Traditional risk factors and nodal yield-still relevant with high-quality risk-adapted adjuvant treatment for locally advanced head and neck cancer?

OBJECTIVE: Patients with locally advanced head and neck cancer (LAHNC) often undergo multimodal therapy including radical resection of the primary tumor and neck dissection (ND) followed by risk-adapted adjuvant radio(chemo)therapy (R(C)T). Quality parameters influencing local control and survival of these patients have been postulated: resection status (R status), extranodal extension (ENE), interval to adjuvant treatment ≤6 weeks, R(C)T given when indicated, and nodal yield (NY) ≥18 lymph nodes per neck. For other solid tumors the trend is towards less extensive lymph node surgery to avoid toxicity such as lymphedema, damage to peripheral nerves, dysesthesia, or paresthesia. The present study aims to investigate whether the number of nodes removed during neck dissection for LAHNC is still predictive for outcome when patients receive risk-adapted adjuvant treatment according to current guidelines. METHODS: Between 2008 and 2015, 468 patients with LAHNC undergoing R(C)T with curative intent were prospectively registered in a database (UICC III/IV). Among them, 359 patients received adjuvant treatment and 295 underwent neck dissection. There were 119 (40%) patients with an oropharyngeal primary, 49 (17%) with cancer of the larynx/hypopharynx, 88 (30%) of the oral cavity, and 39 (13%) of the nasal/paranasal sinuses and cancer of unknown primary (CUP). Median follow-up was 45.6 months. Histopathology revealed an R1 status in 65 (22%) cases and ENE in 93 (31%) cases. 150 (51%) patients received RCT; the median time to adjuvant treatment from the day of tumor resection was 44 days (35-54) and overall treatment time (OTT; time from surgery to the last day of R(C)T) was 90 days (82-101). Factors influencing disease-free survival (DFS) were adjusted and analyzed using CART analysis (removed nodes, number of positive nodes, body mass index (BMI), ENE, T and N classification, R status, and primary site). Local control (LC), distant metastases-free survival (DMFS), and overall survival (OS) were analyzed using Kaplan-Meier statistics and multivariate analysis (MVA) for factors predictive for DFS and OS. RESULTS: CART analysis (Classification and Regression Trees) showed that T classification (T3/4) is the most important predictor for DFS, followed by age (> 61 years) and BMI (< 17.4). Primary site (OPC vs. other) and number of removed nodes (< 17) were shown to be less important for DFS, while ECE, N classification, and R status seem to be of little relevance. MVA revealed number of positive nodes, non-OPC, and T3/4 to be negative predictive factors for DFS. For OS, the number of positive nodes and non-OPC primary were predictive. Five-year rates were 86.1% for LC, 87.9% DMFS, 76.5% DFS, and 67.2% for OS. CONCLUSION: In this patient cohort, the number of removed nodes is not relevant for DFS and OS, while the number of positive nodes and T classification have a negative impact on these endpoints. The high-risk factors positive resection margin and ECE seem to lose their negative impact on DFS and OS. High-quality care in head and oncology is only possible within a close multidisciplinary team and network.

Influence of radiation dose to pharyngeal constrictor muscles on late dysphagia and quality of life in patients with locally advanced oropharyngeal carcinoma.

