From a Clustering of Adverse Symptoms after Colorectal Cancer Therapy to Chronic Fatigue and Low Ability to Work: A Cohort Study Analysis with 3 Months of Follow-Up.

In colorectal cancer (CRC) patients, apart from fatigue, psychological and physical symptoms often converge, affecting their quality of life and ability to work. Our objective was to ascertain symptom clusters within a year following CRC treatment and their longitudinal association with persistent fatigue and reduced work ability at the 3-month follow-up. We used data from MIRANDA, a multicenter cohort study enrolling adult CRC patients who are starting a 3-week in-patient rehabilitation within a year post-curative CRC treatment. Participants completed questionnaires evaluating symptoms at the start of rehabilitation (baseline) and after three months. We performed an exploratory factor analysis to analyze the clustering of symptoms at baseline. Longitudinal analysis was performed using a multivariable linear regression model with dichotomized symptoms at baseline as independent variables, and the change in fatigue and ability to work from baseline to 3-month-follow-up as separate outcomes, adjusted for covariates. We identified six symptom clusters: fatigue, gastrointestinal symptoms, pain, psychosocial symptoms, urinary symptoms, and chemotherapy side effects. At least one symptom from each factor was associated with higher fatigue or reduced ability to work at the 3-month follow-up. This study highlights the interplay of multiple symptoms in influencing fatigue and work ability among CRC patients post-rehabilitation.

Development Trajectories of Fatigue, Quality of Life, and the Ability to Work among Colorectal Cancer Patients in the First Year after Rehabilitation-First Results of the MIRANDA Study.

Cancer-related fatigue, low quality of life (QoL), and low ability to work are highly prevalent among colorectal cancer (CRC) patients after tumor surgery. We aimed to analyze their intercorrelations and trajectories in the first year after in-patient rehabilitation in the German multicenter MIRANDA cohort study. Recruitment is ongoing, and we included the first 147 CRC patients in this analysis. Participants filled out questionnaires at the beginning of in-patient rehabilitation (baseline) and at 3, 6, 9, and 12 months after the baseline. The EORTC-QLQ-C30-General-Health-Status (GHS)/QoL, the FACIT-F-Fatigue Scale, and the FACIT-F-FWB-ability-to-work items were used to evaluate QoL, fatigue, and ability to work, respectively. The fatigue and QoL scales were highly correlated (r = 0.606). A moderate correlation was observed between the fatigue and ability to work scales (r = 0.487) and between the QoL and ability to work scales (r = 0.455). Compared to the baseline, a statistically significant improvement in the QoL, ability to work, and fatigue scales were observed at the 3-month follow-up (Wilcoxson signed rank test, all p < 0.0001). The three scales plateaued afterward until the 12-month follow-up. In conclusion, fatigue, QoL, and ability to work were highly interrelated, improved quickly during/after in-patient rehabilitation, and did not change much afterward in German CRC patients.

Protocol of the optimal study: Optimization of polypharmacy in geriatric oncology - A randomized controlled trial.

BACKGROUND: Polypharmacy is very common in older cancer patients and these patients are particularly vulnerable to drug-drug interactions and adverse drug reactions because they often receive chemotherapy and symptom-relieving agents. METHODS: The primary aim of the randomized, controlled Optimization of Polypharmacy in Geriatric Oncology (OPTIMAL) trial is to test whether an advisory letter with the results of a comprehensive medication review conducted with the Fit fOR The Aged (FORTA) list to the caring physician in rehabilitation clinics improves the quality of life (QoL) of older cancer patients exposed to polypharmacy more than usual care. The FORTA list detects medication overuse, underuse, and potentially inappropriate drug use among older adults. In the oncology departments of approximately 10 German rehabilitation clinics, we aim to recruit 514 cancer patients (22 common cancers; diagnosis or recurrence requiring treatment in the last 5 years; all stages) who are ≥ 65 years old, regularly take ≥ 5 drugs, and have ≥ 1 medication-related problem. All necessary information about the patients will be provided to a pharmacist at the coordinating center (German Cancer Research Center, Heidelberg), who will perform randomization (1:1) and conduct the medication review with the FORTA list. For the intervention group only, the results are sent by letter to the treating physician in the rehabilitation clinics, who shall discuss medication changes with the patient at the discharge visit, as well as implement them afterwards and disclose them in the discharge letter to the general practitioner. The control group gets the usual care provided in German rehabilitation clinics, which usually does not include a comprehensive medication review but can include medication changes. Patients will be blinded, as they cannot know whether proposed medication changes were part of the study or part of usual care. Study physicians cannot be blinded. The primary endpoint will be the EORTC-QLQ-C30 global health status/QoL score, assessed via self-administered questionnaires 8 months after baseline. DISCUSSION: If the planned study shows that a medication review with the FORTA list improves the QoL of older cancer patients in oncological rehabilitation more than usual care, it would provide the necessary evidence to translate the trial's findings into routine care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00031024.

