Treatment of primary or recurrent non-resectable pancreatic cancer with proton beam irradiation combined with gemcitabine-based chemotherapy.

BACKGROUND: Pancreatic cancer accounts for around 4.6% of cancers deaths worldwide per year. Despite many advances in treatment regimes, the prognosis is still poor. Only 20% of tumors are primarily resectable. Recurrences-both with distant metastasis as well as locoregional-are frequent. For patients with primary nonresectable localized disease or localized recurrences, we offered chemoradiation to achieve local control over a long period of time. We here report our results on combined chemoradiation of pancreatic tumors and local recurrences using proton beam therapy. MATERIALS AND METHODS: We report on 25 patients with localized nonresectable pancreatic cancer (15 patients) or local recurrent disease (10 patients). All patients were treated with combined proton radiochemotherapy. Overall survival, progression-free survival, local control, and treatment-related toxicity were analyzed using statistically methods. RESULTS: Median RT dose was 54.0 Gy (RBE) for proton irradiation. The toxicity of treatment was acceptable. Four CTCAE grade III and IV adverse events (bone marrow disfunction, gastrointestinal [GI] disorders, stent dislocation, myocardial infarction) were recorded during or directly after the end of radiotherapy; two of them were related to combined chemoradiation (bone marrow disfunction, GI disorders). Six weeks after radiotherapy, one additional grade IV toxicity was reported (ileus, caused by peritoneal carcinomatosis, not treatment related). The median progression-free survival was 5.9 months and median overall survival was 11.0 months. The pretherapy CA19­9 level was a statistically significant prognostic factor for enhanced overall survival. Local control at 6 months and 12 months were determined to be 86% and 80%, respectively. CONCLUSION: Combined proton chemoradiation leads to high local control rates. Unfortunately, PFS and OS are driven by distant metastasis and were not improved compared to historical data and reports. With this in mind, enhanced chemotherapeutical regimes, in combination with local irradiation, should be evaluated.

Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities.

PURPOSE: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA.

Monocentric evaluation of Ki-67 labeling index in combination with a modified RPA score as a prognostic factor for survival in IDH-wildtype glioblastoma patients treated with radiochemotherapy.

PURPOSE: The prognosis for glioblastoma patients remains dismal despite intensive research on better treatment options. Molecular and immunohistochemical markers are increasingly being investigated as understanding of their role in disease progression grows. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been shown to have prognostic and therapeutic relevance for glioblastoma patients. Other markers implicated in tumor formation and/or malignancy are p53, Alpha thalassemia/mental retardation syndrome X-linked (ATRX), Epidermal Growth Factor Receptor splice variant III (EGFRvIII), and Ki-67, with loss of nuclear ATRX expression and lower Ki-67 index being associated with prolonged survival. For p53 and EGFRvIII the data are contradictory. Our aim was to investigate the markers mentioned above regarding progression-free (PFS) and overall survival (OS) to evaluate their viability as independent prognostic markers for our patient collective. METHODS: In this retrospective study, we collected data on patients undergoing radiotherapy due to isocitrate dehydrogenase (IDH) wildtype glioblastoma at a single university hospital between 2014 and 2020. RESULTS: Our findings confirm Ki-67 labeling index ≤ 20% as an independent prognostic factor for prolonged PFS as well as MGMT promoter methylation for both prolonged PFS and OS, in consideration of age and Eastern Cooperative Oncology Group (ECOG) status, chemotherapy treatment, and total radiation dose for PFS as well as additionally sex, resection status, and receipt of treatment for progression or recurrence for OS. Additionally, Ki-67 labeling index ≤ 20% showed a significant correlation with prolonged OS in univariate analysis. Modification of the recursive partitioning analysis (RPA) score to include Ki-67 labeling index resulted in a classification with the possible ability to distinguish long-term-survivors from patients with unfavorable prognosis. CONCLUSION: MGMT promoter methylation and Ki-67 labeling index were independent predictors of survival in our collective. We see further studies pooling patient collectives to reach larger patient numbers concerning Ki-67 labeling index as being warranted.

