Matthias Hautmann

Pituitary Adenylate Cyclase–Activating Polypeptide Stimulates Renin Secretion via Activation of PAC1 Receptors

Besides of its functional role in the nervous system, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of cardiovascular function. Therefore, PACAP is a potent vasodilator in several vascular beds, including the renal vasculature. Because the kidney expresses both PACAP and PACAP-binding sites, it was speculated that PACAP might regulate cardiovascular function by direct vascular effects and indirectly by regulating renin release from the kidneys. PACAP (1-27) stimulated renin secretion from isolated perfused kidneys of rats 4.9-fold with a half-maximum concentration of 1.9 nmol/L. In addition, PACAP stimulated renin release and enhanced membrane capacitance of isolated juxtaglomerular cells, indicating a direct stimulation of exocytotic events. The effect of PACAP on renin release was mediated by the specific PACAP receptors (PAC1), because PACAP (1-27) applied in concentrations in the physiologic range (10 and 100 pmol/L) did not enhance renin release from isolated kidneys of PAC1 receptor knockout mice (PAC1-/-), whereas it stimulated renin release 1.38- and 2.5-fold in kidneys from wild-type mice. Moreover, plasma renin concentration was significantly lower in PAC1-/- compared with their wild-type littermates under control conditions as well as under a low- or high-salt diet and under treatment with the angiotensin-converting enzyme inhibitor ramipril, whereas no differences in plasma renin concentration between the genotypes were detectable after water deprivation. These data show that PACAP acting on PAC1 receptors potently stimulates renin release, serving as a tonic enhancer of the renin system in vivo.

Heat shock protein 70 (Hsp70) peptide activated Natural Killer (NK) cells for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy (RCTx) - from preclinical studies to a clinical phase II trial

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.

Tumor-Induced Osteomalacia: an Up-to-Date Review

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome resulting in renal phosphate wasting and decreased bone mineralization. TIO is usually induced by small, slowly growing tumors of mesenchymal origin (phosphaturic mesenchymal tumor mixed connective tissue variant [PMTMCT]). Nonspecific symptoms including fatigue, bone pain, and musculoskeletal weakness make the diagnosis elusive and often lead to a delay in treatment. The prognosis of TIO is excellent following complete resection of the neoplasm, which leads to the rapid and complete reversal of all symptoms. If the tumor cannot be detected, treatment relies on supplementation with phosphate and active vitamin D compounds. Subsequent radiotherapy in case of incompletely resected tumors or definitive radiotherapy in unresectable tumors is an important treatment option to avoid recurrence or metastasis even though this occurs rarely. Due to the risk of recurrence or late metastases, long-term monitoring is required even in TIO patients diagnosed with a benign tumor.

AKT and MET signalling mediates antiapoptotic radioresistance in head neck cancer cell lines

OBJECTIVES Induction of apoptosis is a major mechanism of radiosensitivity in different types of cancer. In contrast, EGFR/PI3K/AKT signalling and recently the presence of so-called cancer stem cells are discussed as reasons for radioresistance. MATERIALS AND METHODS The study investigates mechanisms of apoptosis, key oncogenes of the PI3K/AKT pathway and the presence of cancer cells with stem cell properties during irradiation in two cell lines (PCI-9A, and PCI-15) of head and neck squamous cell carcinoma. WST-1-tests, qRT-PCR, western blots and FACS analysis were performed for analysis. RESULTS The two cell lines presented different degrees of cell death upon irradiation. The radiosensitive cell line PCI-9A showed increased apoptosis after irradiation measured by expressed cleaved caspases 3 and 7 while the radioresistant cell line PCI-15 upregulated antiapoptotic Survivin and BCL2A1 mRNA. Besides, increased PI3K/AKT- and ERK1/2-signalling was associated with radioresistance accompanied by loss of PTEN function through phosphorylation on S380. Blockade of pAKT increased radiation-induced cell death, and moreover, led to an upregulation of pMET in the radioresistant cell line. The percentage of ALDH-positive tumour cells was markedly decreased after irradiation in the radiosensitive cell line. CONCLUSIONS Functional apoptosis is mandatory for sensitivity to irradiation in head neck cancer cells. Upregulation of the AKT-pathway seems to be one reason for poor radioresponse. Activated MET may also predict radioresistance, possibly through ERK1/2 signalling. Moreover MET may indicate the presence of cancer stem cells facilitating radioresistance as shown by increased ALDH expression.

Clostridium difficile-associated diarrhea in radiooncology: an underestimated problem for the feasibility of the radiooncological treatment?

