Treatment of agitation in terminally ill patients with intranasal midazolam versus subcutaneous midazolam: study protocol for a randomised controlled open-label monocentric trial (MinTU Study).

BACKGROUND: Intranasal (i.n.) drug application is a widely known and low-invasive route of administration that may be able to achieve rapid symptom control in terminally ill patients. According to the German S3 guideline "Palliative care for patients with incurable cancer", benzodiazepines, such as midazolam, are recommended for the treatment of terminal agitation. To the best of our knowledge there is no evidence for i.n. midazolam in terminally ill patients. We aim to assess the use of i.n. midazolam as an alternative to subcutaneous administration of the drug. METHODS: In this monocentric, randomised, controlled, open-label investigator initiated trial, n = 60 patients treated at the palliative care unit of a University Hospital will be treated with 5 mg midazolam i.n. versus 5 mg subcutaneous (s.c.) midazolam in the control arm when terminal agitation occurs (randomly assigned 1:1). The estimated recruitment period is 18 months. Treatment efficacy is defined as an improvement on the Richmond Agitation Sedation Scale (Palliative Version) (RASS-PAL) and a study specific numeric rating scale (NRS) before and after drug administration. Furthermore, plasma concentration determinations of midazolam will be conducted at t1 = 0 min, t2 = 5 min, and t3 = 20 min using liquid chromatography/mass spectrometry (LC-MS). The primary objective is to demonstrate non-inferiority of midazolam i.n. in comparison to midazolam s.c. for the treatment of agitation in terminally ill patients. DISCUSSION: Midazolam i.n. is expected to achieve at least equivalent reduction of terminal agitation compared to s.c. administration. In addition, plasma concentrations of midazolam i.n. are not expected to be lower than those of midazolam s.c. and the dynamics of the plasma concentration with an earlier increase could be beneficial. TRIAL REGISTRATION: German Clinical Trials Registry DRKS00026775, registered 07.07.2022, Eudra CT No.: 2021-004789-36.

Feasibility, use and benefits of patient-reported outcome measures in palliative care units: a multicentre observational study.

BACKGROUND: Research has shown that routinely assessed, patient-reported outcome measures (PROMs) have positive effects in patients with advanced oncologic diseases. However, the transferability of these results to specialist palliative care is uncertain because patients are more impaired and staff doubt the feasibility and benefits. The aim of this study is to evaluate the feasibility of patient self-assessment of PROMs, their use by staff and the benefits in palliative care wards. METHOD: A multicentre observational study was conducted in the context of the implementation of the Integrated Patient Outcome Scale (IPOS) in three specialist palliative care wards at university hospitals in Germany. All admitted patients who screened positive regarding their ability to complete questionnaires were asked to participate and complete the IPOS on paper weekly, with assistance if necessary. Feasibility of questionnaire completion (e.g. proportion of patients able to complete them), use (e.g. involvement of different professional groups) and benefit (e.g. unexpected information in IPOS as rated by treating physicians) were assessed. Staff members' opinion was obtained in a written, anonymous evaluation survey, patients' opinion in a short written evaluation. RESULTS: A total of 557 patients were screened for eligibility, 235 were assessed as able to complete the IPOS (42.2%) and 137 participated in the study (24.6%). A majority needed support in completing the IPOS; 40 staff members and 73 patients completed the evaluation. Unexpected information was marked by physicians in 95 of the 137 patient questionnaires (69.3%). The staff differed in their opinions on the question of whether this also improved treatment. A majority of 32 staff members (80.0%) were in favour of continuing the use of IPOS (4 against continuation, 4 no answer); 43 (58.9%) patients rated their overall experience of IPOS use as 'positive', 29 (39.7%) as 'neutral' and 1 (1.4%) as 'negative'. CONCLUSIONS: While most staff wished to continue using IPOS, it was a challenge to integrate the effort to support the completion of IPOS into daily practice. Digital implementation was not successful, despite various attempts. To explore the effects on care and patient outcomes, multicentre cluster-randomised trials could be employed. TRIAL REGISTRATION: German Clinical Trials Register DRKS-ID: DRKS00016681 (24/04/2019).