Comparison of carbon ion and photon reirradiation for recurrent glioblastoma.

PURPOSE: Purpose of this study was to investigate overall survival in recurrent glioblastoma treated with either carbon ion reirradiation or photon reirradiation. MATERIALS AND METHODS: In this retrospective study we evaluated 78 consecutive patients with recurrent IDH (Isocitrate dehydrogenase)-wildtype glioblastoma (38 patients carbon ion re-radiotherapy, 40 patients photon re-radiotherapy) treated with either carbon ion reirradiation or stereotactic photon reirradiation. 45 Gy (RBE; 15 fractions) carbon ion reirradiation (CIRT) or 39 Gy (13 fractions) photon reirradiation (FSRT) was administered, respectively. Overall survival was investigated with respect to histological, clinical, and epidemiological features. Kaplan-Meier and multivariate Cox statistics were calculated. A propensity score-matched analysis of the FSRT and CIRT groups using variables from a validated prognosis score was carried out. RESULTS: The type of reirradiation (CIRT vs. FSRT) significantly influenced overall survival-8.0 months vs. 6.5 months (univariate: p = 0.046)-and remained an independent prognostic factor in multivariate analysis (p = 0.017). Propensity score-adjusted analysis with CIRT versus FSRT as the dependent variable yielded a significant overall survival advantage for the CIRT group (median OS 8.9 versus 7.2 months, p = 0.041, 1­year survival 29 versus 10%). Adverse events (AE) were evaluated for both subgroups. For the FSRT group no toxicity ≥ grade 4 occurred. For the CIRT subgroup no grade 5 AE occurred, but 1 patient developed a grade 4 radionecrosis. We encountered 4 grade 3 toxicities. One patient developed a zoster at the trunk, 2 progressed in their paresis, and 1 featured progressive dysesthesia. CONCLUSION: In conclusion, carbon ion treatment is a safe and feasible treatment option for recurrent glioblastoma. Due to the retrospective nature of the study and two different dose levels for CIRT or FSRT, the improved outcome in CIRT reirradiation might be an effect of higher biological impact from carbon ions or a simple dose-escalation effect. This hypothesis needs prospective testing in larger patient cohorts. A prospective phase III randomized trial is in preparation at our center.

Advantage of proton-radiotherapy for pediatric patients and adolescents with Hodgkin's disease.

Radiotherapy is frequently used in the therapy of lymphoma. Since lymphoma, for example Hodgkin's disease, frequently affect rather young patients, the induction of secondary cancer or other long-term adverse effects after irradiation are important issues to deal with. Especially for mediastinal manifestations numerous organs and substructures at risk play a role. The heart, its coronary vessels and cardiac valves, the lungs, the thyroid and, for female patients, the breast tissue are only the most important organs at risk. In this study we investigated if proton-radiotherapy might reduce the dose delivered to the organs at risk and thus minimize the therapy-associated toxicity. METHODS: In this work we compared the dose delivered to the heart, its coronary vessels and valves, the lungs, the thyroid gland and the breast tissue by different volumetric photon plans and a proton plan, all calculated for a dose of 28.8 Gy (EURO-NET-PHL-C2). Target Volumes have been defined by F18-FDG PET-positive areas, following a modified involved node approach. Data from ten young female patients with mediastinal lymphoma have been evaluated. Three different modern volumetric IMRT (VMAT) photon plans have been benchmarked against each other and against proton-irradiation concepts. For plan-evaluation conformity- and homogeneity-indices have been calculated as suggested in ICRU 83. The target volume coverage as well as the dose to important organs at risk as the heart with its substructures, the lungs, the breast tissue, the thyroid and the spinal cord were calculated and compared. For statistical evaluation mean doses to organs at risk were evaluated by non- parametric Kruskal-Wallis calculations with pairwise comparisons. RESULTS: Proton-plans and three different volumetric photon-plans have been calculated. Proton irradiation results in significant lower doses delivered to organ at risk. The median doses and the mean doses could be decreased while PTV coverage is comparable. As well conformity as homogeneity are slightly better for proton plans. For several organs a risk reduction for secondary malignancies has been calculated using literature data as reference. According to the used data derived from literature especially the secondary breast cancer risk, the secondary lung cancer risk and the risk for ischemic cardiac insults can be reduced significantly by using protons for radiotherapy of mediastinal lymphomas. CONCLUSION: Irradiation with protons for mediastinal Hodgkin-lymphoma results in significant lower doses for almost all organs at risk and is suitable to reduce long term side effects for pediatric and adolescent patients.