BACKGROUND AND OBJECTIVE: Patients with oropharyngeal carcinoma (OPC) often have difficulty swallowing, which may affect quality of life (QoL). Radiation dose to constrictor muscles plays an important role. METHODS: 54 patients with locally advanced OPC were evaluated after intensity-modulated radiotherapy. Data were collected at standardized intervals using the EORTC questionnaires QLQ-C30 and QLQ-HN35 within two years. The pharyngeal constrictors (superior, middle, and inferior) were each contoured as an organ at risk. Influence of dose to the constrictors (≥55 Gy vs. <55 Gy) on late dysphagia and QoL was analyzed using the t­test. RESULTS: Late radiation-induced dysphagia depends significantly on the dose to the lower pharyngeal constrictor. At a dose of ≥55 Gy, 14 (64%) patients developed dysphagia grade ≤2 and 8 (36%) patients grade ≥3. At a dose of <55 Gy, the distribution at the end of radiotherapy (RT) was similar: 22 (69%) patients with dysphagia grade ≤2, 10 (31%) with grade ≥3. There was no dose-dependent difference in the severity of dysphagia in the acute phase (p = 0.989). There were differences 18 months after the end of RT: ≥55 Gy: 19 (86%) patients showed dysphagia grade ≤2; 3 (14%) grade ≥3. At <55 Gy, 31 (97%) patients developed grade ≤2, 1 (3%) grade ≥3 (18 months: p = 0.001; 24 months: p = 0.000). Late dysphagia is also dependent on the dose level of the middle constrictor muscle (6 months: p = 0.000; 12 months: p = 0.005, 18 months: p = 0.034). After 24 months, there was no significant difference (p = 0.374). CONCLUSION: Radiation dose to the upper constrictor muscle appears to be of little relevance. The middle and lower constrictor should be given special consideration to avoid late dysphagia. Long-term QoL is independent on radiation dose.

Socioeconomic status and quality of life in patients with locally advanced head and neck cancer.

PURPOSE: Socioeconomic aspects play an important role in health care. Patients with locally advanced head and neck cancer (LAHNC) experience detrimental effects on their quality of life (QoL). This prospective study examines QoL differences between patients with different socioeconomic status (SES) after intensity-modulated radiation therapy (IMRT). PATIENTS AND METHODS: In all, 161 patients were questioned at the end of IMRT and at 12 and 24 months follow-up using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-30 and QLQ-HN35. Patients' QoL 2 years after IMRT was compared to a population reference sample and QoL of patients from lower, middle, and higher social class 2 years after IMRT was analyzed by ANCOVA using baseline QoL (end of radiation treatment) as a covariate. RESULTS: Patients with high SES report worse QoL at the end of IMRT in the domains global health status (-15.2; p = 0.005), role function (-23.8; p = 0.002), and social function (-19.4; p = 0.023) compared to patients with middle and low SES. QoL improved during the first 12 and 24 months. However, 2 years after IMRT, middle and low SES patients report lower QoL in the domains global health status, physical function, and role function, and report a higher general (fatigue, pain, dyspnea) and head and neck cancer-specific symptom burden (pain, swallowing, senses, speech, social eating, opening mouth, and felt ill) than patients with high SES. CONCLUSION: After IMRT for LAHNC, patients with high SES report worse QoL compared to patients with middle or low SES. There is a marked improvement within the first 24 months in many domains. However, the magnitude of improvement in patients with middle or low SES is significantly smaller compared to patients with high SES.

Detrimental social interactions predict loss of dignity among patients with cancer.

PURPOSE: This prospective study aimed to determine the extent to which cancer patients experience loss of dignity during primary cancer care (baseline) and at 3-month follow-up and the contribution of positive social support and detrimental social interactions on loss of dignity at follow-up. METHODS: At baseline, we enrolled N = 270 cancer patients (advanced cancer 57 %) undergoing oncological treatment. At follow-up, n = 178 patients (72 %) participated. Patients completed the following questionnaires: sense of dignity item (SDI), physical problem list of the NCCN Distress Thermometer, Illness-Specific Social Support Scale (SSUK), Patient Health Questionnaire (PHQ-9), and Generalized Anxiety Disorder Questionnaire (GAD-7). We conducted ordinal regression analyses controlling for age, gender, tumor stage, number of physical symptoms, depression, and anxiety. RESULTS: At baseline, 18 % of the patients experienced moderate to extreme loss of dignity (follow-up 23 %, p = 0.27). Detrimental interactions significantly predicted loss of dignity (OR = 1.42, 95 % CI 1.06-1.90) in a model including positive support (OR = 1.10, 95 % CI 0.82-1.49), depression (OR = 1.55, 95 % CI 0.96-2.51), and anxiety (OR = 1.20, 95 % CI 0.83-1.74). Items in relation to detrimental interactions with significant others such as "made you feel like you couldn't take care of yourself" (r = 0.29, p < 0.001) and "felt uncomfortable in illness conversations" (r = 0.24, p = 0.002) showed the highest associations with perceived loss of dignity. CONCLUSION: Loss of dignity was a frequent problem in our mixed cancer patient sample. Detrimental interactions that weaken the sense of dignity may result from discrepancies with patients' needs for autonomy and security. Tailoring social support to attachment-related patient needs may help to conserve patients' sense of dignity.