Efficacy and Safety of a Personalized Vitamin D3 Loading Dose Followed by Daily 2000 IU in Colorectal Cancer Patients with Vitamin D Insufficiency: Interim Analysis of a Randomized Controlled Trial.

A personalized vitamin D3 loading dose has not yet been tested in cancer patients. This interim analysis of the randomized, placebo-controlled VICTORIA trial analyzed the first recruited 74 German adults with nonmetastatic colorectal cancer, a tumor surgery within the past year, and 25-hydroxyvitamin D levels (25(OH)D) < 50 nmol/L. Study participants received a loading dose tailored for a baseline 25(OH)D level and BMI in the first 11 days, followed by a maintenance dose of 2000 IU of vitamin D3 daily until end of trial week 12. The mean 25(OH)D levels were 27.6, 31.0, and 34.1 nmol/L in the placebo group and 25.9, 63.1, and 75.5 nmol/L in the verum group during screening, visit 1 (end of loading dose), and visit 2 (end of maintenance dose), respectively. The prevalence of 25(OH)D) ≥ 50 nmol/L at visits 1 and 2 was 3.5% and 17.4% in the placebo group and 80.0% and 100% in the verum group. No events of 25(OH)D > 150 nmol/L or hypercalcemia were observed. Hypercalciuria events at visit 1 (n = 5 in verum and n = 1 in the placebo group; p = 0.209) receded after discontinuation of the study medication. The personalized loading dose effectively and safely increased the 25(OH)D levels, and 2000 IU of vitamin D3 daily sustained the achieved levels.

Patient competencies, coping self-efficacy, and coping: Do they change during oncological inpatient rehabilitation and beyond?

OBJECTIVE: The construct of Patient Competencies (PCs) has been suggested to allow a more comprehensive understanding of cancer patients' abilities to confront emotion- and problem-focused coping tasks arising from the diagnosis, treatment and survivorship of cancer. While providing a reliable and valid measure of PCs, research thus far has not clarified whether PCs change across time and/or through intervention. This study asks whether PCs change during oncological inpatient rehabilitation and beyond. METHODS: N = 377 breast, colorectal, and prostate cancer patients from clinics for oncological rehabilitation were included to complete self-report measures of PC, coping and self-efficacy for coping with cancer at the beginning and the end of rehabilitation and 9 months afterward. In order to determine differences between tumor diagnostic groups and changes across time 3 (tumor site) x 3 (time) repeated measures analyses of variance were computed. RESULTS: Tumor diagnostic groups differed only marginally in PCs, coping self-efficacy and coping. The PCs of self-regulation and managing distress and coping self-efficacy improved slightly during rehabilitation but returned to initial levels at 9 months. Differential improvement was evident in the competencies of seeking information and interest in social services. Two of five coping behaviors decreased markedly from the end of rehabilitation to follow-up. CONCLUSIONS: This study suggests that oncological inpatient rehabilitation may contribute to advancing PCs, albeit to a limited extent. Aside from addressing conceptual, diagnostic and measurement issues, future research should clarify which interventions may be most effective for advancing problem- and emotion-focused PCs.

[Role of Clinical, Sociomedical and Psychological Factors on Return to Work of Patients with Breast Cancer 6 Months after Rehabilitation]. / Einfluss klinischer, sozialmedizinischer und psychologischer Faktoren auf die berufliche Reintegration von Patientinnen mit Brustkrebs 6 Monate nach der Rehabilitation.