Tumescent local anaesthesia for early dermatosurgery in infants.

BACKGROUND: Early paediatric dermatosurgery reveals excellent cosmetic results due to high skin elasticity and pronounced capacity to recover from trauma. Furthermore, the size of skin lesions increases during life proportionally to skin growth and therefore early removal is of major importance. Selected local anaesthetics like prilocaine can cause methaemoglobinemia. However, in contrast to general anaesthesia, many other local anaesthetics do not bare any major risks for infants. OBJECTIVE: In this retrospective study, we analysed infants aged less than 7 months receiving tumescent local anaesthesia (TLA) followed by dermatosurgery at our department between 2005 and 2015. The analysis is mainly based on our records. Additional information for a subset of patients was gained by a postoperative survey. METHODS: Ninety-two infants (39 male, 53 female) with a median age of 4.2 months (range: 1.5 months; 6.7 months) were included in this study. Additional postoperative information was available for 33 of the 92 studied patients (35%). RESULTS: Infants were mainly operated for removal of a melanocytic naevus (n = 54), followed by haemangioma (n = 23), naevus sebaceous (n = 6) and other lesions (n = 9). The lesions were located on the scalp or neck (n = 31), on the extremities (n = 31), on the trunk (n = 21), in the face (n = 6) or on the buttocks (n = 3). The median size of excision was 509 mm2 (range: 16 mm2 ; 3600 mm2 ). Primary defect closure was performed by intracutaneous (n = 68) or extracutaneous (n = 24) suture techniques. No side-effects of local anaesthesia were observed in any patient. Postoperative complications include pain (1/33; 3%), wound-healing disorder (1/33; 3%) and visible severe scarring (2/33; 6%). CONCLUSIONS: The combination of TLA and dermatosurgery in infants is a suitable outpatient treatment option for small lesions without any major risks or side-effects and the benefit of prolonged postoperative analgesia.

[Characterization of principal predictive biomarkers of targeted therapies in thoracic cancer]. / Caractérisation des principaux biomarqueurs prédictifs de réponse aux thérapies ciblées en oncologie thoracique.

Among non-small cell lung carcinomas, adenocarcinomas are historically the first histological sub-group for which necessary and sufficient mutations driving to cancer can be targeted by tyrosine kinase inhibitors in patients with locally advanced or metastatic forms. In 2013, targeted therapies with a marketing authorization in thoracic oncology are indicated in patients whose tumor has an EGFR-positive or ALK-positive status. Biomarkers KRAS, BRAF, HER2, PI3K, and MET can account for resistance mechanisms to these treatments and are themselves subject to development of new therapeutic inhibitors. Because the systematic detection (or in the process of being) of these biomarkers has become in the last three years an essential task for pathologists and biologists working in hospital platforms of molecular genetics of cancer supported by INCa, this article aims to describe the physiological and pathophysiological role of the main predictive biomarkers of response to targeted therapies indicated in lung adenocarcinomas.

[Precautions for intestinal cancer in the workplace. An initiative for secondary prevention in the BASF joint-stock company]. / Darmkrebs-Vorsorge im Betrieb. Eine Initiative sekundärer Prävention in der BASF Aktiengesellschaft.