Exploring spiritual needs and their associated factors in an urban sample of early and advanced cancer patients.

Although it is widely recognised that people turn to spirituality in times of crises, the interest in exploring the spiritual needs of cancer patients is just beginning to grow. The purpose of this study was to conduct a spiritual needs assessment with cancer patients living in a Northern European metropolitan region in order to (a) examine the relevance and nature of spiritual needs; (b) to clarify the role of demographic and clinical characteristics in spiritual needs; and (c) to identify their associations with dimensions of psychological distress. N = 285 outpatients with mixed cancer sites and of all tumour stages were surveyed cross-sectionally. Instruments included the Spiritual Needs Questionnaire (SpNQ) and measures of anxiety, distress, hopelessness and meaning-related life attitudes. Almost all patients (94%) reported at least one spiritual need. The needs for Inner Peace and Actively Giving emerged to be of greatest importance. Significant, but weak differences were found for age, gender and being in a partnership. No associations for medical characteristics were observed. Regression analyses revealed anxiety as the strongest predictor for the subscales Existential Needs, Inner Peace and Actively Giving. The results emphasise the relevance of spiritual needs in cancer patients. The call for spiritual assessment and interventions to meet spiritual needs in cancer patients is strengthened.

[Establishing an Ambulatory Health-Care Centre (AHCC) at a University Hospital]. / Gründung eines Medizinischen Versorgungszentrums (MVZ) an einem Universitätsklinikum.

BACKGROUND: Since January 2004 hospitals have the opportunity to establish an ambulatory health-care centre (Medizinisches Versorgungszentrum - MVZ) as a result of the introduction of the Health-care Modernisation Act (Gesetz zur Modernisierung der gesetzlichen Krankenversicherung - GMG). After about a half-year preparatory phase, the UKE, in September 2004, began operation of the "Ambulanzzentrum des UKE GmbH" (a limited liability company) as the first MVZ at a university hospital in Germany. We report here on the establishment of the MVZ and the experience made. MATERIALS AND METHODS: In the initial phase, only the medical fields of radiation therapy and nuclear medicine were represented. Both disciplines, especially radiation therapy, were existentially threatened by the extensive loss of ambulatory patients. The central motive for the establishment of the ambulatory health-care centre was to secure the survival of both disciplines and to preserve existing jobs. After it was put into operation, the referrals from practice-based colleagues to both radiation therapy and nuclear medicine increased quickly. The positive developments caused other departments of the UKE to express their interest in supplementing their outpatient activities with facilities in the MVZ. RESULTS: Over the following years, the ambulance centre grew steadily. Now 24 departments are represented in the MVZ, and the centre has a total of 49 positions for physicians contracted by and registered within the German public health insurance system. The number of salaried doctors has risen to 85, although many of these only work part time in the MVZ. Also more than 83 non-medical staff members were hired over the years. These were mostly physiotherapists, radiographers, and medical assistants. With the growing number of departments in the MVZ, the number of treated cases grew steadily. Currently approximately 20 000 cases are treated in each quarter of a year. CONCLUSIONS: The experience made while establishing an ambulatory health-care centre is very positive. Better cross-sectoral medicine, support of referring practice-based colleagues, content of centre-physicians and a strengthening of research and teaching summarise the experience of the last 7 years accurately. The outpatient centre of UKE GmbH will strive to continue to expand its range of medical services into other medical fields whenever it makes sense.