Background and PurposeOver the last years an increasing incidence of Clostridium difficile-associated diarrhea (CDAD) has been reported. Especially haematology-oncology patients are at risk of developing CDAD.The aim of this analysis is to determine the incidence of CDAD in radiooncological patients and to find out what relevance CDAD has for the feasibility of the radiooncological treatment, as well as to detect and describe risk factors.Patients and MethodsIn a retrospective analysis from 2006 to 2010 34 hospitalized radiooncological patients could be identified having CDAD. The risk factors of these patients were registered, the incidence was calculated and the influence on the feasibility of the radiooncological therapy was evaluated. Induced arrangements for prophylaxis of CDAD were identified and have been correlated with the incidence.ResultsThe incidence of CDAD in our collective is 1,6%. Most of the patients suffering from a CDAD were treated for carcinoma in the head and neck area. Common risk factors were antibiotics, proton pump inhibitors, cytostatic agents and tube feeding.Beside a high rate of electrolyte imbalance and hypoproteinemia a decrease of general condition was frequent. 12/34 patients had a prolonged hospitalization, in 14/34 patients radiotherapy had to be interrupted due to CDAD. In 21 of 34 patients a concomitant chemotherapy was planned. 4/21 patients could receive all of the planned cycles and only 2/21 patients could receive all of the planned cycles in time.4/34 patients died due to CDAD. In 4/34 patients an initially curative treatment concept has to be changed to a palliative concept.With intensified arrangements for prophylaxis the incidence of CDAD decreased from 4,0% in 2007 to 0,4% in 2010.ConclusionThe effect of CDAD on the feasibility of the radiotherapy and a concomitant chemotherapy is remarkable. The morbidity of patients is severe with a high lethality.Reducing of risk factors, an intense screening and the use of probiotics as prophylaxis can reduce the incidence of CDAD.

Positive frozen section margins predict local recurrence in R0-resected squamous cell carcinoma of the head and neck

OBJECTIVES The purpose of this study was to analyse the impact of surgical margins on tumour recurrence and survival of patients with carcinomas of the head and neck. MATERIAL AND METHODS A cohort of 156 patients with primary squamous cell carcinoma of the head and neck treated by local resection with negative margins and neck dissection between 2004 and 2012 was investigated. Margin status in frozen sections and permanent paraffin tissues were analysed and compared to clinical and histopathological parameters as well as to tumour recurrence (local, regional and distant) and disease-specific survival (DSS). RESULTS Close margins (<5mm) on permanent sections were correlated to high-grade differentiation (p=0.070), lymphangiosis (p=0.009) and positive neck nodes (p=0.025) implicating regional and distant recurrence (p=0.001) as well as unfavorable DSS (p=0.002). Positive margins on initial frozen section analysis revised into negative margins during further surgery were the strongest predictor for local recurrence in uni- and multivariate analysis (p<0.001, hazard ratio 3.34). However, positive frozen section margins were not significantly predictive for DSS (p=0.150). Significant predictors for DSS in univariate analysis were local recurrence (p=0.026), T-stage (p=0.02), N-stage (p<0.001), grading (p=0.02) and lymphangiosis (p=0.001). Multivariate DSS analysis revealed lymph node metastasis (p=0.005) and local recurrence (p=0.017) as significant negative predictors. CONCLUSION Close margins on permanent sections are associated with aggressive tumour characteristics, regional and distant metastasis implicating worse DSS. The accuracy of frozen section analysis seems limited as positive frozen section margins revised into negative margins bear a high risk of local recurrence.

