Changes in anticancer treatment plans in patients with solid cancer hospitalized with COVID-19: analysis of the nationwide BSMO-COVID registry providing lessons for the future.

BACKGROUND: Solid cancer is an independent prognostic factor for poor outcome with COVID-19. As guidelines for patient management in that setting depend on retrospective efforts, we here present the first analyses of a nationwide database of patients with cancer hospitalized with COVID-19 in Belgium, with a focus on changes in anticancer treatment plans at the time of SARS-CoV-2 infection. METHODS: Nineteen Belgian hospitals identified all patients with a history of solid cancer hospitalized with COVID-19 between March 2020 and February 2021. Demographic, cancer-specific and COVID-specific data were pseudonymously entered into a central Belgian Society of Medical Oncology (BSMO)-COVID database. The association between survival and primary cancer type was analyzed through multivariate multinomial logistic regression. Group comparisons for categorical variables were carried out through a Chi-square test. RESULTS: A total of 928 patients were registered in the database; most of them were aged ≥70 years (61.0%) and with poor performance scores [57.2% Eastern Cooperative Oncology Group (ECOG) ≥2]. Thirty-day COVID-related mortality was 19.8%. In multivariate analysis, a trend was seen for higher mortality in patients with lung cancer (27.6% versus 20.8%, P = 0.062) and lower mortality for patients with breast cancer (13.0% versus 23.3%, P = 0.052) compared with other tumour types. Non-curative treatment was associated with higher 30-day COVID-related mortality rates compared with curative or no active treatment (25.8% versus 14.3% versus 21.9%, respectively, P < 0.001). In 33% of patients under active treatment, the therapeutic plan was changed due to COVID-19 diagnosis, most frequently involving delays/interruptions in systemic treatments (18.6%). Thirty-day COVID-related mortality was not significantly different between patients with and without treatment modifications (21.4% versus 20.5%). CONCLUSION: Interruption in anticancer treatments at the time of SARS-CoV-2 infection was not associated with a reduction in COVID-related mortality in our cohort of patients with solid cancer, highlighting that treatment continuation should be strived for, especially in the curative setting.

[Tamoxifen induced thromboembolic events in breast cancer. Some possible mechanisms]. / Evénements thromboemboliques induits par le tamoxifène dans le cancer du sein. Certains mécanismes potentiels.

Tamoxifen is an antagonist of the oestrogen receptor, used in the treatment of breast cancer. It is known to reduce osteoporotic bone fractures, but it increases the risk of endometrial tumors and venous thromboembolic events (VTEs). VTEs increased significantly during tamoxifen therapy within 3 months of major surgery, immobilization or fracture. Their incidence is associated with patients' risk factors, tumor and tissue induced procoagulation. The mechanisms are still not well known. There is a need for a better understanding in order to develope a prophylactic and therapeutic strategy.

Le tamoxifène est un antagoniste du récepteur de l'oestrogène, utilisé dans le traitement du cancer du sein. Le rôle du tamoxifène dans la réduction du risque de fractures osseuses ostéoporotiques est connu. Par contre il augmente le risque d'apparition de tumeurs de l'endomètre et des événements thromboemboliques veineux (ETEV). L'incidence d'ETEV augmente de manière significative au cours du traitement par le tamoxifène dans les 3 mois d'une chirurgie majeure, suite à une immobilisation ou une fracture. L'incidence est associée aux facteurs de risque des patients et à une hyper coagulabilité tumeur ou tissu induite. Les mécanismes thromboemboliques liés au tamoxifène ne sont pas encore bien connus. Il est nécessaire de mieux les connaître pour développer une stratégie prophylactique et thérapeutique.

Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability.

A single heat shock factor (HSF), mediating the heat shock response, exists from yeast to Drosophila, whereas several related HSFs have been found in mammals. This raises the question of the specific or redundant functions of the different members of the HSF family and in particular of HSF1 and HSF2, which are both ubiquitously expressed. Using immortalized mouse embryonic fibroblasts (iMEFs) derived from wild-type, Hsf1(-/-), Hsf2(-/-) or double-mutant mice, we observed the distinctive behaviors of these mutants with respect to proteasome inhibition. This proteotoxic stress reduces to the same extent the viability of Hsf1(-/-)- and Hsf2(-/-)-deficient cells, but through different underlying mechanisms. Contrary to Hsf2(-/-) cells, Hsf1(-/-) cells are unable to induce pro-survival heat shock protein expression. Conversely, proteasome activity is lower in Hsf2(-/-) cells and the expression of some proteasome subunits, such as Psmb5 and gankyrin, is decreased. As gankyrin is an oncoprotein involved in p53 degradation, we analyzed the status of p53 in HSF-deficient iMEFs and observed that it was strongly stabilized in Hsf2(-/-) cells. This study points a new role for HSF2 in the regulation of protein degradation and suggests that pan-HSF inhibitors could be valuable tools to reduce chemoresistance to proteasome inhibition observed in cancer therapy.

DNA compaction into new DNA vectors based on cyclodextrin polymer: surface enhanced Raman spectroscopy characterization.