[Psychosocial predictors of utilization of medical rehabilitation services among prostate cancer patients]. / Psychosoziale Einflussfaktoren für die Inanspruchnahme medizinischer Rehabilitationsmaßnahmen bei Patienten mit einer Prostatakrebserkrankung.

PURPOSE: Prostate cancer patients often suffer from treatment-associated morbidities which lead to severe physical and mental impairments. Nevertheless, only a relatively small percentage of this patient population uses medical rehabilitation services; there is still a lack of evidence concerning possible factors causing use and non-use of services. Therefore, this study exploratively aims at the identification of predictors of the use of rehabilitation services in a cohort of prostate cancer patients. METHOD: In a prospective multicentre study to evaluate outpatient oncological rehabilitation services, n=242 prostate cancer patients who used outpatient or inpatient rehabilitation services ("users") were compared with n=253 prostate cancer patients who did not use rehabilitation ("non-users") at measure point 1. At the beginning of the rehabilitation programme and at the end of primary treatment, respectively, patients completed a self-report questionnaire consisting of standardized instruments designed to assess the following independent variables: autonomy striving (TPF), self-efficacy expectancy (GSE), distress (distress thermometer), anxiety and depression (HADS-D), quality of life (SF-8), social support (SSUK), rehabilitation motivation: readiness to change, knowledge, scepticism regarding rehabilitation services (PAREMO-20). Illness- and treatment-related variables (tumour state, comorbidity, primary therapies) were documented by the attending oncologists. RESULTS: Only few significant and effective differences between rehabilitation users and non-users are observed: Non-users are suffering more often from gastrointestinal comorbidities (18% vs. 2%, w=0.25). Both patient groups report severe quality-of-life impairments, particularly with respect to their physical functioning. Non-users achieve significantly higher scores on the scale "scepticism" (PAREMO-20) than users (eta²=0.19). The scale "scepticism" is also identified as the dominant predictor of utilization of rehabilitation services (R²=0.23). Suffering from comorbid diseases of the digestive system, self-efficacy expectation and employment status emerge as further significant predictors (R²=0.12, and R²=0.02 each). With increasing scepticism and in case of comorbidity the probability of rehabilitation utilization was decreasing. CONCLUSION: Besides illness-related variables prostate cancer patients' expectancies regarding the effectiveness of rehabilitation services to alleviate their medical conditions seem to be more relevant for rehabilitation utilization than sociodemographic variables or psychosocial distress. Further studies should investigate the replicability of these results and should focus on the doctor-patient-communication and the amount of information about goals and concepts of rehabilitation services prostate cancer patients are told. For clinical practice of information-giving about rehabilitation services it can be recommended not only to assess patients' physical and mental conditions but also to explore their expectations and concerns about rehabilitative treatment options in order to remove any doubts and to be able to optimize oncological care.

Factors influencing taper failure of modular revision hip stems.

Stem modularity of revision hip implant systems offers the advantage of the restoration of individual patient geometry but introduces additional interfaces, which are subjected to repetitive bending loading and have a propensity for fretting corrosion. The male stem taper is the weakest part of the modular junction due to its reduced cross section compared to the outside diameter of the stem. Taper fractures can be the consequence of overloading in combination with corrosion. The purpose of this study was to assess the influence of implant design factors, patient factors, and surgical factors on the risk of taper failure of the modular junction of revision stems. An analytical bending model was used to estimate the strength of the taper connection for pristine, fatigued and corroded conditions. Additionally, a finite element contact model of the taper connection was developed to assess the relative motion and potential for surface damage at the taper interface under physiological loading for varyied assembly and design parameters. Increasing the male taper diameter was shown to be the most effective means for increasing taper strength but would require a concurrent increase in the outer implant diameter to limit a greater risk of total surface damage for a thinner female taper wall. Increasing the assembly force decreases the total surface damage but not local magnitudes, which are probably responsible for crack initiation. It is suggested that in unfavourable loading conditions a monobloc implant system will reduce the risk of failure.

Maximizing the fixation strength of modular components by impaction without tissue damage.