Re-irradiation for painful heel spur syndrome

PurposePainful heel spur syndrome is a common disease with a lifetime prevalence of approximately 10 %. One of the most effective treatment options is radiotherapy. Many authors recommend a second or third series of radiation for recurrent pain and partial or no response to the initial treatment. As the results of re-irradiation have not been systematically analyzed the aim of this study was to document the results of repeated radiation treatment and to identify patients who could benefit from this treatment.Material and methodsThe analysis was performed on patients from 2 German radiotherapy institutions and included 101 re-irradiated heels. Pain was documented with the numeric rating scale (NRS) and carried out before and directly after each radiation therapy as well as for the follow-up period of 24 months. The median age of the patients was 56 years with 30.1 % male and 69.9 % female patients. Pain was caused by plantar fasciitis in 72.3 %, Haglund’s exostosis in 15.8 % and Achilles tendinitis in 11.9 %. Repeated radiation was indicated because the initial radiotherapy resulted in no response in 35.6 % of patients, partial response in 39.6 % and recurrent pain in 24.8 %.ResultsA significant response to re-irradiation could be found. For the whole sample the median NRS pain score was 6 before re-irradiation, 2 after 6 weeks and 0 after 12 and 24 months. Of the patients 73.6 % were free of pain 24 months after re-irradiation. All subgroups, notably those with no response, partial response and recurrent pain had a significant reduction of pain.ConclusionRe-irradiation of painful heel spur syndrome is an effective and safe treatment. All subgroups showed a good response to re-irradiation for at least 24 months.ZusammenfassungHintergrundDer schmerzhafte Fersensporn ist eine der häufigsten Erkrankungen unter den Fußsyndromen. Die Lebenszeitprävalenz liegt bei etwa 10 %. Eine der wirkungsvollsten Therapieoptionen stellt die Strahlentherapie dar. Dabei beschreiben viele Autoren die Durchführung einer Rebestrahlung bei rezidivierten Schmerzen bzw. unzureichendem oder keinem Ansprechen auf die initiale Bestrahlungsserie, eine strukturierte Auswertung der Rebestrahlung existiert allerdings nicht. Ziel dieser Arbeit ist die strukturierte Auswertung der Rebestrahlung beim schmerzhaften Fersenspornsyndrom.Material und MethodeAusgewertet wurden Patienten aus zwei strahlentherapeutischen Institutionen. Insgesamt konnten 101 Fersen analysiert werden. Die Schmerzintensität wurde mit Hilfe der numerischen Rating-Skala (NRS) quantifiziert und zu den Zeitpunkten vor Bestrahlungsbeginn, direkt nach Radiatio, 6 und 12 Wochen, 6, 12 und 24 Monate nach Bestrahlung erfasst.30,1 % der Patienten waren männlich, 69,9 % weiblich bei einem medianen Alter von 56 Jahren. Bei 72,3 % lag eine Plantarfasziitis, bei 15,8 % eine Haglund-Exostose und bei 11,9 % eine Tendinitis der Achillessehne vor. Grund der Rebestrahlung war in 35,6 % kein Ansprechen und in 39,6 % ein unzureichendes Ansprechen auf die erste Bestrahlungsserie sowie in 24,8 % rezidivierte Schmerzen.ErgebnisseEs zeigte sich für das Gesamtkollektiv eine signifikante Schmerzreduktion. Die mediane Schmerzintensität war 6 vor der Rebestrahlung, 2 nach 6 Wochen und 0 nach 12 und 24 Monaten. 73,6 % der Patienten waren 24 Monate nach Rebestrahlung schmerzfrei. Alle Subgruppen, insbesondere Patienten ohne und Patienten mit unzureichendem Ansprechen auf die initiale Bestrahlung bzw. Patienten mit rezidivierten Schmerzen hatten eine signifikante Schmerzreduktion.SchlussfolgerungZusammenfassend zeigt diese Arbeit, dass die Rebestrahlung beim schmerzhaften Fersenspornsyndrom eine effektive Therapie darstellt und dass alle Patientengruppen von der Therapie profitieren.

5-FU-induced cardiac toxicity - an underestimated problem in radiooncology?

Background5-Fluorouracil (5-FU) is an antimetabolite, which is frequently used as chemotherapeutic agent for combined chemoradiotherapy. The purpose of this study was to present the clinical course of three patients who developed severe cardiac toxicity by 5-FU and to give a review of the literature on the cardiotoxic potential of 5-FU.ResultsCardiotoxicity is a rare, but relevant side effect of fluoropyrimidines. It comprehends a wide spectrum of side effects, from electrocardiogram changes (69% of cardiac events) to myocardial infarction (22%) and cardiogenic shock (1%).In this case series three patients with cardiotoxic events during chemoradiotherapy including 5-FU, the reactions characteristics and their influence on further therapy are described. Two of the patients could not be treated with 5-FU any more because they had developed a myocardial ischemia, which was most likely caused by fluorouracil. Another patient, who complained about typical angina pectoris during 5-FU-infusion and had a new left anterior hemiblock, was reexposed with prophylactic administration of nitrendipine.ConclusionCardiotoxicity caused by 5-FU is an underestimated problem in radiooncology. Especially patients without history of cardiac disease are often treated as out-patients and therefore without cardiac monitoring. Consequently asymptomatic and symptomatic cardiac events may be overlooked. The benefit of prophylactic agents remains unclear, so close cardiac monitoring is the most established method to prevent manifest cardiotoxic events.

Influence of dosimetric and clinical criteria on the requirement of artificial nutrition during radiotherapy of head and neck cancer patients

PURPOSE/OBJECTIVE(S) Intensification of radiotherapy and chemotherapy for head-and-neck cancer (HNC) may lead to increased rates of long term dysphagia as a severe side effect. Mucositis and consequent swallowing problems require artificial nutrition in many HNC patients undergoing radiotherapy or chemoradiation. It is unknown, which predict factors for prophylactic PEG tube insertion appear useful. MATERIALS/METHODS From an institutional database, 101 patients (72 male, 29 female, mean age 59.5years) were identified who underwent radiotherapy or chemoradiation for HNC. Primary end point of the investigation was the need for artificial nutrition for more than 4days during radiotherapy. Dose volume parameters of defined normal tissue structures potentially of relevance for swallowing ability as well as clinical factors were used to develop a predictive model using a binary multiple logistic regression model. RESULTS Whereas several dosimetric and clinical factors were significant predictors for the need of artificial nutrition on univariate analysis, on multivariate analysis only three factors remained independently significant: mean dose to the oropharynx+1cm circumferential margin, ECOG performance state (0-1 vs. 2-4), and the use of chemotherapy (yes vs. no). CONCLUSIONS Using a 3 parameter model we could distinguish HNC-patients with different risks for the need of artificial nutrition during radiotherapy. After independent validation, the model could be helpful to decision on prophylactic PEG tube insertion.

