhibitors of TGFβ and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer.

In radiotherapy, in vivo measurement of dose distribution within patients' lymphocytes can be performed by detecting gamma-H2AX foci in lymphocyte nuclei. This method can help in determining the whole-body dose. Options for risk estimations for toxicities in normal tissue and for the incidence of secondary malignancy are still under debate. In this investigation, helical tomotherapy (TOMO) is compared with step-and-shoot IMRT (SSIMRT) of the prostate gland by measuring the dose distribution within patients' lymphocytes. In this prospective study, blood was taken from 20 patients before and 10 min after their first irradiation fraction for each technique. The isolated leukocytes were fixed 2 h after radiation. DNA double-stranded breaks in lymphocyte nuclei were stained immunocytochemically using anti-gamma-H2AX antibodies. Gamma-H2AX foci distribution in lymphocytes was determined for each patient. Using a calibration line, dose distributions in patients' lymphocytes were determined by studying the gamma-H2AX foci distribution, and these data were used to generate a cumulative dose–lymphocyte histogram (DLH). Measured in vivo (DLH), significantly fewer lymphocytes indicated low-dose exposure (<40% of the applied dose) during TOMO compared with SSIMRT. The dose exposure range, between 45 and 100%, was equal with both radiation techniques. The mean number of gamma-H2AX foci per lymphocyte was significantly lower in the TOMO group compared with the SSIMRT group. In radiotherapy of the prostate gland, TOMO generates a smaller fraction of patients' lymphocytes with low-dose exposure relative to the whole body compared with SSIMRT. Differences in the constructional buildup of the different linear accelerator systems, e.g. the flattening filter, may be the cause thereof. The influence of these methods on the incidence of secondary malignancy should be investigated in further studies.