The ability of DNA to bind polycation yielding polyplexes is widely used in nonviral gene delivery. The aim of the present study was to evaluate the DNA compaction with a new DNA vector using Raman spectroscopy. The polyplexes result from an association of a beta-cyclodextrin polymer (polybeta-CD), an amphiphilic cationic connector (DC-Chol or adamantane derivative Ada2), and DNA. The charge of the polymeric vector is effectively controlled by simple addition of cationic connector in the medium. We used surface enhanced Raman spectroscopy (SERS) to characterize this ternary complex, monitoring the accessibility of adenyl residues to silver colloids. The first experiments were performed using model systems based on polyA (polyadenosine monophosphate) well characterized by SERS. This model was then extended to plasmid DNA to study polybeta-CD/Ada2/DNA and polybeta-CD/DC-Chol/DNA polyplexes. The SERS spectra show a decrease of signal intensity when the vector/DNA charge ratio (Z+/-) increases. At the highest ratio (Z+/- = 10) the signal is 6-fold and 3-fold less intense than the DNA reference signal for Ada2 and DC-Chol polyplexes, respectively. Thus adenyl residues have a reduced accessibility as DNA is bound to the vector. Moreover, the SERS intensity variations are in agreement with gel electrophoresis and zeta potential experiments on the same systems. The overall study clearly demonstrates that the cationic charges neutralizing the negative charges of DNA result in the formation of stable polyplexes. In vitro transfection efficiency of those DNA vectors are also presented and compared to the classical DC-Chol lipoplexes (DC-Chol/DNA). The results show an increase of the transfection efficiency 2-fold higher with our vector based on polybeta-CD.

Additional hydrogen bonds and base-pair kinetics in the symmetrical AMP-DNA aptamer complex.

The solution structure of an adenosine monophosphate (AMP)-DNA aptamer complex has been determined previously [Lin, C. H., and Patel, D. J. (1997) Chem. Biol. 4:817-832]. On a symmetrical aptamer complex containing the same binding loop, but with better resolved spectra, we have identified two additional hydrogen bond-mediated associations in the binding loop. One of these involves a rapidly exchanging G imino proton. The phosphate group of the AMP ligand was identified as the acceptor by comparison with other aptamer complexes. Imino proton exchange measurements also yielded the dissociation constants of the stem and binding loop base pairs. This study shows that nuclear magnetic resonance-based imino proton exchange is a good probe for detection of weak hydrogen-bond associations.

The development of a French version of a questionnaire on the quality of life in cancerology (Functional Living Index-Cancer: FLIC).

The quality of life has become an indispensable element in the evaluation of treatments, especially as clinical trials are generally conducted in more than one country. In cancerology, numerous questionnaires have been developed and validated, but most of them are in English. This article presents the stages of translation and validation of the French version of the FLIC (Functional Living Index-Cancer). It applies to a sample of 200 patients, 47% of whom have breast cancer. The acceptability of this questionnaire is good (92.2%). The main psychometric criteria were verified. The Cronbach alpha coefficient, equal to 0.90, shows good reliability. A factor analysis was conducted to examine construct validity; it revealed a 5-factor solution accounting for 62% of the variance. These 5 factors are associated with specific domains; physical, psychological and social functioning, current well-being and disease symptoms. The global scores of the FLIC correlate significantly with those of the different scales of the EORTC QLQ-C30. Moreover, clinical relevance is ensured by its correlation with certain clinical variables (WHO index, location of tumour). The French version of the FLIC can be used to measure the quality of life of patients afflicted with cancer, but further studies are necessary to confirm its reliability.

Effectiveness of cold cap in the prevention of docetaxel-induced alopecia.

Docetaxel is a new taxoid antineoplastic agent with clinical efficacy especially in breast cancer. One of the most distressing side-effects induced by docetaxel is alopecia. We studied the prevention of alopecia by using a cold cap in 98 patients receiving 100 mg/m2 docetaxel by 1 h i.v. infusion every 3 weeks. One patient was lost to follow-up. 83 patients (86%) were evaluated as a success to the cold cap, as they presented WHO grade alopecia < or = 2 and no need to wear a wig. 14 patients (14%) had to wear a wig; among them; 7 patients withdrew before the evaluation at three cycles. The cold cap is a very effective technique with minimal side-effects for docetaxel-treated patients.

Quality of life as an outcome in breast cancer. Clinical application.

In clinical trials of anticancer agents, the assessment of objective effects has historically been the primary end-point. However, because of the limited impact of these agents on survival, the study of quality of life (QOL) has become increasingly important. QOL evaluation is difficult and the approaches of physicians and reimbursors of healthcare are quite different. In addition, QOL is not a simple concept and several different methods have been used to evaluate it. These methods can be divided into the following 2 groups: experimental methods [the best known is the quality-adjusted life-year (QALY), which utilise some kind of experimentation; and observational methods, which use questionnaires and are often multifactorial. Some of these questionnaires are used for patients with all types of pathologies, while others are cancer-specific; all questionnaires must be validated. We conducted 3 QOL studies in patients with breast cancer using the Functional Living Index-Cancer (FLIC) questionnaire. In the first, a French translation of the FLIC questionnaire was validated. The FLIC and Functional Living Index-Emesis (FLIE) questionnaires were used to assess QOL in a second study comparing 2 different antiemetics for the control of nausea and vomiting. Finally, QOL was evaluated in patients with breast cancer during adjuvant chemotherapy. Several other studies employing different questionnaires in patients with breast cancer have been published. Clinical applications for QOL evaluation in oncology may be the prognostic implications of QOL, evaluation of toxicity and duration of treatment, and evaluation of utility and QOL. However, although assessment of QOL is important for both physicians and funders, there is no gold standard method available, and the results of QOL studies have to be interpreted cautiously.