OBJECTIVES: Taper junctions between modular hip arthroplasty femoral heads and stems fail by wear or corrosion which can be caused by relative motion at their interface. Increasing the assembly force can reduce relative motion and corrosion but may also damage surrounding tissues. The purpose of this study was to determine the effects of increasing the impaction energy and the stiffness of the impactor tool on the stability of the taper junction and on the forces transmitted through the patient's surrounding tissues. METHODS: A commercially available impaction tool was modified to assemble components in the laboratory using impactor tips with varying stiffness at different applied energy levels. Springs were mounted below the modular components to represent the patient. The pull-off force of the head from the stem was measured to assess stability, and the displacement of the springs was measured to assess the force transmitted to the patient's tissues. RESULTS: The pull-off force of the head increased as the stiffness of the impactor tip increased but without increasing the force transmitted through the springs (patient). Increasing the impaction energy increased the pull-off force but also increased the force transmitted through the springs. CONCLUSIONS: To limit wear and corrosion, manufacturers should maximize the stiffness of the impactor tool but without damaging the surface of the head. This strategy will maximize the stability of the head on the stem for a given applied energy, without influencing the force transmitted through the patient's tissues. Current impactor designs already appear to approach this limit. Increasing the applied energy (which is dependent on the mass of the hammer and square of the contact speed) increases the stability of the modular connection but proportionally increases the force transmitted through the patient's tissues, as well as to the surface of the head, and should be restricted to safe levels.Cite this article: A. Krull, M. M. Morlock, N. E. Bishop. Maximizing the fixation strength of modular components by impaction without tissue damage. Bone Joint Res 2018;7:196-204. DOI: 10.1302/2046-3758.72.BJR-2017-0078.R2.

Changes in the prevalence of Salmonella serovars associated swine production and correlations of avian, bovine and swine-associated serovars with human-associated serovars in the United States (1997-2015).

As Salmonella enterica is an important pathogen of food animals, surveillance programmes for S. enterica serovars have existed for many years in the United States. Surveillance programmes serve many purposes, one of which is to evaluate alterations in the prevalence of serovars that may signal changes in the ecology of the target organism. The primary aim of this study was to evaluate changes in the proportion of S. enterica serovars isolated from swine over a near 20-year observation period (1997-2015) using four longitudinal data sets from different food animal species. The secondary aim was to evaluate correlations between changes in S. enterica serovars frequently recovered from food animals and changes in S. enterica serovars associated with disease in humans. We found decreasing proportions of S. enterica serovar Typhimurium, serovar Derby and serovar Heidelberg and increasing proportions of S. enterica serovar 4,[5],12:i:-, serovar Infantis and serovar Johannesburg in swine over time. We also found positive correlations for the yearly changes in S. enterica serovar 4,[5],12:i:-, serovar Anatum and serovar Johannesburg between swine and human data; in S. enterica Worthington between avian and human data; and in S. enterica serovar 4,[5],12:i:- between bovine and human data. We found negative correlations for the yearly changes in S. enterica serovar 4,[5],12:i:- and serovar Johannesburg between avian and human data.

Detection of atypical porcine pestivirus in semen from commercial boar studs in the United States.

Atypical porcine pestivirus (APPV) has recently been identified as a cause of congenital tremor (CT) in pigs and has been detected in semen and preputial swabs from boars that were known to be clinically affected with CT. Accordingly, the objectives of this study were to 1) detect the presence of APPV in semen, preputial fluids and preputial swabs from adult boars by quantitative reverse transcription PCR (qRT-PCR) and 2) genetically characterize a subset of positive samples to better understand the ecology of APPV in commercial boar studs and the potential risk of transmission of APPV via semen. A total of 597 samples of semen, preputial fluid and preputial swabs each representing a different boar were obtained from four commercial boar studs located in three different states in the United States. Viral RNA was detected by qRT-PCR in 90 samples (15.08%; 90/597), with the greatest per cent positive from preputial swabs (23.81%; 5/21) followed by preputial fluid (22.81%; 26/114) and semen (12.91%; 59/457). The mean cycle quantification (Cq) between sample types was similar while eleven semen samples had Cq values lower than 27.0 corresponding to approximately 2 × 106  copies/ml. Based on phylogenetic analysis of the Npro gene, different viral strains can be on the same farm at the same and different times. This is the first report of detection of APPV in semen from commercial boar studs. Studies investigating the role of semen in the transmission of APPV and production of CT are needed.