[The potential of complementary music interventions in patients with head and neck cancer]. / Das Potenzial komplementärer Musikinterventionen bei Patienten mit malignen Kopf-Hals-Tumoren.

PURPOSE: The established treatment regimen for patients suffering from cancer in the head and neck region often leads to physical and mental health problems and therefore can significantly reduce the quality of life (QoL) in these patients. The available data indicate that additional complementary treatments, such as music interventions, may improve patients' QoL and compliance and reduce symptoms during therapy. METHODS: Anonymous data collection using a self-designed questionnaire was conducted in patients suffering from cancer in the head and neck area in our outpatient department. The questionnaire particularly asked the patients about their need and interest in music interventions during therapy. RESULTS: In total, 138 patients were consecutively enrolled in the study. The mean age was 64.9 years, including 68.1% men and 31.9% women. Only 11.5% listened to music regularly during their therapy at the time of data collection, yet 52.2% stated that they would be interested in music interventions. Patients especially conceived the relaxing and encouraging effects from listening to music. Most patients would prefer group therapies (56%) or listening to their own music (36.6%). CONCLUSION: Our data suggest that there is a need for music interventions in patients suffering from cancer in the head and neck, as they anticipate they would experience positive effects, including reduced somatic and non-somatic symptoms and improved QoL. The lack of homogenous data emphasizes the need for further trials in the field of complementary music interventions to establish science-based concepts in the future.

The views of physicians and nurses on the potentials of an electronic assessment system for recognizing the needs of patients in palliative care.

OBJECTIVES: Patients in oncological and palliative care (PC) often have complex needs, which require a comprehensive treatment approach. The assessment of patient-reported outcomes (PROs) has been shown to improve identification of patient needs and foster adjustment of treatment. This study explores occupational routines, attitudes and expectations of physicians and nurses with regards to a planned electronic assessment system of PROs. METHODS: Ten physicians and nine nurses from various PC settings in Southern Germany were interviewed. The interviews were analysed with qualitative content analysis. RESULTS: The interviewees were sceptical about the quality of data generated through a patient self-assessment system. They criticised the rigidity of the electronic assessment questionnaire, which the interviewees noted may not fit the profile of all palliative patients. They feared the loss of personal contact between medical staff and patients and favoured in-person conversation and on-site observations on site over the potential system. Interviewees saw potential in being able to discover unseen needs from some patients. Interviewees evaluated the system positively in the case that the system served to broadly orient care plans without affecting or reducing the patient-caregiver relationship. CONCLUSIONS: A significant portion of the results touch upon the symbolic acceptance of the suggested system, which stands for an increasing standardisation and technisation of medicine where interpersonal contact and the professional expertise are marginalized. The study results can provide insight for processes and communication in the run-up to and during the implementation of electronic assessment systems.

[Quality of life and Potential Incriminating Factors Among Palliative Care Givers: A German Survey of the KOMPACT Working Group]. / Belastungen im Berufsalltag von Palliativpflegekräften ­ eine Befragung in Kooperation mit dem KompetenzZentrum Palliative Care Baden-Württemberg (KOMPACT).

