Safety and Efficacy of a Mobiderm Compression Bandage During Intensive Phase of Decongestive Therapy in Patients with Breast Cancer-Related Lymphedema: A Randomized Controlled Trial.

Background: Breast cancer-related lymphedema (BCRL) after primary therapy is a common condition, causing physical and psychological distress. Decongestive lymphedema therapy (DLT) using multi-layered compression bandages is an effective treatment. We conducted a randomized controlled trial evaluating the use of a specific mobilizing bandage (Mobiderm®) on lymphedema volume reduction during the intensive phase of DLT. Methods and Results: Fifty female BCRL patients were randomized to receive either conventional multi-layered bandages or mobilizing bandaging by using Mobiderm. Affected limb volume and excess volume were evaluated at baseline (D0) and after 15 days. The primary outcome was change in affected limb volume after adjustment for baseline. Symptom scores were evaluated by visual analogue scale (VAS); safety and tolerability were also assessed. Baseline characteristics were comparable. Affected limb volume reduction was observed in both study groups after 15 days: by 19.0% in the Mobiderm arm and 8.6% in controls (adjusted values). The between-group mean difference in adjusted volume reduction at day 15 was 256 mL (95% confidence interval [CI], 92.5 to 421.3 mL; p = 0.003) favoring Mobiderm. Reductions in excess volume of 57.3% (Mobiderm) and 25.1% (controls) were observed (adjusted values); with between-group mean difference in adjusted excess volume of 220.2 mL (95% CI, 69.3 to 371.3 mL; p = 0.006) favoring Mobiderm. Pain/heaviness VAS scores fell significantly in both groups, with mean reductions of 1.84 (Mobiderm) versus 0.83 (control; p = 0.001). Both regimens were well tolerated. Conclusion: The use of Mobiderm in multilayer compression bandaging shows benefit in lymphedema reduction and in alleviating functional symptoms/pain in patients with BRCL.

Home hospitalization for palliative cancer care: factors associated with unplanned hospital admissions and death in hospital.

BACKGROUND: Home hospitalization at the end of life can sometimes be perturbed by unplanned hospital admissions (UHAs, defined as any admission that is not part of a preplanned care procedure), which increase the likelihood of death in hospital. The objectives were to describe the occurrence and causes of UHAs in cancer patients receiving end-of-life care at home, and to identify factors associated with UHAs and death in hospital. METHODS: A retrospective, single-center study (performed at a regional cancer center in the city of Lille, northern France) of advanced cancer patients discharged to home hospitalization between January 2014 and December 2017. We estimated the incidence of UHA over time using Kaplan-Meier method and Kalbfleish and Prentice method. We investigated factors associated with the risk UHA in cause-specific Cox models. We evaluated factors associated with death in hospital in logistic regressions. RESULTS: One hundred and forty-two patients were included in the study. Eighty-two patients (57.7 %) experienced one or more UHAs, a high proportion of which occurred within 1 month after discharge to home. Most UHAs were related to physical symptoms and were initiated by the patient's family physician. A post-discharge palliative care consultation was associated with a significantly lower incidence of UHAs. Sixty-five patients (47.8 % of the deaths) died in hospital. In a multivariate analysis, living alone and the presence of one or more children at home were associated with death in hospital. CONCLUSIONS: More than 40 % of cancer patients receiving end of life home hospitalization were not readmitted to hospital, reflecting the effectiveness of this type of palliative care setting. However, over half of the UHAs were due to an acute intercurrent event. Our results suggest that more efforts should be focused on anticipating these events at home - primarily via better upstream coordination between hospital physicians and family physicians.

Midazolam sedation in palliative medicine: retrospective study in a French center for cancer control.

