Digital Therapeutic (Mika) Targeting Distress in Patients With Cancer: Results From a Nationwide Waitlist Randomized Controlled Trial.

BACKGROUND: Distress is highly prevalent among patients with cancer, but supportive care needs often go unmet. Digital therapeutics hold the potential to overcome barriers in cancer care and improve health outcomes. OBJECTIVE: This study conducted a randomized controlled trial to investigate the efficacy of Mika, an app-based digital therapeutic designed to reduce distress across the cancer trajectory. METHODS: This nationwide waitlist randomized controlled trial in Germany enrolled patients with cancer across all tumor entities diagnosed within the last 5 years. Participants were randomized into the intervention (Mika plus usual care) and control (usual care alone) groups. The participants completed web-based assessments at baseline and at 2, 6, and 12 weeks. The primary outcome was the change in distress from baseline to week 12, as measured by the National Comprehensive Cancer Network Distress Thermometer. Secondary outcomes included depression, anxiety (Hospital Anxiety and Depression Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and quality of life (Clinical Global Impression-Improvement Scale). Intention-to-treat and per-protocol analyses were performed. Analyses of covariance were used to test for outcome changes over time between the groups, controlling for baseline. RESULTS: A total of 218 patients (intervention: n=99 and control: n=119) were included in the intention-to-treat analysis. Compared with the control group, the intervention group reported greater reductions in distress (P=.03; ηp²=0.02), depression (P<.001; ηp²=0.07), anxiety (P=.03; ηp²=0.02), and fatigue (P=.04; ηp²=0.02). Per-protocol analyses revealed more pronounced treatment effects, with the exception of fatigue. No group difference was found for quality of life. CONCLUSIONS: Mika effectively diminished distress in patients with cancer. As a digital therapeutic solution, Mika offers accessible, tailored psychosocial and self-management support to address the unmet needs in cancer care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00026038; https://drks.de/search/en/trial/DRKS00026038.

Unmet supportive care needs among cancer patients: exploring cancer entity-specific needs and associated factors.

PURPOSE: Recognizing unmet care needs among cancer patients is crucial for improving a person-centered and tailored approach to survivorship care. This study aimed to explore the prevalence of unmet supportive care needs, pinpointing entity-specific areas of burden, and to identify factors associated with unmet needs within a diverse sample of cancer patients. METHODS: In this cross-sectional sub-study of a large multicenter study, 944 adult cancer patients reported supportive care needs via the well-validated SCNS. Most frequent diagnoses included breast (n = 276), prostate (n = 237), hematological (n = 90) and gynecological cancer (n = 74), which were analyzed for entity-specific care needs. RESULTS: Across most cancer entities, health system and information, and psychological needs were most commonly reported, with fear of the cancer spreading and information regarding cancer control/diminishment ranking as the most prevalent individual concerns. Notable differences in entity-specific needs emerged for gynecological cancer patients, who exhibited more psychological (p = 0.007, OR = 2.01) and physical needs (p = 0.005, OR = 2.02), and prostate cancer patients, who showed higher sexuality needs (p < 0.001, OR = 2.95) but fewer psychological (p < 0.001, OR = 0.55), physical (p < 0.001, OR = 0.31) and patient care needs (p = 0.006, OR = 0.62). Non-distressed participants had fewer supportive care needs in each domain (all p < 0.001). Patients with functional impairments and female respondents reported increased unmet needs across most domains. CONCLUSION: The high prevalence of patients feeling inadequately informed about their disease and care aspects, particularly among those with functional impairments, reflects a key challenge in the healthcare system. Specific interventions and improvements in patient-doctor communication are essential to address cancer entity-specific care needs.

Compliance with medical regimen among hematological cancer patients and its association with symptoms of posttraumatic stress disorder and adjustment disorder.

Background: Hematological cancer patients must comply with extensive medical instructions to prevent cancer progression or relapse. Psychological comorbidities and patient characteristics have been shown to affect compliance. However, the impact of posttraumatic stress disorder (PTSD) and adjustment disorder (AjD) on compliance in cancer patients remains unclear. This study aims to evaluate compliance in hematological cancer patients more comprehensively and to investigate its association with PTSD and AjD symptomatology as well as sociodemographic and medical factors. Methods: Hematological cancer patients were cross-sectionally assessed via validated questionnaires for PTSD (PCL-5) and AjD (ADMN-20), and three internally developed items on compliance with medical regimen, with two referring to compliance behavior and one item assessing perceived difficulties with complying. Each compliance item was analyzed descriptively. Multiple linear regression models tested the association between compliance and PTSD and AjD symptomatology, sociodemographic and medical factors. Results: In total, 291 patients were included (response rate 58%). Nine out of ten patients reported to either never (67%) or rarely (25%) change their medical regimen. However, 8% reported to change it once in a while or often. Compliance behavior was mostly rated as very easy (36%) or easy (45%) to implement. Nevertheless, 19% perceived it to be partly difficult or difficult to follow medical regimen. Symptoms of AjD (ß = 0.31, p < 0.001) were associated with more difficulties to comply. Higher compliance behavior in turn was associated with stem cell transplantation (SCT) treatment (ß = -0.21, p < 0.001) and lower education (ß = -0.19, p = 0.002). Conclusion: Although most patients indicated that they comply with medical regimen, a considerable subgroup of patients indicated subjectively perceived difficulties and thus seem to require additional support in implementing medical instructions possibly through improved medical communication and patient health literacy or shared decision-making.