AIM OF THE STUDY: The majority of patients with non-metastatic breast cancer return to work after tumor therapy. A rate of up to 80% is given in national and international studies, which can vary considerably depending on the study population and the various social systems. However, it is unclear how many patients are reintegrated into work after medical rehabilitation and which clinical, sociodemographic and psychological factors play a role. METHODS: In a multicentre study, clinical and sociodemographic data were collected from breast cancer patients at the beginning of their medical rehabilitation. Subjectively experienced deficits in attention performance (FEDA), depressive symptoms (PHQ-9) and health-related quality of life (EORTC QLQ-C30) were recorded using standardized questionnaires. The cognitive performance was also examined using a computer-based test battery (NeuroCog FX). A follow-up survey was carried out 6-9 months after medical rehabilitation. The subjective assessment of one's own cognitive performance (FEDA) was recorded again at this time. RESULTS: 396 of the originally 476 patients were included in the study. In the follow-up survey, 323/396 patients (82%) were again employed. In a regression model, sociodemographic factors proved to be particularly predictive with regard to occupational reintegration: employment at the time of the tumor diagnosis, job preserved after medical rehabilitation, employee status and gradual reintegration according to the Hamburg model (Nagelkerke R2=0.685). This model could not be improved by adding psychological variables. The subjective patient information in all questionnaires was highly correlated (r>0.57; p<0.001). CONCLUSION: The vast majority of breast cancer patients return to work after medical rehabilitation. Socio-demographic factors play a crucial role in this. The regression model developed here, including the employment status, professional orientation and gradual reintegration, is of predictive importance and can be used in medical rehabilitation.

Protocol of the VICTORIA study: personalized vitamin D supplementation for reducing or preventing fatigue and enhancing quality of life of patients with colorectal tumor - randomized intervention trial.

BACKGROUND: Cancer-related fatigue represents one major cause of reduced quality of life in cancer patients and can seriously affect the physical, emotional, and cognitive functioning impeding coping with the disease. Options for effective treatment of cancer-related fatigue are limited, consisting only of non-pharmacologic interventions like physical activity, psychosocial, and mind-body interventions. Recent evidence suggests that vitamin D3 supplementation might alleviate cancer-related fatigue. However, confirmation in a randomized controlled trial is needed. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 456 colorectal cancer (CRC) patients aged 18 years and older are being recruited in three German rehabilitation clinics. Study inclusion requires hospitalization of at least 3 weeks at such a clinic, a diagnosis of non-metastatic CRC (stage I-III), surgical removal of the tumor within the past 9 months, and season-adapted vitamin D insufficiency or deficiency. Eligible patients are randomly assigned to a personalized regimen of vitamin D3 or placebo for 12 weeks. In the intervention group, a loading dose of 20,000 or 40,000 IU vitamin D3 will be administered daily during the first 11 days, followed by a maintenance dose of 2000 IU daily. Patients will complete questionnaires for secondary outcomes (fatigue subdomains, quality of life and subdomains, depression, functional well-being, and infection frequency). Blood and urine samples will be collected for analyses of safety parameters (hypervitaminosis D, hypercalcemia, hypercalciuria, and renal impairment) and efficacy biomarkers (25-hydroxyvitamin D, HbA1c, white blood cell count, leukocyte subtype counts, serum C-reactive protein, uric acid, creatinine, triglycerides, total, low- and high-density lipoprotein cholesterol). DISCUSSION: This trial tests whether a personalized vitamin D3 dosing regimen reduces or prevents fatigue among non-metastatic CRC patients by treating the underlying vitamin D deficiency/insufficiency. If efficacy can be confirmed, personalized vitamin D3 supplementation could be used as a tertiary prevention measure in addition to non-pharmacological treatments of cancer-related fatigue in CRC patients. We expect to detect an effect of vitamin D3 supplementation on secondary outcomes like quality of life, depression, functional well-being, infections, inflammatory biomarkers, diabetes mellitus, and dyslipidemia. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT-No: 2019-000502-30, January 21, 2019; German Clinical Trials Register (DRKS): DRKS00019907 , April 30, 2019.

NeuroCog FX study: A multicenter cohort study on cognitive dysfunction in patients with early breast cancer.