Re-irradiation for painful heel spur syndrome. Retrospective analysis of 101 heels.

PurposePainful heel spur syndrome is a common disease with a lifetime prevalence of approximately 10 %. One of the most effective treatment options is radiotherapy. Many authors recommend a second or third series of radiation for recurrent pain and partial or no response to the initial treatment. As the results of re-irradiation have not been systematically analyzed the aim of this study was to document the results of repeated radiation treatment and to identify patients who could benefit from this treatment.Material and methodsThe analysis was performed on patients from 2 German radiotherapy institutions and included 101 re-irradiated heels. Pain was documented with the numeric rating scale (NRS) and carried out before and directly after each radiation therapy as well as for the follow-up period of 24 months. The median age of the patients was 56 years with 30.1 % male and 69.9 % female patients. Pain was caused by plantar fasciitis in 72.3 %, Haglund’s exostosis in 15.8 % and Achilles tendinitis in 11.9 %. Repeated radiation was indicated because the initial radiotherapy resulted in no response in 35.6 % of patients, partial response in 39.6 % and recurrent pain in 24.8 %.ResultsA significant response to re-irradiation could be found. For the whole sample the median NRS pain score was 6 before re-irradiation, 2 after 6 weeks and 0 after 12 and 24 months. Of the patients 73.6 % were free of pain 24 months after re-irradiation. All subgroups, notably those with no response, partial response and recurrent pain had a significant reduction of pain.ConclusionRe-irradiation of painful heel spur syndrome is an effective and safe treatment. All subgroups showed a good response to re-irradiation for at least 24 months.ZusammenfassungHintergrundDer schmerzhafte Fersensporn ist eine der häufigsten Erkrankungen unter den Fußsyndromen. Die Lebenszeitprävalenz liegt bei etwa 10 %. Eine der wirkungsvollsten Therapieoptionen stellt die Strahlentherapie dar. Dabei beschreiben viele Autoren die Durchführung einer Rebestrahlung bei rezidivierten Schmerzen bzw. unzureichendem oder keinem Ansprechen auf die initiale Bestrahlungsserie, eine strukturierte Auswertung der Rebestrahlung existiert allerdings nicht. Ziel dieser Arbeit ist die strukturierte Auswertung der Rebestrahlung beim schmerzhaften Fersenspornsyndrom.Material und MethodeAusgewertet wurden Patienten aus zwei strahlentherapeutischen Institutionen. Insgesamt konnten 101 Fersen analysiert werden. Die Schmerzintensität wurde mit Hilfe der numerischen Rating-Skala (NRS) quantifiziert und zu den Zeitpunkten vor Bestrahlungsbeginn, direkt nach Radiatio, 6 und 12 Wochen, 6, 12 und 24 Monate nach Bestrahlung erfasst.30,1 % der Patienten waren männlich, 69,9 % weiblich bei einem medianen Alter von 56 Jahren. Bei 72,3 % lag eine Plantarfasziitis, bei 15,8 % eine Haglund-Exostose und bei 11,9 % eine Tendinitis der Achillessehne vor. Grund der Rebestrahlung war in 35,6 % kein Ansprechen und in 39,6 % ein unzureichendes Ansprechen auf die erste Bestrahlungsserie sowie in 24,8 % rezidivierte Schmerzen.ErgebnisseEs zeigte sich für das Gesamtkollektiv eine signifikante Schmerzreduktion. Die mediane Schmerzintensität war 6 vor der Rebestrahlung, 2 nach 6 Wochen und 0 nach 12 und 24 Monaten. 73,6 % der Patienten waren 24 Monate nach Rebestrahlung schmerzfrei. Alle Subgruppen, insbesondere Patienten ohne und Patienten mit unzureichendem Ansprechen auf die initiale Bestrahlung bzw. Patienten mit rezidivierten Schmerzen hatten eine signifikante Schmerzreduktion.SchlussfolgerungZusammenfassend zeigt diese Arbeit, dass die Rebestrahlung beim schmerzhaften Fersenspornsyndrom eine effektive Therapie darstellt und dass alle Patientengruppen von der Therapie profitieren.