BACKGROUND: French legislation about sedation in palliative medicine evolved in 2016 with the introduction of a right to deep and continuous sedation, maintained until death. The objective was to describe midazolam sedation at the COL (Centre Oscar Lambret [Oscar Lambret Center], French regional center for cancer control), in order to establish a current overview before the final legislative changes. METHODS: Descriptive, retrospective and single-center study, concerning major patients in palliative care hospitalized from 01/01/2014 to 12/31/2015, who had been sedated by midazolam. The proven sedations (explicitly named) and the probable sedations were distinguished. RESULTS: A total of 54 sedations were identified (48 proven, 6 probable). Refractory symptoms accounted for 48.1% of indications, complications with immediate risk of death 46.3%, existential suffering 5.6%. Titration was performed in 44.4% of cases. Sedation was continuous until death for 98.1% of the cases. Probable sedation had a higher failure rate than proven sedation. Significant differences existed for the palliative care unit compared to other units regarding information to the patient, their consent, anticipation, mention by correspondence and carrying out titrations. When patients had already been treated with midazolam, the induction doses, initial maintenance doses, and doses at the time of death were significantly higher. For those receiving opioids, the maintenance dose at the time of death was higher. No comparison found a difference in overall survival. CONCLUSIONS: After a sufficient follow-up has enabled teams to familiarize with this new legislation, reflection on sedation should be conducted to adapt to final recommendations.

Refractory psycho-existential distress and continuous deep sedation until death in palliative care: The French perspective.

OBJECTIVE: Since February 2016, French Claeys-Leonetti law has recognized patients' right to confront incurable diseases with short-term prognosis and refractory physical or psychological or existential symptoms by requesting continuous deep sedation until death (CDSUD). Determining when psychological or existential distress is refractory and unbearable remains complex and controversial.This review provides a comprehensive thought on CDSUD for advanced incurable patients with refractory psychological and/or existential distress in palliative care settings. It offers guidance on psychiatric or psychological diagnosis for explaining patients' requests for CDSUD. METHOD: A narrative literature review (2000-2019) was conducted on the MedLine search about the use of palliative sedation in cases of refractory psychological and/or existential distress. RESULTS: (1) Definitions of "refractory symptom," "refractory psychological distress," and "refractory existential distress" are inconsistent; (2) alternative diagnoses might obscure or be obscured by psycho-existential distress; and (3) criteria on meanings, reasons for requests, decision-making processes, and functions are evolving in practice. SIGNIFICANCE OF RESULTS: Before implementing CDSUD, palliative healthcare professionals should seek input from psycho-oncologists in palliative care. Mental health professionals should analyze and assess the reasons for psychological and/or existential distress, consider the intentionality processes of requests, and explore alternative diagnoses, such as depressive or adjustment disorders, demoralization syndrome, desire to hasten death, and desire for euthanasia. Therapeutic responses (e.g., pharmacological and psychotherapeutic) should be implemented before deciding that psycho-existential distress is refractory.

PALLIA-10, a screening tool to identify patients needing palliative care referral in comprehensive cancer centers: A prospective multicentric study (PREPA-10).

PURPOSE: The identification and referral of patients in need of palliative care should be improved. The French society for palliative support and care recommended to use the PALLIA-10 questionnaire and its score greater than 3 to refer patients to palliative care. We explored the use of the PALLIA-10 questionnaire and its related score in a population of advanced cancer patients. METHODS: This prospective multicentric study is to be conducted in authorized French comprehensive cancer centers on hospitalized patients on a given day. We aimed to use the PALLIA-10 score to determine the proportion of palliative patients with a score >3. Main secondary endpoints were to determine the proportion of patients already managed by palliative care teams at the study date or referred to palliative care in six following months, the prevalence of patients with a score greater than 5, and the overall survival using the predefined thresholds of 3 and 5. RESULTS: In 2015, eighteen French cancer centers enrolled 840 patients, including 687 (82%) palliative patients. 479 (69.5%) patients had a score >3, 230 (33.5%) had a score >5, 216 (31.4%) patients were already followed-up by a palliative care team, 152 patients were finally referred to PC in the six subsequent months. The PALLIA-10 score appeared as a reliable predictive (adjusted ORRef≤3 : 1.9 [1.17-3.16] and 3.59 [2.18-5.91]) and prognostic (adjusted HRRef≤3  = 1.58 [95%CI 1.20-2.08] and 2.18 [95%CI 1.63-2.92]) factor for patients scored 4-5 and >5, respectively. CONCLUSION: The PALLIA-10 questionnaire is an easy-to-use tool to refer cancer inpatients to palliative care in current practice. However a score greater than 5 using the PALLIA-10 questionnaire would be more appropriate for advanced cancer patients hospitalized in comprehensive cancer center.