New progress in an old debate? Applying the DSM-5 criteria to assess traumatic events and stressor-related disorders in cancer survivors.

OBJECTIVE: The rather broad definition of medical trauma within DSM-IV has contributed to long-lasting debates on the applicability of Posttraumatic Stress Disorder (PTSD) in oncological patients and its differentiation from Adjustment Disorder (AjD) which results from non-traumatic critical life events. The DSM-5 criteria have introduced a narrower definition of medical traumatization. However, studies on updated prevalence rates in cancer patients are missing. METHODS: Within a cross-sectional study, we assessed hematological cancer survivors using the Structured Clinical Interview for DSM-5. We investigated (i) the frequency and type of cancer-related stressors, (ii) the proportion of stressors qualifying as traumatic according to DSM-5 (i.e., an event of sudden and catastrophic character) and (iii) the prevalence of PTSD, AjD and cancer-related PTSD according to DSM-5. RESULTS: 291 patients participated (response rate: 58%). Mean age was 54 years, 60% were male. 168 patients (59%) reported cancer-related stressors, with the most frequent being cancer diagnosis disclosure (n = 58, 27%). Eight percent of reported stressors qualified as traumatic events according to DSM-5. Five (1.8%), 15 (5.3%) and 20 (7.0%) cancer survivors met DSM-5 criteria for current PTSD, lifetime PTSD and AjD, respectively. Among all PTSD cases, three were cancer-related (1.1%). In addition, seven patients (2.5%) met all symptoms for cancer-related PTSD, but not the DSM-5 criterion for medical trauma. Considering receiving the cancer diagnosis as traumatic event, which is debatable according to DSM-5, 38% of stressors qualified as traumatic and six patients (2.1%) met criteria for cancer-related PTSD. CONCLUSIONS: DSM-5 criteria enable a clear identification of traumatic events in the context of cancer. This change may inform discussions on the appropriateness of PTSD in cancer patients and facilitates its differentiation from AjD. Larger studies need to validate our findings.

Symptoms of posttraumatic stress disorder and adjustment disorder in hematological cancer patients with different treatment regimes.

BACKGROUND: Symptoms of posttraumatic stress disorder (PTSD) and adjustment disorder (AjD) are common in hematological cancer patients as they face severe stressors during their serious disease and often intensive treatment, such as stem cell transplantation (SCT). Aims of the present study were to provide frequency and risk factors for PTSD and AjD based on updated diagnostic criteria that are lacking to date. MATERIAL AND METHODS: In a cross-sectional study, hematological cancer patients were assessed for stressor-related symptoms via validated self-report questionnaires based on updated criteria for PTSD (PCL-5) and AjD (ADMN-20). Frequency and symptom severity were estimated among the total sample and SCT subgroups (allogeneic, autologous, no SCT). SCT subgroups were compared using Chi-squared-tests and ANOVAs. Linear regression models investigated sociodemographic and medical factors associated with symptomatology. RESULTS: In total, 291 patients were included (response rate: 58%). 26 (9.3%), 66 (23.7%) and 40 (14.2%) patients met criteria for cancer-related PTSD, subthreshold PTSD and AjD, respectively. Symptom severity and frequency of criteria-based PTSD and AjD did not differ between SCT subgroups (all p > 0.05). Factors associated with elevated symptomatology were younger age (PTSD: p < 0.001; AjD: p = 0.02), physical comorbidity (PTSD: p < 0.001; AjD: p < 0.001) and active disease (PTSD: p = 0.12; AjD: p = 0.03). CONCLUSION: Based on new criteria, a considerable part of hematological cancer patients reports PTSD and AjD symptoms. Younger patients and patients with physical symptom burden might be particularly at risk and need to be monitored closely to enable effective treatment at an early stage.

Effect of depression, anxiety, and distress screeners on the need, intention, and utilization of psychosocial support services among cancer patients.