Monitoring of small laboratory animal experiments by a designated web-based database.

Multiple-parametric small animal experiments require, by their very nature, a sufficient number of animals which may need to be large to obtain statistically significant results.(1) For this reason database-related systems are required to collect the experimental data as well as to support the later (re-) analysis of the information gained during the experiments. In particular, the monitoring of animal welfare is simplified by the inclusion of warning signals (for instance, loss in body weight >20%). Digital patient charts have been developed for human patients but are usually not able to fulfill the specific needs of animal experimentation. To address this problem a unique web-based monitoring system using standard MySQL, PHP, and nginx has been created. PHP was used to create the HTML-based user interface and outputs in a variety of proprietary file formats, namely portable document format (PDF) or spreadsheet files. This article demonstrates its fundamental features and the easy and secure access it offers to the data from any place using a web browser. This information will help other researchers create their own individual databases in a similar way. The use of QR-codes plays an important role for stress-free use of the database. We demonstrate a way to easily identify all animals and samples and data collected during the experiments. Specific ways to record animal irradiations and chemotherapy applications are shown. This new analysis tool allows the effective and detailed analysis of huge amounts of data collected through small animal experiments. It supports proper statistical evaluation of the data and provides excellent retrievable data storage.

Clinical and neuropsychological characteristics of patients with late-onset schizophrenia.

OBJECTIVE: The goal was to compare clinical and neuropsychological characteristics of patients with late-onset schizophrenia, a poorly studied and controversial entity, with those of patients with early-onset schizophrenia and normal subjects. METHOD: The authors evaluated 25 patients who met DSM-III-R criteria as well as their own research criteria for late-onset schizophrenia (i.e., schizophrenia with onset after age 45) and compared them with 39 patients with early-onset schizophrenia and 35 normal subjects in this nonepidemiologic study. RESULTS: Patients with late-onset schizophrenia were similar to patients with early-onset schizophrenia and different from normal subjects on most clinical and neuropsychological variables assessed, such as psychopathology, family history, childhood social adjustment, and overall pattern of neuropsychological impairment. Compared with the early-onset group, the group with late-onset schizophrenia had a higher percentage of patients who were ever married, a better work history, and a greater frequency of paranoid subtype. CONCLUSIONS: These results support the diagnostic validity of schizophrenia with onset after the age of 45 years.

Combination of fractionated irradiation with nicotinamide and carbogen in R1H-tumours of the rat and its pulmonary metastases.

BACKGROUND AND PURPOSE: The combination of radiotherapy with nicotinamide and carbogen is a promising method to improve treatment outcome. The aim of the present study was to investigate its effect on rat lungs, the R1H-tumour and its pulmonary metastases. MATERIALS AND METHODS: Subcutaneous tumours and artificially induced pulmonary metastases of the rhabdomyosarcoma R1H of the rat were treated either with fractionated irradiation alone or in combination with nicotinamide and carbogen. Local metastatic control, net growth delay and lethal lung damage were used as endpoints. RESULTS: Radiosensitivity of the lungs of WAG/Rij rats increased by a factor of 1.13, while no positive effect of the combined treatment either on subcutaneous R1H-tumours or on pulmonary metastases could be detected. This resulted in a therapeutic loss of 18% (P = 0.003). CONCLUSION: The results indicate that deleterious effects of the combination of radiotherapy with nicotinamide and carbogen cannot be excluded under all circumstances.

Influence of dose per fraction and overall treatment time on the response of pulmonary micrometastases of the R1H-tumour to fractionated irradiation.