[Supportive care for malignant ascites in palliative phase: Place of paracentesis and diuretics]. / Prise en charge symptomatique de l'ascite maligne en phase palliative: place de la paracentèse et des diurétiques.

Malignant ascites, occurring in advanced stages of cancer, is linked with poor prognosis and can cause invalidating symptoms. Physiopathological mechanisms of ascites formation are complex and have yet to be fully elucidated. In most cases, ascites is due to peritoneal carcinomatosis in which vascular permeability is enhanced by VEGF production while lymphatic drainage decreases. Ascites can also be secondary to portal hypertension, for example in case of multiple liver metastases, or due to lymphatic obstruction. While paracentesis and diuretics are commonly used, their efficiency has never been compared in a randomized controlled study. Paracentesis brings immediate but temporary relief in over 90% of cases, and implies multiple hospitalizations. Literature reports ascites control by aldosterone alone or in association with furosemide. But, available data is controversial, and there is no predictive factor to identify patients that respond to diuretic treatment. The indication of diuretic treatment is left to the appreciation of physicians. Existing recommendations are old, and practices influenced by results obtained in non-neoplastic ascites. Additional evidences are required before guidelines can be established for the palliative management of malignant ascites.

Selection of ultimately ill cancer patients able to fulfill a questionnaire: Identification of inherent biases.

AIM: Physical or psychological well-being is an essential component of quality care assessment in palliative unit. This assessment is mainly based on self-assessment (questionnaires or interviews). The aim of this study is to compare the clinical characteristics of patients able to fulfill a questionnaire and those not able to do that. METHODS: The clinical characteristics of 166 cancer patients admitted in palliative care unit from December 2006 to February 2008 have been collected. Characteristics of patients able to fulfill a questionnaire (80, 48.2%) have been compared to other patients (86, 51.8%). Moreover, functional independence measure (FIM) had been evaluated by nurses. RESULTS: Median age (60 versus 62) and sex ratio (40/40 versus 42/44) are similar in both groups. Lung primaries are significantly less frequent in patients able to fulfill the questionnaire (4% versus 17%, P=0.005). Patients able to fulfill the questionnaire had had better performance status (Karnofsky Index≤30%: 54% versus 21%, P<0.0001). The total score of FIM (56.0 versus 91.5, P<0.00001) and the median overall survivals (2.3 weeks versus 6.6 weeks, P=0.0001) were significantly lower in the group of patients non able to fulfill the questionnaire. CONCLUSIONS: Patients able to fulfill a questionnaire represent only 48.2% of all consecutive admitted patients. These patients are not representative of all patients since they had better performance status, they are less dependent and they display significant better survival. We have to think about new methods to avoid the biases generated by the use of patient-reported outcomes.

Open-label uncontrolled pilot study to evaluate complementary therapy with Ruta graveolens 9c in patients with advanced cancer.