OBJECTIVE: Complaints about cognitive dysfunction (CD) reportedly persist in approximately one third of breast cancer patients, but the nature of CD and possible risk factors are unknown. METHODS: A cross-sectional, multicenter study was set up at 9 German oncological rehabilitation centers. Objective cognitive performance was assessed by the NeuroCog FX test, a short computerized screening (duration <30 minutes) which assesses working memory, alertness, verbal/figural memory, and language/executive. Patients' test performance was correlated with treatment factors (chemo-, radiotherapy), subjective performance (FEDA), depression (PHQ-9), quality of life (EORTC QLQ-30), and clinical characteristics. RESULTS: From February 2013 to December 2014, a clinically homogenous sample of 476 patients was recruited (early tumor stage [T0-T2]: 93%; node-negative: 67%; chemotherapy: 61%; radiotherapy: 84%). NeuroCog FX could be administered in 439 patients (92%; median age: 50 [24-62] years). Patients showed decreased performance in attentional-executive functions (but not verbal/figural memory) and a 3-fold rate of CD in terms of below average performance in at least 1 cognitive domain (42%). Approximately 40% of the patients also reported subjective cognitive impairment (FEDA). No therapy-specific effect on test performance was obtained in the NeuroCog FX test. CONCLUSIONS: Breast cancer survivors showed objective attentional-executive and subjective cognitive impairments. No therapy-specific adverse side effect on objective cognitive performance was found. Depression strongly contributed to objective and subjective cognitive complaints and reduced quality of life.

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

To determine the frequency, mutation spectrum and phenotype of the recently described autosomal recessive MUTYH-associated polyposis (MAP), we performed a systematic search for MUTYH (MYH) mutations by sequencing the complete coding region of the gene in 329 unselected APC mutation-negative index patients with the clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP). Biallelic germline mutations in MUTYH were identified in 55 of the 329 unselected patients (17%) and in another 9 selected index cases. About one-fifth (20%) of the 64 unrelated MAP patients harboured none of the 2 hot-spot missense mutations Y165C and/or G382D. Including 7 affected relatives, almost all MAP patients presented with either an attenuated (80%) or with an atypical phenotype (18%). Fifty percentage of the MAP patients had colorectal cancer at diagnosis. Duodenal polyposis was found in 18%, thyroid and stomach cancer in 1 case, other extraintestinal manifestations associated with FAP were not observed. In 8 families, vertical segregation was suspected; in 2 of these families, biallelic mutations were identified in 2 generations. Monoallelic changes with predicted functional relevance were found in 0.9% of the 329 patients, which is in accordance with the carrier frequency in the general population. In conclusion, biallelic MUTYH mutations are the underlying genetic basis in a substantial fraction of patients with adenomatous polyposis. The phenotype of MAP is best characterised as attenuated or atypical, respectively. Colorectal surveillance starting at about 18 years of age is recommended for biallelic mutation carriers and siblings of MAP patients, who refuse predictive testing.

Familial adenomatous polyposis: aberrant splicing due to missense or silent mutations in the APC gene.

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, the relevance of rare exonic single-base substitutions at nucleotide positions close to splice sites that are predicted to result in missense or silent (SNP) variants or substitutions in introns at splice-site positions that are not highly conserved has not been systematically examined in FAP patients. In 34 index patients, we identified 26 different heterozygous single-base substitutions at or close to the splice sites. We characterized five exonic mutations in exon 4 (c.423G>T), exon 14 (c.1956C>T, c.1957A>G, and c.1957A>C), and exon 15 (c.1959G>A) by transcript analysis and by splice-prediction programs (BDGP, SpliceSiteFinder, and ESEfinder). The splicing patterns of these variants were compared to those of 16 different substitutions at highly or less-conserved intronic splice-site positions, and to normal controls. In addition, we analyzed cosegregation of the variants with affected family members and examined the genotype-phenotype correlation. We could demonstrate that the four unclear variants in exon 4 and 14 that are predicted to result in missense or silent mutations in fact lead to complete exon skipping due to aberrant splicing; one possible explanation for this observed effect might be the disruption of exonic splicing enhancer (ESE) motifs. In contrast, the substitution at the first position of exon 15 seems to actually be a silent variant. We present the first systematic evaluation of different single-base substitutions in APC at or close to splice sites at transcript level. We show that the consequence of exonic mutations cannot be evaluated only by the predicted change in amino acid sequence but rather by the change at DNA level. The functional analysis of variants with unknown pathogenic effect plays an important role in increasing the mutation detection rate and achieving validation of predictive testing.

Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis.

A predominance of de novo mutations in the paternal germ line has been reported for several disorders; however, in familial adenomatous polyposis (FAP), the parental origin of APC mutations has been scarcely analysed so far. Among 563 unrelated FAP families with known family history, we identified 58 patients with a suspected de novo mutation in the APC gene. A germline mutation was detected in 52 of them; in 38 patients, the mutation could be excluded in both parents. The five base pair deletion at codon 1309 (c.3927_3931delAAAGA) was over-represented in the group of patients with suspected de novo mutations (17/58=29%), when compared to the group of familial cases (26/505=5%); thus, the high frequency of this mutation is not due to a founder effect but rather due to de novo mutation events. Parental origin of de novo mutations could be traced in 16 families, including three families with large chromosomal deletions. Four mutations were of maternal and 12 of paternal origin, pointing to a moderate preponderance towards paternal origin. Sex-related differences of mutation types could be observed: large deletions and single-base substitutions were exclusively of paternal origin, whereas the small deletions were equally distributed (maternal/paternal ratio 4:4).

Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma.

Therapeutic vaccination with dendritic cells (DC) can lead to tumor regression in animal models and has shown promising results in the first clinical trials of metastatic renal cell carcinoma and malignant melanoma. In vitro data and results of a clinical phase I/II trial using DC tumor fusions in patients with progressive metastatic renal cell carcinoma are presented here. In addition to toxicity and feasibility, complex immune monitoring was a point of interest. DC precursor cells were obtained from the peripheral blood mononuclear cells (PBMCs) of healthy donors and were fused with either allogeneic (8 patients) or autologous (4 patients) renal tumor cells. In total, 12 patients with progressive metastatic renal cell carcinoma were treated with an average of 2.8 x 10(7) tumor cells fused with 1.8 x 10(7) DC each administered on days 0, 28, and 56 intradermally. Fusion efficacy for the tumor cells used was 14.3% +/- 7.8%. Cell viability was 59.8% +/- 6.8% after fusion and irradiation. We observed no adverse effects and no difference in clinical outcome between the allogeneic and the autologous treatment. Eight patients remained in a progressive disease state and four patients in a stable disease state. T-cell immunity was carefully monitored before, during, and after treatment. Delayed-type hypersensitivity (DTH) reaction using tumor cells was positive after treatment in 7 of 12 patients, 2 of whom were found to have stable disease. An increase in the reactivity against recall antigens was seen in most patients. Interestingly, cytotoxicity of peripheral blood lymphocytes (PBLs) against renal cell carcinoma cells increased during treatment as well as the percentage of interferon-gamma-secreting cells. This effect was significantly enhanced within the group that had stable disease. The lack of adverse effects together with positive immunologic signs justifies further investigation of this novel therapeutic approach. Further studies are necessary to test for clinical effectiveness in patients with tumors, especially those with less advanced disease.

Arylamine N-acetyltransferase type 2 and glutathione S-transferases M1 and T1 polymorphisms in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) exhibits a variable phenotype even in carriers of the same adenomatous polyposis coli germline mutation. Xenobiotic-metabolizing enzymes such as N-acetyltransferases (NATs) and glutathione S-transferases (GSTs) were reported to modify the individual risk for colorectal cancer. We examined whether the polymorphisms of the NAT2, GSTM1, and GSTT1 enzymes affect age at diagnosis of first colorectal adenomas or extracolonic manifestations in 411 FAP patients. Neither age at diagnosis of colorectal adenomas nor occurrence of extra-intestinal tumors differed significantly between genotypes at the NAT2 and GSTM1 loci, whereas GSTT1 polymorphism showed an uncertain association with extra-intestinal manifestations. Combinations of supposed at risk genotypes of the three enzymes showed no significant differences either. Thus, NAT2, GSTM1, or GSTT1 are unlikely to modify the disease phenotype in FAP patients.