AIM OF THE STUDY: Due to the aging population in Germany, the need for palliative care institutions will increase. Considering the lack of resources, work stress of palliative care nurses could increase significantly. It was the aim of this study to identify risk factors for job overload and work stress of palliative care nurses in the inpatient and outpatient setting. METHODS: In cooperation with the KOMPACT Working Group, we conducted an anonymous survey of palliative care givers in Baden-Württemberg, Germany. We used a paper questionnaire to inquire about job stress and workload, self-assessment of health condition and aspects about mental and emotional well-being. 167 palliative care nurses from 34 different institutions participated in the survey. RESULTS: The results showed a significant difference between inpatient and outpatient palliative care workers regarding the type and intensity of work stress. The overall stress level was significantly higher for the nurses in inpatient palliative care units (p<0.001). A high weekly working time combined with missing work experience in the field of palliative care led to a poorer compatibility of job and family. Higher stress levels resulted in a lower satisfaction with the work. Dissatisfaction with the working conditions was associated with a worse health status defined by self-assessment. Mental and emotional condition of palliative care nurses was significantly worse in comparison with the norm sample, many nurses showed "strikingly" or even "seriously" high values. The survey also showed that the structural conditions in inpatient palliative care units were not optimal. CONCLUSION: Compared to outpatient palliative care services, working conditions seem to be worse in inpatient palliative care setting, which could result in higher stress for the nurses. Interventions to reduce work-related stress appear not to be well implemented in the daily work of palliative care nurses. Standards for care as well as advanced training programs for palliative care nurses should be reevaluated.

Analysis of Burnout Prevalence among German Physicians Working in a Palliative Care Setting: A Survey of the AIO Quality of Life Working Group.

INTRODUCTION: Palliative care physicians (Pcps) face special challenges caring for terminally ill patients. We conducted this study to evaluate the burnout (bo) prevalence among pcps and sought to identify risk as well as protective factors as a basis for the development of preventive measures. METHODS: Participants (Pcs) were invited via e-mail to complete an online survey between May and June 2022. Besides the Oldenburg Burnout Inventory assessing the bo dimensions of exhaustion (exh) and disengagement (dis), sociodemographic data were collected. RESULTS: The study found that 58% (cut-off mean value [M] ≥2.18) or more specifically, 38% (cut-off M ≥2.5) of the pcs showed increased scores in the exh subscale as a key dimension of bo. All dimensions were correlated with the level of medical and palliative care training, with higher scores for physicians in training. Furthermore, pcs without preventive measures like employee appraisals at work were more likely to be considered exhausted, disengaged, or burned out. The discrepancy between high exh and low dis scores shows that the polled pcps, despite feeling exh, nevertheless considered their work meaningful. CONCLUSION: Bo prevalence among pcps exceeds that of the general population and other specialties, whereas inexperienced pcps might be at high risk of shifting from exh to bo and could therefore benefit from tailored support. Further preventive measures including individual and organizational aspects are necessary to prevent bo and promote health among medical staff, thereby preserving quality of patient care. Elementary preventive measures such as employee appraisals can have a protective effect against bo.

Quality of life and symptom evaluation in daily oncology practice: a survey of 150 patients with advanced gastrointestinal tumours receiving palliative chemotherapy.

BACKGROUND: Quality of life (QoL) is frequently investigated as a secondary endpoint in clinical trials but is rarely evaluated in clinical practice. The present survey sought to assess the QoL of patients with advanced gastrointestinal tumours receiving palliative chemotherapy. Furthermore, we wanted to compare the results of subscales of the generic EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, version 3.0) using assessment tools with an emphasis on pain and depression. PATIENTS AND METHODS: 150 patients with gastrointestinal tumours undergoing palliative chemotherapy completed 3 questionnaires. QoL was assessed using the EORTC QLQ-C30, Beck depression inventory (BDI) was utilised to measure the severity of patients' depression and a visual analogue scale (VAS) was applied to measure patient's pain intensity. Correlations between these assessments were calculated. RESULTS: The survey revealed that treatment of pain and depression appeared to be inadequate in the present cohort of patients with metastatic gastrointestinal cancer. Good correlations between EORTC QLQ-C30 subscales and the VAS (r = 0.86), as well as the BDI (r = 0.63) were found. CONCLUSION: The present analysis indicates the need for better symptom control regarding the examples 'pain' and 'depression'. In view of the good correlation between the EORTC QLQ-C30 and the BDI and VAS, further studies on the implementation of the EORTC QLQ-C30 as a screening tool, or for follow-up measurements in daily practice are warranted.

Characteristics, treatment and prognostic factors of patients with gynaecological malignancies treated in a palliative care unit at a university hospital.