BACKGROUND: Patients with advanced metastatic disease are often treated aggressively with multiple lines of chemotherapy, even in the last month of life. The benefit of such an approach remains uncertain. The objective of the study was to investigate whether Ruta graveolens 9c homeopathic medicine can improve quality of life (QoL) and tumour progression in patients with advanced cancer. MATERIAL AND METHODS: This was a single-centre, open-label, uncontrolled, pilot study. Patients (>18-years, life-expectancy ≥3 months, performance status ≤2) with locally-advanced solid tumours or metastases, previously treated with all available standard anti-cancer treatments were recruited. Oral treatment consisted of two 1-mL ampoules of Ruta graveolens (9c dilution) given daily for a minimum of 8 weeks, or until tumour and/or clinical progression. Primary outcome was QoL measured using the EORTC QLQ-C30 questionnaire. Secondary outcome measures were anxiety/depression measured using the Hospital Anxiety and Depression Scale (HADS), WHO performance status (PS), tumour progression assessed using RECIST criteria and tumour markers, survival and tolerance. RESULTS: Thirty-one patients were included (mean age: 64.3 years). Mean duration of treatment was 3.3 months (median: 2.1). QoL global health status improved significantly between baseline and week 8 (P < 0.001) and week 16 (P = 0.035), but was at the limit of significance (P = 0.057) at the end of the study. There was no significant change in anxiety/depression or PS during treatment. Ruta graveolens 9c had no obvious effect on tumour progression. Median survival was 6.7 months [95%CI: 4.8-14.9]. Ruta graveolens 9c was well-tolerated. CONCLUSION: Some patients treated with Ruta graveolens 9c had a transitory improvement in QoL, but the effectiveness of this treatment remains to be confirmed in further studies.

In vitro characterization of viral fitness of therapy-resistant hepatitis B variants.

BACKGROUND & AIMS: Because of the overlapping of polymerase and envelope genes in the hepatitis B virus (HBV) genome, nucleoside analog therapy can lead to the emergence of complex HBV variants that harbor mutations in both the reverse transcriptase and the envelope proteins. To understand the selection process of HBV variants during antiviral therapy, we analyzed the in vitro fitness (the ability to produce infectious progeny) of 4 mutant viral genomes isolated from one patient who developed resistance to a triple therapy (lamivudine, adefovir, and anti-HBV immunoglobulins). METHODS: The 4 mutant and the wild-type forms of HBV were expressed from vectors in hepatoma cell lines; replication and viral particle secretion capacities then were analyzed. The impact of envelope gene mutations on infectivity was tested in HepaRG cells using the hepatitis delta virus (HDV) model as a reporter for infection. RESULTS: The dominant HBV variant characterized from the therapy-resistant patient was found to have the best replicative capacity in vitro in the presence of high concentrations of lamivudine and adefovir. The expression of envelope proteins and secretion of subviral and Dane particles by this mutant was comparable with that of wild-type HBV. HDV particles enveloped by surface proteins from the selected mutant had the highest rates of infection in HepaRG cells compared with other mutants. CONCLUSIONS: These results illustrate the importance of viral fitness and infectivity as a major determinant of antiviral therapy resistance in patients. Understanding HBV mutant selection in vivo will help to optimize new anti-HBV therapeutic strategies.

Activation/proliferation and apoptosis of bystander goat lymphocytes induced by a macrophage-tropic chimeric caprine arthritis encephalitis virus expressing SIV Nef.

Caprine arthritis encephalitis virus (CAEV) is the natural lentivirus of goats, well known for its tropism for macrophages and its inability to cause infection in lymphocytes. The viral genome lacks nef, tat, vpu and vpx coding sequences. To test the hypothesis that when nef is expressed by the viral genome, the virus became toxic for lymphocytes during replication in macrophages, we inserted the SIVsmm PBj14 nef coding sequences into the genome of CAEV thereby generating CAEV-nef. This recombinant virus is not infectious for lymphocytes but is fully replication competent in goat macrophages in which it constitutively expresses the SIV Nef. We found that goat lymphocytes cocultured with CAEV-nef-infected macrophages became activated, showing increased expression of the interleukin-2 receptor (IL-2R). Activation correlated with increased proliferation of the cells. Interestingly, a dual effect in terms of apoptosis regulation was observed in exposed goat lymphocytes. Nef was found first to induce a protection of lymphocytes from apoptosis during the first few days following exposure to infected macrophages, but later it induced increased apoptosis in the activated lymphocytes. This new recombinant virus provides a model to study the functions of Nef in the context of infection of macrophages, but in absence of infection of T lymphocytes and brings new insights into the biological effects of Nef on lymphocytes.

Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient.

BACKGROUND/AIMS: Complex mutants may be selected under sequential anti-VHB pressures. We analyzed the genotypic and phenotypic evolution of the viral quasi-species of a patient who developed resistance to entecavir following lamivudine breakthrough. METHODS: The polymerase gene was amplified, cloned and sequenced at different time points. Hepatoma cell lines were transfected to compare the replication capacity of HBV mutants and their drug susceptibility. RESULTS: A mixture of lamivudine-resistant HBV strains coexisted following viral breakthrough to lamivudine, all harboring the rtM204V mutation. The rtV173L+L180M+M204V dominant mutant displayed strong lamivudine-resistance and the highest replication capacity. Following the switch to entecavir, the viral load dropped but the lamivudine-resistant strains continued to be selected. Three years later, the viral load rose again, and a complex mixture of entecavir-resistant strains, all harboring the lamivudine-resistance signature rtL180M+M204V and the rtS202G mutation were observed. Although the rtL180M+S202G+M204V variant, that prevailed at the end of entecavir therapy, did not show the highest viral genome replication capacity, it conferred one of the strongest resistance levels to entecavir. CONCLUSIONS: We report the selection of complex HBV mutants that escaped lamivudine and entecavir antiviral pressures. Genotypic and phenotypic analysis provided additional information to understand the process of HBV variant selection.

Prognosis of hypercalcemia in aerodigestive tract cancers: study of 136 recent cases.

Recent data issuing the prognostic impact of hypercalcemia on outcome of aerodigestive tract cancers are spare. To assess the prognosis and the survival of head and neck cancer patients with hypercalcemia, we reviewed 136 recent successive cases, including also oesophageal and lung cancers. Data were collected from a retrospective database (July 2002-January 2004). Hypercalcemia was defined by calcemia level above 2.55 mmol/l. Univariate analysis for prognosis was performed with Mann-Whitney test (continuous variables) and Odd Ratio with 95% confidence interval (categorical variables). The primary locations were : oropharynx and oral cavity (79, 58%), hypopharynx (13, 9.5%), larynx (10, 7.3%), oesophagus (17, 12.5%) and lung (17, 12.5%). There were 23 females and 123 males, with a median age of 53 (18-86). The incidence of bone metastasis was low: 20/136, 14.5%. At cancer diagnosis, 32 hypercalcemia were observed. With a median follow-up of 88 days (2-553), we observed 98 deaths (overall mortality=72%). The median overall survival was 35 days (2-553+). The pejorative prognostic factors were: male gender (OR=2.64 CI 95% 1.07-6.82), age inferior to 50 (OR=2.67 CI 95% 1.23-5.8), presence of distant metastasis (OR=4.45 CI 95% 1.8-11.01), elevation of alkaline phosphatases (OR=7 CI 95% 2.73-17.9) and need of hospitalization for intravenous hydratation (OR=5.11 CI 95% 1.99-13.17). We observed 39 recurrences of hypercalcemia. The predictive factors for recurrence of hypercalcemia were: age superior to 50 (OR=4.61 CI 95% 2.02-10.52), male gender (OR=38.22 CI 95% 12.2-89), calcemia level superior to 2.7 mmol/l (OR=3.08 CI 95% 1.42-6.64) and absence of diphosphonates (bisphosphonates: OR=2.16 CI 95% 1.01-4.63). Despite use of diphosphonates (infusions of pamidronate), hypercalcemia is associated with very poor prognosis. Tumour location and level of calcemia had no prognostic value.