BACKGROUND AND PURPOSE: Macroscopic subcutaneously growing R1H-tumours have been shown to respond almost independently of the dose per fraction when treated under ambient conditions. In addition decelerated repopulation during fractionated irradiation has been shown for this experimental tumour. The aim of the present study was to investigate whether this is also the case for pulmonary micrometastases which are assumed to be fully oxygenated or whether differences in the oxygenation status of the tumour possibly alters its response to fractionation. The influence of the dose per fraction and overall treatment time on the response of micrometastases to fractionated irradiation was studied. MATERIALS AND METHODS: Pulmonary metastases were induced by i.v. injection of viable tumour cells. Treatment was started 14 days later, when metastases reached an average size of four cells. Total doses of 16 to 28 Gy were administered within an overall treatment time of 11 or 25 days, using doses per fraction of 1, 2, or 4 Gy. Tumour response was quantified by metastatic control (MCD(37%)). RESULTS: Fractionation had a significant influence on local control (P=0.009). After application of 1, 2, or 4 Gy and an overall treatment time of 11 days the MCD(37%) was 25.4 (95% C.I.: 21.5-32.0) Gy, 20.7 (17. 0-24.0) Gy, and 18.5 (14.9-21.6) Gy, respectively. When overall treatment time was prolonged to 25 days the MCD(37%) increased to 25. 5 (21.3-33.5) Gy when fractions of 2 Gy where applied, but this difference was not significant (P=0.13). The doubling time of 12.8 days determined for the metastatic clonogenic tumour cells during fractionated irradiation was significantly longer than the 4.1 days observed for untreated metastases (P=0.006). CONCLUSIONS: The results show a strong influence of fractionation on treatment outcome and a decelerated repopulation during fractionated irradiation treatment for well oxygenated pulmonary metastases of the R1H-tumour.

Comparison of total body irradiation vs busulfan in combination with cyclophosphamide as conditioning for unrelated stem cell transplantation in CML patients.

We compared fractionated total body irradiation (12 Gy)/cyclophosphamide (120 mg/kg) with busulfan (16 mg/kg)/cyclophosphamide (120 mg/kg) as preparative therapy in unrelated donor stem cell transplantation of CML patients. Fifty patients with CML (1.CP = 46; aP = 4) and a median age of 36 years (range 16-52) were enrolled in this sequential trial between 1994 and 1999. In both groups patients were well balanced with respect to age, disease status, stem cell source and CMV status. All patients received standard doses of cyclosporin A, methotrexate and anti-thymocyte globulin (ATG) as GVHD prophylaxis. No graft failures occurred in either group. The median day of leukocyte engraftment was earlier in the Bu/Cy than in the TBI/Cy group (day 15 vs 17; P = 0.006). The incidence of grade II-IV GVHD was 40% in the TBI/Cy and 36% in the Bu/Cy group, whereas severe grade III/IV GVHD was only observed in 12% of patients in both groups. The incidence of chronic GVHD (limited and extensive) at 1 year was higher in the Bu/Cy arm (65% vs 30%; P = 0.02). More toxicity grade I/II of the liver (88% vs 44%; P = 0.002) and more hemorrhagic cystitis (32% vs 8%; P = 0.02) were observed in the Bu/Cy regimen. Seven relapses in the TBI and no relapse in the Bu/Cy group were observed after a median follow-up of 44 and 15 months, respectively. The estimated 3 year OS and DFS was 72% (95% CI: 55-98%) and 58% (95% CI: 39-77%) in the TBI and 70% (95% CI: 51-89%) for DFS and OS in the Bu/Cy group. We conclude that the anti-leukemic effect of the Bu/Cy regimen seems to be at least as effective as the TBI/Cy combination in unrelated stem cell transplantation of CML patients, with no graft failures, but that it correlates with a higher incidence of liver toxicity, hemorrhagic cystitis and chronic GVHD. Longer follow-up is necessary to determine the late relapse rate and late toxicity.

Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy.