Pulmonary ventilation, mechanics, gas exchange and haemodynamics in calves following intratracheal inoculation of Pasteurella haemolytica.

A Pasteurella haemolytica A1 broth was injected intratracheally in eight calves and measurements of pulmonary function values (PFV) were made once before and hourly post inoculation (p.i.). Changes in PFVs, included increased respiratory rate and minute ventilation (up to 158% of baseline 2 h p.i.) and decreased tidal volume and lung dynamic compliance (up to 33% of baseline 3 h p.i.). Total pulmonary resistance was not affected. At and after 3 h p.i. there was a progressive impairement of gas exchange, as judged from arterial O2 tension which decreased up to 65% of baseline. In contrast, arterial CO2 tension was not affected. Pulmonary hypertension was observed during the 3 last h of the study and was attributable to an increased pulmonary vascular resistance. Severe neutropenia was observed at 3 h p.i. and post-mortem histological findings were consistent with an acute fibrinohemorragic bronchopneumonia. In conclusion, P. haemolytica airway challenge unequiovocally resulted in acute pneumonia, providing a reproducible pathophysiological model for investigations regarding new therapeutic strategies.

[Insufficient efficacy of the use of a single 8 mg tablet of ondansetron in the prevention of nausea and vomiting induced by FEC chemotherapy]. / Efficacité insuffisante de l'utilisation d'un seul comprimé de 8 mg d'ondansétron dans la prévention des troubles émétiques induits par une chimiothérapie de type FEC.

This study was performed in a group of 89 patients treated for breast carcinoma with a FEC regimen (5-fluorouracil, epirubicin, cyclophosphamide). The aim was to evaluate the antiemetic efficacy of one 8 mg tablet ondansetron (OND), and in case of failure, to measure the recovering level by the administration of 8 mg i.v. OND. One tablet of OND was given before the first course. A complete or major control of emetic episodes (EE) (0-2 EE) over the 24 first hours was obtained in 55 patients (62%). A complete or major control of nausea (absent or mild) was obtained in 46 patients (52%). A success, defined as a complete or major control for EE and nausea during the first 5 days, was obtained in 36 patients (40%). These 36 patients were treated again with 8 mg oral OND at the second course, with a success level of 61% (22/36). Among the 53 patients unresponsive to the oral OND, 38 were treated by 8 mg i.v. OND at the second course. A complete or major control for EE and for nausea over the first 24 hours was obtained respectively in 11 patients (29%), and 11 patients (29%). No success was obtained. The 15 remaining patients, who had a very bad tolerance at the first course were excluded from the study and treated by OND-methylprednisolon, with only one success obtained. This study shows that the exclusive use of one 8 tablet OND is not sufficient in prevention of emesis induced by a FEC regimen, and that failures are only partially recovered by the i.v. route.

[Immunotherapy of malignant melanoma. New prospects]. / Immunothérapie du mélanome malin. Nouvelles perspectives.

Malignant melanoma is an immunogenic tumor which can induce host humoral and cellular responses, and is a good model for development of anti-cancer immunotherapy. During the last decade systemically-administrated interferon and interleukin-2 have been used. Advances in immunology and molecular biology could allow a more specific and active immunotherapy. Perspectives include chemo-immunotherapy, monoclonal antibodies alone or in combination with cytotoxic agents, adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL), gene therapy designed to increase tumor immunogenicity, and active immunotherapy with vaccines.

[Antiemetic treatment and chemotherapy: general review]. / Traitement antiémétique et chimiothérapie: revue générale.

Chemotherapy-induced nausea and emesis are frequent and patients fearful. Emesis caused by cytotoxic agents can be related to their effects on central chemoreceptor or on the gut chemoreceptor by serotonin. 5HT3 receptor antagonists produce a major improvement in the control of cisplatin induced-emesis (70 to 80% of patients). The 5HT3-antagonist efficacy is significantly better than metoclopramide alone, or antimemetic combinations in highly emetogenic chemotherapy regimens but less good in moderately emetogenic chemotherapy. Studies with 5HT3 receptor antagonist plus corticosteroids show advantage over 5HT3 antagonist alone. Comparison studies between the different setrons didn't show any significant difference. Anticipary emesis are treated with anxiolytic drugs. The prevention of delayed emesis, not yet well controlled by 5HT3 antagonist, is a great therapeutic deal. Finally, some therapeutic problems are not resolved: minimal dose, use of oral route, efficacy in fractionated chemotherapy, treatment after loss of efficacy of 5HT3 antagonist.