BACKGROUND: Limited clinical data have been published on patients suffering from advanced gynaecological malignancies treated in palliative care units, and little is known about prognostic factors. METHODS: In a retrospective study, the data of 225 patients with breast, ovarian and cervical cancer treated in the palliative care unit of a university hospital between 1998 and 2009 were assembled. Clinical aspects and baseline symptoms, laboratory parameters, the clinical course, and outcome were evaluated. RESULTS: 225 patients (497 cases; cancer diagnoses: breast 79%, ovarian 13%, and cervix 8%) were included in the analysis. The main symptoms were weakness/fatigue (71%), pain (65%), anorexia/nausea (62%), and dyspnea (46%). Pain control was achieved in 85% of all cases, satisfying control of other symptoms in 80%. The median overall survival (OS) was 59 days. 53% of the patients died at the palliative care unit. In the Cox proportional hazards model, 8 parameters indicated an unfavourable outcome: anorexia/nausea, disordered mental status, elevated lactate dehydrogenase, γ-glutamyltransferase, leukocyte count, hypoalbuminaemia, anaemia and hypercalcaemia. Based on these parameters 3 risk groups were defined: low risk (0-2 factors), intermediate risk (3-5 factors), and high risk (6-8 factors). Median survival for high-risk group was 13 days, for intermediate group 61 days, and for low-risk patients 554 days (p < 0.0001). CONCLUSION: Weakness/fatigue, pain and anorexia were the main symptoms leading to the hospitalisation of patients with gynaecological malignancies. Symptom and pain control was accomplished in 80% of cases. 8 parameters were identified as indicating a poor outcome, and patients showing at least 6 or more of these factors had a very limited prognosis. Although studied retrospectively, these results may be helpful for individual treatment decisions in patients with advanced gynaecological malignancies. Prospective data and the introduction of documentation systems could help to gain more powerful knowledge about the quality of palliative care.

Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.

BACKGROUND: Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine. METHODS: This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. FINDINGS: Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). INTERPRETATION: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. FUNDING: Roche Pharma AG (Grenzach-Wyhlen, Germany).

Burnout among German oncologists: a cross-sectional study in cooperation with the Arbeitsgemeinschaft Internistische Onkologie Quality of Life Working Group.

PURPOSE: Oncologists are at an increased risk of developing burnout, leading to negative consequences in patient care and in professional satisfaction and quality of life. This study was designed to investigate exhaustion and disengagement among German oncologists and assess the prevalence of burnout among oncologists within different professional settings. Furthermore, we wanted to examine possible relations between sociodemographic factors, the oncological setting, professional experience and different aspects of burnout. METHODS: In a cross-sectional study design, an Internet-based survey was conducted with 121 oncologists between April and July 2020 using the Oldenburg Burnout Inventory, which contains items on exhaustion, disengagement, and burnout. Furthermore, sociodemographic data of the participants were assessed. The participants were members of the Working Group Medical Oncology (Arbeitsgemeinschaft Internistische Onkologie) within the German Cancer Society. RESULTS: The survey showed a burnout prevalence of 43.8%, which correlated with age and professional experience; that is, the prevalence is particularly high among younger oncologists. Exhaustion is closely related to employment status; that is, it was significantly higher among employed oncologists. There were remarkably low levels of disengagement among oncologists, highlighting the own demand to fulfil job requirements despite imminent or actual overburdening in daily work. CONCLUSION: More support is necessary to mitigate the professional stressors in the healthcare system. To ensure quality medical care, employees should be offered preventive mental health services early in their careers.

Assessment and Evaluation of Psychosocial Distress in Outpatients with Cancer at a University Hospital in Germany.