In advanced stage mantle cell lymphoma, conventional chemotherapy yields a complete remission rate below 40%, and the median survival rate is only about 3 years. Between 1991 and 1996 we treated nine such patients (six male; three female) with high-dose chemotherapy (six of these also with 12 Gy fractionated total body irradiation (TBI)) and peripheral stem cell support (n = 8) or allogeneic bone marrow transplantation (n = 1). The median age was 47 years (range, 28-61). At the time of high-dose chemotherapy, five patients were in first complete remission (CR), two in first partial remission (PR) and two in second remission (CR = 1; PR = 1). High-dose chemotherapy included TBI (12 Gy), etoposide and cyclophosphamide (patients 1-5), TBI and cyclophosphamide (patient 7), busulfan, etoposide and cyclophosphamide (patients 6 and 9), cyclophosphamide and busulfan (patient 8). The patterns of toxicity according to the Bearman score were usually mild (mucositis grade 2, n = 7; renal grade I, n = 2) with no therapy-related fatality. Only one patient developed hepatic toxicity grade III (veno-occlusive disease) but recovered completely. The median time to neutrophil engraftment was 10 days (range, 8-15). After high-dose chemotherapy all patients achieved complete remission. After a median follow-up of 22 months (range, 9.4-64) all patients remain in continuous complete remission. These encouraging results suggest that high-dose chemotherapy can be applied safely and leads to long-term disease-free survival in otherwise incurable disease.

European results of neutron therapy in soft tissue sarcomas.

The purpose of this publication is to review the data of European neutron therapy facilities in the treatment of soft tissue sarcoma. In the past locally advanced soft tissue sarcoma was a common indication for neutron therapy in several European centers. Data from 1171 patients treated at 11 centers were analysed on the basis of published data or personal communication. Neutron therapy was of benefit especially for patients with primary radiotherapy of inoperable tumors, and with macroscopic disease after surgery. Local control was about 50% in these patients. These results are superior to those from photon therapy from the literature. Results for postoperative neutron therapy after R0- and R1-resection are similar to those from photon therapy. The incidence of late side effects was considerably high in some neutron series. This is influenced by the treatment of most patients with first-generation machines of limited technical standard, and that in most cases large treatment volumes were irradiated.

Neutron therapy in malignant salivary gland tumors: results at European centers.

Malignant salivary gland tumors are relatively rare and account for only 3%-4% of all head and neck cancers. Especially in adenoid cystic carcinoma, the incidence of local recurrence and distant metastases is influenced by the perineural spread of tumor. In advanced salivary gland tumors, surgery alone has a high incidence of local failure. The results of conventional radiotherapy are suboptimal in inoperable or not completely resected salivary gland tumors and in recurrent disease. The pooled data of some international series for low linear energy transfer radiation show a local control of only 28%. Especially in advanced salivary gland tumors, neutron therapy can improve local control. In Europe at least 570 patients with salivary gland tumors have been treated with neutrons alone or with combined modalities. The clinical data of different centers in Europe and the United States result in a similar local control rate of 67% in gross disease. An analysis of different European series shows on average a complication rate of 10.6% for severe radiation-related morbidity. Modern neutron machines and the use of three-dimensional treatment planning systems are now available in a few institutions and may further reduce side effects.

Use of neutron therapy in the management of locally advanced nonresectable primary or recurrent rectal cancer.

Inoperable locally advanced or inoperable recurrent rectal cancer is a difficult problem. Tenesmus, discharge, bleeding and pelvic pain are frequently present and often are associated with infiltration of the sacral plexus. The value of radiotherapy in managing such patients is being appreciated, although up to 40% of the treated patients have no symptomatic response. Improvement in tumor response and control has been scored through efforts to overcome the radio resistance of the hypoxic tumor cells by neutron irradiation. This article is an account of the activity of neutron radiotherapy in such patients. Over 350 patients were entered in studies comparing neutrons used alone and neutrons used in a mixed-beam treatment schedule. At present no therapeutic gain for long-lasting survival has been achieved; however, local control and pain improvement seems to be better with neutrons than with photons.