Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FindingsOf 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1•84, 95% CI 1•53-2•21), male sex (1•63, 1•07-2•48), smoking status (former smoker vs never smoked: 1•60, 1•03-2•47), number of comorbidities (two vs none: 4•50, 1•33-15•28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3•89, 2•11-7•18), active cancer (progressing vs remission: 5•20, 2•77-9•77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2•93, 1•79-4•79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0•24, 0•07-0•84) or the US-Midwest (0•50, 0•28-0•90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

SummaryLenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the CRL4CRBN E3 ubiquitin ligase, resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for lenalidomide's therapeutic window in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4CRBN. These findings have implications for the clinical activity of lenalidomide and related compounds and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.

LEARNING OBJECTIVES1. Enumerate procoagulant factors present in malignancy and the risk for thromboembolic events.2. Describe the morbidity associated with nonbacterial thrombotic endocarditis.3. List the recommended evaluations and treatments for nonbacterial thrombotic endocarditis.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThrombophilia is a well-described consequence of cancer and its treatment. The pathogenesis of this phenomenon is complex and multifactorial. Nonbacterial thrombotic endocarditis (NBTE) is a serious and potentially underdiagnosed manifestation of this prothrombotic state that can cause substantial morbidity in affected patients, most notably recurrent or multiple ischemic cerebrovascular strokes. Diagnosis of NBTE requires a high degree of clinical suspicion as well as the judicious use of two-dimensional echocardiography to document the presence of valvular thrombi. In the absence of contraindications to therapy, treatment consists of systemic anticoagulation, which may ameliorate symptoms and prevent further thromboembolic episodes, as well as control of the underlying malignancy whenever possible. The Oncologist 2007;12:518 -523 Disclosure of potential conflicts of interest is found at the end of this article.

The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches.

Objective To examine whether pretreatment emotional distress in women is associated with achievement of pregnancy after a cycle of assisted reproductive technology. Design Meta-analysis of prospective psychosocial studies. Data sources PubMed, Medline, Embase, PsycINFO, PsychNET, ISI Web of Knowledge, and ISI Web of Science were searched for articles published from 1985 to March 2010 (inclusive). We also undertook a hand search of reference lists and contacted 29 authors. Eligible studies were prospective studies reporting a test of the association between pretreatment emotional distress (anxiety or depression) and pregnancy in women undergoing a single cycle of assisted reproductive technology. Review methods Two authors independently assessed the studies for eligibility and quality (using criteria adapted from the Newcastle-Ottawa quality scale) and extracted data. Authors contributed additional data not included in original publication. Results Fourteen studies with 3583 infertile women undergoing a cycle of fertility treatment were included in the meta-analysis. The effect size used was the standardised mean difference (adjusted for small sample size) in pretreatment anxiety or depression (priority on anxiety where both measured) between women who achieved a pregnancy (defined as a positive pregnancy test, positive fetal heart scan, or live birth) and those who did not. Pretreatment emotional distress was not associated with treatment outcome after a cycle of assisted reproductive technology (standardised mean difference −0.04, 95% confidence interval −0.11 to 0.03 (fixed effects model); heterogeneity I²=14%, P=0.30). Subgroup analyses according to previous experience of assisted reproductive technology, composition of the not pregnant group, and timing of the emotional assessment were not significant. The effect size did not vary according to study quality, but a significant subgroup analysis on timing of the pregnancy test, a contour enhanced funnel plot, and Egger's test indicated the presence of moderate publication bias. ConclusionsThe findings of this meta-analysis should reassure women and doctors that emotional distress caused by fertility problems or other life events cooccurring with treatment will not compromise the chance of becoming pregnant.

Summary Background Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase. Methods This is a first-in-human pharmacokinetic (PK)- and pharmacodynamic (PD)-guided Phase 1 dose-escalation study in adults with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with MDS or AML refractory to, or relapsed after, standard treatment were randomly assigned to one of two regimens of subcutaneous (SC) guadecitabine: Daily×5 or Once Weekly for three weeks. Stratification was based on disease (MDS vs. AML). Treatment assignment was not blinded. A Twice Weekly for three weeks regimen was later added to the study. All regimens were given in 28-day cycles. The primary objective was the safety profile of all regimens and the recommended dose and schedule for phase 2 by either maximum tolerated dose (MTD) or biologically effective dose (BED). All patients who received at least one treatment were included in the analyses. Enrollment is complete and all patients have finished treatment. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings 93 patients were treated (74 AML and 19 MDS): 44 on Daily×5 (3–125 mg/m2/d), 34 on Once Weekly (6–125 mg/m2/d), and 15 on Twice Weekly (60 and 90 mg/m2/d). Guadecitabine SC produced a longer exposure window and half-life, and lower Cmax, of plasma DAC than intravenous DAC. The MTD was 90 mg/m2 in MDS on the Daily×5 regimen but was not reached in AML or on the other regimens. The most common Grade ≥3 adverse events were febrile neutropenia (38/93, 41%), pneumonia (27/93, 29%), thrombocytopenia and anemia (23/93, 25% each), and sepsis (16/93, 17%). The most common serious adverse events (SAEs) were febrile neutropenia (29/93, 31%), pneumonia (26/93, 28%), and sepsis (16/93, 17%). Potent dose-related DNA demethylation occurred on the daily regimen, reaching a plateau at 60 mg/m2 Daily×5 (designated as BED). Responses were seen in heavily pretreated patients including six responders (two complete response [CR], two CR with incomplete blood count recovery [CRi], one CR with incomplete platelet recovery [CRp], and one partial response [PR]) in AML patients and two marrow complete response (mCR) in MDS patients. Responders showed significantly more demethylation than non-responders. Interpretation Guadecitabine SC at 60 mg/m2 Daily×5 is well-tolerated, easily administered, and biologically and clinically active in both MDS and AML; it warrants testing in phase 2 studies.

Myeloid growth factors (MGFs) are given as supportive care to patients receiving myelosuppressive chemotherapy to reduce the incidence of neutropenia. This selection from the NCCN Guidelines for MGFs focuses on the evaluation of regimen- and patient-specific risk factors for the development of febrile neutropenia (FN), the prophylactic use of MGFs for the prevention of chemotherapy-induced FN, and assessing the risks and benefits of MGF use in clinical practice.

The cancer-testis/cancer-germline antigen NY-ESO-1 is a vaccine target in epithelial ovarian cancer (EOC), but its limited expression is a barrier to vaccine efficacy. As NY-ESO-1 is regulated by DNA methylation, we hypothesized that DNA methyltransferase (DNMT) inhibitors may augment NY-ESO-1 vaccine therapy. In agreement, global DNA hypomethylation in EOC was associated with the presence of circulating antibodies to NY-ESO-1. Pre-clinical studies using EOC cell lines showed that decitabine treatment enhanced both NY-ESO-1 expression and NY-ESO-1-specific CTL-mediated responses. Based on these observations, we performed a phase I dose-escalation trial of decitabine, as an addition to NY-ESO-1 vaccine and doxorubicin liposome (doxorubicin) chemotherapy, in 12 patients with relapsed EOC. The regimen was safe, with limited and clinically manageable toxicities. Both global and promoter-specific DNA hypomethylation occurred in blood and circulating DNAs, the latter of which may reflect tumor cell responses. Increased NY-ESO-1 serum antibodies and T cell responses were observed in the majority of patients, and antibody spreading to additional tumor antigens was also observed. Finally, disease stabilization or partial clinical response occurred in 6/10 evaluable patients. Based on these encouraging results, evaluation of similar combinatorial chemo-immunotherapy regimens in EOC and other tumor types is warranted.