INTRODUCTION: Cancer patients (pts) suffer from a significant amount of psychosocial distress related to tumor disease itself or straining treatments. Despite recommendations on how to screen for and to deal with psychosocial distress in cancer pts, data about implementation of psycho-oncological interventions (poi) in outpatient settings of cancer pts are scarce. The aim of this study was to identify outpatients with cancer in need of poi and to evaluate different assessment instruments. METHODS: N = 200 outpatients with hemat-/oncological malignancies were interviewed between October 2015 and December 2017 at the University Hospital Mannheim using the Basic Documentation for Psycho-Oncology (PO-Bado) and the Hornheider Screening Instrument (HSI) - both clinician-administered assessment tools - followed by descriptive, univariate, and agreement analysis. RESULTS: N = 61 cancer pts (31%) were identified to be in need for poi considering the results of both questionnaires. The number of identified pts in need of poi was lower when analyzing the results of the PO-Bado (n = 42, 21%) and the HSI (n = 39, 20%) separately. The degree of agreement between the results of PO-Bado and HSI was low (kappa = 0.3655). Several factors like gender, age and diagnosis were identified to have significant impact on the need for poi (p ≤ 0.05). CONCLUSION: Our study underlines that different screening instruments for psychosocial distress may identify disparate populations of cancer pts. The study data also revealed significant characteristics that might be associated with elevated levels of psychosocial distress and a clear indication for poi. However, further analyses on larger populations of cancer pts are needed to provide information how to transfer positive screening to poi in clinical routine.

Analysis of end-of-life treatment and physician perceptions at a university hospital in Germany.

PURPOSE: Providing state-of-the-art palliative care is crucial in all areas of in- and outpatient settings. Studies on the implementation of palliative care standards for dying patients are rare. METHODS: N = 141 physicians from all internal departments were polled anonymously about the treatment of dying patients using a self-designed questionnaire. Furthermore, we evaluated the terminal care of n = 278 patients who died in internal medicine departments at University Hospital Mannheim between January and June, 2019 based on clinical data of the last 48 h of life. We defined mandatory criteria for good palliative practice both regarding treatment according to patients' records and answers in physicians' survey. RESULTS: Fifty-six physicians (40%) reported uncertainties in the treatment of dying patients (p < 0.05). Physicians caring for dying patients regularly stated to use sedatives more frequently and to administer less infusions (p < 0.05, respectively). In multivariate analysis, medical specialization was identified as an independent factor for good palliative practice (p < 0.05). Physicians working with cancer patients regularly were seven times more likely to use good palliative practice (p < 0.05) than physicians who did not. Cancer patients received good palliative practice more often than patients dying from non-malignant diseases (p < 0.05). CONCLUSION: Guideline-based palliative care for dying patients was found to be implemented more likely and consistent within the oncology department. These results point to a potential lack of training of fellows in non-oncological departments in terms of good end-of-life care.

Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy.

BACKGROUND: For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R) and Transketolase-like-1 (TKTL1) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab. METHODS: Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR. RESULTS: Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers. CONCLUSION: High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.

Cancer patients and the Internet: a survey of the 'Quality of Life' Working Groups of the Arbeitsgemeinschaft für Internistische Onkologie and the Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie.

BACKGROUND: Patient-reported outcomes, such as quality of life (QoL) assessment, are becoming more important as endpoint in clinical trials and for decision making regarding new anticancer product approvals. Nevertheless, numerous obstacles exist regarding the implementation of QoL assessment in the daily practice of medical oncologists. Regular, computerized or internet home-based QoL assessments could be a step forward. METHODS: Using a 15-item paper questionnaire, we conducted a survey among 1580 cancer patients regarding their willingness to use internet QoL assessment, and collected personal data and information about current disease and performance status. RESULTS: Younger patients (i.e. ≤65 years) significantly more often had internet access (78% versus 36%; χ(2) test, p < 0.001). Moreover, the availability of internet access correlated with higher education levels. 55% of all polled patients are willing to use an internet-based QoL assessment tool, regardless of the type of internet access, whereas almost two-thirds (n = 600; 65%) of patients with their own internet access would be willing to use it for providing statements about QoL. Of these, especially younger patients in good health status with higher education degrees indicated their willingness to use such tools. CONCLUSION: These data may serve as a basis for identifying patient groups willing to participate in pilot projects to evaluate the implementation of internet-based regular assessment of QoL in cancer.

Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system.

PURPOSE: Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors. METHODS: Detailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed. RESULTS: Objective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold. CONCLUSION: Our case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients.

Presentation, treatment, and analysis of prognostic factors of terminally ill patients with gastrointestinal tumors.

BACKGROUND: Few data have been published about terminally ill patients with gastrointestinal tumors treated in palliative care units. PATIENTS AND METHODS: We analyzed the data of 737 admissions of 435 patients that were treated in a palliative care unit, and tried to identify prognostic factors for survival. RESULTS: Most frequent diagnoses at admission were colorectal, gastric, esophageal, and pancreatic cancer. Major clinical symptoms were pain (66.9%), anorexia (60.8%), weight loss (39.2%), and nausea/vomiting (36.6%). In 71.6% of the patients, morphine derivatives were administered. In 33.0% of cases, red blood cell transfusions were applied, parenteral nutrition was given in 31.3%. Median survival, calculated from the day of first hospitalization, was 35 days. On univariate analysis, several clinical and laboratory parameters were identified as prognostically important factors. In the multivariate Cox regression analysis, 5 parameters were significant: ascites and anorexia, elevated leukocyte count and lactate dehydrogenase activity, as well as decreased albumine levels. Using these parameters, patients were divided into 3 risk groups: low-risk (presence of 0-1 factors), intermediate risk (2-3 factors), and poor-risk patients (4-5 factors). Median survival for poor-risk patients was 18 days, intermediate- and low-risk patients survived 43 and 136 days, respectively (p < 0.0001). CONCLUSION: In multivariate analysis, 5 prognostic factors were identified, and 3 patient groups were defined. After multicenter validation, these factors may help to guide treatment decisions in terminally ill patients with gastrointestinal tumors.

Cancer patients and music: (prospective) results from a survey to evaluate potential complementary treatment approaches.

PURPOSE: Many cancer patients (PTS) suffer from somatic or non-somatic symptoms. Studies have shown positive effects of music intervention (MI) on aspects of quality of life or symptom management. METHODS: Since there are poor data available about patient's needs regarding the use of MI as an adjunct to cancer treatment, n = 548 tumor PTS were polled anonymously at the outpatient department of the University Hospital Mannheim Tumor Center using a self-designed questionnaire. Univariate and multivariate analyses were performed. RESULTS: 486 data sets were eligible for analysis. 240 of the PTS were male and median age was 63 years. 38% had metastatic disease. 81% (n = 386) were currently receiving anti-tumor treatment. The majority of the PTS stated to have somatic symptoms. However, some of the PTS reported non-somatic symptoms like anxiety, loneliness, and depression. N = 187 (40%) of the PTS reported interest in complementary MI. In the univariate and multivariate analyses, especially PTS with non-somatic complaints and PTS, actively playing or making music showed significantly more interest in complementary MI, hoping for a relaxing therapeutic effect. PTS who play instruments would prefer more active forms of MI. CONCLUSION: 40% of PTS reported interest in additional MI during cancer treatment. PTS with non-somatic symptoms as well as patients affine to music might benefit from the use of MI potentially reducing their symptom burden. The inconsistent and heterogeneous data from randomized trials underline the importance of systematic research approaches with more relevant and standardized endpoints.

Comparison of double-plate appliance/facemask combination and facemask therapy in treating class III malocclusions.

