Epidermal development requires the transcription factor p63, as p63À/À mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (DNp63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63a and/or DNp63a under the K5 promoter into p63À/À mice by in vivo genetic complementation. Whereas p63À/À and p63À/À;TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63À/À;DN mice showed significant epidermal basal layer formation. Double TAp63a/ DNp63a complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, DNp63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.

To compare single-agent gemtuzumab ozogamicin (GO) with best supportive care (BSC) including hydroxyurea as first-line therapy in older patients with acute myeloid leukemia unsuitable for intensive chemotherapy. Patients and MethodsIn this trial, patients at least 61 years old were centrally randomized (1:1) to receive either a single induction course of GO (6 mg/m 2 on day 1 and 3 mg/m 2 on day 8) or BSC. Patients who did not progress after GO induction could receive up to eight monthly infusions of the immunoconjugate at 2 mg/m 2 . Randomization was stratified by age, WHO performance score, CD33 expression status, and center. The primary end point was overall survival (OS) by intention-to-treat analysis. ResultsA total of 237 patients were randomly assigned (118 to GO and 119 to BSC). The median OS was 4.9 months (95% CI, 4.2 to 6.8 months) in the GO group and 3.6 months (95% CI, 2.6 to 4.2 months) in the BSC group (hazard ratio, 0.69; 95% CI, 0.53 to 0.90; P = .005); the 1-year OS rate was 24.3% with GO and 9.7% with BSC. The OS benefit with GO was consistent across most subgroups, and was especially apparent in patients with high CD33 expression status, in those with favorable/ intermediate cytogenetic risk profile, and in women. Overall, complete remission (CR [complete remission] + CRi [CR with incomplete recovery of peripheral blood counts]) occurred in 30 of 111 (27%) GO recipients. The rates of serious adverse events (AEs) were similar in the two groups, and no excess mortality from AEs was observed with GO. ConclusionFirst-line monotherapy with low-dose GO, as compared with BSC, significantly improved OS in older patients with acute myeloid leukemia who were ineligible for intensive chemotherapy. No unexpected AEs were identified and toxicity was manageable.J Clin Oncol 34.

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Fungemia, mostly due to Candida spp., was rare in cancer patients from EORTC centers but was associated with substantial mortality. Antifungal prophylaxis and remission of cancer predicted better survival.

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behaviour and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not admitted cohort, n=388), or required hospitalization (n=468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95%CI 11-15%) and 23% (95%CI 20-27%), respectively. Anti-lymphoma treatment, including anti-CD20 containing regimens, did not impact on survival. Patients with Hodgkin's lymphoma had the more favourable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment for their underlying disease, and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

Currently, 17–19% of all new primary malignancies occur in survivors of cancer, causing substantial morbidity and mortality. Research has shown that cancer treatments are important contributors to second malignant neoplasm (SMN) risk.In this paper we summarise current knowledge with regard to treatment-related SMNs and provide recommendations for future research. We address the risks associated with radiotherapy and systemic treatments, modifying factors of treatment-related risks (genetic susceptibility, lifestyle) and the potential benefits of screening and interventions. Research priorities were identified during a workshop at the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer.Recently, both systemic cancer treatments and radiotherapy approaches have evolved rapidly, with the carcinogenic potential of new treatments being unknown. Also, little knowledge is available about modifying factors of treatment-associated risk, such as genetic variants and lifestyle. Therefore, large prospective studies with biobanking, high quality treatment data (radiation dose–volume, cumulative drug doses), and data on other cancer risk factors are needed. International collaboration will be essential to have adequate statistical power for such investigations. While screening for SMNs is included in several follow-up guidelines for cancer survivors, its effectiveness in this special population has not been demonstrated. Research into the pathogenesis, tumour characteristics and survival of SMNs is essential, as well as the development of interventions to reduce SMN-related morbidity and mortality. Prediction models for SMN risk are needed to inform initial treatment decisions, balancing chances of cure and SMNs and to identify high-risk subgroups of survivors eligible for screening.

In 2008, a European registry of relapsed acute promyelocytic leukemia was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (P=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the 3-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90 and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in second CR (n=93), the 3-year OS was 80% compared with 59% without transplantation (n=55) (P=0.03). Multivariable analysis demonstrated the favorable prognostic impact of first remission duration ⩾1.5 years, achievement of mCR and allogeneic or autologous transplantation on OS of patients alive after induction (P=0.03, P=0.01, P=0.01) and on leukemia-free survival (P=0.006, P<0.0001, P=0.003), respectively.