PURPOSE: In clinical cancer care, distress screening is recommended to identify highly burdened patients in objective need for psychosocial support to improve psychological distress and quality of life and to enhance patient empowerment. It is however unclear whether distress screeners are suitable for psychosocial care planning and thus whether they can predict the willingness that is need, intention, and utilization, to seek psychosocial support. METHODS: In a secondary analysis of a cluster intervention study, we assessed cancer patients with three distress screeners (DT, PHQ-9, GAD-7) at baseline. The willingness to seek psychosocial support services was assessed binary for psychosocial services at 3 and 6 months. Logistic regression models were applied to examine the predictive effect of the screeners on need, intention, and utilization. We corrected all models for multiple testing. RESULTS: The 660 patients included in the study were on average 60 years, 54% were male. At the 3- and 6-month follow-up, 353 and 259 patients participated, respectively. The screeners were best in predicting the need for support (OR reaching up to 1.15, 1.20, and 1.22 for the PHQ-9, GAD-7, and DT respectively). The intention was predicted by the PHQ-9 and GAD-7, whereas utilization of psychosocial support services was not predicted by the screeners. CONCLUSION: The three distress screeners might be useful in psychosocial care planning, as they are able to predict the need and to some degree the intention to seek psychosocial support. Future research needs to examine potential barriers and supporting factors that may explain utilization of psychosocial support. TRIAL REGISTRATION: The study was retrospectively registered (2/2021) at ClinicalTrials.gov (number: NCT04749056).

Content features and its implementation in novel app-based psycho-oncological interventions for cancer survivors: a narrative review.

PURPOSE OF REVIEW: The interest in and availability of app-based psycho-oncological interventions for cancer survivors has grown rapidly. In this narrative review, we therefore aim to provide an overview of the psychological content features included in psycho-oncological apps and how the content is implemented in the apps. RECENT FINDINGS: A total of 19 studies (six randomized controlled trials, six studies with prepost design, five study protocols and two app developments), all published in the last 18 months (July 2020 to December 2021), were analyzed in terms of the described app-based interventions and their psycho-oncological content. Apps for cancer survivors are conducted for a variety of different diagnoses and often target a specific patient population, for example patients with a specific therapy. The most frequent content features are psychoeducation, self-monitoring of symptoms, and some sort of exercise or relaxation program. Depending on the app's purpose, some offer specific content, such as decision aids, medication schedules or modules to improve coping strategies. Most apps combine informative and interactive elements. SUMMARY: Psycho-oncological apps for cancer survivors target many relevant psychological problem areas and aim to improve patient empowerment. Available mHealth interventions can therefore be seen as a good complement for cancer care and also offer the possibility to improve patient involvement.

Phloem small RNAs, nutrient stress responses, and systemic mobility.

BACKGROUND: Nutrient availabilities and needs have to be tightly coordinated between organs to ensure a balance between uptake and consumption for metabolism, growth, and defense reactions. Since plants often have to grow in environments with sub-optimal nutrient availability, a fine tuning is vital. To achieve this, information has to flow cell-to-cell and over long-distance via xylem and phloem. Recently, specific miRNAs emerged as a new type of regulating molecules during stress and nutrient deficiency responses, and miR399 was suggested to be a phloem-mobile long-distance signal involved in the phosphate starvation response. RESULTS: We used miRNA microarrays containing all known plant miRNAs and a set of unknown small (s) RNAs earlier cloned from Brassica phloem sap 1, to comprehensively analyze the phloem response to nutrient deficiency by removing sulfate, copper or iron, respectively, from the growth medium. We show that phloem sap contains a specific set of sRNAs that is distinct from leaves and roots, and that the phloem also responds specifically to stress. Upon S and Cu deficiencies phloem sap reacts with an increase of the same miRNAs that were earlier characterized in other tissues, while no clear positive response to -Fe was observed. However, -Fe led to a reduction of Cu- and P-responsive miRNAs. We further demonstrate that under nutrient starvation miR399 and miR395 can be translocated through graft unions from wild type scions to rootstocks of the miRNA processing hen1-1 mutant. In contrast, miR171 was not transported. Translocation of miR395 led to a down-regulation of one of its targets in rootstocks, suggesting that this transport is of functional relevance, and that miR395, in addition to the well characterized miR399, could potentially act as a long-distance information transmitter. CONCLUSIONS: Phloem sap contains a specific set of sRNAs, of which some specifically accumulate in response to nutrient deprivation. From the observation that miR395 and miR399 are phloem-mobile in grafting experiments we conclude that translocatable miRNAs might be candidates for information-transmitting molecules, but that grafting experiments alone are not sufficient to convincingly assign a signaling function.

Identification of high levels of phytochelatins, glutathione and cadmium in the phloem sap of Brassica napus. A role for thiol-peptides in the long-distance transport of cadmium and the effect of cadmium on iron translocation.