OBJECTIVE: To compare the treatment effects of double-plate appliance/facemask (DPA-FM) combined therapy and facemask (FM) therapy in treating Class III malocclusions. MATERIALS AND METHODS: The material consisted of lateral cephalometric radiographs of 45 children with skeletal and dental Class III malocclusion. The first treatment group comprised 15 patients (mean age  =  11 years) treated with FM. The second treatment group comprised 15 patients (mean age  = 10 years 9 months) treated with DPA-FM. The third group comprised 15 patients (mean age  =  10 years 5 months) used as controls. The paired t-test was used to evaluate the treatment effects and changes during the treatment and observation period in each group. Differences between the groups were determined by variance analysis and the Duncan test. RESULTS: With the DPA-FM and FM appliances, the SNA and ANB angles increased significantly. These changes were statistically different compared with the control group. Lower facial height showed a greater increase in both treatment groups than in the control group. Molar relation showed a greater increase in the DPA-FM group than in the FM group. The increase in U6/ANS-PNS angle in the FM group was significantly different from the DPA-FM and control groups. The L1/NB angle and Pg-T increased significantly only in the FM group, but no significant difference was found between the treatment groups. CONCLUSIONS: In the treatment of Class III malocclusion, both appliances were effective. The significant sagittal changes in the lower incisors and pogonion in the FM group compared with the nonsignificant changes in the DPA-FM group might be due to the restriction effect of acrylic blocks in the DPA-FM group.

Mapisal Versus Urea Cream as Prophylaxis for Capecitabine-Associated Hand-Foot Syndrome: A Randomized Phase III Trial of the AIO Quality of Life Working Group.

PURPOSE: Hand-foot syndrome (HFS) is a frequently occurring adverse event associated with anticancer drugs. This study compares a newly introduced ointment containing several antioxidants and exhibiting high radical protection factor, which has been available on the German market since 2011, with urea cream for prevention of HFS in patients treated with capecitabine. PATIENTS AND METHODS: Patients with GI tumors or breast cancer treated with capecitabine were included in this randomized phase III study. The primary end point was prevention of HFS of any grade within 6 weeks of treatment as indicated by a standardized patient diary. The study had 80% power to show a 20% reduction of the incidence of HFS with the new ointment. Secondary end points included time to development of HFS greater than grade 1, evaluation of capecitabine dose intensity, and quality of life analyses. RESULTS: A total of 152 patients were evaluable. In total, 47 of 152 patients experienced HFS (30.9%), 39.5% with the new ointment and 22.4% in the urea arm (stratified odds ratio, 2.37; P = .02). Time to HFS greater than grade 1 was comparable, but time to any-grade HFS was significantly longer in the urea group (P = .03). Capecitabine dose intensity, time under study, and percentage of days with correct administration of study medication were identical, as were adverse events except for HFS. Skin-related quality of life was significantly worse in the group treated with the new ointment at the end of study treatment. CONCLUSION: This trial demonstrated that 10% urea cream was superior to the new ointment at preventing HFS over the first 6 weeks of treatment with capecitabine.

Modified tandem traction bow appliance compared with facemask therapy in treating Class III malocclusions.

OBJECTIVE: To compare the effects of the modified tandem traction bow appliance (MTTBA) and the facemask in treating patients with Class III malocclusion. MATERIALS AND METHODS: The material consisted of the pre-post treatment\pre-post observation lateral cephalograms of 65 subjects with skeletal and dental Class III malocclusion. In the first group 21 patients (mean age: 10 years, 6 months) were treated with a Delaire-type facemask (FM). In the second group 22 patients treated (mean age: 10 years) with MTTBA. The remaining 22 children (mean age: 9 years, 7 months) were observed without treatment for 11 months. RESULTS: Increase in SNA, N-FH ⊥ A, and ANB angles were significantly greater in the treatment groups compared to the control group. However, ANB angle showed a significantly greater increase in the FM group (2.8 ± 0.30°) than in the MTTBA group (2.0 ± 0.18°). The overjet and molar relation increased significantly in both treatment groups, but in the FM group (5.2 ± 0.40 mm) increase in overjet was significantly greater than in the MTTBA group (4.0 ± 0.27 mm). Mesial movement of upper molar and incisor were found to be greater in the FM group compared to the modified TTBA group. CONCLUSIONS: Both appliances were found to be effective in the treatment of Class III malocclusion. Their skeletal and dental effects showed differences due to their design.