BACKGROUND AND OBJECTIVE: The annual incidence of colorectal cancer in Germany is estimated at 27000 in men and 30000 in women. If the diagnosis is made early the cure rate is over 90%. Against this background the department of occupational medicine and health protection of the BASF Aktiengesellschaft initiated a study on the potential prevention of colorectal cancer among the staff at its Ludwigshafen site. SUBJECTS AND METHODS: The target group included all 13265 actively working employees aged 45 years or above. Those expressing interest were given a standardized questionnaire concerning risk factors for colorectal cancer and a test for occult fecal blood (FOBT). If the test was positive and/or a positive answer was given to the question on blood in the stool or on a positive family history, coloscopy - to be arranged via the general practitioner - was advised, in line with the recommendations of the German Society of Digestive and Metabolic diseases (Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen). RESULTS: At the end of the study 3732 employees (337 women, 3395 men, mean age 52 years) had completed the questionnaire and the FOBT results were available. Coloscopy was recommended to 688 employees, 323 of whom (47%) underwent the investigation. Nine of the subjects already had manifest cancer, six of them in the early stage T1 or T2. Adenomatous polyps were found in an additional 61 and subsequently excised. Cost-benefit considerations at the company level or in the area of the health system, respectively, gave favourable ratios of 1:10 and 1:14. CONCLUSION: It requires considerable expenditure to increase the number of participants in the cancer prevention programme and obtain a consequent clarification of suspicious findings. Health care within a company is a valuable complementation in Germany of medical care provided by general practitioners or specialist, if close cooperation between practitioners in the given region is assured. Initiatives like the one presented here protect people personally affected against pain and distress and are also of economic value.

Capture of cytokine-responsive genes (NACA and RBM3) using a gene trap approach.

We have developed a gene trap approach to select specific cytokine receptor/ligand responsive genes in the cell line TF-1. This cell line exhibits a dependency on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) and responds to interleukin-5 (IL-5). In an attempt to detect genes modulated by one of these factors, cells were infected with the Rosabetageo retrovirus in the presence of GM-CSF, IL-3, or IL-5 and clones were selected for retroviral integration on the basis of G418 resistance. Housekeeping and cytokine-regulated trapped genes were then differentiated on the basis of G418 resistance versus sensitivity in the presence of the different cytokines. To determine the reliability of this screen, DNA sequences upstream of the proviral integration site were identified by 5' rapid amplification of DNA ends polymerase chain reaction (RACE PCR) from selected GM-CSF-treated and -infected clones. Comparison of the sequences with those in the Genbank database revealed that 2 sequences correspond to known genes: NACA and RBM3. NACA was recently defined as a coactivator of c-jun-mediated transcription factors in osteoblasts, and RBM3 as a protein from the heterogeneous nuclear ribonucleoprotein family. Data from transcriptional analysis of these 2 genes in TF-1 cells showed a specific up-regulation by GM-CSF. Both transcripts were also found to be up-regulated in purified CD34(+) cells, suggesting their involvement in proliferative processes during hematopoiesis. Interestingly, down-regulation was observed during monocytic differentiation of TF-1 cells, suggesting their extinction could contribute to monocytic lineage development. This study demonstrates that this gene trap approach is a useful method for identifying novel, specific cytokine-responsive genes that are involved in the regulation of hematopoiesis. (Blood. 2000;95:3750-3757)

The human PRR2 gene, related to the human poliovirus receptor gene (PVR), is the true homolog of the murine MPH gene.

Until now it was assumed that the murine poliovirus (PV) receptor homolog gene (MPH) had been identified. Alternative splicing of MPH transcripts generates two glycoproteins named MPH alpha and MPH beta which share an identical N-terminal region composed of three immunoglobulin (Ig)-like domains and different C-terminal regions. Using a degenerate PCR strategy, we describe the identification of a second human PVR-related gene (PRR2), which encodes two glycoproteins, PRR2 alpha (short form) and PRR2 delta (long form). They present 69 and 73% identity with MPH alpha and MPH beta, respectively. In contrast, the human PVR protein exhibits 51% identity which is moreover restricted to the three Ig domains of the murine protein. We therefore propose that PRR2, and not PVR, is the true human homolog of MPH. In addition, Northern blot analysis showed that two mRNA isoforms of 3.0 kb (PRR2 alpha) and 4.4 kb (PRR2 delta) are ubiquitously found in various normal human tissues. In situ hybridization allowed us to map PRR2 to the 19q13.2-q13.4 bands of the human genome, in the same chromosomal region as PVR.