Phytochelatins (PCs) are glutathione-derived peptides that function in heavy metal detoxification in plants and certain fungi. Recent research in Arabidopsis has shown that PCs undergo long-distance transport between roots and shoots. However, it remains unknown which tissues or vascular systems, xylem or phloem, mediate PC translocation and whether PC transport contributes to physiologically relevant long-distance transport of cadmium (Cd) between shoots and roots. To address these questions, xylem and phloem sap were obtained from Brassica napus to quantitatively analyze which thiol species are present in response to Cd exposure. High levels of PCs were identified in the phloem sap within 24 h of Cd exposure using combined mass spectrometry and fluorescence HPLC analyses. Unexpectedly, the concentration of Cd was more than four-fold higher in phloem sap compared to xylem sap. Cadmium exposure dramatically decreased iron levels in xylem and phloem sap whereas other essential heavy metals such as zinc and manganese remained unchanged. Data suggest that Cd inhibits vascular loading of iron but not nicotianamine. The high ratios [PCs]/[Cd] and [glutathione]/[Cd] in the phloem sap suggest that PCs and glutathione (GSH) can function as long-distance carriers of Cd. In contrast, only traces of PCs were detected in xylem sap. Our results suggest that, in addition to directional xylem Cd transport, the phloem is a major vascular system for long-distance source to sink transport of Cd as PC-Cd and glutathione-Cd complexes.

Identification and characterization of small RNAs from the phloem of Brassica napus.

Systemic signalling is indispensable for the coordination of diverse physiological processes during development, defence and nutrient allocation. Indirect evidence suggests that plant small RNAs (smRNAs) could be involved in long-distance information transfer via the vasculature of the plant. Analyses of the smRNA complements of vascular exudates from oilseed rape (Brassica napus) showed that xylem sap is devoid of RNA, whereas phloem sap contained a large number of smRNAs. In addition to 32 annotated microRNAs (miRNAs) from 18 different families that could be identified and approved, a set of unknown smRNAs, predominantly of 21 and 24 nucleotides in length, was obtained, and selected candidates were found to be highly abundant in phloem sap. Moreover, we could demonstrate that the levels of three miRNAs known to respond to nutrient deprivation in non-vascular tissue, miR395 (sulphate), miR398 (copper) and miR399 (phosphate), were increased in phloem sap during the growth of plants under the respective starvation conditions. Interestingly, only mature miRNA molecules were found to be stress responsive, demonstrating that single-stranded sense miRNAs are most likely to represent the physiologically relevant molecules. The strong responses in the phloem suggest a role of miRNAs in systemic information transfer via this long-distance transport system.

Inhibition of de novo pyrimidine synthesis in growing potato tubers leads to a compensatory stimulation of the pyrimidine salvage pathway and a subsequent increase in biosynthetic performance.

Pyrimidine nucleotides are of general importance for many aspects of cell function, but their role in the regulation of biosynthetic processes is still unclear. In this study, we investigate the influence of a decreased expression of UMP synthase (UMPS), a key enzyme in the pathway of de novo pyrimidine synthesis, on biosynthetic processes in growing potato (Solanum tuberosum) tubers. Transgenic plants were generated expressing UMPS in the antisense orientation under the control of the tuber-specific patatin promoter. Lines were selected with markedly decreased expression of UMPS in the tubers. Decreased expression of UMPS restricted the use of externally supplied orotate for de novo pyrimidine synthesis in tuber tissue, whereas the uridine-salvaging pathway was stimulated. This shift in the pathways of UMP synthesis was accompanied by increased levels of tuber uridine nucleotides, increased fluxes of [(14)C]sucrose to starch and cell wall synthesis, and increased amounts of starch and cell wall components in the tubers, whereas there were no changes in uridine nucleotide levels in leaves. Decreased expression of UMPS in tubers led to an increase in transcript levels of carbamoylphosphate synthase, uridine kinase, and uracil phosphoribosyltransferase, the latter two encoding enzymes in the pyrimidine salvage pathways. Thus, the results show that antisense inhibition of the de novo pathway of pyrimidine synthesis leads to a compensatory stimulation of the less energy-consuming salvage pathways, probably via increased expression and activity of uridine kinase and uracil phosphoribosyltransferase. This results in increased uridine nucleotide pool levels in tubers and improved biosynthetic performance.

Starch content and yield increase as a result of altering adenylate pools in transgenic plants.

Starch represents the most important carbohydrate used for food and feed purposes. With the aim of increasing starch content, we decided to modulate the adenylate pool by changing the activity of the plastidial adenylate kinase in transgenic potato plants. As a result, we observed a substantial increase in the level of adenylates and, most importantly, an increase in the level of starch to 60% above that found in wild-type plants. In addition, concentrations of several amino acids were increased by a factor of 2-4. These results are particularly striking because this genetic manipulation also results in an increased tuber yield. The modulation of the plastidial adenylate kinase activity in transgenic plants therefore represents a potentially very useful strategy for increasing formation of major storage compounds in heterotrophic tissues of higher plants.