Persistence of BCR/ABL mRNA-expressing bone-marrow cells in patients with chronic myelogenous leukemia in complete cytogenetic remission induced by interferon-alpha therapy.

Complete hematologic and cytogenetic responses can be obtained with interferon-alpha (IFN-alpha) in 15-25% of the patients with chronic myelogenous leukemia (CML). In these patients, reverse-transcription polymerase chain reaction (RT-PCR) can be used to evaluate minimal residual disease. We studied 12 patients who remained Philadelphia-negative for a median period of 21 months on IFN-alpha therapy. Using RT-PCR, the specific transcript was found in all bone marrow (BM) samples. Ten patients still exhibiting a persistent residual clone remained in cytogenetic remission for a median period of 14 months. As we observed a dissociation between bcr-abl expression in BM and peripheral blood (PB) cells, and given the known fluctuations of the bcr-abl PCR results, we suggest that PB negative results should be confirmed on BM specimens. Alternatively, it remains to be demonstrated whether longitudinal monitoring of residual disease would benefit from quantitative PCR or double fluorescence in situ hybridization.

Complementary DNA characterization and chromosomal localization of a human gene related to the poliovirus receptor-encoding gene.

The human poliovirus (PV) receptor (PVR) is a member of the immunoglobulin (Ig) superfamily with unknown cellular function. We have isolated a human PVR-related (PRR) cDNA. The deduced amino acid (aa) sequence of PRR showed, in the extracellular region, 51.7 and 54.3% similarity with human PVR and with the murine PVR homolog, respectively. The cDNA coding sequence is 1.6-kb long and encodes a deduced 57-kDa protein; this protein has a structural organization analogous to that of PVR, that is, one V- and two C-set Ig domains, with a conserved number of aa. Northern blot analysis indicated that a major 5.9-kb transcript is present in all normal human tissues tested. In situ hybridization showed that the PRR gene is located at bands q23-q24 of human chromosome 11.

[Functional colonic pain. An important clinical and sonographic differential diagnosis]. / Funktionelle Kolonschmerzen. Eine wichtige klinische und sonographische Differentialdiagnose.

Functional abdominal pain may often be sonographically attributed to the colon. Typically a segment of the colon is painful at direct palpation, but the wall is not thickened. The contractions between the haustra are often marked. The haustra are clearly outlined and cast acoustic shadows. If the patient also experiences spontaneous pain in this region, functional colonic pain, explained as spasms of the muscle coat, may be assumed. Clinically there are often other symptoms of the irritable bowel disease or a spastic constipation. In daily practice functional colonic pain is as frequent as dyspepsia. Differential diagnosis includes intestinal (peptic ulcer, Crohn's disease, appendicitis, diverticulitis, colon cancer) and extraintestinal diseases (e.g. of the gallbladder, pancreas and female adnexes).

[Accumulation of risk factors before acute gastroduodenal hemorrhage: analgesic/antirheumatic drugs, alcohol and ulcer anamnesis]. / Kumulation von Risikofaktoren vor der akuten gastroduodenalen Blutung: Schmerz-/Rheumamittel, Alkohol und Ulkusanamnese.

72 patients with acute hemorrhage from gastroduodenal peptic lesions were asked about their drug and alcohol consumption as well as about their smoking habits, 43 of them (60%) had used analgetic or antiinflammatory drugs on at least 3 days during the week preceding the gastrointestinal (g. i.) hemorrhage, 20 patients had used more than on drug, 4 patients an overdose of one drug. During a therapy with corticosteroids alone only one thrombopenic patient bled. 21 patients (29%) had an abnormal high alcohol consumption. In the control group significantly fewer patients had such a drug and alcohol history (p less than 0.01 and p less than 0.05, respectively). The relative risk of a g. i. hemorrhage following an exposition with analgetic/antiinflammatory drugs was RR = +7.41 +/- 5.8. Strikingly, 43 patients (60%) had an ulcer history or a g.i. hemorrhage in the past. In 46 per cent of all patients the risk factors analgesic/antiinflammatory drug, alcohol and ulcer history accumulated before the acute hemorrhage. A more careful indication and dosage of analgesic and antiinflammatory drug therapy might reduce the frequency of g.i. hemorrhage. Most of the patients were male (76%). 39 patients (54%) were older than 60 years. The average age of the 6 patients who died was 73 +/- 6.3 years. After analgesic/antiinflammatory treatment the clinical course was by no means better than in the case of spontaneously occurring lesions. Endoscopically, following exposition with analgesic/antiinflammatory drugs more frequently erosions (p less than 0.05), multiple ulcers and gastric ulcers (no statistical significance) were observed.

Adult hypophosphatasia without apparent skeletal disease: "odontohypophosphatasia" in four heterozygote members of a family.

Twenty members of a family with adult hypophosphatasia were examined clinically and biochemically. Severe caries causing early loss of permanent teeth was the only clinical symptom which could be attributed to hypophosphatasia. None of them had a history of defective bone mineralization, rachitic skeletal alterations, and recurrent pseudofractures or fractures. An iliac crest bone biopsy of the proposita showed a normal finding corresponding to the age of the patient. Four family members in two subsequent generations were affected, thus suggesting an autosomal dominant inheritance. Their serum and leukocyte alkaline phosphatases were reduced. The phosphoethanolamine (PEA) excretion in the urine was increased to a level which suggests a heterozygote state. The serum alkaline phosphatase activity could be ascribed to the liver isoenzyme fraction. This was shown by polyacrylamide electrophoresis, by inhibition studies with organ-specific inhibitors, heat inactivation, inhibition by antibodies, and treatment with neuraminidase. The proposita had an unexplained, diffuse fatty infiltration of the liver. Thus, not only alterations of bone but also of liver metabolism in hypophosphatasia should be considered. The variety of adult hypophosphatasia described in this paper is characterized by the lack of severe bone abnormalities, the apparently autosomal dominant inheritance, and the reduction of bone and intestinal isoenzyme in the serum. Our study suggests that hypophosphatasia is a heterogeneous disorder which includes both severe and clinically mild forms.

[Gallbladder sludge: a sonographically recognizable stage of lithogenesis]. / Gallenblasen-"Sludge": ein sonografisch erkennbares Stadium der Lithogenese.

The appearance and the natural course of gallbladder sludge were studied by ultrasonography in 82 patients. Sludge was found in conditions with a functional or organic disturbance of gallbladder emptying: alcoholic cirrhosis and an atonic gallbladder in the fasting state, e.g., extrahepatic ductal obstruction and obstruction of the cystic duct. No clinical complaints could be attributed to sludge. After the normal bile flow had re-established the sludge disappeared in many cases. In 9 of 82 sludge-positive patients (10,9 per cent) ultrasonography revealed gallstone formation. Newly-formed stones obtained from 2 patients had the aspect of pigment stones and were analyzed by infrared spectroscopy. They consisted of calcium bilirubinate. This material constitutes the pigment granules which are suspended in the sludge. It was concluded that sludge was an early phase of stone formation. Alcoholic cirrhosis, obstruction of the biliary tract, gastrectomy, celiac sprue and prolonged fasting may predispose to lithiasis secondary to the precipitation of sludge in a large, atonic or distended gallbladder. Ultrasonography is instrumental to detect an early state of gallstone formation in those patients who carry a risk.